The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

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.

Two characters stand at the epicenter of this story—both contemporaries, both idealists, both children of the boom in postwar science and technology in America, and both caught in the swirl of a hypnotic, obsessive quest to launch a national “War on Cancer.” The first is Sidney Farber, the father of modern chemotherapy, who accidentally discovers a powerful anti-cancer chemical in a vitamin analogue and begins to dream of a universal cure for cancer. The second is Mary Lasker, the Manhattan socialite of legendary social and political energy, who joins Farber in his decades-long journey. But Lasker and Farber only exemplify the grit, imagination, inventiveness, and optimism of generations of men and women who have waged a battle against cancer for four thousand years. In a sense, this is a military history—one in which the adversary is formless, timeless, and pervasive. Here, too, there are victories and losses, campaigns upon campaigns, heroes and hubris, survival and resilience—and inevitably, the wounded, the condemned, the forgotten, the dead. 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 was an all-consuming presence in our lives. It invaded our imaginations; it occupied our memories; it infiltrated every conversation, every thought. And if we, as physicians, found ourselves immersed in cancer, then our patients found their lives virtually obliterated by the disease. In Aleksandr Solzhenitsyn’s novel Cancer Ward, Pavel Nikolayevich Rusanov, a youthful Russian in his midforties, discovers that he has a tumor in his neck and is immediately whisked away into a cancer ward in some nameless hospital in the frigid north. The diagnosis of cancer—not the disease, but the mere stigma of its presence—becomes a death sentence for Rusanov. The illness strips him of his identity. It dresses him in a patient’s smock (a tragicomically cruel costume, no less blighting than a prisoner’s jumpsuit) and assumes absolute control of his actions. To be diagnosed with cancer, Rusanov discovers, is to enter a borderless medical gulag, a state even more invasive and paralyzing than the one that he has left behind. (Solzhenitsyn may have intended his absurdly totalitarian cancer hospital to parallel the absurdly totalitarian state outside it, yet when I once asked a woman with invasive cervical cancer about the parallel, she said sardonically, “Unfortunately, I did not need any metaphors to read the book. The cancer ward was my confining state, my prison.”)

How old is cancer? What are the roots of our battle against this disease? Or, as patients often asked me: Where are we in the “war” on cancer? How did we get here? Is there an end? Can this war even be won? This book grew out of the attempt to answer these questions. I delved into the history of cancer to give shape to the shape-shifting illness that I was confronting. I used the past to explain the present. The isolation and rage of a thirty-six-year-old woman with stage III breast cancer had ancient echoes in Atossa, the Persian queen who swaddled her diseased breast in cloth to hide it and then, in a fit of nihilistic and prescient fury, possibly had a slave cut it off with a knife. A patient’s desire to amputate her stomach, ridden with cancer—“sparing nothing,” as she put it to me—carried the memory of the perfection-obsessed nineteenth-century surgeon William Halsted, who had chiseled away at cancer with larger and more disfiguring surgeries, all in the hopes that cutting more would mean curing more.

I explained the situation as best I could. Her day ahead would be full of tests, a hurtle from one lab to another. I would draw a bone marrow sample. More tests would be run by pathologists. But the preliminary tests suggested that Carla had acute lymphoblastic leukemia. It is one of the most common forms of cancer in children, but rare in adults. And it is—I paused here for emphasis, lifting my eyes up—often curable. Curable. Carla nodded at that word, her eyes sharpening. Inevitable questions hung in the room: How curable? What were the chances that she would survive? How long would the treatment take? I laid out the odds. Once the diagnosis had been confirmed, chemotherapy would begin immediately and last more than one year. Her chances of being cured were about 30 percent, a little less than one in three. We spoke for an hour, perhaps longer. It was now nine thirty in the morning. The city below us had stirred fully awake. The door shut behind me as I left, and a whoosh of air blew me outward and sealed Carla in.

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.” —Hilaire Belloc

Doctors and nurses shuttled busily between the rooms, checking charts, writing orders, and dispensing medicines. But Farber’s lab was listless and empty, a bare warren of chemicals and glass jars connected to the main hospital through a series of icy corridors. The sharp stench of embalming formalin wafted through the air. There were no patients in the rooms here, just the bodies and tissues of patients brought down through the tunnels for autopsies and examinations. Farber was a pathologist. His job involved dissecting specimens, performing autopsies, identifying cells, and diagnosing diseases, but never treating patients. Farber’s specialty was pediatric pathology, the study of children’s diseases. He had spent nearly twenty years in these subterranean rooms staring obsessively down his microscope and climbing through the academic ranks to become chief of pathology at Children’s. But for Farber, pathology was becoming a disjunctive form of medicine, a discipline more preoccupied with the dead than with the living. Farber now felt impatient watching illness from its sidelines, never touching or treating a live patient. He was tired of tissues and cells. He felt trapped, embalmed in his own glassy cabinet. And so, Farber had decided to make a drastic professional switch. Instead of squinting at inert specimens under his lens, he would try to leap into the life of the clinics upstairs—from the microscopic world that he knew so well into the magnified real world of patients ...

Renaming the disease—from the florid “suppuration of blood” to the flat weisses Blut—hardly seems like an act of scientific genius, but it had a profound impact on the understanding of leukemia. An illness, at the moment of its discovery, is a fragile idea, a hothouse flower—deeply, disproportionately influenced by names and classifications. (More than a century later, in the early 1980s, another change in name—from gay related immune disease (GRID) to acquired immuno deficiency syndrome (AIDS)—would signal an epic shift in the understanding of that disease.*) Like Bennett, Virchow didn’t understand leukemia. But unlike Bennett, he didn’t pretend to understand it. His insight lay entirely in the negative. By wiping the slate clean of all preconceptions, he cleared the field for thought.

Virchow entered medicine in the early 1840s, when nearly every disease was attributed to the workings of some invisible force: miasmas, neuroses, bad humors, and hysterias. Perplexed by what he couldn’t see, Virchow turned with revolutionary zeal to what he could see: cells under the microscope. In 1838, Matthias Schleiden, a botanist, and Theodor Schwann, a physiologist, both working in Germany, had claimed that all living organisms were built out of fundamental building blocks called cells. Borrowing and extending this idea, 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.

In children, leukemia was most commonly ALL—lymphoblastic leukemia—and was almost always swiftly lethal. In 1860, a student of Virchow’s, Michael Anton Biermer, described the first known case of this form of childhood leukemia. Maria Speyer, an energetic, vivacious, and playful five-year-old daughter of a Würzburg carpenter, was initially seen at the clinic because she had become lethargic in school and developed bloody bruises on her skin. The next morning, she developed a stiff neck and a fever, precipitating a call to Biermer for a home visit. That night, Biermer drew a drop of blood from Maria’s veins, looked at the smear using a candlelit bedside microscope, and found millions of leukemia cells in the blood. Maria slept fitfully late into the evening. Late the next afternoon, as Biermer was excitedly showing his colleagues the specimens of “exquisit Fall von Leukämie” (an exquisite case of leukemia), Maria vomited bright red blood and lapsed into a coma. By the time Biermer returned to her house that evening, the child had been dead for several hours. From its first symptom to diagnosis to death, her galloping, relentless illness had lasted no more than three days.

White blood cells are produced in the bone marrow. Carla’s bone marrow biopsy, which I saw under the microscope the morning after I first met her, was deeply abnormal. Although superficially amorphous, bone marrow is a highly organized tissue—an organ, in truth—that generates blood in adults. Typically, bone marrow biopsies contain spicules of bone and, within these spicules, islands of growing blood cells—nurseries for the genesis of new blood. In Carla’s marrow, this organization had been fully destroyed. Sheet upon sheet of malignant blasts packed the marrow space, obliterating all anatomy and architecture, leaving no space for any production of blood.

Sidney Farber was born in Buffalo, New York, in 1903, one year after Virchow’s death in Berlin. His father, Simon Farber, a former bargeman in Poland, had immigrated to America in the late nineteenth century and worked in an insurance agency. The family lived in modest circumstances at the eastern edge of town, in a tight-knit, insular, and often economically precarious Jewish community of shop owners, factory workers, bookkeepers, and peddlers. Pushed relentlessly to succeed, the Farber children were held to high academic standards. Yiddish was spoken upstairs, but only German and English were allowed downstairs. The elder Farber often brought home textbooks and scattered them across the dinner table, expecting each child to select and master one book, then provide a detailed report for him. Sidney, the third of fourteen children, thrived in this environment of high aspirations. He studied both biology and philosophy in college and graduated from the University of Buffalo in 1923, playing the violin at music halls to support his college education. Fluent in German, he trained in medicine at Heidelberg and Freiburg, then, having excelled in Germany, found a spot as a second-year medical student at Harvard Medical School in Boston. (The circular journey from New York to Boston via Heidelberg was not unusual. In the mid-1920s, Jewish students often found it impossible to secure medical-school spots in America—often succeeding in European, even German, medical schools before ...

And sitting in his basement laboratory in the summer of 1947, Farber had a single inspired idea: he chose, among all cancers, to focus his attention on one of its oddest and most hopeless variants—childhood leukemia. To understand cancer as a whole, he reasoned, you needed to start at the bottom of its complexity, in its basement. And despite its many idiosyncrasies, leukemia possessed a singularly attractive feature: it could be measured. Science begins with counting. To understand a phenomenon, a scientist must first describe it; to describe it objectively, he must first measure it. If cancer medicine was to be transformed into a rigorous science, then cancer would need to be counted somehow—measured in some reliable, reproducible way. In this, leukemia was different from nearly every other type of cancer. In a world before CT scans and MRIs, quantifying the change in size of an internal solid tumor in the lung or the breast was virtually impossible without surgery: you could not measure what you could not see. But leukemia, floating freely in the blood, could be measured as easily as blood cells—by drawing a sample of blood or bone marrow and looking at it under a microscope. If leukemia could be counted, Farber reasoned, then any intervention—a chemical sent circulating through the blood, say—could be evaluated for its potency in living patients. He could watch cells grow or die in the blood and use that to measure the success or failure of a drug. He could perform an ...

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), was by the early fifties being produced in thousand-gallon vats. 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. New antibiotics followed in the footsteps of penicillin: chloramphenicol in 1947, tetracycline in 1948. In the winter of 1949, when yet another miraculous antibiotic, streptomycin, was purified out of a clod of mold from a chicken farmer’s barnyard, Time magazine splashed the phrase “The remedies are in our own backyard,” prominently across its cover. In a brick building on the far corner of Children’s Hospital, in Farber’s own backyard, a microbiologist named John Enders was culturing poliovirus in rolling plastic flasks, the first step that culminated in the development of the Sabin and Salk polio vaccines. New drugs appeared at an astonishing rate: by 1950, more than half the medicines in common medical use had been unknown merely a decade earlier.

Typhoid fever, a contagion whose deadly swirl could decimate entire districts in weeks, melted away as the putrid water supplies of several cities were cleansed by massive municipal efforts. Even tuberculosis, the infamous “white plague” of the nineteenth century, was vanishing, its incidence plummeting by more than half between 1910 and 1940, largely due to better sanitation and public hygiene efforts. The life expectancy of Americans rose from forty-seven to sixty-eight in half a century, a greater leap in longevity than had been achieved over several previous centuries.

In 1899, when Roswell Park, a well-known Buffalo surgeon, had argued that cancer would someday overtake smallpox, typhoid fever, and tuberculosis to become the leading cause of death in the nation, his remarks had been perceived as a rather “startling prophecy,” the hyperbolic speculations of a man who, after all, spent his days and nights operating on cancer. But by the end of the decade, Park’s remarks were becoming less and less startling, and more and more prophetic by the day. Typhoid, aside from a few scattered outbreaks, was becoming increasingly rare. Smallpox was on the decline; by 1949, it would disappear from America altogether. Meanwhile cancer was already outgrowing other diseases, ratcheting its way up the ladder of killers. Between 1900 and 1916, cancer-related mortality grew by 29.8 percent, edging out tuberculosis as a cause of death. By 1926, cancer had become the nation’s second most common killer, just behind heart disease.

If leukemia “belonged” anywhere, it was within hematology, the study of normal blood. If a cure for it was to be found, Farber reasoned, it would be found by studying blood. If he could uncover how normal blood cells were generated, he might stumble backward into a way to block the growth of abnormal leukemic cells. His strategy, then, was to approach the disease from the normal to the abnormal—to confront cancer in reverse.

Every decade has a unique hematological riddle, and for Minot’s era, that riddle was pernicious anemia. Anemia is the deficiency of red blood cells—and its most common form arises from a lack of iron, a crucial nutrient used to build red blood cells. But pernicious anemia, the rare variant that Minot studied, was not caused by iron deficiency (indeed, its name derives from its intransigence to the standard treatment of anemia with iron). By feeding patients increasingly macabre concoctions—half a pound of chicken liver, half-cooked hamburgers, raw hog stomach, and even once the regurgitated gastric juices of one of his students (spiced up with butter, lemon, and parsley)—Minot and his team of researchers conclusively demonstrated in 1926 that pernicious anemia was caused by the lack of a critical micronutrient, a single molecule later identified as vitamin B12. In 1934, Minot and two of his colleagues won the Nobel Prize for this pathbreaking work.

Eight thousand miles away, in the cloth mills of Bombay (owned by English traders and managed by their cutthroat local middlemen), wages had been driven to such low levels that the mill workers lived in abject poverty, malnourished and without medical care. When English physicians tested these mill workers in the 1920s to study the effects of this chronic malnutrition, they discovered that many of them, particularly women after childbirth, were severely anemic. (This was yet another colonial fascination: to create the conditions of misery in a population, then subject it to social or medical experimentation.)

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.

Farber’s supply of folic acid for his disastrous first trial had come from the laboratory of an old friend, a chemist, Yellapragada Subbarao (SubbaRow)—or Yella, as most of his colleagues called him. Yella was a pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology. His scientific meanderings had been presaged by more desperate and adventuresome physical meanderings. He had arrived in Boston in 1923, penniless and unprepared, having finished his medical training in India and secured a scholarship for a diploma at the School of Tropical Health at Harvard. The weather in Boston, Yella discovered, was far from tropical. Unable to find a medical job in the frigid, stormy winter (he had no license to practice medicine in the United States), he started as a night porter at the Brigham and Women’s Hospital, opening doors, changing sheets, and cleaning urinals. The proximity to medicine paid off. Subbarao made friends and connections at the hospital and switched to a day job as a researcher in the Division of Biochemistry. His initial project involved purifying molecules out of living cells, dissecting them chemically to determine their compositions—in essence, performing a biochemical “autopsy” on cells. The approach required more persistence than imagination, but it produced remarkable dividends. Subbarao purified a molecule called ATP, the source of energy in all living beings (ATP carries chemical “energy” in the c...

The chemical reactions to make folic acid brought a serendipitous bonus. Since the reactions had several intermediate steps, Subbarao’s team* could create variants of folic acid through slight alterations in the recipe. These variants of folic acid—closely related molecular mimics—possessed counterintuitive properties. Enzymes and receptors in cells typically work by recognizing molecules using their chemical structure. But a “decoy” molecular structure—one that nearly mimics the natural molecule—can bind to the receptor or enzyme and block its action, like a false key jamming a lock. Some of Yella’s molecular mimics could thus behave like antagonists to folic acid. These were precisely the antivitamins that Farber had been fantasizing about. Farber wrote to Subbarao asking him if he could use their folate antagonists on patients with leukemia. Subbarao consented. In the late summer of 1947, the first package of antifolate left Lederle’s labs in New York and arrived in Farber’s laboratory.

On September 6, 1947, Farber began to inject Sandler with pteroylaspartic acid or PAA, the first of Lederle’s antifolates. (Consent to run a clinical trial for a drug—even a toxic drug—was not typically required. 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.)

Farber’s paper, published on June 3, 1948, was seven pages long, jam-packed with tables, figures, microscope photographs, laboratory values, and blood counts. Its language was starched, formal, detached, and scientific. Yet, like all great medical papers, it was a page-turner. And like all good novels, it was timeless: to read it today is to be pitched behind the scenes into the tumultuous life of the Boston clinic, its patients hanging on for life as Farber and his assistants scrambled to find new drugs for a dreadful disease that kept flickering away and returning. It was a plot with a beginning, a middle, and, unfortunately, an end.

We reveal ourselves in the metaphors we choose for depicting the cosmos in miniature. —Stephen Jay Gould

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.

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.

Where was cancer “born”? How old is cancer? Who was the first to record it as an illness? In 1862, Edwin Smith—an unusual character: part scholar and part huckster, an antique forger and self-made Egyptologist—bought (or, some say, stole) a fifteen-foot-long papyrus from an antiques seller in Luxor in Egypt. The papyrus was in dreadful condition, with crumbling, yellow pages filled with cursive Egyptian script. It is now thought to have been written in the seventeenth century BC, a transcription of a manuscript dating back to 2500 BC. The copier—a plagiarist in a terrible hurry—had made errors as he had scribbled, often noting corrections in red ink in the margins. Translated in 1930, the papyrus is now thought to contain the collected teachings of Imhotep, a great Egyptian physician who lived around 2625 BC. Imhotep, among the few nonroyal Egyptians known to us from the Old Kingdom, was a Renaissance man at the center of a sweeping Egyptian renaissance. As a vizier in the court of King Djozer, he dabbled in neurosurgery, tried his hand at architecture, and made early forays into astrology and astronomy. Even the Greeks, encountering the fierce, hot blast of his intellect as they marched through Egypt centuries later, cast him as an ancient magician and fused him to their own medical god, Asclepius. But the surprising feature of the Smith papyrus is not magic and religion but the absence of magic and religion. In a world immersed in spells, incantations, and charms, Imhote...

But with case forty-five, Imhotep fell atypically silent. Under the section titled “Therapy,” he offered only a single sentence: “There is none.” With that admission of impotence, cancer virtually disappeared from ancient medical history. Other diseases cycled violently through the globe, leaving behind their cryptic footprints in legends and documents. A furious plague—typhus, perhaps—blazed through the port city of Avaris in 1715 BC, decimating its population. Smallpox erupted volcanically in pockets, leaving its telltale pockmarks on the face of Ramses V in the twelfth century BC. Tuberculosis rose and ebbed through the Indus valley like its seasonal floods. But if cancer existed in the interstices of these massive epidemics, it existed in silence, leaving no easily identifiable trace in the medical literature—or in any other literature. More than two millennia pass after Imhotep’s description until we once more hear of cancer.