The Emperor of All Maladies: A Biography of Cancer

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.

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.

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. Cancer is built into our genomes: the genes that unmoor normal cell division are not foreign to our bodies, but rather mutated, distorted versions of the very genes that perform vital cellular functions.

Physicians of the Utmost Fame Were called at once; but when they came They answered, as they took their Fees, “There is no Cure for this Disease.”

Virchow set out to create a “cellular theory” of human biology, basing it on two fundamental tenets. First, that human bodies (like the bodies of all animals and plants) were made up of cells. Second, that cells only arose from other cells—omnis cellula e cellula, as he put it.

By the time Virchow died in 1902, a new theory of cancer had slowly coalesced out of all these observations. Cancer was a disease of pathological hyperplasia in which cells acquired an autonomous will to divide. This aberrant, uncontrolled cell division created masses of tissue (tumors) that invaded organs and destroyed normal tissues. These tumors could also spread from one site to another, causing outcroppings of the disease—called metastases—in distant sites, such as the bones, the brain, or the lungs. Cancer came in diverse forms—breast, stomach, skin, and cervical cancer, leukemias and lymphomas. But all these diseases were deeply connected at the cellular level. In every case, cells had all acquired the same characteristic: uncontrollable pathological cell division.

The Fortune article was titled “Cancer: The Great Darkness,” and the “darkness,” the authors suggested, was as much political as medical. Cancer medicine was stuck in a rut not only because of the depth of medical mysteries that surrounded it, but because of the systematic neglect of cancer research: “There are not over two dozen funds in the U.S. devoted to fundamental cancer research. They range in capital from about $500 up to about $2,000,000, but their aggregate capitalization is certainly not much more than $5,000,000.… The public willingly spends a third of that sum in an afternoon to watch a major football game.”

These links—between vitamins, bone marrow, and normal blood—kept Farber preoccupied in the early summer of 1946. In fact, his first clinical experiment, inspired by this very connection, turned into a horrific mistake. Lucy Wills had observed that folic acid, if administered to nutrient-deprived patients, could restore the normal genesis of blood. Farber wondered whether administering folic acid to children with leukemia might also restore normalcy to their blood. Following that tenuous trail, he obtained some synthetic folic acid, recruited a cohort of leukemic children, and started injecting folic acid into them. In the months that passed, Farber found that folic acid, far from stopping the progression of leukemia, actually accelerated it. In one patient, the white cell count nearly doubled. In another, the leukemia cells exploded into the bloodstream and sent fingerlings of malignant cells to infiltrate the skin. Farber stopped the experiment in a hurry. He called this phenomenon acceleration, evoking some dangerous object in free fall careering toward its end.

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.”

But cancer is not simply a clonal disease; it is a clonally evolving disease. If growth occurred without evolution, cancer cells would not be imbued with their potent capacity to invade, survive, and metastasize. 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. This mirthless, relentless cycle of mutation, selection, and overgrowth generates cells that are more and more adapted to survival and growth. In some cases, the mutations speed up the acquisition of other mutations. The genetic instability, like a perfect madness, only provides more impetus to generate mutant clones. 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. If cancer existed, it remained submerged under the sea of other illnesses. 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.

It was in the time of Hippocrates, around 400 BC, that a word for cancer first appeared in the medical literature: karkinos, from the Greek word for “crab.” The tumor, with its clutch of swollen blood vessels around it, reminded Hippocrates of a crab dug in the sand with its legs spread in a circle. The image was peculiar (few cancers truly resemble crabs), but also vivid. Later writers, both doctors and patients, added embellishments. For some, the hardened, matted surface of the tumor was reminiscent of the tough carapace of a crab’s body. Others felt a crab moving under the flesh as the disease spread stealthily throughout the body. For yet others, the sudden stab of pain produced by the disease was like being caught in the grip of a crab’s pincers.

Another Greek word would intersect with the history of cancer—onkos, a word used occasionally to describe tumors, from which the discipline of oncology would take its modern name. Onkos was the Greek term for a mass or a load, or more commonly a burden; cancer was imagined as a burden carried by the body. In Greek theater, the same word, onkos, would be used to denote a tragic mask that was often “burdened” with an unwieldy conical weight on its head to denote the psychic load carried by its wearer.

The physician Claudius Galen, a prolific writer and influential Greek doctor who practiced among the Romans around AD 160, brought Hippocrates’ humoral theory to its apogee. 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. (Only one other disease, replete with metaphors, would be attributed to an excess of this oily, viscous humor: depression. Indeed, melancholia, the medieval name for “depression,” would draw its name from the Greek melas, “black,” and khole, “bile.” Depression and cancer, the psychic and physical diseases of black bile, were thus intrinsically intertwined.) Galen proposed that cancer was “trapped” black bile—static bile unable to escape from a site and thus congealed into a matted mass. “Of blacke cholor [bile], without boyling cometh cancer,” Thomas Gale, the English surgeon, wrote of Galen’s theory in the sixteenth century, “and if the humor be sharpe, it maketh ulceration, and for this cause, these tumors are more blacker in color.”

The word autopsy comes from the Greek “to see for oneself”; as Vesalius learned to see for himself, he could no longer force Galen’s mystical visions to fit his own. The lymphatic system carried a pale, watery fluid; the blood vessels were filled, as expected, with blood. Yellow bile was in the liver. But black bile—Galen’s oozing carrier of cancer and depression—could not be found anywhere. Vesalius now found himself in a strange position. He had emerged from a tradition steeped in Galenic scholarship; he had studied, edited, and republished Galen’s books. But black bile—that glistening centerpiece of Galen’s physiology—was nowhere to be found. Vesalius hedged about his discovery. Guiltily, he heaped even more praise on the long-dead Galen. But, an empiricist to the core, Vesalius left his drawings just as he saw things, leaving others to draw their own conclusions. There was no black bile. Vesalius had started his anatomical project to save Galen’s theory, but, in the end, he quietly buried it.

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?

In a waste ore called pitchblende, a black sludge that came from the peaty forests of Joachimsthal in what is now the Czech Republic, the Curies found the first signal of a new element—an element many times more radioactive than uranium. The Curies set about distilling the boggy sludge to trap that potent radioactive source in its purest form. From several tons of pitchblende, four hundred tons of washing water, and hundreds of buckets of distilled sludge waste, they finally fished out one-tenth of a gram of the new element in 1902. The metal lay on the far edge of the periodic table, emitting X-rays with such feverish intensity that it glowered with a hypnotic blue light in the dark, consuming itself. Unstable, it was a strange chimera between matter and energy—matter decomposing into energy. Marie Curie called the new element radium, from the Greek word for “light.” Radium, by virtue of its potency, revealed a new and unexpected property of X-rays: they could not only carry radiant energy through human tissues, but also deposit energy deep inside tissues. Röntgen had been able to photograph his wife’s hand because of the first property: his X-rays had traversed through flesh and bone and left a shadow of the tissue on the film. Marie Curie’s hands, in contrast, bore the painful legacy of the second effect: having distilled pitchblende into a millionth part for week after week in the hunt for purer and purer radioactivity, the skin in her palm had begun to chafe and peel ...

With the Curies’ discovery of radium in 1902, surgeons could beam thousandfold more powerful bursts of energy on tumors. Conferences and societies on high-dose radiation therapy were organized in a flurry of excitement. Radium was infused into gold wires and stitched directly into tumors, to produce even higher local doses of X-rays. Surgeons implanted radon pellets into abdominal tumors. By the 1930s and ’40s, America had a national surplus of radium, so much so that it was being advertised for sale to laypeople in the back pages of journals. Vacuum-tube technology advanced in parallel; by the mid-1950s variants of these tubes could deliver blisteringly high doses of X-ray energy into cancerous tissues.

Marie Curie died of leukemia in July 1934. Emil Grubbe, who had been exposed to somewhat weaker X-rays, also succumbed to the deadly late effects of chronic radiation. By the mid-1940s, Grubbe’s fingers had been amputated one by one to remove necrotic and gangrenous bones, and his face was cut up in repeated operations to remove radiation-induced tumors and premalignant warts. In 1960, at the age of eighty-five, he died in Chicago, with multiple forms of cancer that had spread throughout his body.

But even Hofmann knew that the boundary between the synthetic world and the natural world was inevitably collapsing. In 1828, a Berlin scientist named Friedrich Wöhler had sparked a metaphysical storm in science by boiling ammonium cyanate, a plain, inorganic salt, and creating urea, a chemical typically produced by the kidneys. The Wöhler experiment—seemingly trivial—had enormous implications. Urea was a “natural” chemical, while its precursor was an inorganic salt. That a chemical produced by natural organisms could be derived so easily in a flask threatened to overturn the entire conception of living organisms: for centuries, the chemistry of living organisms was thought to be imbued with some mystical property, a vital essence that could not be duplicated in a laboratory—a theory called vitalism. 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.

Every drug, the sixteenth-century physician Paracelsus once opined, is a poison in disguise. Cancer chemotherapy, consumed by its fiery obsession to obliterate the cancer cell, found its roots in the obverse logic: every poison might be a drug in disguise.

It was Disney World fused with Cancerland.

In October 1943, Lasker persuaded a friend at the Digest to run a series of articles on the screening and detection of cancer. Within weeks, the articles set off a deluge of postcards, telegrams, and handwritten notes to the magazine’s office, often accompanied by small amounts of pocket money, personal stories, and photographs. A soldier grieving the death of his mother sent in a small contribution: “My mother died from cancer a few years ago.… We are living in foxholes in the Pacific theater of war, but would like to help out.” A schoolgirl whose grandfather had died of cancer enclosed a dollar bill. Over the next months, the Digest received thousands of letters and $300,000 in donations, exceeding the ASCC’s entire annual budget.

In a deeply influential report to President Truman entitled Science the Endless Frontier, first published in 1945, Bush had laid out a view of postwar research that had turned his own model of wartime research on its head: “Basic research,” Bush wrote, “is performed without thought of practical ends. It results in general knowledge and an understanding of nature and its laws. This general knowledge provides the means of answering a large number of important practical problems, though it may not give a complete specific answer to any one of them.… “Basic research leads to new knowledge. It provides scientific capital. It creates the fund from which the practical applications of knowledge must be drawn.… Basic research is the pacemaker of technological progress. In the nineteenth century, Yankee mechanical ingenuity, building largely upon the basic discoveries of European scientists, could greatly advance the technical arts. Now the situation is different. A nation which depends upon others for its new basic scientific knowledge will be slow in its industrial progress and weak in its competitive position in world trade, regardless of its mechanical skill.”

Directed, targeted research—“programmatic” science—the cause célèbre during the war years, Bush argued, was not a sustainable model for the future of American science. As Bush perceived it, even the widely lauded Manhattan Project epitomized the virtues of basic inquiry. True, the bomb was the product of Yankee “mechanical ingenuity.” But that mechanical ingenuity stood on the shoulders of scientific discoveries about the fundamental nature of the atom and the energy locked inside it—research performed, notably, with no driving mandate to produce anything resembling the atomic bomb. While the bomb might have come to life physically in Los Alamos, intellectually speaking it was the product of prewar physics and chemistry rooted deeply in Europe. The iconic homegrown product of wartime American science was, at least philosophically speaking, an import. A lesson Bush had learned from all of this was that goal-directed strategies, so useful in wartime, would be of limited use during periods of peace. “Frontal attacks” were useful on the war front, but postwar science could not be produced by fiat. So Bush had pushed for a radically inverted model of scientific development, in which researchers were allowed full autonomy over their explorations and open-ended inquiry was prioritized.

The National Science Foundation (NSF), founded in 1950, was explicitly created to encourage scientific autonomy, turning in time, as one historian put it, into a veritable “embodiment [of Bush’s] grand design for reconciling government money and scientific independence.” A new culture of research—“long-term, basic scientific research rather than sharply focused quests for treatment and disease prevention”—rapidly proliferated at the NSF and subsequently at the NIH.

One such antibiotic came from a rod-shaped microbe called Actinomyces. Waksman called it actinomycin D. An enormous molecule shaped like an ancient Greek statue, with a small, headless torso and two extended wings, actinomycin D was later found to work by binding and damaging DNA. It potently killed bacterial cells—but unfortunately it also killed human cells, limiting its use as an antibacterial agent. But a cellular poison could always excite an oncologist.

Every evening, Farber came to the wards, forcefully driving his own sailless boat through this rough and uncharted sea. He paused at each bed, taking notes and discussing the case, often barking out characteristically brusque instructions. A retinue followed him: medical residents, nurses, social workers, psychiatrists, nutritionists, and pharmacists. Cancer, he insisted, was a total disease—an illness that gripped patients not just physically, but psychically, socially, and emotionally. Only a multipronged, multidisciplinary attack would stand any chance of battling this disease. He called the concept “total care.” But despite all efforts at providing “total care,” death stalked the wards relentlessly. In the winter of 1956, a few weeks after David’s visit, a volley of deaths hit Farber’s clinic. Betty, a child with leukemia, was the first to die. Then it was Jenny, the four-year-old with the aluminum teakettle. Teddy, with retinoblastoma, was next. A week later, Axel, another child with leukemia, bled to death, with hemorrhages in his mouth. Goldstein observed, “Death assumes shape, form, and routine. Parents emerge from their child’s room, as they have perhaps done periodically for days for short rests. A nurse takes them to the doctor’s small office; the doctor comes in and shuts the door behind him. Later, a nurse brings coffee. Still later, she hands the parents a large brown paper bag, containing odds and ends of belongings. A few minutes later, back at our promenad...

To ration streptomycin, an objective experiment to determine its efficacy in human tuberculosis was needed. But what sort of experiment? An English statistician named Bradford Hill (a former victim of TB himself) proposed an extraordinary solution. Hill began by recognizing that doctors, of all people, could not be entrusted to perform such an experiment without inherent biases. Every biological experiment requires a “control” arm—untreated subjects against whom the efficacy of a treatment can be judged. But left to their own devices, doctors were inevitably likely (even if unconsciously so) to select certain types of patients upfront, then judge the effects of a drug on this highly skewed population using subjective criteria, piling bias on top of bias. Hill’s 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. Hill’s randomized trial was a success. The streptomycin arm of the trial clearly showed an improved response over the placebo arm, enshrining the antibiotic as a new anti-TB drug. But perhaps more important, it was Hill’s methodological invention that was permanently enshrined. For medical scientists, the randomized trial became the most stringent means to evaluate the efficacy of any intervention in the most unbiased m...

As Farber and Burchenal had discovered to their chagrin in Boston and New York, leukemia treated with a single drug would inevitably grow resistant to the drug, resulting in the flickering, transient responses followed by the devastating relapses.

Like cancer cells, mycobacteria—the germs that cause tuberculosis—also became resistant to antibiotics if the drugs were used singly. Bacteria that survived a single-drug regimen divided, mutated, and acquired drug resistance, thus making that original drug useless. To thwart this resistance, doctors treating TB had used a blitzkrieg of antibiotics—two or three used together like a dense pharmaceutical blanket meant to smother all cell division and stave off bacterial resistance, thus extinguishing the infection as definitively as possible.

As Freireich, Frei, and Zubrod studied the growing list of anti-leukemia drugs, the notion of combining drugs emerged with growing clarity: toxicities notwithstanding, annihilating leukemia might involve using a combination of two or more drugs. The first protocol was launched to test different doses of Farber’s methotrexate combined with Burchenal’s 6-MP, the two most active antileukemia drugs. Three hospitals agreed to join: the NCI, Roswell Park, and the Children’s Hospital in Buffalo, New York. The aims of the trial were kept intentionally simple. One group would be treated with intensive methotrexate dosing, while the other group would be treated with milder and less intensive dosing. Eighty-four patients enrolled. On arrival day, parents of the children were handed white envelopes with the randomized assignment sealed inside. Despite the multiple centers and the many egos involved, the trial ran surprisingly smoothly. Toxicities multiplied; the two-drug regimen was barely tolerable. But the intensive group fared better, with longer and more durable responses. The regimen, though, was far from a cure: even the intensively treated children soon relapsed and died by the end of one year.

In the winter of 1957, the leukemia group launched yet another modification to the first experiment. This time, one group received a combined regimen, while the other two groups were given one drug each. And with the question even more starkly demarcated, the pattern of responses was even clearer. Given alone, either of the drugs performed poorly, with a response rate between 15 and 20 percent. But when methotrexate and 6-MP were administered together, the remission rate jumped to 45 percent.

Trial by trial, the group crept forward, like a spring uncoiling to its end. In just six pivotal years, the leukemia study group had slowly worked itself to giving patients not one or two, but four chemotherapy drugs, often in succession. By the winter of 1962, the compass of leukemia medicine pointed unfailingly in one direction. If two drugs were better than one, and if three better than two, then what if four antileukemia drugs could be given together—in combination, as with TB?

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. The hcg level—the hormone secreted by choriocarcinoma—had turned out to be its real fingerprint, its marker. In the decades that followed, trial after trial would prove this principle. But in 1960, oncology was not yet ready for this proposal. Not until several years later did it strike the board that had fired Li so hastily that the patients he had treated with the prolonged maintenance strategy would never relapse. This strategy—which cost Min Chiu Li his job—resulted in the first chemotherapeutic cure of cancer in adults.

Although originally intended as an antidiabetic, vincristine at small doses was found to kill leukemia cells. Rapidly growing cells, such as those of leukemia, typically create a skeletal scaffold of proteins (called microtubules) that allows two daughter cells to separate from each other and thereby complete cell division. Vincristine works by binding to the end of these microtubules and then paralyzing the cellular skeleton in its grip—thus, quite literally, evoking the Latin word after which it was originally named.

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.

“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.

In the folklore of science, there is the often-told story of the moment of discovery: the quickening of the pulse, the spectral luminosity of ordinary facts, the overheated, standstill second when observations crystallize and fall together into patterns, like pieces of a kaleidoscope. The apple drops from the tree. The man jumps up from a bathtub; the slippery equation balances itself. But there is another moment of discovery—its antithesis—that is rarely recorded: the discovery of failure. It is a moment that a scientist often encounters alone. A patient’s CT scan shows a relapsed lymphoma. A cell once killed by a drug begins to grow back. A child returns to the NCI with a headache.

What Frei and Freireich discovered in the spinal fluid left them cold: leukemia cells were growing explosively in the spinal fluid by the millions, colonizing the brain. The headaches and the numbness were early signs of much more profound devastations to come. In the months that followed, one by one, all the children came back to the institute with a spectrum of neurological complaints—headaches, tinglings, abstract speckles of light—then slumped into coma. Bone marrow biopsies were clean. No cancer was found in the body. But the leukemia cells had invaded the nervous system, causing a quick, unexpected demise. It was a consequence of the body’s own defense system subverting cancer treatment. 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. But the same system had likely also kept VAMP out of the nervous system, creating a natural “sanctuary” for cancer within the body. The leukemia had grown out in that sanctuary, colonizing the one place that is fundamentally unreachable by chemotherapy. The children died one after the other—felled by virtue of the adaptation designed to protect them.

Why did Kaplan succeed where others had failed? First, because Kaplan meticulously restricted radiotherapy to patients with early-stage disease. He went to exhaustive lengths to stage patients before unleashing radiation on them. By strictly narrowing the group of patients treated, Kaplan markedly increased the likelihood of his success. And second, he succeeded because he had picked the right disease. Hodgkin’s was, for the most part, a regional illness. “Fundamental to all attempts at curative treatment of Hodgkin’s disease,” one reviewer commented memorably in the New England Journal of Medicine in 1968, “is the assumption that in the significant fraction of cases, [the disease] is localized.” Kaplan treated the intrinsic biology of Hodgkin’s disease with utmost seriousness. If Hodgkin’s lymphoma had been more capricious in its movement through the body (and occult areas of spread more common, as in some forms of breast cancer), then Kaplan’s staging strategy, for all his excruciatingly detailed workups, would inherently have been doomed to fail. Instead of trying to tailor the disease to fit his medicine, Kaplan learned to tailor his medicine to fit the right disease.

This simple principle—the meticulous matching of a particular therapy to a particular form and stage of cancer—would eventually be given its due merit in cancer therapy. Early-stage, local cancers, Kaplan realized, were often inherently different from widely spread, metastatic cancers—even within the same form of cancer. A hundred instances of Hodgkin’s disease, even though pathologically classified as the same entity, were a hundred variants around a common theme. Cancers possessed temperaments, personalities—behaviors. And biological heterogeneity demanded therapeutic heterogeneity; the same treatment could not indiscriminately be applied to all. But even if Kaplan understood it fully in 1963 and made an example of it in treating Hodgkin’s disease, it would take decades for a generation of oncologists to come to the same realization.

The next step—the complete cure—is almost sure to follow. —Kenneth Endicott, NCI director, 1963

The role of aggressive multiple drug therapy in the quest for long-term survival [in cancer] is far from clear. —R. Stein, a scientist in 1969

At the end of half a year, thirty-five of the forty-three patients had achieved a complete remission. The MOPP trial did not have a control group, but one was not needed to discern the effect. The response and remission rate were unprecedented for advanced Hodgkin’s disease. The success would continue in the long-term: more than half the initial cohort of patients would be cured.

The treatment protocol that emerged from these guiding principles could only be described as, as one of Pinkel’s colleagues called it, “an allout combat.” To start with, the standard antileukemic drugs were given in rapid-fire succession. Then, at defined intervals, methotrexate was injected into the spinal canal using a spinal tap. The brain was irradiated with high doses of X-rays. Then, chemotherapy was bolstered even further with higher doses of drugs and alternating intervals, “in maximum tolerated doses.” Antibiotics and transfusions were usually needed, often in succession, often for weeks on end. The treatment lasted up to two and a half years; it involved multiple exposures to radiation, scores of blood tests, dozens of spinal taps, and multiple intravenous drugs—a strategy so precise and demanding that one journal refused to publish it, concerned that it was impossible to even dose it and monitor it correctly without killing several patients in the trials. Even at St. Jude’s, the regimen was considered so overwhelmingly toxic that the trial was assigned to relatively junior physicians under Pinkel’s supervision because the senior researchers, knowing its risks, did not want to run it. Pinkel called it “total therapy.”

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

But then Rous stumbled on an even more peculiar result. Shuttling tumors from one bird to another, he began to pass the cells through a set of filters, a series of finer and finer cellular sieves, until the cells had been eliminated from the mix and all that was left was the filtrate derived from the cells. Rous expected the tumor transmission to stop, but instead, the tumors continued propagating with a ghostly efficacy—at times even increasing in transmissibility as the cells had progressively vanished. The agent responsible for carrying the cancer, Rous concluded, was not a cell or an environmental carcinogen, but some tiny particle lurking within a cell. The particle was so small that it could easily pass through most filters and keep producing cancer in animals. The only biological particle that had these properties was a virus. His virus was later called Rous sarcoma virus, or RSV for short.

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.

In the 1950s, in the throes of the Cold War, Americans were preoccupied with the fear of annihilation from the outside: from bombs and warheads, from poisoned water reservoirs, communist armies, and invaders from outer space. The threat to society was perceived as external. Horror 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.