The Emperor of All Maladies

by Siddhartha Mukherjee

  But many epidemiologists argued that such cause-effect relationships could only be established for infectious diseases, where there was a known pathogen and a known carrier (called a vector) for a disease—the mosquito for malaria or the tsetse fly for sleeping sickness. Chronic, noninfectious diseases such as cancer and diabetes were too complex and too variable to be associated with single vectors or causes, let alone “preventable” causes. The notion that a chronic disease such as lung cancer might have a “carrier” of its own sort, to be gilded and hung like an epidemiological trophy on one of those balconies, was dismissed as nonsense.

  In this charged, brooding atmosphere, Hill and Doll threw themselves into work. They were an odd couple, the younger Doll formal, dispassionate, and cool, the older Hill lively, quirky, and humorous, a pukka Englishman and his puckish counterpart. The postwar economy was brittle, and the treasury on the verge of a crisis. When the price of cigarettes was increased by a shilling to collect additional tax revenues, “tobacco tokens” were issued to those who declared themselves “habitual users.” During breaks in the long hours and busy days, Doll, a “habitual user” himself, stepped out of the building to catch a quick smoke.

  Doll and Hill’s study was initially devised as mainly a methodological exercise. Patients with lung cancer (“cases”) versus patients admitted for other illnesses (“controls”) were culled from twenty hospitals in and around London and interviewed by a social worker in a hospital. And since even Doll believed that tobacco was unlikely to be the true culprit, the net of associations was spread widely. The survey included questions about the proximity of gasworks to patients’ homes, how often they ate fried fish, and whether they preferred fried bacon, sausage, or ham for dinner. Somewhere in that haystack of questions, Doll buried a throwaway inquiry about smoking habits.

  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 St. Louis, meanwhile, the Wynder-Graham team had arrived at similar results. (The two studies, performed on two populations across two continents, had converged on almost precisely the same magnitude of risk—a testament to the strength of the association.) Doll and Hill scrambled to get their paper to a journal. In September of that year, their seminal study, “Smoking and Carcinoma of the Lung,” was published in the British Medical Journal. Wynder and Graham had already published their study a few months earlier in the Journal of the American Medical Association.

  It is tempting to suggest that Doll, Hill, Wynder, and Graham had rather effortlessly proved the link between lung cancer and smoking. But they had, in fact, proved something rather different. To understand that difference—and it is crucial—let us return to the methodology of the case-control study.

  In a case-control study, risk is estimated post hoc—in Doll’s and Wynder’s case by asking patients with lung cancer whether they had smoked. In an often-quoted statistical analogy, this is akin to asking car accident victims whether they had been driving under the influence of alcohol—but interviewing them after their accident. The numbers one derives from such an experiment certainly inform us about a potential link between accidents and alcohol. But it does not tell a drinker his or her actual chances of being involved in an accident. It is risk viewed as if from a rearview mirror, risk assessed backward. And as with any distortion, subtle biases can creep into such estimations. What if drivers tend to overestimate (or underestimate) their intoxication at the time of an accident? Or what if (to return to Doll and Hill’s case) the interviewers had unconsciously probed lung cancer victims more aggressively about their smoking habits while neglecting similar habits in the control group?

  Hill knew the simplest method to counteract such biases: he had invented it. If a cohort of people could be randomly assigned to two groups, and one group forced to smoke cigarettes and the other forced not to smoke, then one could follow the two groups over time and determine whether lung cancer developed at an increased rate in the smoking group. That would prove causality, but such a ghoulish human experiment could not even be conceived, let alone performed on living people, without violating fundamental principles of medical ethics.

  But what if, recognizing the impossibility of that experiment, one could settle for the next-best option—for a half-perfect experiment? Random assignment aside, the problem with the Doll and Hill study thus far was that it had estimated risk retrospectively. But what if they could set the clocks back and launch their study before any of the subjects developed cancer? Could an epidemiologist watch a disease such as lung cancer develop from its moment of inception, much as an embryologist might observe the hatching of an egg?

  In the early 1940s, a similar notion had gripped the eccentric Oxford geneticist Edmund Ford. A firm believer in Darwinian evolution, Ford nonetheless knew that Darwin’s theory suffered from an important limitation: thus far, the evolutionary progression had been inferred indirectly from the fossil record, but never demonstrated directly on a population of organisms. The trouble with fossils, of course, is that they are fossilized—static and immobile in time. The existence of three fossils A, B, and C, representing three distinct and progressive stages of evolution, might suggest that fossil A generated B and fossil B generated C. But this proof is retrospective and indirect; that three evolutionary stages exist suggests, but cannot prove, that one fossil had caused the genesis of the next.

  The only formal method to prove the fact that populations undergo defined genetic changes over time involves capturing that change in the real world in real time—prospectively. Ford became particularly obsessed with devising such a prospective experiment to watch Darwin’s cogwheels in motion. To this end, he persuaded several students to tramp through the damp marshes near Oxford collecting moths. Each time a moth was captured, it was marked with a cellulose pen and released back into the wild. Year after year, Ford’s students had returned with galoshes and moth nets, recapturing and studying the moths that they had marked in the prior years and their unmarked descendants—in effect, creating a “census” of wild moths in the field. Minute changes in that cohort of moths, such as shifts in wing markings or variations in size, shape, and color, were recorded each year with great care. By charting those changes over nearly a decade, Ford had begun to watch evolution in action. He had documented gradual changes in the color of moth coats (and thus changes in genes), grand fluctuations in populations and signs of natural selection by moth predators—a macrocosm caught in a marsh.*

  Both Doll and Hill had followed this work with deep interest. And the notion of using a similar cohort of humans occurred to Hill in the winter of 1951—purportedly, like most great scientific notions, while in his bath. Suppose a large group of men could be marked, à la Ford, with some fantastical cellulose pen, and followed, decade after decade after decade. The group would contain some natural mix of smokers and nonsmokers. If smoking truly predisposed subjects to lung cancer (much like bright-winged moths might be predisposed to being hunted by predators), then the smokers would begin to succumb to cancer at an increased rate. By following that cohort over time—by peering into that natural marsh of human pathology—an epidemiologist could calculate the precise relative risk of lung cancer among smokers versus nonsmokers.

  But how might one find a large enough cohort? Again, coincidences surfaced. In Britain, efforts to nationalize health care had resulted in a centralized registry of all doctors, containing more than sixty thousand names. Every time a doctor in the registry died, the registrar was notified, often with a relatively detailed description of the cause of death. The result, as Doll’s collaborator and student Richard Peto described it, wa
s the creation of a “fortuitous laboratory” for a cohort study. On October 31, 1951, Doll and Hill mailed out letters to about 59,600 doctors containing their survey. The questions were kept intentionally brief: respondents were asked about their smoking habits, an estimation of the amount smoked, and little else. Most doctors could respond in less than five minutes.

  An astonishing number—41,024 of them—wrote back. Back in London, Doll and Hill created a master list of the doctors’ cohort, dividing it into smokers and nonsmokers. Each time a death in the cohort was reported, they contacted the registrar’s office to determine the precise cause of death. Deaths from lung cancer were tabulated for smokers versus nonsmokers. Doll and Hill could now sit back and watch cancer unfold in real time.

  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.

  * It was Ford’s student Henry B. D. Kettlewell who used this moth-labeling technique to show that dark-colored moths—better camouflaged on pollution-darkened trees—tended to be spared by predatory birds, thus demonstrating “natural selection” in action.

  “A thief in the night”

  By the way, [my cancer] is a squamous cell cancer apparently like all the other smokers’ lung cancers. I don’t think anyone can bring up a very forcible argument against the idea of a causal connection with smoking because after all I had smoked for about 50 years before stopping.

  —Evarts Graham to Ernst Wynder, 1957

  We believe the products that we make are not injurious to health. We always have and always will cooperate closely with those whose task it is to safeguard public health.

  —“A Frank Statement to Cigarette Smokers,”

  a full-page advertisement produced

  by the tobacco industry in 1954

  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.

  To stoke its explosive growth in the postwar period, the cigarette industry poured tens, then hundreds, of millions of dollars into advertising. And if advertising had transformed the tobacco industry in the past, the tobacco industry now transformed advertising. The most striking innovation of this era was the targeting of cigarette advertising to highly stratified consumers, as if to achieve exquisite specificity. In the past, cigarettes had been advertised quite generally to all consumers. By the early 1950s, though, cigarette ads, and cigarette brands, were being “designed” for segmented groups: urban workers, housewives, women, immigrants, African-Americans—and, to preemptively bell the medical cat—doctors themselves. “More doctors smoke Camels,” one advertisement reminded consumers, thus reassuring patients of the safety of their smoking. Medical journals routinely carried cigarette advertisements. At the annual conferences of the American Medical Association in the early 1950s, cigarettes were distributed free of charge to doctors, who lined up outside the tobacco booths. In 1955, when Philip Morris introduced the Marlboro Man, its most successful smoking icon to date, sales of the brand shot up by a dazzling 5,000 percent over eight months. Marlboro promised a nearly erotic celebration of tobacco and machismo rolled into a single, seductive pack: “Man-sized taste of honest tobacco comes full through. Smooth-drawing filter feels right in your mouth. Works fine but doesn’t get in the way.” 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.

  Public health organizations in America in the mid-1950s were largely unperturbed by the link between tobacco and cancer delineated by the Doll and Hill studies. Initially, few, if any, organizations highlighted the study as an integral part of an anticancer campaign (although this would soon change). But the tobacco industry was far from complacent. Concerned that the ever-tightening link between tar, tobacco, and cancer would eventually begin to frighten consumers away, cigarette makers began to proactively tout the benefits of filters added to the tips of their cigarettes as a “safety” measure. (The iconic Marlboro Man, with his hypermasculine getup of lassos and tattoos, was an elaborate decoy set up to prove that there was nothing effeminate or sissy about smoking filter-tipped cigarettes.)

  On December 28, 1953, three years before Doll’s prospective study had been released to the public, the heads of several tobacco companies met preemptively at the Plaza Hotel in New York. Bad publicity was clearly looming on the horizon. To counteract the scientific attack, an equal and opposite counterattack was needed.

  The centerpiece of that counterattack was an advertisement titled “A Frank Statement,” which saturated the news media in 1954, appearing simultaneously in more than four hundred newspapers over a few weeks. Written as an open letter from tobacco makers to the public, the statement’s purpose was to address the fears and rumors about the possible link between lung cancer and tobacco. In about six hundred words, it would nearly rewrite the research on tobacco and cancer.

  “A Frank Statement” was anything but frank. The speciousness began right from its opening lines: “Recent reports on experiments with mice have given wide publicity to a theory that cigarette smoking is in some way linked with lung cancer in human beings.” Nothing, in fact, could have been further from the truth. The most damaging of the “recent experiments” (and certainly the ones that had received the “widest publicity”) were the Doll/Hill and Wynder/Graham retrospective studies—both of which had been performed not on mice, but on humans. By making the science seem obscure and arcane, those sentences sought to render its results equally arcane. Evolutionary distance would force emotional distance: after all, who could possibly care about lung cancer in mice? (The epic perversity of all this was only to be revealed a decade later when, confronted with a growing number of superlative human studies, the tobacco lobby would counter that smoking had never been effectively shown to cause lung cancer in, of all things, mice.)

  Obfuscation of facts, though, was only the first line of defense. The more ingenious form of manipulation was to gnaw at science’s own self-doubt: “The statistics purporting to link cigarette smoking with the disease could apply with equal force to any one of many other aspects of modern life. Indeed the validity of the statistics themselves is questioned by numerous scientists.” By half revealing and half concealing the actual disagreements among scientists, the advertisement performed a complex dance of veils. What, precisely, was being “questioned by numerous scientists” (or what link was being claimed between lung cancer and other features of “modern life”) was left entirely to the reader’s imagination.

  Obfuscation of facts and the reflection of self-doubt—the proverbial combination of smoke and mirrors—might have sufficed for any ordinary public relations campaign. But the final ploy was unrivaled in its genius. Rather than discourage further research into the link between tobacco and cancer, tobacco companies proposed letting scient
ists have more of it: “We are pledging aid and assistance to the research effort into all phases of tobacco use and health . . . in addition to what is already being contributed by individual companies.” The implication was that if more research was needed, then the issue was still mired in doubt—and thus unresolved. Let the public have its addiction, and let the researchers have theirs.

  To bring this three-pronged strategy to fruition, the tobacco lobby had already formed a “research committee,” which it called the Tobacco Industry Research Committee, or the TIRC. Ostensibly, the TIRC would act as an intermediary between an increasingly hostile academy, an increasingly embattled tobacco industry, and an increasingly confused public. In January 1954, after a protracted search, the TIRC announced that it had finally chosen a director, who had—as the institute never failed to remind the public—been ushered in from the deepest realms of science. Their choice, as if to close the circle of ironies, was Clarence Cook Little, the ambitious contrarian that the Laskerites had once deposed as president of the American Society for the Control of Cancer (ASCC).

  If Clarence Little had not been discovered by the tobacco lobbyists in 1954, then they might have needed to invent him: he came preformed to their precise specifications. Opinionated, forceful, and voluble, Little was a geneticist by training. He had set up a vast animal research laboratory at Bar Harbor in Maine, which served as a repository for purebred strains of mice for medical experiments. Purity and genetics were Little’s preoccupations. He was a strong proponent of the theory that all diseases, including cancer, were essentially hereditary, and that these illnesses, in a form of medical ethnic-cleansing, would eventually carry away those with such predispositions, leaving a genetically enriched population resistant to diseases. This notion—call it eugenics lite—was equally applied to lung cancer, which he also considered principally the product of a genetic aberration. Smoking, Little argued, merely unveiled that inherent aberration, causing that bad germ to emerge and unfold in a human body. Blaming cigarettes for lung cancer, then, was like blaming umbrellas for bringing on the rain. The TIRC and the tobacco lobby vociferously embraced that view. Doll and Hill, and Wynder and Graham, had certainly correlated smoking and lung cancer. But correlation, Little insisted, could not be equated with cause. In a guest editorial written for the journal Cancer Research in 1956, Little argued that if the tobacco industry was being blamed for scientific dishonesty, then antitobacco activists bore the blame for scientific disingenuousness. How could scientists so easily conflate a mere confluence of two events—smoking and lung cancer—with a causal relationship?