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

In 2010, about six hundred thousand Americans, and more than 7 million humans around the world, will die of cancer. In the United States, one in three women and one in two men will develop cancer during their lifetime. A quarter of all American deaths, and about 15 percent of all deaths worldwide, will be attributed to cancer. In some nations, cancer will surpass heart disease to become the most common cause of death.

In the end, cancer truly emerges, as a nineteenth-century surgeon once wrote in a book’s frontispiece, as “the emperor of all maladies, the king of terrors.”

Cancer, we now know, is a disease caused by the uncontrolled growth of a single cell. This growth is unleashed by mutations—changes in DNA that specifically affect genes that incite unlimited cell growth. In a normal cell, powerful genetic circuits regulate cell division and cell death. In a cancer cell, these circuits have been broken, unleashing a cell that cannot stop growing.

Cell division allows us as organisms to grow, to adapt, to recover, to repair—to live. And distorted and unleashed, it allows cancer cells to grow, to flourish, to adapt, to recover, and to repair—to live at the cost of our living. Cancer cells can grow faster, adapt better. They are more perfect versions of ourselves. The secret to battling cancer, then, is to find means to prevent these mutations from occurring in susceptible cells, or to find means to eliminate the mutated cells without compromising normal growth. The conciseness of that statement belies the enormity of the task.

Penicillin, that precious chemical that had to be milked to its last droplet during World War II (in 1939, the drug was reextracted from the urine of patients who had been treated with it to conserve every last molecule),

In 1942, when Merck had shipped out its first batch of penicillin—a mere five and a half grams of the drug—that amount had represented half of the entire stock of the antibiotic in America. A decade later, penicillin was being mass-produced so effectively that its price had sunk to four cents for a dose, one-eighth the cost of a half gallon of milk.

The elaborate armamentarium of “antivitamins” that Farber had dreamed up so vividly in his fantasies did not exist.

Parents were occasionally cursorily informed about the trial; children were almost never informed or consulted. The Nuremberg code for human experimentation, requiring explicit voluntary consent from patients, was drafted on August 9, 1947, less than a month before the PAA trial. It is doubtful that Farber in Boston had even heard of any such required consent code.)

Children with cancer, as one surgeon noted, were typically “tucked in the farthest recesses of the hospital wards.” They were on their deathbeds anyway, the pediatricians argued; wouldn’t it be kinder and gentler, some insisted, to just “let them die in peace”? When one clinician suggested that Farber’s novel “chemicals” be reserved only as a last resort for leukemic children, Farber, recalling his prior life as a pathologist, shot back, “By that time, the only chemical that you will need will be embalming fluid.”

Institutional support was minimal. Farber’s assistants sharpened their own bone marrow needles, a practice as antiquated as a surgeon whetting his knives on a wheel. Farber’s staff tracked the disease in patients with meticulous attention to detail: every blood count, every transfusion, every fever, was to be recorded. If leukemia was going to be beaten, Farber wanted every minute of that battle recorded for posterity—even if no one else was willing to watch it happen.

If consumption once killed its victims by pathological evisceration (the tuberculosis bacillus gradually hollows out the lung), then cancer asphyxiates us by filling bodies with too many cells; it is consumption in its alternate meaning—the pathology of excess. Cancer is an expansionist disease; it invades through tissues, sets up colonies in hostile landscapes, seeking “sanctuary” in one organ and then immigrating to another. It lives desperately, inventively, fiercely, territorially, cannily, and defensively—at times, as if teaching us how to survive. To confront cancer is to encounter a parallel species, one perhaps more adapted to survival than even we are.

Cancer thus exploits the fundamental logic of evolution unlike any other illness. If we, as a species, are the ultimate product of Darwinian selection, then so, too, is this incredible disease that lurks inside us.

Cancer is an age-related disease—sometimes exponentially so. The risk of breast cancer, for instance, is about 1 in 400 for a thirty-year-old woman and increases to 1 in 9 for a seventy-year-old. In most ancient societies, people didn’t live long enough to get cancer. Men and women were long consumed by tuberculosis, dropsy, cholera, smallpox, leprosy, plague, or pneumonia.

Indeed, cancer’s emergence in the world is the product of a double negative: it becomes common only when all other killers themselves have been killed. Nineteenth-century doctors often linked cancer to civilization: cancer, they imagined, was caused by the rush and whirl of modern life, which somehow incited pathological growth in the body. The link was correct, but the causality was not: civilization did not cause cancer, but by extending human life spans—civilization unveiled it.

Stomach cancer, for instance, was highly prevalent in certain populations until the late nineteenth century, likely the result of several carcinogens found in pickling reagents and preservatives and exacerbated by endemic and contagious infection with a bacterium that causes stomach cancer. With the introduction of modern refrigeration (and possibly changes in public hygiene that have diminished the rate of endemic infection), the stomach cancer epidemic seems to have abated. In contrast, lung cancer incidence in men increased dramatically in the 1950s as a result of an increase in cigarette smoking during the early twentieth century. In women, a cohort that began to smoke in the 1950s, lung cancer incidence has yet to reach its peak.

By way of illustration [of the destructive power of X-rays] let us recall that nearly all pioneers in the medical X-ray laboratories in the United States died of cancers induced by the burns. —The Washington Post, 1945

Those who have not been trained in chemistry or medicine may not realize how difficult the problem of cancer treatment really is. It is almost—not quite, but almost—as hard as finding some agent that will dissolve away the left ear, say, and leave the right ear unharmed. So slight is the difference between the cancer cell and its normal ancestor. —William Woglom

Etymologically, patient means sufferer. It is not suffering as such that is most deeply feared but suffering that degrades. —Susan Sontag, Illness as Metaphor Sidney Farber’s entire purpose consists only of “hopeless cases.” —Medical World News, November 25, 1966

In 1831, Alexis de Tocqueville, the French aristocrat, toured the United States and was astonished by the obsessive organizational energy of its citizens. “Americans of all ages, all conditions, and all dispositions constantly form associations… of a thousand other kinds—religious, moral, serious, futile, general or restricted, enormous or diminutive,” Tocqueville wrote. “Americans make associations to give entertainments, to found seminaries, to build inns, to construct churches, to diffuse books, to send missionaries to the antipodes.… If it is proposed to inculcate some truth or to foster some feeling by the encouragement of a great example, they form a society.”

For Lasker, her mother’s death brought to a boil the fury and indignation that had been building within her for decades. She had found her mission. “I am opposed to heart attacks and cancer,” she would later tell a reporter, “the way one is opposed to sin.” Mary Lasker chose to eradicate diseases as some might eradicate sin—through evangelism. If people did not believe in the importance of a national strategy against diseases, she would convert them, using every means at her disposal.

In many ways, Memphis was the antipode of Boston. Convulsing with bitter racial tensions and rock-and-roll music—gyrating between the gold and pink of the Graceland mansion in its south and the starkly segregated black neighborhoods in its north—Memphis was turbulent, unpredictable, colorful, perennially warm, and, medically speaking, virtually a no-man’s-land. Pinkel’s new hospital, called St. Jude’s (named, aptly enough, after the patron saint of lost causes), rose like a marooned concrete starfish out of a concrete parking lot on a barren field. In

I am not opposed to optimism, but I am fearful of the kind that comes from self-delusion. —Marvin Davis, in the New England Journal of Medicine, talking about the “cure” for cancer

Religious movements and cults are often founded on a tetrad of elements: a prophet, a prophecy, a book, and a revelation.

Fisher wrote in an article. He was willing to have faith in divine wisdom, but not in Halsted as divine wisdom. “In God we trust,” he brusquely told a journalist. “All others [must] have data.”

The group treated with the radical mastectomy had paid heavily in morbidity, but accrued no benefits in survival, recurrence, or mortality. Between 1891 and 1981, in the nearly one hundred years of the radical mastectomy, an estimated five hundred thousand women underwent the procedure to “extirpate” cancer. Many chose the procedure. Many were forced into it. Many others did not even realize that it was a choice. Many were permanently disfigured; many perceived the surgery as a benediction; many suffered its punishing penalties bravely, hoping that they had treated their cancer as aggressively and as definitively as possible. Halsted’s “cancer storehouse” grew far beyond its original walls at Hopkins. His ideas entered oncology, then permeated its vocabulary, then its psychology, its ethos, and its self-image. When radical surgery fell, an entire culture of surgery thus collapsed with it. The radical mastectomy is rarely, if ever, performed by surgeons today.

The idea of preventive medicine is faintly un-American. It means, first, recognizing that the enemy is us. —Chicago Tribune, 1975

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

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.

In 1955, when Philip Morris introduced the Marlboro Man, its most successful smoking icon to date, sales of the brand shot up by a dazzling 5,000 percent over eight months.

The centerpiece of that counterattack was an advertisement titled “A Frank Statement,” which saturated the news media in 1954, appearing simultaneously in more than four hundred newspapers over a few weeks. Written as an open letter from tobacco makers to the public, the statement’s purpose was to address the fears and rumors about the possible link between lung cancer and tobacco. In about six hundred words, it would nearly rewrite the research on tobacco and cancer.

By the mid-1950s, the link between smoking and cancer had sufficiently alarmed cigarette makers that many had begun to advertise new filter tips on cigarettes—to supposedly filter away carcinogens and make cigarettes “safe.”

they voluntarily requested regulation by Congress. The gambit had a deeply calculated logic. Congress, it was well-known, would inherently be more sympathetic to the interests of tobacco makers. Tobacco was the economic lifeblood of Southern states, and the industry had bribed politicians and funded campaigns so extensively over the years that negative political action was inconceivable. Conversely, the FTC’s unilateral activism on tobacco had turned out to be such a vexing embarrassment to politicians that Congress was expected to at least symbolically rap the wrist of the vigilante commission—in part, by lightening its blow to 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.”

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.

“Statistics,” the journalist Paul Brodeur once wrote, “are human beings with the tears wiped off,”

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.

The Pap smear had, in effect, pushed the clock of cancer detection forward by nearly two decades, and changed the spectrum of cervical cancer from predominantly incurable to predominantly curable.

Mammography, in short, was not going to be the unequivocal “savior” of all women with breast cancer. Its effects, as the statistician Donald Berry describes it, “are indisputable for a certain segment of women—but also indisputably modest in that segment.” Berry wrote, “Screening is a lottery. Any winnings are shared by the minority of women.… The overwhelming proportion of women experience no benefit and they pay with the time involved and the risks associated with screening.… The risk of not having a mammogram until after age 50 is about the same as riding a bicycle for 15 hours without a helmet.”

A mammogram, it turns out, is not a particularly good tool for detecting early breast cancer. Its false-positive and false-negative rates make it far from an ideal screening test. But the fatal flaw in mammography lies in that these rates are not absolute: they depend on age. For women above fifty-five, the incidence of breast cancer is high enough that even a relatively poor screening tool can detect an early tumor and provide a survival benefit.

In the end, a mammogram or a Pap smear is a portrait of cancer in its infancy. Like any portrait, it is drawn in the hopes that it might capture something essential about the subject—its psyche, its inner being, its future, its behavior. “All photographs are accurate,” the artist Richard Avedon liked to say, “[but] none of them is the truth.”

Cancer therapy is like beating the dog with a stick to get rid of his fleas. —Anna Deavere Smith, Let Me Down Easy

In the end, though, Spiegelman’s effort turned out to be systematically flawed. In his frenzied hunt for human cancer retroviruses, Spiegelman had pushed the virus-detection test so hard that he saw viruses or traces of viruses that did not exist. When other labs around the nation tried to replicate the work in the mid-1970s, Spiegelman’s viruses were nowhere to be found. Only one human cancer, it turned out, was caused by a human retrovirus—a rare leukemia endemic in some parts of the Caribbean. “The hoped-for human virus slipped quietly away into the night,” Weinberg wrote. “The hundreds of millions of dollars spent by the SVCP… could not make it happen. The rocket never left its launching pad.” Spiegelman’s conjecture about human retroviruses was half-right and half-wrong: he was looking for the right kind of virus but in the wrong kind of cell. Retroviruses would turn out to be the cause of a different disease—not cancer. Spiegelman died in 1983 of pancreatic cancer, having heard of a strange illness erupting among gay men and blood-transfusion recipients in New York and San Francisco. One year after Sol Spiegelman’s death in New York, the cause of that disease was finally identified. It was a human retrovirus called HIV.

Science is often described as an iterative and cumulative process, a puzzle solved piece by piece, with each piece contributing a few hazy pixels of a much larger picture. But the arrival of a truly powerful new theory in science often feels far from iterative. Rather than explain one observation or phenomenon in a single, pixelated step, an entire field of observations suddenly seems to crystallize into a perfect whole. The effect is almost like watching a puzzle solve itself.

In Lewis Carroll’s poem, when the hunters finally capture the deceptive Snark, it reveals itself not to be a foreign beast, but one of the human hunters sent to trap it. And so it had turned out with cancer. Cancer genes came from within the human genome. Indeed the Greeks had been peculiarly prescient yet again in their use of the term oncos. Cancer was intrinsically “loaded” in our genome, awaiting activation. We were destined to carry this fatal burden in our genes—our own genetic “oncos.” Varmus and Bishop were awarded the Nobel Prize for their discovery of the cellular origin of retroviral oncogenes in 1989. At the banquet in Stockholm, Varmus, recalling his former life as a student of literature, read lines from the epic poem Beowulf,

We have not slain our enemy, the cancer cell, or figuratively torn the limbs from his body,” Varmus said. “In our adventures, we have only seen our monster more clearly and described his scales and fangs in new ways—ways that reveal a cancer cell to be, like Grendel, a distorted version of our normal selves.”

Cancer was not disorganized chromosomal chaos. It was organized chromosomal chaos: specific and identical mutations existed in particular forms of cancer.

Activating or inactivating any single gene, he postulated, produced only the first steps toward carcinogenesis. Cancer’s march was long and slow and proceeded though many mutations in many genes over many iterations. In genetic terms, our cells were not sitting on the edge of the abyss of cancer. They were dragged toward that abyss in graded, discrete steps.

Tumor angiogenesis exploits the same pathways that are used when blood vessels are created to heal wounds. Nothing is invented; nothing is extraneous. Cancer’s life is a recapitulation of the body’s life, its existence a pathological mirror of our own. Susan Sontag warned against overburdening an illness with metaphors. But this is not a metaphor. Down to their innate molecular core, cancer cells are hyperactive, survival-endowed, scrappy, fecund, inventive copies of ourselves.

Before Genentech, protein drugs, although recognizably potent, had been notoriously difficult to produce. Insulin, for instance, was produced by grinding up cow and pig innards into a soup and then extracting the protein from the mix—one pound of insulin from every eight thousand pounds of pancreas. Growth hormone, used to treat a form of dwarfism, was extracted from pituitary glands dissected out of thousands of human cadavers. Clotting drugs to treat bleeding disorders came from liters of human blood. Recombinant DNA technology allowed Genentech to synthesize human proteins de novo: rather than extracting proteins from animal and human organs, Genentech could “engineer” a human gene into a bacterium, say, and use the bacterial cell as a bioreactor to produce vast quantities of that protein. The technology was transformative. In 1982, Genentech unveiled the first “recombinant” human insulin; in 1984, it produced