The Emperor of All Maladies

by Siddhartha Mukherjee

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.

Cancer cells 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. Malignant growth and normal growth are so genetically intertwined that unbraiding the two might be one of the most significant scientific challenges faced by our species.

(mutations in cancer genes accumulate with aging; cancer is thus intrinsically related to age).

The universe,” the twentieth-century biologist6 J. B. S. Haldane liked to say, “is not only queerer than we suppose, but queerer than we can suppose”—and so is the trajectory of science.)

In solving a problem of this sort7, the grand thing is to be able to reason backwards. That is a very useful accomplishment, and a very easy one, but people do not practice it much.

Science begins with counting. To understand a phenomenon, a scientist must first describe it; to describe it objectively, he must first measure it.

Every generation of cancer cells creates a small number of cells that is genetically different from its parents. When a chemotherapeutic drug or the immune system attacks cancer, mutant clones that can resist the attack grow out. The fittest cancer cell survives.

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.

Longevity, although certainly the most important contributor to the prevalence of cancer in the early twentieth century, is probably not the only contributor. Our capacity to detect cancer earlier and earlier, and to attribute deaths accurately to it, has also dramatically increased in the last century.

Antisepsis and anesthesia were twin technological breakthroughs that released surgery from its constraining medieval chrysalis.

The second limit was far more insidious: radiation produced cancers. The very effect of X-rays killing rapidly dividing cells—DNA damage—also created cancer-causing mutations in genes.

By then, the other inhabitants of Ehrlich’s train compartment had dozed off to sleep. But this rant in a train compartment was one of medicine’s most important ideas in its distilled, primordial form. “Chemotherapy,” the use of specific chemicals to heal the diseased body, was conceptually born in the middle of the night.

large? Scientists often study the past as obsessively as historians because few other professions depend so acutely on it. Every experiment is a conversation with a prior experiment, every new theory a refutation of the old.

Perhaps there is only one cardinal sin256: impatience. Because of impatience we were driven out of Paradise, because of impatience we cannot return.

Fund-raising—and, more important, friend-raising—was instilled in their blood, and the depth and breadth of their social connections allowed them to reach deeply into the minds—and pockets—of private donors and of the government.

Hill’s319 proposed solution was to remove such biases by randomly assigning patients to treatment with streptomycin versus a placebo. By “randomizing” patients to each arm, any doctors’ biases in patient assignment would be dispelled. Neutrality would be enforced—and thus a hypothesis could be strictly tested.

Li had stumbled on a deep and fundamental principle of oncology: cancer needed to be systemically treated long after every visible sign of it had vanished.

A model is a lie that helps334 you see the truth.

Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing.

movies—the thermometers of anxiety in popular culture—featured alien invasions, parasitic occupations of the brain, and body snatching: It Came from Outer Space or The Man from Planet X. But by the early 1970s, the locus of anxiety—the “object of horror,” as Salecl describes it—had dramatically shifted from the outside to the inside. The rot, the horror—the biological decay and its concomitant spiritual decay—was now relocated within the corpus of society and, by extension, within the body of man. American society was still threatened, but this time, the threat came from inside. The names of horror films reflected the switch: The Exorcist; They Came from Within.

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.

“An all-out effort at this time458 would be like trying to land a man on the moon without knowing Newton’s laws of gravity.”

In science, ideology tends to corrupt479; absolute ideology, [corrupts] absolutely.

“In God we trust,”509 he brusquely told a journalist. “All others [must] have data.”

“Saving the individual patient521 is not the essential mission. Enormous efforts are made to do so, or at least to prolong the patient’s life to the last possible moment. But the basic purpose is not to save that patient’s particular life but to find means of saving the lives of others.”

That number was to be contrasted with the annual incidence of cancer in 1985—448 new cancer cases diagnosed for every 100,000 Americans, or about 1 million every year—and the mortality from cancer in 1985— 211 deaths for every 100,000, or 500,000 deaths every year. In short, even with relatively liberal estimates about lives saved, less than one in twenty patients diagnosed with cancer in America, and less than one in ten of the total number of patients who would die of cancer, had benefited from the advances in therapy and screening.

To stoke its explosive growth in the postwar period, the cigarette industry poured tens, then hundreds641, of millions of dollars into advertising. And if advertising had transformed the tobacco industry in the past, the tobacco industry now transformed advertising. The most striking innovation of this era was the targeting of cigarette advertising to highly stratified consumers, as if to achieve exquisite specificity.

Medical journals routinely carried cigarette advertisements.

At the annual conferences of the American Medical Association643 in the early 1950s, cigarettes were distributed free of charge to doctors, who lined up outside the tobacco booths.

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.” The implication was that if more research was needed, then the issue was still mired in doubt—and thus unresolved. Let the public have its addiction, and let the researchers have theirs.

Led by Clements and Fortas, tobacco makers crafted a strategy that, at first glance, seemed counterintuitive: rather than being regulated by the FTC, they voluntarily requested regulation by Congress676. 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. The effect would be a double boon. By voluntarily pushing for congressional control, the tobacco industry would perform a feat of political acrobatics—a leap from the commission’s hostile fire to the much milder frying pan of Congress.

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.”

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,681 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.

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.

In one letter, Fred Panzer694, a public relations manager at the Tobacco Research Institute, wrote to Horace Kornegay, its president, to explain the industry’s three-pronged marketing strategy—“creating doubt about the health charge without actually denying it, advocating the public’s right to smoke without actually urging them to take up the practice [and] encouraging objective scientific research as the only way to resolve the question of health hazard.”

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.

Using survival as an end point for a screening test is flawed because early detection pushes the clock of diagnosis backward. Hope’s tumor and Prudence’s tumor possess exactly identical biological behavior. But since doctors detected Hope’s tumor earlier, it seems, falsely, that she lived longer and that the screening test was beneficial.

A static picture cannot capture this qualitative growth. Seeing a “small” tumor and extracting it from the body does not guarantee our freedom from cancer—a fact that we still struggle to believe. 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,”780 the artist Richard Avedon liked to say, “[but] none of them is the truth.”

“There you are, the future patient,854 quietly progressing with other passengers toward a distant destination when, astonishingly (Why me?) a large hole opens in the floor next to you. People in white coats appear, help you into a parachute and—no time to think—out you go. “You descend. You hit the ground. . . . But where is the enemy? What is the enemy? What is it up to? . . . No road. No compass. No map. No training. Is there something you should know and don’t?

“The white coats are far, far away, strapping others into their parachutes. Occasionally they wave but, even if you ask them, they don’t know the answers. They are up there in the Jumbo, involved with parachutes, not map-making.”

The pattern that emerged from this analysis was sobering. Between 1970 and 1994, cancer mortality had, if anything, increased slightly, about 6 percent, from 189 deaths per 100,000 to 201 deaths. Admittedly, the death rate had plateaued somewhat in the last ten years, but even so, this could hardly be construed as a victory. Cancer, Bailar concluded, was still reigning “undefeated.” Charted as a graph, the nation’s progress on cancer was a flat line; the War on Cancer had, thus far, yielded a stalemate.

As Bailar and Gornik probed their own data further, they began to discern such forces counterpoised against each other with almost exquisite precision. When cancer mortality between 1970 and 1994 was split into two age groups, the counterbalancing of forces was immediately obvious: in men and women above fifty-five, cancer mortality had increased, while in men and women under fifty-five, cancer mortality had decreased by exactly the same proportion. (Part of the reason for this will become clear below.)

‘Cancer’ is, in truth, a variety of diseases.857 Viewing it as a single disease that will yield to a single approach is no more logical than viewing neuropsychiatric disease as a single entity that will respond to one strategy. It is unlikely that we will soon see a ‘magic bullet’ for the treatment of cancer. But it is just as unlikely that there will be a magic bullet of prevention or early detection that will knock out the full spectrum of cancers. . . . We are making progress. Although we also have a long way to go, it is facile to claim that the pace of favorable trends in mortality reflects poor policies or mistaken priorities.”

The cells, technically speaking, are immortal. The woman from whose body they were once taken has been dead for thirty years.

Boveri found himself circling back to Galen—to the age-old notion that all cancers were connected by a common abnormality—the “unitary cause of carcinoma,”865 as Boveri called it. Cancer was not “an unnatural group of different maladies,”866 Boveri wrote. Instead, a common feature lurked behind all cancers, a uniform abnormality that emanated from abnormal chromosomes—and was therefore internal to the cancer cell. Boveri could not put his finger on the nature of this deeper internal abnormality. But the “unitary cause” of carcinoma lay in this disarray—not a chaos of black bile, but a chaos of blue chromosomes.

(When DNA is copied during cell division, a copying error occasionally generates an accidental change in genes, thus causing mutations.)

Influenza virus, for instance, infects lung cells and produces more influenza virus, but it does not leave a permanent fingerprint in our genes; when the virus goes away, our DNA is left untouched. But Rous’s virus behaved differently. 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.*

Temin’s announcement that he had identified the long-sought-after enzyme activity in the virus-infected cells left little doubt about the theory. RNA could generate DNA. A cancer-causing virus’s genome could become a physical part of a cell’s genes. Temin returned to Madison the next

A theory began to convulse out of these results, a theory so magnificent and powerful that it would explain decades of disparate observations in a single swoop: perhaps src, the precursor to the cancer-causing gene, was endogenous to the cell. Perhaps viral src had evolved out of cellular src. Retrovirologists had long believed that the virus had introduced an activated src into normal cells to transform them into malignant cells. But the src gene had not originated in the virus. It had originated from a precursor gene that existed in a cell—in all cells. Cancer biology’s decades-long hunt had started with a chicken and ended, metaphorically, in the egg—in a progenitor gene present in all human cells.

Rowley examined case after case of CML patients. In every single case, she found this same translocation in the cells. Chromosomal abnormalities in cancer cells had been known since the days of von Hansemann and Boveri. But Rowley’s results argued a much more profound point. Cancer was not disorganized chromosomal chaos. It was organized chromosomal chaos: specific and identical mutations existed in particular forms of cancer.