The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

Unable to find a unifying explanation for it, and seeking a name for this condition, Virchow ultimately settled for weisses Blut—white blood—no more than a literal description of the millions of white cells he had seen under his microscope. In 1847, he changed the name to the more academic-sounding “leukemia”—from leukos, the Greek word for “white.”

(This was yet another colonial fascination: to create the conditions of misery in a population, then subject it to social or medical experimentation.)

TB (or consumption) was Victorian romanticism brought to its pathological extreme—febrile, unrelenting, breathless, and obsessive. It was a disease of poets: John Keats involuting silently toward death in a small room overlooking the Spanish Steps in Rome, or Byron, an obsessive romantic, who fantasized about dying of the disease to impress his mistresses. “Death and disease are often beautiful, like… the hectic glow of consumption,” Thoreau wrote in 1852. In Thomas Mann’s The Magic Mountain, this “hectic glow” releases a feverish creative force in its victims—a clarifying, edifying, cathartic force that, too, appears to be charged with the essence of its era.

Cancer, in contrast, is riddled with more contemporary images. The cancer cell is a desperate individualist, “in every possible sense, a nonconformist,”

There are several reasons behind this absence. 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.

This preoccupation with hydraulics also flowed into Greek medicine and pathology. To explain illness—all illness—Hippocrates fashioned an elaborate doctrine based on fluids and volumes, which he freely applied to pneumonia, boils, dysentery, and hemorrhoids. The human body, Hippocrates proposed, was composed of four cardinal fluids called humors: blood, black bile, yellow bile, and phlegm.

Like Hippocrates, Galen set about classifying all illnesses in terms of excesses of various fluids. Inflammation—a red, hot, painful distension—was attributed to an overabundance of blood. Tubercles, pustules, catarrh, and nodules of lymph—all cool, boggy, and white—were excesses of phlegm. Jaundice was the overflow of yellow bile. For cancer, Galen reserved the most malevolent and disquieting of the four humors: black bile.

Frustrated with these ad hoc dissections, Vesalius decided to create his own anatomical map. He needed his own specimens, and he began to scour the graveyards around Paris for bones and bodies.

The gibbet and the graveyard—the convenience stores for the medieval anatomist—yielded

Ha

the humors in the tumors,

Born in 1821, Billroth studied music and surgery with almost equal verve. (The professions still often go hand in hand. Both push manual skill to its limit; both mature with practice and age; both depend on immediacy, precision, and opposable thumbs.)

Wöhler’s experiment demolished vitalism. Organic and inorganic chemicals, he proved, were interchangeable. Biology was chemistry: perhaps even a human body was no different from a bag of busily reacting chemicals—a beaker with arms, legs, eyes, brain, and soul.

“I am opposed to heart attacks and cancer,” she would later tell a reporter, “the way one is opposed to sin.”

Since the children were usually too exhausted to walk, tiny wooden go-carts were scattered about the room so that the patients could move around with relative freedom. IV poles for chemotherapy were strung up on the carts to allow chemo to be given at all times during the day.

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 helps you see the truth. —Howard Skipper

Second, Skipper found that by adding drugs in combination, he could often get synergistic effects on killing. Since different drugs elicited different resistance mechanisms, and produced different toxicities in cancer cells, using drugs in concert dramatically lowered the chance of resistance and increased cell killing.

Zubrod was stunned. “It is the dose that makes a poison,” runs the old adage in medicine: all medicines were poisons in one form or another merely diluted to an appropriate dose. But chemotherapy was poison even at the correct dose.*

The brain and spinal cord are insulated by a tight cellular seal called the blood-brain barrier that prevents foreign chemicals from easily getting into the brain. It is an ancient biological system that has evolved to keep poisons from reaching the brain.

It took plain old courage to be a chemotherapist in the 1960s and certainly the courage of the conviction that cancer would eventually succumb to drugs. —Vincent DeVita, National Cancer Institute investigator (and eventually NCI director)

cancer of the scrotum, endemic among chimney sweeps,

On December 9, 1969, on a chilly Sunday morning, a full-page advertisement appeared in the Washington Post:*

https://profiles.nlm.nih.gov/spotlight/tl/catalog/nlm:nlmuid-101584665X20-doc

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.”

Dogs, humans, and lions are the only animals known to develop prostate cancer,

As 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.

(“Syphilis,” as the saying ran, “was one night with Venus, followed by a thousand nights with mercury.”)

And when a risk factor for a disease becomes so highly prevalent in a population, it paradoxically begins to disappear into the white noise of the background. As the Oxford epidemiologist Richard Peto put it: “By the early 1940s, asking about a connection between tobacco and cancer was like asking about an association between sitting and cancer.” If nearly all men smoked, and only some of them developed cancer, then how might one tease apart the statistical link between one and the other?

“More doctors smoke Camels,” one advertisement reminded consumers, thus reassuring patients of the safety of their smoking. Medical journals routinely carried cigarette advertisements. At the annual conferences of the American Medical Association in the early 1950s, cigarettes were distributed free of charge to doctors, who lined up outside the tobacco booths.

Retroviruses, Temin had shown, shuttle constantly out of the cell’s genome: RNA to DNA to RNA. During this cycling, they can pick up pieces of the cell’s genes and carry them, like barnacles, from one cell to another. Rous’s sarcoma virus had likely picked up an activated src gene from a cancer cell and carried it in the viral genome, creating more cancer.

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.

Frei’s award, for curing leukemia, and Erikson’s award, for identifying the function of a critical oncogene, might almost have been given to two unconnected pursuits. “I don’t remember any enthusiasm among the clinicians to reach out to the cancer biologists to synthesize the two poles of knowledge about cancer,” Erikson recalled. The two halves of cancer, cause and cure, having feasted and been feted together, sped off in separate taxis into the night.

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.

When Berry assessed the effect of each intervention independently using statistical models, it was a satisfying tie: both cancer prevention and chemotherapy had diminished breast cancer mortality equally—12 percent for mammography and 12 percent for chemotherapy, adding up to the observed 24 percent reduction in mortality.

(Druker jokes that he has achieved the perfect inversion of the goals of cancer medicine: his drug has increased the prevalence of cancer in the world.)

The bedlam of the cancer genome, in short, is deceptive. If one listens closely, there are organizational principles. The language of cancer is grammatical, methodical, and even—I hesitate to write—quite beautiful. Genes talk to genes and pathways to pathways in perfect pitch, producing a familiar yet foreign music that rolls faster and faster into a lethal rhythm.

“There are far more good historians than there are good prophets,” Klausner wrote. “It is extraordinarily difficult to predict scientific discovery, which is often propelled by seminal insights coming from unexpected directions. The classic example—Fleming’s discovery of penicillin on moldy bread and the monumental impact of that accidental finding—could not easily have been predicted, nor could the sudden demise of iron-lung technology when evolving techniques in virology allowed the growth of poliovirus and the preparation of vaccine. Any extrapolation of history into the future presupposes an environment of static discovery—an oxymoron.”

There’s a loose consensus in the field that spending $30,000 to $40,000 for a year of life extension is “worth it”—but

We need a great degree of intelligence to judge the “cost effectiveness” of a drug. In lymphoblastic leukemia, every trial in the 1950s and 1960s typically added between six and ten weeks of survival benefit. By the late 1960s, a substantial fraction of patients, about sixty percent, were being cured. If we had judged the cost effectiveness of Aminopterin in Sidney Farber’s trials—which showed a survival benefit of only a few weeks in only some children—we might have abandoned the drug altogether. Judge “cost effectiveness” too early and you might throw out powerful drugs that have not been adequately tested.