Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

  The implication of Pott's work was far-reaching. If soot, and not some mystical, numinous humor (a la Galen), caused scrotal cancer, then two facts had to be true. First, external agents, rather than imbalances of internal fluids, had to lie at the root of carcinogenesis--a theory so radical for its time that even Pott hesitated to believe it. "All this makes it (at first) a very different case from a cancer which appears in an elderly man, whose fluids are become acrimonious from time," he wrote (paying sly homage to Galen, while undermining Galenic theory).

  Second, if a foreign substance was truly the cause, then cancer was potentially preventable. There was no need to purge the body of fluids. Since the illness was man-made, its solution could also be man-made. Remove the carcinogen--and cancer would stop appearing.

  But the simplest means of removing the carcinogen was perhaps the most difficult to achieve. Eighteenth-century England was a land of factories, coal, and chimneys--and by extension, of child labor and chimney sweeps servicing these factories and chimneys. Chimney sweeping, though still a relatively rare occupation for children--by 1851, Britain had about eleven hundred sweeps under the age of fifteen--was emblematic of an economy deeply dependent on children's labor. Orphans, often as young as four and five years old, were "apprenticed" to master sweeps for a small price. ("I wants a 'prentis, and I am ready to take him," says Mr. Gamfield, the dark, malevolent chimney sweep in Dickens's Oliver Twist. By an odd stroke of luck, Oliver is spared from being sold to Gamfield, who has already sent two previous apprentices to their deaths by asphyxiation in chimneys.)

  But political winds changed. By the late eighteenth century, the embarrassing plight of London's climbing-boys was publicly exposed, and social reformers in England sought to create laws to regulate the occupation. In 1788, the Chimney Sweepers Act was passed in Parliament, preventing master sweeps from employing children under eight (children over eight were allowed to be apprenticed). In 1834, the age was raised to fourteen, and in 1840 to sixteen years. By 1875, the use of young climbing-boys was fully forbidden and the profession vigorously policed to prevent infractions. Pott did not live to see the changes--he contracted pneumonia and died in 1788--but the man-made epidemic of scrotal cancer among sweeps vanished over several decades.

  If soot could cause cancer, then were such preventable causes--and their cancer "artificia"--strewn about in the world?

  In 1761, more than a decade before Pott had published his study on soot cancer, an amateur scientist and apothecary in London, John Hill, claimed that he had found one such carcinogen concealed in another innocuous-seeming substance. In a pamphlet entitled Cautions against the Immoderate Use of Snuff, Hill argued that snuff--oral tobacco--could also cause lip, mouth, and throat cancer.

  Hill's evidence was no weaker or stronger than Pott's. He, too, had drawn a conjectural line between a habit (snuff use), an exposure (tobacco), and a particular form of cancer. His culprit substance, often smoked as well as chewed, even resembled soot. But Hill--a self-professed "Bottanist, apothecary, poet, stage player, or whatever you please to call him"--was considered the court jester of British medicine, a self-promoting amateur dabbler, part scholar and part buffoon. While Pott's august monograph on soot cancer circulated through the medical annals of England drawing admiration and praise, Hill's earlier pamphlet, written in colorful, colloquial language and published without the backing of any medical authority, was considered a farce.

  In England, meanwhile, tobacco was rapidly escalating into a national addiction. In pubs, smoking parlors, and coffeehouses--in "close, clouded, hot, narcotic rooms"--men in periwigs, stockings, and lace ruffs gathered through the day and night to pull smoke from pipes and cigars or sniff snuff from decorated boxes. The commercial potential of this habit was not lost on the Crown or its colonies. Across the Atlantic, where the tobacco had originally been discovered and the conditions for cultivating the plant were almost providentially optimal, production increased exponentially decade by decade. By the mid-1700s, the state of Virginia was producing thousands of tons of tobacco every year. In England, the import of tobacco escalated dramatically between 1700 and 1770, nearly tripling from 38 million pounds to more than 100 million per year.

  It was a relatively minor innovation--the addition of a piece of translucent, combustible paper to a plug of tobacco--that further escalated tobacco consumption. In 1855, legend runs, a Turkish soldier in the Crimean War, having run out of his supply of clay pipes, rolled up tobacco in a sheet of newspaper to smoke it. The story is likely apocryphal, and the idea of packing tobacco in paper was certainly not new. (The papirossi, or papelito, had traveled to Turkey through Italy, Spain, and Brazil.) But the context was pivotal: the war had squeezed soldiers from three continents into a narrow, blasted peninsula, and habits and mannerisms were destined to spread quickly through its trenches like viruses. By 1855, English, Russian, and French soldiers were all puffing their tobacco rations rolled up in paper. When these soldiers returned from the war, they brought their habits, like viruses again, to their respective homelands with them.

  The metaphor of infection is particularly apposite, since cigarette smoking soon spread like a fierce contagion through all those nations and then leapt across the Atlantic to America. In 1870, the per capita consumption in America was less than one cigarette per year. A mere thirty years later, Americans were consuming 3.5 billion cigarettes and 6 billion cigars every year. By 1953, the average annual consumption of cigarettes had reached thirty-five hundred per person. On average, an adult American smoked ten cigarettes every day, an average Englishman twelve, and a Scotsman nearly twenty.

  Like a virus, too, the cigarette mutated, adapting itself to diverse contexts. In the Soviet gulags, it became an informal currency; among English suffragettes, a symbol of rebellion; among American suburbanites, of rugged machismo, among disaffected youth, of generational rift. In the turbulent century between 1850 and 1950, the world offered conflict, atomization, and disorientation. The cigarette offered its equal and opposite salve: camaraderie, a sense of belonging, and the familiarity of habits. If cancer is the quintessential product of modernity, then so, too, is its principal preventable cause: tobacco.

  It was precisely this rapid, viral ascendancy of tobacco that made its medical hazards virtually invisible. Our intuitive acuity about statistical correlations, like the acuity of the human eye, performs best at the margins. When rare events are superposed against rare events, the association between them can be striking. Pott, for instance, had discovered the link between scrotal cancer and chimney sweeping because chimney sweeping (the profession) and scrotal cancer (the disease) were both uncommon enough that the juxtaposition of the two stood out starkly like a lunar eclipse--two unusual occurrences in precise overlap.

  But as cigarette consumption escalated into a national addiction, it became harder and harder to discern an association with cancer. By the early twentieth century, four out of five--and, in some parts of the world, nearly nine of ten--men were smoking cigarettes (women would soon follow). And when a risk factor for a disease becomes so highly prevalent in a population, it paradoxically begins to disappear into the white noise of the background. As the Oxford epidemiologist Richard Peto put 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?

  Even surgeons, who encountered lung cancer most frequently, could no longer perceive any link. In the 1920s, when Evarts Graham, the renowned surgeon in St. Louis who had pioneered the pneumonectomy (the resection of the lung to remove tumors), was asked whether tobacco smoking had caused the increased incidence of lung cancer, he countered dismissively, "So has the use of nylon stockings."

  Tobacco, like the nylon stockings of cancer epidemiology, thus vanished from the view of preventive medicine. And with its medical hazards largely hidden, cigare
tte usage grew even more briskly, rising at a dizzying rate throughout the western hemisphere. By the time the cigarette returned to visibility as arguably the world's most lethal carrier of carcinogens, it would be far too late. The lung cancer epidemic would be in full spate, and the world would be deeply, inextricably ensconced, as the historian Allan Brandt once characterized it, in "the cigarette century."

  * Soot is a mixture of chemicals that would eventually be found to contain several carcinogens.

  The Emperor's Nylon Stockings

  Whether epidemiology alone can, in strict logic, ever prove causality, even in this modern sense, may be questioned, but the same must also be said of laboratory experiments on animals.

  --Richard Doll

  In the early winter of 1947, government statisticians in Britain alerted the Ministry of Health that an unexpected "epidemic" was slowly emerging in the United Kingdom: lung cancer morbidity had risen nearly fifteenfold in the prior two decades. It is a "matter that ought to be studied," the deputy registrar wrote. The sentence, although couched in characteristic English understatement, was strong enough to provoke a response. In February 1947, in the midst of a bitterly cold winter, the ministry asked the Medical Research Council to organize a conference of experts on the outskirts of London to study this inexplicable rise of lung cancer rates and to hunt for a cause.

  The conference was a lunatic comedy. One expert, having noted parenthetically that large urban towns (where cigarette consumption was the highest) had much higher rates of lung cancer than villages (where consumption was the lowest), concluded that "the only adequate explanation" was the "smokiness or pollution of the atmosphere." Others blamed influenza, the fog, lack of sunshine, X-rays, road tar, the common cold, coal fires, industrial pollution, gasworks, automobile exhaust--in short, every breathable form of toxin except cigarette smoke.

  Befuddled by this variance in opinions, the council charged Austin Bradford Hill, the eminent biostatistician who had devised the randomized trial in the 1940s, to devise a more systematic study to identify the risk factor for lung cancer. Yet the resources committed for the study were almost comically minimal: on January 1, 1948, the council authorized a part-time salary of PS600 for a student, PS350 each for two social workers, and PS300 for incidental expenses and supplies. Hill recruited a thirty-six-year-old medical researcher, Richard Doll, who had never performed a study of comparable scale or significance.

  Across the Atlantic, too, the link between smoking and cancer was seemingly visible only to neophytes--young interns and residents "uneducated" in surgery and medicine who seemed to make an intuitive connection between the two. In the summer of 1948, Ernst Wynder, a medical student on a surgical rotation in New York, encountered an unforgettable case of a forty-two-year-old man who had died of bronchogenic carcinoma--cancer of the airways of the lung. The man had been a smoker, and as in most autopsies of smokers, his body had been scarred with the stigmata of chronic smoking: tar-stained bronchi and soot-blackened lungs. The surgeon who was operating on the case made no point of it. (As with most surgeons, the association had likely become invisible to him.) But for Wynder, who had never encountered such a case before, the image of cancer growing out of that soot-stained lung was indelible; the link was virtually staring him in the face.

  Wynder returned to St. Louis, where he was in medical school, and applied for money to study the association between smoking and lung cancer. He was brusquely told that the effort would be "futile." He wrote to the U.S. surgeon general quoting prior studies that had hypothesized such an association, but was told that he would be unable to prove anything. "The same correlation could be drawn to the intake of milk. . . . No kind of interviewing [can] get satisfactory results from patients. . . . Since nothing had been proved there exists no reason why experimental work should be conducted along this line."

  Thwarted in his attempts to convince the surgeon general's office, Wynder recruited an unlikely but powerful mentor in St. Louis: Evarts Graham, of "nylon stockings" fame. Graham didn't believe the connection between smoking and cancer either. The great pulmonary surgeon, who operated on dozens of lung cancer cases every week, was rarely seen without a cigarette himself. But he agreed to help Wynder with the study in part to conclusively disprove the link and lay the issue to rest. Graham also reasoned the trial would teach Wynder about the complexities and nuances of study design and allow him to design a trial to capture the real risk factor for lung cancer in the future.

  Wynder and Graham's trial followed a simple methodology. Lung cancer patients and a group of control patients without cancer were asked about their history of smoking. The ratio of smokers to nonsmokers within the two groups was measured to estimate whether smokers were overrepresented in lung cancer patients compared to other patients. This setup (called a case-control study) was considered methodologically novel, but the trial itself was thought to be largely unimportant. When Wynder presented his preliminary ideas at a conference on lung biology in Memphis, not a single question or comment came from the members of the audience, most of whom had apparently slept through the talk or cared too little about the topic to be roused. In contrast, the presentation that followed Wynder's, on an obscure disease called pulmonary adenomatosis in sheep, generated a lively, half-hour debate.

  Like Wynder and Graham in St. Louis, Doll and Hill could also barely arouse any interest in their study in London. Hill's department, called the Statistical Unit, was housed in a narrow brick house in London's Bloomsbury district. Hefty Brunsviga calculators, the precursors of modern computers, clacked and chimed in the rooms, ringing like clocks each time a long division was performed. Epidemiologists from Europe, America, and Australia thronged the statistical seminars. Just a few steps away, on the gilded railings of the London School of Tropical Medicine, the seminal epidemiological discoveries of the nineteenth century--the mosquito as the carrier for malaria, or the sand fly for black fever--were celebrated with plaques and inscriptions.

  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 af
ter 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?