The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

The replacement of Nixon’s science adviser, Lee DuBridge, a scholarly, old-school atomic physicist from Caltech, with Ed David, an impulsive, fast-paced engineer-turned-manager from the Bell research labs, was meant as a signal to the scientific community to get into shape. David was the first presidential science adviser to emerge out of an industrial lab and to have no direct connection with a university. His mandate was to get an effective science operation that would redirect its energies toward achieving defined national goals. What scientists needed—what the public demanded—was not an “endless frontier” (à la Vannevar Bush) but a discipline with pragmatic frontiers and well-defined ends.

The panel’s final report, entitled the National Program for the Conquest of Cancer, was issued in the winter of 1970, and its conclusions were predictable: “In the past, when the Federal Government has desired to give top priority to a major scientific project of the magnitude of that involved in the conquest of cancer, it has, on occasion, with considerable success, given the responsibility for the project to an independent agency.” While tiptoeing around the idea, the panel was proposing the creation of an independent cancer agency—a NASA for cancer. The agency would start with a budget of $400 million, then its allocations would increase by $100 million to $150 million per year, until, by the mid-1970s, it would stand at $1 billion. When Schmidt was asked if he thought that the country could “afford such a program,” he was unhesitant in his reply: “Not only can we afford the effort, we cannot afford not to do it.”

The swift and decisive victory in the Senate was precisely as the Laskerites had planned it. The cancer bill was now destined for the House, but its passage there promised to be a much tougher hurdle. The Laskerites had few allies and little influence in the lower chamber. The House wanted more testimony—and not just testimony from the Laskerites’ carefully curated panel. It solicited opinions from physicians, scientists, administrators and policymakers—and those opinions, it found, diverged sharply from the ones presented to the Senate. Philip Lee, the former assistant secretary of health complained, “Cancer is not simply an island waiting in isolation for a crash program to wipe it out. It is in no way comparable to a moon shot—to a Gemini or an Apollo program—which requires mainly the mobilization of money, men, and facilities to put together in one imposing package the scientific knowledge we already possess.” The Apollo mission and the Manhattan Project, the two models driving this War on Cancer were both technological achievements that stood on the shoulders of long and deep scientific discoveries (atomic physics, fluid mechanics, and thermodynamics). In contrast, even a cursory understanding of the process that made cells become malignant was missing. Seizing on the Laskerites’ favorite metaphor, Sol Spiegelman, the Columbia University cancer scientist, argued, “An all-out effort at this time would be like trying to land a man on the moon without knowing Newton’s la...

On December 23, 1971, on a cold, windswept afternoon in Washington, Nixon signed the National Cancer Act at a small ceremony in the White House. The doors to the State Dining Room were thrown open, and the president seated himself at a small wooden desk. Photographers parried for positions on the floor around the desk. Nixon leaned over and signed the act with a quick flourish. He handed the pen as a gift to Benno Schmidt, the chair of the Panel of Consultants. Mary Lasker beamed forcefully from her chair. Farber chose not to attend.

Haagensen transformed from surgeon to shaman: “To some extent,” he wrote about his patients, “no doubt, they transfer the burden [of their disease] to me.” Another surgeon wrote—chillingly—that he sometimes “operated on cancer of the breast solely for its effect on morale.” He also privately noted, “I do not despair of carcinoma being cured somewhere in the future, but this blessed achievement will, I believe, never be wrought by the knife of the surgeon.”

Emboldened by his success, between 1924 and 1928, Keynes attempted other variations on the same strategy. The most successful of these permutations, he found, involved a careful mixture of surgery and radiation, both at relatively small doses. He removed the malignant lumps locally with a minor operation (i.e., without resorting to radical or ultraradical surgery). He followed the surgery with radiation to the breast. There was no stripping of nodes, no cracking or excavation of clavicles, no extirpations that stretched into six or eight hours. Nothing was radical, yet, in case after case, Keynes and his colleagues found that their cancer recurrence rate was at least comparable to those obtained in New York or Baltimore—achieved without grinding patients through the terrifying crucible of radical surgery.

Like Crile and Keynes, he, too, had lost faith in the centrifugal theory of cancer. The more he revisited Keynes’s and Crile’s data, the more Fisher was convinced that radical mastectomy had no basis in biological reality. The truth, he suspected, was quite the opposite. “It has become apparent that the tangled web of threads on the wrong side of the tapestry really represented a beautiful design when examined properly, a meaningful pattern, a hypothesis… diametrically opposite to those considered to be ‘halstedian,’” Fisher wrote.

By the late 1960s, the relationship between doctors and patients had begun to shift dramatically. Medicine, once considered virtually infallible in its judgment, was turning out to have deep fallibilities—flaws that appeared to cluster pointedly around issues of women’s health. Thalidomide, prescribed widely to control pregnancy-associated nausea and “anxiety,” was hastily withdrawn from the market in 1961 because of its propensity to cause severe fetal malformations. In Texas, Jane Roe (a pseudonym) sued the state for blocking her ability to abort her fetus at a medical clinic—launching the Roe v. Wade case on abortion and highlighting the complex nexus between the state, medical authority, and women’s bodies. Political feminism, in short, was birthing medical feminism—and the fact that one of the most common and most disfiguring operations performed on women’s bodies had never been formally tested in a trial stood out as even more starkly disturbing to a new generation of women. “Refuse to submit to a radical mastectomy,” Crile exhorted his patients in 1973.

In 1967, bolstered by the activism of patients and the public attention swirling around breast cancer, Fisher became the new chair of the National Surgical Adjuvant Breast and Bowel Project (NSABP), a consortium of academic hospitals modeled self-consciously after Zubrod’s leukemia group that would run large-scale trials in breast cancer. Four years later, the NSABP proposed to test the operation using a systematic, randomized trial. It was, coincidentally, the eightieth “anniversary” of Halsted’s original description of the radical mastectomy. The implicit, nearly devotional faith in a theory of cancer was finally to be put to a test. “The clinician, no matter how venerable, must accept the fact that experience, voluminous as it might be, cannot be employed as a sensitive indicator of scientific validity,” Fisher wrote in an article. He was willing to have faith in divine wisdom, but not in Halsted as divine wisdom. “In God we trust,” he brusquely told a journalist. “All others [must] have data.”

The ominous toppling of radical surgery off its pedestal may have given cancer chemotherapists some pause for reckoning. But they had their own fantasy of radicalism to fulfill, their own radical arsenal to launch against cancer. Surgery, the traditional battle-ax against cancer, was considered too primitive, too indiscriminate, and too weary. A “large-scale chemotherapeutic attack,” as one doctor put it, was needed to obliterate cancer.

These wards created not just a psychological isolation chamber but also a physical microenvironment, a sterile bubble where the core theory of cancer chemotherapy—eradicating cancer with a death-defying bombardment of drugs—could be adequately tested. It was, undeniably, an experiment. At the NIH, Alsop wrote pointedly, “Saving the individual patient is not the essential mission. Enormous efforts are made to do so, or at least to prolong the patient’s life to the last possible moment. But the basic purpose is not to save that patient’s particular life but to find means of saving the lives of others.”

The NCI meanwhile was turning into a factory of toxins. The influx of money from the National Cancer Act had potently stimulated the institute’s drug-discovery program, which had grown into an even more gargantuan effort and was testing hundreds of thousands of chemicals each year to discover new cytotoxic drugs. The strategy of discovery was empirical—throwing chemicals at cancer cells in test tubes to identify cancer killers—but, by now, unabashedly and defiantly so. The biology of cancer was still poorly understood. But the notion that even relatively indiscriminate cytotoxic agents discovered largely by accident would cure cancer had captivated oncology.

Between 1984 and 1985, at the midpoint of the most aggressive expansion of chemotherapy, nearly six thousand articles were published on the subject in medical journals. Not a single article reported a new strategy for the definitive cure of an advanced solid tumor by means of combination chemotherapy alone.

Prostate cancer represents a full third of all cancer incidence in men—sixfold that of leukemia and lymphoma. In autopsies of men over sixty years old, nearly one in every three specimens will bear some evidence of prostatic malignancy.

Huggins found that prostate cancer cells also retained a physiological “memory” of their origin. When he removed the testicles of prostate cancer–bearing dogs, thus acutely depriving the cancer cells of testosterone, the tumors also involuted within days. In fact, if normal prostate cells were dependent on testosterone for survival, then malignant prostate cells were nearly addicted to the hormone—so much so that the acute withdrawal acted like the most powerful therapeutic drug conceivable. “Cancer is not necessarily autonomous and intrinsically self-perpetuating,” Huggins wrote. “Its growth can be sustained and propagated by hormonal function in the host.” The link between the growth-sustenance of normal cells and of cancer cells was much closer than previously imagined: cancer could be fed and nurtured by our own bodies.

In the late 1890s, an adventurous Scottish surgeon named George Beatson, trying to devise new surgical methods to treat breast cancer, had learned from shepherds in the Scottish highlands that the removal of the ovaries from cows altered their capacity to lactate and changed the quality of their udders. Beatson did not understand the basis for this phenomenon (estrogen, the ovarian hormone, had not yet been discovered by Doisy), but intrigued by the inexplicable link between ovaries and breasts, Beatson had surgically removed the ovaries of three women with breast cancer. In an age before the hormonal circuits between the ovary and the breast were even remotely established, this was unorthodox beyond description—like removing the lung to cure a brain lesion. But to Beatson’s astonishment, his three cases revealed marked responses to the ovarian removal—the breast tumors shrank dramatically.

An Italian team came to the rescue. In 1972, as the NCI was scouring the nation for a site where “adjuvant chemotherapy” after surgery could be tested, the oncologist Gianni Bonadonna came to Bethesda to visit the institute. Suave, personable, and sophisticated, impeccably dressed in custom-cut Milanese suits, Bonadonna made an instant impression at the NCI. He learned from DeVita, Canellos, and Carbone that they had been testing combinations of drugs to treat advanced breast cancer and had found a concoction that would likely work: Cytoxan (a cousin of nitrogen mustard), methotrexate (a variant of Farber’s aminopterin), and fluorouracil (an inhibitor of DNA synthesis). The regimen, called CMF, could be tolerated with relatively minimal side effects, yet was active enough in combination to thwart microscopic tumors—an ideal combination to be used as an adjuvant in breast cancer. Bonadonna worked at a large cancer center in Milan called the Istituto Tumori, where he had a close friendship with the chief breast surgeon, Umberto Veronesi. Convinced by Carbone (who was still struggling to get a similar trial launched in America), Bonadonna and Veronesi, the only surgeon-chemotherapist pair seemingly on talking terms with each other, proposed a large randomized trial to study chemotherapy after breast surgery for early-stage breast cancer. They were immediately awarded the contract for the NCI trial. The irony of that award could hardly have escaped the researchers at the insti...

In January 1977, five years after Cole had published her results on tamoxifen in metastatic cancer, Fisher recruited 1,891 women with estrogen receptor–positive (ER-positive) breast cancer that had spread only to the axillary nodes. He treated half with adjuvant tamoxifen and the other half with no tamoxifen. By 1981, the two groups had deviated sharply. Treatment with tamoxifen after surgery reduced cancer relapse rates by nearly 50 percent. The effect was particularly pronounced among women above fifty years old—a group most resistant to standard chemotherapy regimens and most likely to relapse with aggressive, metastatic breast cancer. Three years later, in ’85, when Fisher reanalyzed the deviating curves of relapse and survival, the effect of tamoxifen treatment was even more dramatic. Among the five-hundred-odd women older than fifty assigned to each group, tamoxifen had prevented fifty-five relapses and deaths. Fisher had altered the biology of breast cancer after surgery using a targeted hormonal drug that had barely any significant side effects.

The word resurrection implies a burial, and since the Fortune article of 1937, composite assessments of the War on Cancer had virtually been buried—oddly, in an overwhelming excess of information. Every minor footfall and every infinitesimal step had been so obsessively reported in the media that it had become nearly impossible to discern the trajectory of the field as a whole. In part, Cairns was reacting to the overgranularity of the view from the prior decade. He wanted to pull away from the details and offer a bird’s-eye view. Were patients with cancer surviving longer in general? Had the enormous investments in the War on Cancer since 1971 translated into tangible clinical achievements?

One thing was frightfully obvious: cancer mortality was not declining in the United States. There is “no evidence,” Bailar and Smith wrote darkly, “that some thirty-five years of intense and growing efforts to improve the treatment of cancer have had much overall effect on the most fundamental measure of clinical outcome—death.” They continued, “We are losing the war against cancer notwithstanding progress against several uncommon forms of the disease [such as childhood leukemia and Hodgkin’s disease], improvements in palliation and extension of productive years of life.… Some thirty-five years of intense effort focused largely on improving treatment must be judged a qualified failure.”

To illustrate his point, Breslow proposed an alternative metric. If chemotherapy cured a five-year-old child of ALL, he argued, then it saved a full sixty-five years of potential life (given an overall life expectancy of about seventy). In contrast, the chemotherapeutic cure in a sixty-five-year-old man contributed only five additional years given a life expectancy of seventy. But Bailar and Smith’s chosen metric—age-adjusted mortality—could not detect any difference in the two cases. A young woman cured of lymphoma, with fifty additional years of life, was judged by the same metric as an elderly woman cured of breast cancer, who might succumb to some other cause of death in the next year. If “years of life saved” was used as a measure of progress on cancer, then the numbers turned far more palatable. Now, instead of losing the War on Cancer, it appeared that we were winning it.

“By the early 1940s, asking about a connection between tobacco and cancer was like asking about an association between sitting and cancer.” If nearly all men smoked, and only some of them developed cancer, then how might one tease apart the statistical link between one and the other?

By May 1, 1948, 156 interviews had come in. And as Doll and Hill sifted through the preliminary batch of responses, only one solid and indisputable statistical association with lung cancer leapt out: cigarette smoking. As more interviews poured in week after week, the statistical association strengthened. Even Doll, who had personally favored road-tar exposure as the cause of lung cancer, could no longer argue with his own data. In the middle of the survey, sufficiently alarmed, he gave up smoking.

In the twenty-nine months between October 1951 and March 1954, 789 deaths were reported in Doll and Hill’s original cohort. Thirty-six of these were attributed to lung cancer. When these lung cancer deaths were counted in smokers versus nonsmokers, the correlation virtually sprang out: all thirty-six of the deaths had occurred in smokers. The difference between the two groups was so significant that Doll and Hill did not even need to apply complex statistical metrics to discern it. The trial designed to bring the most rigorous statistical analysis to the cause of lung cancer barely required elementary mathematics to prove its point.

Richard Doll and Bradford Hill published their prospective study on lung cancer in 1956—the very year that the fraction of smokers in the adult American population reached its all-time peak at 45 percent. It had been an epochal decade for cancer epidemiology, but equally, an epochal decade for tobacco. Wars generally stimulate two industries, ammunition and cigarettes, and indeed both the World Wars had potently stimulated the already bloated tobacco industry. Cigarette sales had climbed to stratospheric heights in the mid-1940s and continued to climb in the ’50s. In a gargantuan replay of 1864, as tobacco-addicted soldiers returned to civilian life, they brought even more public visibility to their addiction.

By the early 1960s, the gross annual sale of cigarettes in America peaked at nearly $5 billion, a number unparalleled in the history of tobacco. On average, Americans were consuming nearly four thousand cigarettes per year or about eleven cigarettes per day—nearly one for every waking hour.

Indeed, like many of his epidemiologist peers, Graham was becoming exasperated with the exaggerated scrutiny of the word cause. That word, he believed, had outlived its original utility and turned into a liability. In 1884, the microbiologist Robert Koch had stipulated that for an agent to be defined as the “cause” of a disease, it would need to fulfill at least three criteria. The causal agent had to be present in diseased animals; it had to be isolated from diseased animals; and it had to be capable of transmitting the disease when introduced into a secondary host. But Koch’s postulates had arisen, crucially, from the study of infectious diseases and infectious agents; they could not simply be “repurposed” for many noninfectious diseases. In lung cancer, for instance, it would be absurd to imagine a carcinogen being isolated from a cancerous lung after months, or years, of the original exposure. Transmission studies in mice were bound to be equally frustrating. As Bradford Hill argued, “We may subject mice, or other laboratory animals, to such an atmosphere of tobacco smoke that they can—like the old man in the fairy story—neither sleep nor slumber; they can neither breed nor eat. And lung cancers may or may not develop to a significant degree. What then?”

For studies on chronic and complex human diseases such as cancer, Hill suggested, the traditional understanding of causality needed to be broadened and revised. If lung cancer would not fit into Koch’s straitjacket, then the jacket needed to be loosened. Hill acknowledged epidemiology’s infernal methodological struggle with causation—this was not an experimental discipline at its core—but he rose beyond it. At least in the case of lung cancer and smoking, he argued, the association possessed several additional features: It was strong: the increased risk of cancer was nearly five- or tenfold in smokers. It was consistent: Doll and Hill’s study, and Wynder and Graham’s study, performed in vastly different contexts on vastly different populations, had come up with the same link. It was specific: tobacco was linked to lung cancer—precisely the site where tobacco smoke enters the body. It was temporal: Doll and Hill had found that the longer one smoked, the greater the increase in risk. It possessed a “biological gradient”: the more one smoked in quantity, the greater the risk for lung cancer. It was plausible: a mechanistic link between an inhaled carcinogen and a malignant change in the lung was not implausible. It was coherent; it was backed by experimental evidence: the epidemiological findings and the laboratory findings, such as Graham’s tar-painting experiments in mice, were concordant. It behaved similarly in analogous situations: smoking had been correlated with lung c...

In the winter of 1954, three years before his untimely death, Evarts Graham wrote a strikingly prescient essay in a book entitled Smoking and Cancer. At the end of the essay, Graham wondered about how the spread of tobacco in human societies might be combated in the future. Medicine, he concluded, was not powerful enough to restrict tobacco’s spread. Academic investigators could provide data about risks and argue incessantly about proof and causality, but the solution had to be political. “The obstinacy of [policymakers],” he wrote, “compels one to conclude that it is their own addiction… which blinds them. They have eyes to see, but see not because of their inability or unwillingness to give up smoking. All of this leads to the question… are the radio and the television to be permitted to continue carrying the advertising material of the cigarette industry? Isn’t it time that the official guardian of the people’s health, the United States Public Health Service, at least make a statement of warning?”

The precise and meticulous Cochran devised a new mathematical insight to judge the trials. Rather than privilege any particular study, he reasoned, perhaps one could use a method to estimate the relative risk as a composite number through all trials in the aggregate. (This method, termed meta-analysis, would deeply influence academic epidemiology in the future.)

In a nation obsessed with cancer, the attribution of a vast preponderance of a major cancer to a single, preventable cause might have been expected to provoke a powerful and immediate response. But front-page coverage notwithstanding, the reaction in Washington was extraordinarily anergic. “While the propaganda blast was tremendous,” George Weissman, a public relations executive, wrote smugly to Joseph Cullman, the president of Philip Morris, “… I have a feeling that the public reaction was not as severe nor did it have the emotional depth I might have feared. Certainly, it is not of a nature that caused prohibitionists to go out with axes and smash saloons.”

So it proved to be. In Congress, the FTC’s recommendation was diluted and rediluted as it changed hands from hearing to hearing and committee to subcommittee, leading to a denervated and attenuated shadow of the bill’s former self. Entitled the Federal Cigarette Labeling and Advertising Act (FCLAA) of 1965, it changed the FTC’s warning label to Caution: Cigarette smoking may be hazardous to your health. The dire, potent language of the original label—most notably the words cancer, cause, and death—was expunged. To ensure uniformity, state laws were also enfolded into the FCLAA—in effect, ensuring that no stronger warning label could exist in any state in America. The result, as the journalist Elizabeth Drew noted in the Atlantic Monthly, was “an unabashed act to protect private industry from government regulation.” Politicians were far more protective of the narrow interests of tobacco than of the broad interest of public health. Tobacco makers need not have bothered inventing protective filters, Drew wrote drily: Congress had turned out to be “the best filter yet.”

With Geller’s consent, Banzhaf filed his case against the TV station in court. Predictably, tobacco companies protested vociferously, arguing that legal action of this sort would have a chilling effect on free speech and vowing to fight the case to its bitter end. Faced with the prospect of a prolonged court battle, Banzhaf approached the American Cancer Society, the American Lung Association, and several other public health organizations for support. In all cases, he was rebuffed. Banzhaf chose to go to trial anyway. Dragged into court in 1968, he squared off against “a squadron of the best-paid lawyers in the country, row after row of them in pinstripe suits and cuff links”—and, to the utter shock of the tobacco industry, won his case. The court held that “proportional airtime” had to be given to protobacco and antitobacco advertising. The FCC and Geller leapt back into the arena. In February 1969, the commission issued a public announcement that it would rigorously police the “proportional airtime” clause and, given the public-health hazard of tobacco, seek to ban cigarette commercials from television altogether. Tobacco makers appealed and reappealed the Banzhaf decision, but the Supreme Court refused to hear the case, letting the decision stand.

A barrage of antismoking commercials appeared on television. In 1968, a worn and skeletal-looking William Talman, a veteran actor and former smoker, announced in a prime-time advertisement that he was dying from lung cancer. Narcotized on painkilling medicines, his words slurring, Talman nonetheless had a clear message for the public: “If you do smoke—quit. Don’t be a loser.”

“Statistics,” the journalist Paul Brodeur once wrote, “are human beings with the tears wiped off,”

beleaguered in America, the Marlboro Man has simply sought out new Marlboro countries. With their markets and profits dwindling and their legal costs mounting, cigarette manufacturers have increasingly targeted developing countries as new markets, and the number of smokers in many of these nations has risen accordingly. Tobacco smoking is now a major preventable cause of death in both India and China. Richard Peto, an epidemiologist at Oxford and a close collaborator of Richard Doll’s (until Doll’s death in 2005), recently estimated that the number of smoking-related deaths among adults in India would rise to 1 million per year in the 2010s and continue to rise in the next decade. In China, lung cancer is already a leading cause of death attributable to smoking in men.

In a recent editorial in the British Medical Journal, Stanton Glantz, an epidemiologist at the University of California, San Francisco, described this as yet another catastrophe in the making: “Multinational cigarette companies act as a vector that spreads disease and death throughout the world. This is largely because the tobacco industry uses its wealth to influence politicians to create a favourable environment to promote smoking. The industry does so by minimising restrictions on advertising and promotion and by preventing effective public policies for tobacco control such as high taxes, strong graphic warning labels on packets, smoke-free workplaces and public places, aggressive countermarketing media campaigns, and advertising bans. Unlike mosquitoes, another vector of worldwide disease, the tobacco companies quickly transfer the information and strategies they learn in one part of the world to others.”

is difficult for me to convey the range and depth of devastation that I witnessed in the cancer wards that could be directly attributed to cigarette smoking. An ebullient, immaculately dressed young advertising executive who first started smoking to calm his nerves had to have his jawbone sliced off to remove an invasive tongue cancer. A grandmother who taught her grandchildren to smoke and then shared cigarettes with them was diagnosed with esophageal cancer. A priest with terminal lung cancer swore that smoking was the only vice that he had never been able to overcome. Even as these patients were paying the ultimate price for their habit, the depth of denial in some of them remained astonishing; many of my patients continued to smoke, often furtively, during their treatment for cancer (I could smell the acrid whiff of tobacco on their clothes as they signed the consent forms for chemotherapy). A surgeon who practiced in Britain in the seventies—a time when lung cancer incidence was ascending to its macabre peak—recalled his first nights in the wards when patients awoke from their cancer operations and then walked like zombies through the corridors begging the nurses for cigarettes.

Ames observed that mutations in these essential genes could enable or disable the growth of bacteria on a petri dish. A strain of Salmonella normally unable to grow on galactose, say, could acquire a gene mutation that enabled this growth. Once growth-enabled, a single bacterium would form a minuscule colony on a petri dish. By counting the number of growth-enabled colonies formed, Ames could quantify the mutation rate in any experiment. Bacteria exposed to a certain substance might produce six such colonies, while bacteria exposed to another substance might produce sixty. This second substance, in other words, had a tenfold capacity to initiate changes in genes—or a tenfold rate of mutation.

Ames could now test thousands of chemicals to create a catalog of chemicals that increased the mutation rate—mutagens. And as he populated his catalog, he made a seminal observation: chemicals that scored as mutagens in his test tended to be carcinogens as well. Dye derivatives, known to be potent human carcinogens, scored floridly, causing hundreds of colonies of bacteria. So did X-rays, benzene compounds, and nitrosoguanidine derivatives—all known to cause cancers in rats and mice. In the tradition of all good tests, Ames’s test transformed the unobservable and immeasurable into the observable and measurable. The invisible X-rays that had killed the Radium girls in the 1920s could now be “seen” as revertant colonies on a petri dish.

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.

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.

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.

There was little precedent in other diseases for such an astonishing diversity of causes. Diabetes, a complex illness with complex manifestations, 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 carcinogenesis.

It was a revelation,” one of his students recalled. “A Pap smear would give a woman a chance to receive preventive care [and] greatly decrease the likelihood of her ever developing cancer.” Cervical cancer typically arises in an outer layer of the cervix, then grows in a flaky, superficial whirl before burrowing inward into the surrounding tissues. By sampling asymptomatic women, Papanicolaou speculated that his test, albeit imperfect, might capture the disease at its first stages. He would, in essence, push the diagnostic clock backward—from incurable, invasive cancers to curable, preinvasive malignancies.

But the real proof of Papanicolaou’s principle lay in another discovery: astonishingly, 557 women were found to have preinvasive cancers or even precancerous changes—early-stage, localized lesions curable by relatively simple surgical procedures. Nearly all these women were asymptomatic; had they never been tested, they would never have been suspected of harboring preinvasive lesions. Notably, the average age of diagnosis of women with such preinvasive lesions was about twenty years lower than the average age of women with invasive lesions—once again corroborating the long march of carcinogenesis. The Pap smear had, in effect, pushed the clock of cancer detection forward by nearly two decades, and changed the spectrum of cervical cancer from predominantly incurable to predominantly curable.

A screening test’s path to success is thus surprisingly long and narrow. It must avoid the pitfalls of overdiagnosis and underdiagnosis. It must steer past the narrow temptation to use early detection as an end in itself. Then, it must navigate the treacherous straits of bias and selection. “Survival,” seductively simple, cannot be its end point. And adequate randomization at each step is critical. Only a test capable of meeting all these criteria—proving mortality benefit in a genuinely randomized setting with an acceptable over- and underdiagnosis rate—can be judged a success. With the odds stacked so steeply, few tests are powerful enough to withstand this level of scrutiny and truly provide benefit in cancer.

In aggregate, over the course of fifteen years, mammography had resulted in 20 to 30 percent reductions in breast cancer mortality for women aged fifty-five to seventy. But for women below fifty-five, the benefit was barely discernible.

In women above fifty-five, where the “font size” of breast cancer incidence is large enough, a mammogram performs adequately. But in women between forty and fifty, the mammogram begins to squint at an uncomfortable threshold—exceeding its inherent capacity to become a discriminating test. No matter how intensively we test mammography in this group of women, it will always be a poor screening tool.