Number of words: 1,187

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?

Graham, who knew Little from his days at the ASCC, was livid. In a stinging rebuttal written to the editor, he complained, “A causal relationship between heavy cigarette smoking and cancer of the lung is stronger than for the efficacy of vaccination against smallpox, which is only statistical.

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?”

Indeed, what then? With Wynder and other coworkers, Graham had tried to expose mice to a toxic

“atmosphere of tobacco smoke”—or at least its closest conceivable equivalent. Persuading mice to chain-smoke was obviously unlikely to succeed. So, in an inspired experiment performed in his lab in St. Louis, Graham had invented a “smoking machine,” a contraption that would puff the equivalent of hundreds of cigarettes all day (Lucky Strikes were chosen) and deposit the tarry black residue, through a maze of suction chambers, into a distilling flask of acetone. By serially painting the tar on the skins of mice, Graham and Wynder had found that they could create tumors on the backs of mice. But these studies had, if anything, fanned up even more controversy. Forbes magazine had famously spoofed the research by asking Graham, “How many men distill their tar from their tobacco and paint it on their backs?” And critics such as Little might well have complained that this experiment was akin to distilling an orange to a millionth of a million parts and then inferring, madly, that the original fruit was too poisonous to eat.

Epidemiology, like the old man in Hill’s fairy story, was thus itself huffing against the stifling economy of Koch’s postulates. The classical triad—association, isolation, retransmission—would simply not suffice; what preventive medicine needed was its own understanding of “cause.”

Once again, Bradford Hill, the éminence grise of epidemiology, proposed a solution to this impasse. 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 cancer, and also with lip, throat, tongue, and esophageal cancer.

Hill used these criteria to advance a radical proposition. Epidemiologists, he argued, could infer causality by using that list of nine criteria. No single item in that list proved a causal relationship. Rather, Hill’s list functioned as a sort of à la carte menu, from which scientists could pick and choose criteria to strengthen (or weaken) the notion of a causal relationship. For scientific purists, this seemed rococo—and, like all things rococo, all too easy to mock: imagine a mathematician or physicist choosing from a “menu” of nine criteria to infer causality. Yet Hill’s list would charge epidemiological research with pragmatic clarity. Rather than fussing about the metaphysical idea about causality (what, in the purest sense, constitutes “cause”?), Hill changed its emphasis to a functional or operational idea. Cause is what cause does, Hill claimed. Often, like the weight of proof in a detective case, the preponderance of small bits of evidence, rather than a single definitive experiment, clinched cause.

Excerpted from pages 253-256 of ‘The Emperor of All Maladies: A biography of Cancer’ by Siddharth Mukherjee