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

by Siddhartha Mukherjee

  Dey: That's correct. . . .

  Edell: And this was to save rats, right? Or mice? You spent all this money to save mice the problem of developing tumors?

  Exchanges such as this epitomized the troubles of the tobacco industry. As the cigarette industry mavens muddled their way through Edell's cross-examination, the depth of deception made even the industry's own attorneys cringe in horror. Cover-ups were covered up with nonsensical statistics; lies concealed within other lies. Edell's permission to exhume the internal files of tobacco makers created a historic legal precedent, allowing others to potentially raid that same cabinet of horrors to pull out their own sooty exhibits for future tort cases.

  After four long years of legal wrangling, the Cipollone cancer trial appeared before the court in 1987. Despite the hopes and predictions of many observers, the verdict was a terrible disappointment for Edell and Cipollone's family. The jury found Rose Cipollone 80 percent responsible for her cancer. Liggett, the maker of the brand that she had smoked before 1966 (i.e., before the warning labels had been mandated), was assigned the rest of the responsibility--20 percent. Philip Morris and Lorillard got off scot-free. The jury awarded Anthony Cipollone $400,000 in damages--barely enough to cover even the clerical costs of four years of obsessive litigation. If this was counted as a win, then, as the tobacco industry pointed out gleefully, it was the very definition of a Pyrrhic victory.

  Yet the real legacy of the Cipollone case had little to do with legal victories or losses. Lampooned in court as a weak-willed, ill-informed, and dim-witted addict unaware of the "obvious" dangers of tobacco, Rose Cipollone nonetheless turned into a heroic icon of a cancer victim battling her disease--even from her grave.

  A flurry of cases followed the Cipollone case. The tobacco industry defended itself vigorously against these cases, reflexively waving the warning labels on cigarette packets as proof that their liability was negligible. But the precedents set by these cases fueled even more tort suits. Demonized, demoralized, and devastated by the negative publicity, cigarette makers found themselves increasingly beleaguered and increasingly the butt of blame and liability.

  By 1994, the per capita consumption of cigarettes in America had dropped for twenty straight years (from 4,141 in 1974 to 2,500 in 1994), representing the most dramatic downturn in smoking rates in history. It had been a long and slow battle of attrition. No intervention had single-handedly decimated tobacco, but the cumulative force of scientific evidence, political pressure, and legal inventiveness had worn the industry down over a decade.

  Yet, old sins have long shadows, and carcinogenic sins especially so. The lag time between tobacco exposure and lung cancer is nearly three decades, and the lung cancer epidemic in America will have an afterlife long after smoking incidence has dropped. Among men, the age-adjusted incidence of lung adenocarcinoma, having peaked at 102 per 100,000 in 1984, dropped to 77 in 2002. Among women, though, the epidemic still runs unabated. The stratospheric rise of smoking among women in Rose Cipollone's generation is still playing itself out in the killing fields of lung cancer.

  Twenty-seven years have passed since Marc Edell filed his unusual case in the New Jersey courtroom, and tort lawsuits against tobacco companies have now grown into a deluge. In 1994, in yet another landmark case in the history of tobacco litigation, the state of Mississippi filed suit against several tobacco companies seeking to recover over a billion dollars of health-care costs incurred by the state from smoking-related illnesses--including, most prominently, lung cancer. (Michael Moore, the attorney general, summarized the argument for tobacco companies: "You caused the health crisis; you pay for it.") Several other states then followed, notably Florida, Texas, and Minnesota.

  In June 1997, facing a barrage of similar suits, tobacco companies proposed a global agreement. In 1998, forty-six states thus signed the Master Settlement Agreement (MSA) with four of the largest cigarette manufacturers--Philip Morris, R. J. Reynolds, Brown & Williamson, and Lorillard Tobacco Company. (Since 1998, an additional forty-seven cigarette manufacturing companies have joined the agreement.) The agreement includes strong restrictions on cigarette advertising, disbands trade associations and industry lobby groups, allows for free access to internal research documents, and proposes the creation of a national forum to educate the public on the health hazards of tobacco. The MSA represents one of the largest liability settlements ever reached, and, perhaps more profoundly, the most public admission of collusion and guilt in the history of the tobacco industry.

  Does the MSA constitute Rose Cipollone's long-awaited legal victory over tobacco? In some respects, quite precisely not. In a perverse recapitulation of the FCLAA "warning labels act" of the 1970s, in fact, the agreement likely creates yet another safe harbor for the tobacco industry. By granting relative protection from future legal action, by restricting cigarette advertising, and by allowing its signatory companies to fix prices, the agreement provides a virtual monopoly to the companies that have signed the MSA. Small independent manufacturers dare not enter or compete in the business, leaving big tobacco to become even bigger tobacco. The influx of annual settlement payments from cigarette makers creates "client-states" that depend on this money to fund escalating medical costs. Indeed, the real cost of the agreement is borne by addicted smokers who now pay more for cigarettes, and then pay with their lives.

  Nor has the MSA signaled the death of the industry in a more global sense; 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 the leading cause of death, attributable to smoking in men.

  This steady assault of tobacco on the developing world has been accompanied by bold political maneuvering backstage. In 2004, tobacco companies signed a barely publicized agreement with the Ministry of Health in Mexico that provides generous "contributions" from the tobacco makers to a public health-insurance program in return for sharply reduced regulations on cigarette-packet warnings and advertisements--in effect "robbing Pedro to pay Paolo," as a recent editorial noted. In the early 1990s, a study noted, British American Tobacco signed a similar agreement with the government of Uzbekistan to establish a production monopoly, then lobbied vigorously to overturn recent laws that banned tobacco advertising. Cigarette smoking grew by about 8 percent a year in Uzbekistan after the BAT investment, and cigarette sales increased by 50 percent between 1990 and 1996.

  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."

  It 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 c
alm 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.

  Yet despite the evident seriousness of this addiction and its long-term consequences, tobacco consumption continues relatively unfettered even today. Smoking rates, having plateaued for decades, have begun to rise again in certain demographic pockets, and lackluster antismoking campaigns have lost their grip on public imagination. The disjunction between the threat and the response is widening. It remains an astonishing, disturbing fact that in America--a nation where nearly every new drug is subjected to rigorous scrutiny as a potential carcinogen, and even the bare hint of a substance's link to cancer ignites a firestorm of public hysteria and media anxiety--one of the most potent and common carcinogens known to humans can be freely bought and sold at every corner store for a few dollars.

  * No relation of Sidney Farber's.

  "Curiouser and curiouser"

  You're under a lot of stress, my dear. You haven't really got anything wrong with yourself. We'll give you an antidepressant.

  --Barry Marshall on the treatment of women

  with gastritis, a precancerous lesion,

  in the 1960s

  The classification of tobacco smoke as a potent carcinogen--and the slow avalanche of forces unleashed to regulate cigarettes in the 1980s--is rightfully counted as one of cancer prevention's seminal victories. But it equally highlighted an important lacuna in cancer epidemiology. Statistical methods to identify risk factors for cancer are, by their very nature, descriptive rather than mechanistic: they describe correlations, not causes. And they rely on a certain degree of foreknowledge. To run a classical "case-control" trial to identify an unknown risk factor, paradoxically, an epidemiologist must know the questions to ask. Even Doll and Hill, in devising their classic case-control and prospective studies, had relied on decades of prior knowledge--centuries, if one counts John Hill's pamphlet--about the possible link between tobacco and cancer.

  This does not diminish the incredible power of the case-control method. In the early 1970s, for instance, a series of studies definitively identified the risk factor for a rare and fatal form of lung cancer called mesothelioma. When mesothelioma "cases" were compared to "controls," this cancer appeared to cluster densely in certain professions: insulation installers, firefighters, shipyard workers, heating equipment handlers, and chrysolite miners. As with Pott and scrotal cancer, the statistical confluence of a rare profession and a rare tumor swiftly identified the causal agent in this cancer: exposure to asbestos. Tort litigation and federal oversight soon followed, precipitating a reduction in the occupational exposure to asbestos that, in turn, reduced the risk of mesothelioma.

  In 1971, yet another such study identified an even more unusual carcinogen, a synthetic hormonal medicine called diethylstilbestrol (DES). DES was widely prescribed to pregnant women in the 1950s to prevent premature deliveries (although it was of only questionable benefit in this regard). A generation later, when women with vaginal and uterine cancer were questioned about their exposures to estrogens, a peculiar pattern emerged: the women had not been exposed to the chemical directly, but their mothers had been. The carcinogen had skipped a generation. It had caused cancers not in the DES-treated women, but in their daughters exposed to the drug in utero.

  But what if the behavior or exposure responsible for the cancer is completely unknown? What if one did not even know enough about the natural history of mesothelioma, or the link between estrogen and vaginal cancer, to ask those afflicted about their occupational history, or their exposure to asbestos and estrogen? Could carcinogens be discovered a priori--not by the statistical analysis of cancer-afflicted populations, but by virtue of some intrinsic property of all carcinogens?

  In the late 1960s, a bacteriologist named Bruce Ames at Berkeley, working on an unrelated problem, stumbled on a test for chemical carcinogens. Ames was studying mutations in Salmonella, a bacterial genus. Salmonella, like any bacteria, possesses genes that allow it to grow under certain conditions--a gene to "digest" galactose, for instance, is essential for a bacterium to survive on a petri dish where the only sugar source is galactose.

  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.

  Ames's test was far from perfect. Not every known carcinogen scored in the test: neither DES nor asbestos sprinkled on the disabled Salmonella caused significant numbers of mutant bacteria. (In contrast, chemical constituents of tobacco smoke did cause mutation in the bacteria, as noted by several cigarette manufacturers who ran the test and, finding it disconcertingly positive, quickly buried the results.) But despite its shortcomings, the Ames test provided an important link between a purely descriptive approach toward cancer prevention and a mechanistic approach. Carcinogens, Ames suggested, had a common, distinctive functional property: they altered genes. Ames could not fathom the deeper reason behind this observation: why was the capacity to cause mutations linked to the ability to induce cancer? But he had demonstrated that carcinogens could be found experimentally--not retrospectively (by investigating cases and controls in human subjects) but by prospectively identifying chemicals that could cause mutations in a rather simple and elegant biological assay.

  Chemicals, it turned out, were not the only carcinogens; nor was Ames's test the only method to find such agents. In the late 1960s, Baruch Blumberg, a biologist working in Philadelphia, discovered that a chronic, smoldering inflammation caused by a human hepatitis virus could also cause cancer.

  A biochemistry student at Oxford in the 1950s, Blumberg had become interested in genetic anthropology, the study of genetic variations in human populations. Traditional biological anthropology in the 1950s mainly involved collecting, measuring, and categorizing human anatomical specimens. Blumberg wanted to collect, measure, and categorize human genes--and he wanted to link genetic variations in humans to the susceptibility for diseases.

  The problem, as Blumberg soon discovered, was the lack of human genes to be measured or categorized. Bac
terial genetics was still in its infancy in the 1950s--even the structure of DNA and the nature of the genes was still largely undiscovered--and human genes had not even been seen or analyzed. The only tangible hint of variations in human genetics came from an incidental observation. Proteins in the blood, called blood antigens, varied between individuals and were inherited in families, thus implying a genetic source for this variation. These blood proteins could be measured and compared across populations using relatively simple tests.

  Blumberg began to scour far-flung places in the world for blood, drawing tubes of serum from Fulani tribesmen in Africa one month and Basque shepherds the next. In 1964, after a brief tenure at the NIH, he moved to the Institute for Cancer Research in Philadelphia (later renamed the Fox Chase Cancer Center) to systematically organize the variant blood antigens that he had cataloged, hoping to link them to human diseases. It was a curiously inverted approach, like scouring a dictionary for a word and then looking for a crossword puzzle into which that word might fit.

  One blood antigen that intrigued him was present in several Australian aboriginal subjects and found frequently in Asian and African populations, but was typically absent in Europeans and Americans. Suspecting that this antigen was the fingerprint of an ancient genetic factor inherited in families, Blumberg called it the Australia antigen or Au for short.

  In 1966, Blumberg's lab set out to characterize the aboriginal antigen in greater detail. He soon noted an odd correlation: individuals carrying the Au antigen often suffered from chronic hepatitis, an inflammation of the liver. These inflamed livers, studied pathologically, showed signs of chronic cycles of injury and repair--death of cells in some pockets and compensatory attempts to repair and regenerate liver cells in others, resulting in scarred, shrunken, and burnt-out livers, a condition termed chronic cirrhosis.