The Emperor of All Maladies

by Siddhartha Mukherjee

Bailar and Smith found that even Cairns had been overgenerous: between 1962 and 1985, cancer-related deaths had increased by 8.7 percent. That increase reflected many factors—most potently, an increase in smoking rates in the 1950s that had resulted in an increase in lung cancer.

Some thirty-five years of intense effort focused largely on improving treatment must be judged a qualified failure.”

But the obverse idea—that maximizing chemotherapy would maximize gains in survival—was also untested.

The appraisal of diseases depends, Breslow argued, on our self-appraisal. Society and illness often encounter each other in parallel mirrors, each holding up a Rorschach test for the other. Bailar might have been willing to concede these philosophical points, but he had a more pragmatic agenda.

Cairns had already pointed out, the only intervention ever known to reduce the aggregate mortality for a disease—any disease—at a population level was prevention.

Coffins of black” When my mother died I was very young601, And my father sold me while yet my tongue, Could scarcely cry weep weep weep weep, So your chimneys I sweep & in soot I sleep . . . And so he was quiet, & that very night. As Tom was a sleeping he had such a sight That thousands of sweepers Dick, Joe, Ned, & Jack Were all of them lock’d up in coffins of black —William Blake

If soot, and not some mystical, numinous humor (à 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 case605 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.

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 scientists 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.”

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.

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.)

Piece by piece, a highly incontrovertible and consistent picture emerged. The relationship between smoking and lung cancer, the committee found, was one of the strongest in the history of cancer epidemiology—remarkably significant, remarkably conserved between diverse populations, remarkably durable over time, and remarkably reproducible in trial after trial.

“The word ‘cause,’ ” the report read669, leaning heavily on Hill’s prior work, “is capable of conveying the notion of a significant, effectual relationship between an agent and an associated disorder or disease in the host. . . . Granted that these complexities were recognized, it is to be noted clearly that the Committee’s considered decision [was] to use the words ‘a cause,’ or ‘a major cause,’ . . . in certain conclusions about smoking and health.”

Ever since the spectacularly flawed attempts to regulate alcohol during Prohibition, Congress had conspicuously disabled the capacity of any federal agency to regulate an industry. Few agencies wielded direct control over any industry. (The Food and Drug Administration was the most significant exception to this rule.

Caution: Cigarette Smoking Is Dangerous to Health. It May Cause Death from Cancer and Other Diseases.

Entitled the Federal Cigarette Labeling and Advertising Act677 (FCLAA) of 1965, it changed the FTC’s warning label to Caution: Cigarette smoking may be hazardous to your health.

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.”

In 1966, a young attorney barely out of law school, John Banzhaf, pushed that strategy even further. Brash, self-confident, and iconoclastic, Banzhaf was lounging at home during the Thanksgiving holiday of 1966 (watching the omnipresent cigarette ads) when his mind raced to an obscure legal clause. In 1949, Congress had issued the “fairness doctrine,” which held that public broadcast media had to allow “fair” airtime to opposing viewpoints on controversial issues.

In the early summer of 1967, Banzhaf678 dashed off a letter to the Federal Communications Commission (the agency responsible for enforcing the fairness doctrine) complaining that a New York TV station was dedicating disproportional airtime to tobacco commercials with no opposing antitobacco commercials. The complaint was so unusual that Banzhaf, then on a four-week cruise, expected no substantial response. But Banzhaf’s letter had landed, surprisingly, on sympathetic ears.

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,680 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 late 1970, faced with the daily brunt of negative publicity, tobacco makers voluntarily withdrew cigarette advertising from broadcast media (thus nullifying the need for a proportional representation of antitobacco commercials).

The mid-1970s thus marked the beginning of the end of an extraordinary era for the tobacco industry. The surgeon general’s report, the FCLAA label warning, and the attack on cigarette advertising represented high-impact, sequential assaults on an industry once thought virtually impregnable.

That astonishing rise was the product of arguably the most successful targeted campaign ever launched in the history of American advertising—to persuade women to smoke. In this, tobacco rode on the back of a much deeper social change: in a world increasingly unsteady for women—with women juggling personal identity, child care, homemaking, and work—tobacco was marketed as a normalizing, steadying, even liberating force. Camel’s campaign depicted a naval officer firing a torpedo in the high seas, while his wife at home calmed her stormy nerves with a cigarette. “[It’s] a game only for steady nerves,”688 the copy ran.

Edell, however, refused to read any writing on any walls. He acknowledged openly that Rose Cipollone was aware of the risks of smoking. Yes, she had read the warning labels on cigarettes and the numerous magazine articles cut out so painstakingly by Tony Cipollone. Yet, unable to harness her habit, she had remained addicted. Cipollone was far from innocent, Edell conceded. But what mattered was not how much Rose Cipollone knew about tobacco risks; what mattered was what cigarette makers knew, and how much of the cancer risk they had revealed to consumers such as Rose.

Armed with powerful legal injunctions to investigate these private files, Edell unearthed a saga of epic perversity. Many of the cigarette makers had not only known about the cancer risks of tobacco and the potent addictive properties of nicotine, but had also actively tried to quash internal research that proved it. Document after document revealed frantic struggles within the industry to conceal risks, often leaving even its own employees feeling morally queasy.

Pharmacological research on nicotine left no doubt about why women such as Rose Cipollone found it so difficult to quit tobacco—not because they were weak-willed, but because nicotine subverted will itself. “Think of the cigarette pack as a storage container696 for a day’s supply of nicotine,” a researcher at Philip Morris wrote. “Think of the cigarette as a dispenser for a dose unit of nicotine. . . . Think of a puff of smoke as the vehicle of nicotine.”

Demonized, demoralized, and devastated by the negative publicity, cigarette makers found themselves increasingly beleaguered and increasingly the butt of blame and liability.

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.

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 Oxford718 in the 1950s, Blumberg719 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.

One blood antigen that intrigued him722 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 characterize723 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.

But how could an “intrinsic” gene cause sudden seroconversion and hepatitis?724 Genes, after all, do not typically flicker on and off at will. Blumberg’s beautiful theory about genetic variation had been slain by an ugly fact. Au, he realized, could not mark an inherent variation in a human gene. In fact, Au was soon found to be neither a human protein nor a blood antigen. Au was a piece of a viral protein floating in the blood, the sign of an infection.

“You might read somewhere that for your particular form of cancer, there is a high chance of local recurrence or metastasis,” he said. “Perhaps even fifty or sixty percent.” She nodded, tensing up. “Well, there are ways that we will tend to it when that happens.” I noted that he had said “when,” not “if.” The numbers told a statistical truth, but the sentence implied nuance. “We will tend to it,” he said, not “we will obliterate it.” Care, not cure. The conversation ran for nearly an hour. In his hands, information was something live and molten, ready to freeze into a hard shape at any moment, something crystalline yet negotiable; he nudged and shaped it like glass in the hands of a glassblower.

Ars longa, vita brevis. The art of medicine is long, Hippocrates tells us, “and life is short; opportunity fleeting; the experiment perilous; judgment flawed.”

Transplant was big business: big medicine, big money, big infrastructure, big risks. At large academic centers, such as the Beth Israel hospital in Boston, entire floors were refitted into transplant units, with case volumes that ran into several dozens each week.

Johannesburg, more than 90 percent831 of women treated with the megadose regimen had achieved a complete response—a rate that even the powerhouse academic centers in the United States had been unable to achieve.

Carla smells overenthusiasm with deep suspicion: a doctor who raves disproportionately about small victories is the same doctor who might be preparing his patient for some ultimate defeat.

real cancer in a living organism. Cancer researchers knew that X-rays, soot, cigarette smoke, and asbestos represented vastly more common risk factors for human cancers.

Rous sarcoma virus, having infected the cells, had physically attached itself to the cell’s DNA and thereby altered the cell’s genetic makeup, its genome. “The virus, in some structural as well as functional sense,881 becomes part of the genome of the cell,” Temin wrote.

he was stuck in a perpetual penumbra,

When the cell decides to divide, it tags Rb with a phosphate group, a molecular signal that inactivates the gene and thus forces the protein to release its partners. Rb thus acts as a gatekeeper for cell division, opening a series of key molecular floodgates each time cell division is activated and closing them sharply when the cell division is completed. Mutations in Rb inactivate this function. The cancer cell perceives its gates as perpetually open and is unable to stop dividing.

In the decade between 1983 and 1993, a horde of other oncogenes and anti-oncogenes924 (tumor suppressor genes) were swiftly identified in human cancers: myc, neu, fos, ret, akt (all oncogenes), and p53, VHL, APC (all tumor suppressors).

Similarly, Auerbach had noted, premalignant cells were seen in smokers’ lungs long before lung cancer appeared. Colon cancer in humans also underwent graded and discrete changes in its progression, from a noninvasive premalignant lesion called an adenoma to the highly invasive terminal stage called an invasive carcinoma.

the early 1990s, cancer biologists could begin to model the genesis of cancer in terms of molecular changes in genes. To understand that model, let us begin with a normal cell, say a lung cell that resides in the left lung of a forty-year-old fire-safety-equipment installer. One morning in 1968, a minute sliver of asbestos from his equipment wafts through the air and lodges in the vicinity of that cell. His body reacts to the sliver with an inflammation. The cells around the sliver begin to divide furiously, like a minuscule wound trying to heal, and a small clump of cells derived from the original cell arises at the site.

In one cell in that clump an accidental mutation occurs in the ras gene. The mutation creates an activated version of ras. The cell containing the mutant gene is driven to grow more swiftly than its neighbors and creates a clump within the original clump of cells. It is not yet a cancer cell, but a cell in which uncontrolled cell division has partly been unleashed—

decade passes. The small collection of ras-mutant cells continues to proliferate, unnoticed, in the far periphery of the lung. The man smokes cigarettes, and a carcinogenic chemical in tar reaches the periphery of the lung and collides with the clump of ras-mutated cells. A cell in this clump acquires a second mutation in its genes, activating a second oncogene. Another decade passes. Yet another cell in that secondary mass of cells is caught in the path of an errant X-ray and acquires yet another mutation, this time inactivating a tumor suppressor gene. This mutation has little effect since the cell possesses a second copy of that gene. But in the next yea...

Now a fatal march is on; an unraveling begins. The cells, now with four mutations, begin to outgrow their brethren. As the cells grow, they acquire additional mutations and they activate pathways, resulting in cells even further adapted for growth and survival. One mutation in the tumor allows it to incite blood vessels to grow; another mutation within thi...

Mutant cells beget cells. A gene that increases the mobility of the cells is activated in a cell. This cell, having acquired motility, can migrate through the lung tissue and enter the bloodstream. A descendant of this mobile cancer cell acquires the capacity to survive in the bone. This cell, having migrated through the blood, reaches the outer edge of the pelvis, where it begins yet another cycle of surviv...

He feels a tingle of pain in the periphery of his lung. Occasionally, he senses something moving under his rib cage when he walks. Another year passes, and the sensations accelerate. The man visits a physician and a CT scan is performed, revealing a rindlike mass wrapped around a bronchus in the lung. A biopsy reveals lung cancer. A surgeon examines the man and the CT scan of the chest and deems the cancer inoperable. Three weeks after that visit, the man returns to t...

Intravenous chemotherapy is initiated. The cells in the lung tumor respond. The man soldiers through a punishing regimen of multiple cell-killing drugs. But during the treatment, one cell in the tumor acquires yet another mutation that makes it resistant to the drug used to treat the cancer. Seven months after his initial diagnosis, the tumor relapses all over the body—in the lungs, the bones, the liver. On the morning of October, 17, 2004, deeply narcotized on opiates in a hospital bed in Boston and surrounded by his wife and his chi...

Medicine, I said, begins with storytelling. Patients tell stories to describe illness; doctors tell stories to understand it. Science tells its own story to explain diseases. This story of one cancer’s genesis—of carcinogens causing mutations in internal genes, unleashing cascading pathways in cells that then cycle through mutation, selection, and survival—represents the most cogent outline we have of cancer’s birth.