The Emperor of All Maladies

—William Castle, describing leukemia in 1950

In a damp

(#litres_trial_promo) fourteen-by-twenty-foot laboratory in Boston on a December morning in 1947, a man named Sidney Farber waited impatiently for the arrival of a parcel from New York. The “laboratory” was little more than a chemist’s closet, a poorly ventilated room buried in a half-basement of the Children’s Hospital, almost thrust into its back alley. A few hundred feet away, the hospital’s medical wards were slowly thrumming to work. Children in white smocks moved restlessly on small wrought-iron cots. 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

(#litres_trial_promo), 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 and illnesses. He would try to use the knowledge he had gathered from his pathological specimens to devise new therapeutic interventions. The parcel from New York contained a few vials of a yellow crystalline chemical named aminopterin. It had been shipped to his laboratory in Boston on the slim hope that it might halt the growth of leukemia in children.

Had Farber asked any of the pediatricians circulating in the wards above him about the likelihood of developing an antileukemic drug, they would have advised him not to bother trying. Childhood leukemia had fascinated, confused, and frustrated doctors for more than a century. The disease had been analyzed, classified, subclassified, and subdivided meticulously; in the musty, leatherbound books on the library shelves at Children’s—Anderson’s Pathology or Boyd’s Pathology of Internal Diseases—page upon page was plastered with images of leukemia cells and appended with elaborate taxonomies to describe the cells. Yet all this knowledge only amplified the sense of medical helplessness. The disease had turned into an object of empty fascination—a wax-museum doll—studied and photographed in exquisite detail but without any therapeutic or practical advances. “It gave physicians plenty to wrangle over

(#litres_trial_promo) at medical meetings,” an oncologist recalled, “but it did not help their patients at all.” A patient with acute leukemia was brought to the hospital in a flurry of excitement, discussed on medical rounds with professorial grandiosity, and then, as a medical magazine drily noted, “diagnosed, transfused—and sent home to die.”

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The study of leukemia had been mired in confusion and despair ever since its discovery. On March 19, 1845, a Scottish physician, John Bennett, had described an unusual case, a twenty-eight-year-old slate-layer with a mysterious swelling in his spleen. “He is of dark complexion,”

(#litres_trial_promo) Bennett wrote of his patient, “usually healthy and temperate; [he] states that twenty months ago, he was affected with great listlessness on exertion, which has continued to this time. In June last he noticed a tumor in the left side of his abdomen which has gradually increased in size till four months since, when it became stationary.”

The slate-layer’s tumor might have reached its final, stationary point, but his constitutional troubles only accelerated. Over the next few weeks, Bennett’s patient spiraled from symptom to symptom—fevers, flashes of bleeding, sudden fits of abdominal pain—gradually at first, then on a tighter, faster arc, careening from one bout to another. Soon the slate-layer was on the verge of death with more swollen tumors sprouting in his armpits, his groin, and his neck. He was treated with the customary leeches and purging, but to no avail. At the autopsy a few weeks later, Bennett was convinced that he had found the reason behind the symptoms. His patient’s blood was chock-full of white blood cells. (White blood cells, the principal constituent of pus, typically signal the response to an infection, and Bennett reasoned that the slate-layer had succumbed to one.) “The following case seems to me particularly valuable,” he wrote self-assuredly, “as it will serve to demonstrate the existence of true pus, formed universally within the vascular system.”* (#litres_trial_promo)

It would have been a perfectly satisfactory explanation except that Bennett could not find a source for the pus. During the necropsy, he pored carefully through the body, combing the tissues and organs for signs of an abscess or wound. But no other stigmata of infection were to be found. The blood had apparently spoiled—suppurated—of its own will, combusted spontaneously into true pus. “A suppuration of blood,” Bennett called his case. And he left it at that.

Bennett was wrong, of course, about his spontaneous “suppuration” of blood. A little over four months after Bennett had described the slater’s illness, a twenty-four-year-old German researcher, Rudolf Virchow, independently published

(#litres_trial_promo) a case report with striking similarities to Bennett’s case. Virchow’s patient was a cook in her midfifties. White cells had explosively overgrown her blood, forming dense and pulpy pools in her spleen. At her autopsy, pathologists had likely not even needed a microscope to distinguish the thick, milky layer of white cells floating above the red.

Virchow, who knew of Bennett’s case, couldn’t bring himself to believe Bennett’s theory. Blood, Virchow argued, had no reason to transform impetuously into anything. Moreover, the unusual symptoms bothered him: What of the massively enlarged spleen? Or the absence of any wound or source of pus in the body? Virchow began to wonder if the blood itself was abnormal. Unable to find a unifying explanation for it, and seeking a name for this condition

(#litres_trial_promo), 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.”

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

(#litres_trial_promo)—from gay related immune disease (GRID) to acquired immuno deficiency syndrome (AIDS)—would signal an epic shift in the understanding of that disease.* (#litres_trial_promo)) 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.

The humility of the name (and the underlying humility about his understanding of cause) epitomized Virchow’s approach to medicine

(#litres_trial_promo). As a young professor at the University of Würzburg, Virchow’s work soon extended far beyond naming leukemia. A pathologist by training, he launched a project that would occupy him for his life: describing human diseases in simple cellular terms.

It was a project born of frustration. 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.

The two tenets might have seemed simplistic, but they allowed Virchow to propose a crucially important hypothesis about the nature of human growth. If cells only arose from other cells, then growth could occur in only two ways: either by increasing cell numbers or by increasing cell size. Virchow called these two modes hyperplasia and hypertrophy. In hypertrophy, the number of cells did not change; instead, each individual cell merely grew in size—like a balloon being blown up. Hyperplasia, in contrast, was growth by virtue of cells increasing in number. Every growing human tissue could be described in terms of hypertrophy and hyperplasia. In adult animals, fat and muscle usually grow by hypertrophy. In contrast, the liver, blood, the gut, and the skin all grow through hyperplasia—cells becoming cells becoming more cells, omnis cellula e cellula e cellula.

That explanation was persuasive, and it provoked a new understanding not just of normal growth, but of pathological growth as well. Like normal growth, pathological growth could also be achieved through hypertrophy and hyperplasia. When the heart muscle is forced to push against a blocked aortic outlet, it often adapts by making every muscle cell bigger to generate more force, eventually resulting in a heart so overgrown that it may be unable to function normally—pathological hypertrophy.

Conversely, and importantly for this story, Virchow soon stumbled upon the quintessential disease of pathological hyperplasia—cancer. Looking at cancerous growths through his microscope, Virchow discovered an uncontrolled growth of cells—hyperplasia in its extreme form. As Virchow examined the architecture of cancers, the growth often seemed to have acquired a life of its own, as if the cells had become possessed by a new and mysterious drive to grow. This was not just ordinary growth, but growth redefined, growth in a new form. Presciently (although oblivious of the mechanism) Virchow called it neoplasia—novel, inexplicable, distorted growth, a word that would ring through the history of cancer.* (#litres_trial_promo)

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.

With this understanding, pathologists who studied leukemia in the late 1880s now circled back to Virchow’s work. Leukemia, then, was not a suppuration of blood, but neoplasia of blood. Bennett’s earlier fantasy

(#litres_trial_promo) had germinated an entire field of fantasies among scientists, who had gone searching (and dutifully found) all sorts of invisible parasites and bacteria bursting out of leukemia cells. But once pathologists stopped looking for infectious causes and refocused their lenses on the disease, they discovered the obvious analogies between leukemia cells and cells of other forms of cancer. Leukemia was a malignant proliferation of white cells in the blood. It was cancer in a molten, liquid form.

With that seminal observation, the study of leukemias suddenly found clarity and spurted forward. By the early 1900s, it was clear that the disease came in several forms. It could be chronic and indolent, slowly choking the bone marrow and spleen, as in Virchow’s original case (later termed chronic leukemia). Or it could be acute and violent, almost a different illness in its personality, with flashes of fever, paroxysmal fits of bleeding, and a dazzlingly rapid overgrowth of cells—as in Bennett’s patient.

This second version of the disease, called acute leukemia, came in two further subtypes, based on the type of cancer cell involved. Normal white cells in the blood can be broadly divided into two types of cells—myeloid cells or lymphoid cells. Acute myeloid leukemia (AML) was a cancer of the myeloid cells. Acute lymphoblastic leukemia (ALL) was cancer of immature lymphoid cells. (Cancers of more mature lymphoid cells are called lymphomas.)

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

(#litres_trial_promo) 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

(#litres_trial_promo), her galloping, relentless illness had lasted no more than three days.

Although nowhere as aggressive as Maria Speyer’s leukemia, Carla’s illness was astonishing in its own right. Adults, on average, have about five thousand white blood cells circulating per milliliter of blood. Carla’s blood contained ninety thousand cells per milliliter—nearly twentyfold the normal level. Ninety-five percent of these cells were blasts—malignant lymphoid cells produced at a frenetic pace but unable to mature into fully developed lymphocytes. In acute lymphoblastic leukemia, as in some other cancers, the overproduction of cancer cells is combined with a mysterious arrest in the normal maturation of cells. Lymphoid cells are thus produced in vast excess, but, unable to mature, they cannot fulfill their normal function in fighting microbes. Carla had immunological poverty in the face of plenty.

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.

Carla was at the edge of a physiological abyss. Her red cell count had dipped so low that her blood was unable to carry its full supply of oxygen (her headaches, in retrospect, were the first sign of oxygen deprivation). Her platelets, the cells responsible for clotting blood, had collapsed to nearly zero, causing her bruises.

Her treatment would require extraordinary finesse. She would need chemotherapy to kill her leukemia, but the chemotherapy would collaterally decimate any remnant normal blood cells. We would push her deeper into the abyss to try to rescue her. For Carla, the only way out would be the way through.

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 returning to study medicine in their native country.) Farber thus arrived at Harvard as an outsider. His colleagues found him arrogant and insufferable, but, he too, relearning lessons that he had already learned, seemed to be suffering through it all. He was formal, precise, and meticulous, starched in his appearance and his mannerisms and commanding in presence. He was promptly nicknamed Four-Button Sid for his propensity for wearing formal suits to his classes.

Farber completed his advanced training

(#litres_trial_promo) in pathology in the late 1920s and became the first full-time pathologist at the Children’s Hospital in Boston. He wrote a marvelous study on the classification of children’s tumors and a textbook, The Postmortem Examination, widely considered a classic in the field. By the mid-1930s, he was firmly ensconced in the back alleys of the hospital as a preeminent pathologist—a “doctor of the dead.”

Yet the hunger to treat patients still drove Farber. 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 “experiment” on cancer.

The idea mesmerized Farber. In the 1940s and ’50s, young biologists were galvanized by the idea of using simple models to understand complex phenomena. Complexity was best understood by building from the ground up. Single-celled organisms such as bacteria would reveal the workings of massive, multicellular animals such as humans. What is true for E. coli

(#litres_trial_promo) [a microscopic bacterium], the French biochemist Jacques Monod would grandly declare in 1954, must also be true for elephants.

For Farber, leukemia epitomized this biological paradigm. From this simple, atypical beast he would extrapolate into the vastly more complex world of other cancers; the bacterium would teach him to think about the elephant. He was, by nature, a quick and often impulsive thinker. And here, too, he made a quick, instinctual leap. The package from New York was waiting in his laboratory that December morning. As he tore it open, pulling out the glass vials of chemicals, he scarcely realized that he was throwing open an entirely new way of thinking about cancer.

“A monster more insatiable than the guillotine” (#ulink_ee8c0dac-6081-5abb-bdc0-b756f3746163)

The medical importance of leukemia