The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

Illness is the night-side of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the kingdom of the well and in the kingdom of the sick. Although we all prefer to use only the good passport, sooner or later each of us is obliged, at least for a spell, to identify ourselves as citizens of that other place. —Susan Sontag

Hippocrates had once abstrusely opined that cancer was “best left untreated, since patients live longer that way.”

In the 1870s, when Halsted had left for Europe to learn from the great masters of the art, surgery was a discipline emerging from its adolescence. By 1898, it had transformed into a profession booming with self-confidence, a discipline so swooningly self-impressed with its technical abilities that great surgeons unabashedly imagined themselves as showmen. The operating room was called an operating theater, and surgery was an elaborate performance often watched by a tense, hushed audience of observers from an oculus above the theater.

Yet all this uncertainty did little to stop other surgeons from operating just as aggressively. “Radicalism” became a psychological obsession, burrowing its way deeply into cancer surgery. Even the word radical was a seductive conceptual trap. Halsted had used it in the Latin sense of “root” because his operation was meant to dig out the buried, subterranean roots of cancer. But radical also meant “aggressive,” “innovative,” and “brazen,” and it was this meaning that left its mark on the imaginations of patients. What man or woman, confronting cancer, would willingly choose non-radical, or “conservative,” surgery? Indeed, radicalism became central not only to how surgeons saw cancer, but also in how they imagined themselves. “With no protest from any other quarter and nothing to stand in its way, the practice of radical surgery,” one historian wrote, “soon fossilized into dogma.”

Surgeons often counted themselves lucky if their patients merely survived these operations. “There is an old Arabian proverb,” a group of surgeons wrote at the end of a particularly chilling discussion of stomach cancer in 1933, “that he is no physician who has not slain many patients, and the surgeon who operates for carcinoma of the stomach must remember that often.”

But to measure the genius of the Jimmy campaign in dollars and cents is to miss its point. For Farber, the Jimmy Fund campaign was an early experiment—the building of another model. The campaign against cancer, Farber learned, was much like a political campaign: it needed icons, mascots, images, slogans—the strategies of advertising as much as the tools of science. For any illness to rise to political prominence, it needed to be marketed, just as a political campaign needed marketing. A disease needed to be transformed politically before it could be transformed scientifically. If Farber’s antifolates were his first discovery in oncology, then this critical truth was his second. It set off a seismic transformation in his career that would far outstrip his transformation from a pathologist to a leukemia doctor. This second transformation—from a clinician into an advocate for cancer research—reflected the transformation of cancer itself. The emergence of cancer from its basement into the glaring light of publicity would change the trajectory of this story. It is a metamorphosis that lies at the heart of this book.

When a disease insinuates itself so potently into the imagination of an era, it is often because it impinges on an anxiety latent within that imagination. AIDS loomed so large on the 1980s in part because this was a generation inherently haunted by its sexuality and freedom; SARS set off a panic about global spread and contagion at a time when globalism and social contagion were issues simmering nervously in the West. Every era casts illness in its own image. Society, like the ultimate psychosomatic patient, matches its medical afflictions to its psychological crises; when a disease touches such a visceral chord, it is often because that chord is already resonating. So it was with cancer.

The House wanted more testimony—and not just testimony from the Laskerites’ carefully curated panel. It solicited opinions from physicians, scientists, administrators and policymakers—and those opinions, it found, diverged sharply from the ones presented to the Senate. Philip Lee, the former assistant secretary of health complained, “Cancer is not simply an island waiting in isolation for a crash program to wipe it out. It is in no way comparable to a moon shot—to a Gemini or an Apollo program—which requires mainly the mobilization of money, men, and facilities to put together in one imposing package the scientific knowledge we already possess.” The Apollo mission and the Manhattan Project, the two models driving this War on Cancer were both technological achievements that stood on the shoulders of long and deep scientific discoveries (atomic physics, fluid mechanics, and thermodynamics). In contrast, even a cursory understanding of the process that made cells become malignant was missing.

“The resistance to providing palliative care to patients,” a ward nurse recalls, “was so deep that doctors would not even look us in the eye when we recommended that they stop their efforts to save lives and start saving dignity instead… doctors were allergic to the smell of death. Death meant failure, defeat—their death, the death of medicine, the death of oncology.” Providing end-of-life care required a colossal act of reimagination and reinvention. Trials on pain and pain relief—trials executed with no less rigor or precision than those launched to test novel drugs and surgical protocols—toppled several dogmas about pain and revealed new and unexpected foundational principles. Opiates, used liberally and compassionately on cancer patients, did not cause addiction, deterioration, and suicide; instead, they relieved the punishing cycle of anxiety, pain, and despair. New antinausea drugs were deployed that vastly improved the lives of patients on chemotherapy.

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.

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.”

Tobacco makers appealed and reappealed the Banzhaf decision, but the Supreme Court refused to hear the case, letting the decision stand. The industry tried to mount an aggressive countercampaign. An unpublicized internal report drawn up in 1969 to respond to the looming threat of the FCC advertising ban concluded, “Doubt is our product, since it is the best means of competing with the ‘body of fact.’” But antismoking advocates had also learned the tricks of the trade; if tobacco sellers had “doubt” to sow into public minds, then tobacco opponents had something just as visceral: fear—in particular, fear of the ultimate illness. A barrage of antismoking commercials appeared on television. In 1968, a worn and skeletal-looking William Talman, a veteran actor and former smoker, announced in a prime-time advertisement that he was dying from lung cancer.

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 last cigarette commercial was broadcast on television on January 1, 1971. At 11:59 p.m., on the first night of the New Year, the Virginia Slims slogan You’ve come a long way, baby flashed momentarily on TV screens, then vanished forever. Talman did not live to see that final advertisement. He had already died in 1968 of lung cancer that had metastasized to his liver, bones, and brain.

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. The argument took the tobacco companies by surprise. Edell’s insistence that he needed to know what cigarette makers knew about smoking risks allowed him to ask the courts for unprecedented access to the internal files of Philip Morris, Liggett, and Lorillard. 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.

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.

Patients, in short, had lost patience. They did not want trials; they wanted drugs and cures. ACT UP, parading on the streets of New York and Washington, had made the FDA out to be a woolly bureaucratic grandfather—exacting but maddeningly slow, whose sole purpose was to delay access to critical medicines.

The epic fall of Werner Bezwoda was a terminal blow to the ambitions of megadose chemotherapy. In the summer of 1999, a final trial was designed to examine whether STAMP might increase survival among women with breast cancer that had spread to multiple lymph nodes. Four years later, the answer was clear. There was no discernible benefit. Of the five hundred patients assigned to the high-dose group, nine died of transplantation-related complications. An additional nine developed highly aggressive, chemotherapy-resistant acute myeloid leukemias as a consequence of their treatments—cancers far worse than the cancers that they had begun with.

In 1926, Avery found that in certain species of bacteria, genes could also be transmitted laterally between two organisms—from one bacterium to its neighbor. Even dead, inert bacteria—no more than a conglomeration of chemicals—could transmit genetic information to live bacteria. This implied that an inert chemical was responsible for carrying genes. Avery separated heat-killed bacteria into their chemical components. And by testing each chemical component for its capacity to transmit genes, Avery and his colleagues reported in 1944 that genes were carried by one chemical, deoxyribonucleic acid, or DNA. What scientists had formerly disregarded as a form of cellular stuffing with no real function—a “stupid molecule,” as the biologist Max Delbruck once called it dismissively—turned out to be the central conveyor of genetic information between cells, the least stupid of all molecules in the chemical world.

Genetics has two distinct ways to “see” genes. The first is structural: genes can be envisioned as physical structures—pieces of DNA lined up along chromosomes, just as Morgan and Flemming had first envisioned them. The second is functional: genes can be imagined, à la Mendel, as the inheritance of traits that move from one generation to the next.

Cancer genes, Knudson proposed, came in two flavors. “Positive” genes, such as src, are mutant activated versions of normal cellular genes. In normal cells, these genes accelerate cell division, but only when the cell receives an appropriate growth signal. In their mutant form, these genes are driven into perpetual hyperactivity, unleashing cell division beyond control. An activated proto-oncogene, to use Bishop’s analogy, is “a jammed accelerator” in a car. A cell with such a jammed accelerator careens down the path of cell division, unable to cease mitosis, dividing and dividing again relentlessly.

“Negative” genes, such as Rb, suppress cell division. In normal cells, these anti-oncogenes, or tumor suppressor genes, provide the “brakes” to cellular proliferation, shutting down cell division when the cell receives appropriate signals. In cancer cells, these brakes have been inactivated by mutations. In cells with missing brakes, to use Bishop’s analogy again, the “stop” signals for mitosis can no longer be registered. Again, the cell divides and keeps dividing, defying all signals to stop. Both abnormalities, activated proto-oncogenes and inactivated tumor suppressors (“jammed accelerators” and “missing brakes”), represent the core molecular defects in the cancer cell.

Cancer is not a concentration camp, but it shares the quality of annihilation: it negates the possibility of life outside and beyond itself; it subsumes all living. The daily life of a patient becomes so intensely preoccupied with his or her illness that the world fades away. Every last morsel of energy is spent tending the disease.

Glowing, beautiful, and cherubic, Leela was born on a warm night at Massachusetts General Hospital, then swaddled in blankets and brought to the newborn unit on the fourteenth floor. The unit is directly across from the cancer ward. (The apposition of the two is hardly a coincidence. As a medical procedure, childbirth is least likely to involve infectious complications and is thus the safest neighbor to a chemotherapy ward, where any infection can turn into a lethal rampage. As in so much in medicine, the juxtaposition between the two wards is purely functional and yet just as purely profound.)