The Emperor of All Maladies Read online

  In 1937, the indefatigable Neely, reelected to the Senate, launched yet another effort to launch a national attack on cancer, this time jointly with Senator Homer Bone and Representative Warren Magnuson. By now, cancer had considerably magnified in the public eye. The Fortune and Time articles had fanned anxiety and discontent, and politicians were eager to demonstrate a concrete response. In June, a joint Senate-House conference was held to craft legislation to address the issue. After initial hearings, the bill raced through Congress and was passed unanimously by a joint session on July 23, 1937. Two weeks later, on August 5, President Roosevelt signed the National Cancer Institute Act.

  The act created a new scientific unit called the National Cancer Institute (NCI), designed to coordinate cancer research and education.* An advisory council of scientists for the institute was assembled from universities and hospitals. A state-of-the-art laboratory space, with gleaming halls and conference rooms, was built among leafy arcades and gardens in suburban Bethesda, a few miles from the nation’s capital. “The nation is marshaling its forces to conquer cancer, the greatest scourge that has ever assailed the human race,” Senator Bone announced reassuringly while breaking ground for the building on October 3, 1938. After nearly two decades of largely fruitless efforts, a coordinated national response to cancer seemed to be on its way at last.

  All of this was a bold, brave step in the right direction—except for its timing. By the early winter of 1938, just months after the inauguration of the NCI campus in Bethesda, the battle against cancer was overshadowed by the tremors of a different kind of war. In November, Nazi troops embarked on a nationwide pogrom against Jews in Germany, forcing thousands into concentration camps. By late winter, military conflicts had broken out all over Asia and Europe, setting the stage for World War II. By 1939, those skirmishes had fully ignited, and in December 1941, America was drawn inextricably into the global conflagration.

  The war necessitated a dramatic reordering of priorities. The U.S. Marine Hospital in Baltimore, which the NCI had once hoped to convert into a clinical cancer center, was now swiftly reconfigured into a war hospital. Scientific research funding stagnated and was shunted into projects directly relevant to the war. Scientists, lobbyists, physicians, and surgeons fell off the public radar screen—“mostly silent,” as one researcher recalled, “their contributions usually summarized in obituaries.”

  An obituary might as well have been written for the National Cancer Institute. Congress’s promised funds for a “programmatic response to cancer” never materialized, and the NCI languished in neglect. Outfitted with every modern facility imaginable in the 1940s, the institute’s sparkling campus turned into a scientific ghost town. One scientist jokingly called it “a nice quiet place out here in the country. In those days,” the author continued, “it was pleasant to drowse under the large, sunny windows.”*

  The social outcry about cancer also drifted into silence. After the brief flurry of attention in the press, cancer again became the great unmentionable, the whispered-about disease that no one spoke about publicly. In the early 1950s, Fanny Rosenow, a breast cancer survivor and cancer advocate, called the New York Times to post an advertisement for a support group for women with breast cancer. Rosenow was put through, puzzlingly, to the society editor of the newspaper. When she asked about placing her announcement, a long pause followed. “I’m sorry, Ms. Rosenow, but the Times cannot publish the word breast or the word cancer in its pages.

  “Perhaps,” the editor continued, “you could say there will be a meeting about diseases of the chest wall.”

  Rosenow hung up, disgusted.

  When Farber entered the world of cancer in 1947, the public outcry of the past decade had dissipated. Cancer had again become a politically silent illness. In the airy wards of the Children’s Hospital, doctors and patients fought their private battles against cancer. In the tunnels downstairs, Farber fought an even more private battle with his chemicals and experiments.

  This isolation was key to Farber’s early success. Insulated from the spotlights of public scrutiny, he worked on a small, obscure piece of the puzzle. Leukemia was an orphan disease, abandoned by internists, who had no drugs to offer for it, and by surgeons, who could not possibly operate on blood. “Leukemia,” as one physician put it, “in some senses, had not [even] been cancer before World War II.” The illness lived on the borderlands of illnesses, a pariah lurking between disciplines and departments—not unlike Farber himself.

  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.

  Much of what Farber knew about normal blood he had learned from George Minot. A thin, balding aristocrat with pale, intense eyes, Minot ran a laboratory in a colonnaded, brick-and-stone structure off Harrison Avenue in Boston, just a few miles down the road from the sprawling hospital complex on Longwood Avenue that included Children’s Hospital. Like many hematologists at Harvard, Farber had trained briefly with Minot in the 1920s before joining the staff at Children’s.

  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. Minot had shown that replacing a single molecule could restore the normalcy of blood in this complex hematological disease. Blood was an organ whose activity could be turned on and off by molecular switches.

  There was another form of nutritional anemia that Minot’s group had not tackled, an anemia just as “pernicious”—although in the moral sense of that word. 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.)

  In 1928, a young English physician named Lucy Wills, freshly out of the London School of Medicine for Women, traveled on a grant to Bombay to study this anemia. Wills was an exotic among hematologists, an adventurous woman driven by a powerful curiosity about blood willing to travel to a faraway country to solve a mysterious anemia on a whim. She knew of Minot’s work. But unlike Minot’s anemia, she found that the anemia in Bombay couldn’t be reversed by Minot’s concoctions or by vitamin B12. Astonishingly, she found she could cure it with Marmite, the dark, yeasty spread then popular among health fanatics in England and Australia. Wills could not determine the key chemical nutrient of Marmite. She called it the Wills factor.

  Wills factor turned out to be folic acid, or folate, a vitamin-like substance found in fruits and vegetables (and amply in Marmite). When cells divide, they need to make copies of DNA—the chemical that carries all the genetic informati
on in a cell. Folic acid is a crucial building block for DNA and is thus vital for cell division. Since blood cells are produced by arguably the most fearsome rate of cell division in the human body—more than 300 billion cells a day—the genesis of blood is particularly dependent on folic acid. In its absence (in men and women starved of vegetables, as in Bombay) the production of new blood cells in the bone marrow halts. Millions of half-matured cells spew out, piling up like half-finished goods bottlenecked in an assembly line. The bone marrow becomes a dysfunctional mill, a malnourished biological factory oddly reminiscent of the cloth factories of Bombay.

  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.

  Pediatricians at Children’s Hospital were furious about Farber’s trial. The folate analogues had not just accelerated the leukemia; they had likely hastened the death of the children. But Farber was intrigued. If folic acid accelerated the leukemia cells in children, what if he could cut off its supply with some other drug—an antifolate? Could a chemical that blocked the growth of white blood cells stop leukemia?

  The observations of Minot and Wills began to fit into a foggy picture. If the bone marrow was a busy cellular factory to begin with, then a marrow occupied with leukemia was that factory in overdrive, a deranged manufacturing unit for cancer cells. Minot and Wills had turned the production lines of the bone marrow on by adding nutrients to the body. But could the malignant marrow be shut off by choking the supply of nutrients? Could the anemia of the mill workers in Bombay be re-created therapeutically in the medical units of Boston?

  In his long walks from his laboratory under Children’s Hospital to his house on Amory Street in Brookline, Farber wondered relentlessly about such a drug. Dinner, in the dark-wood-paneled rooms of the house, was usually a sparse, perfunctory affair. His wife, Norma, a musician and writer, talked about the opera and poetry; Sidney, of autopsies, trials, and patients. As he walked back to the hospital at night, Norma’s piano tinkling practice scales in his wake, the prospect of an anticancer chemical haunted him. He imagined it palpably, visibly, with a fanatic’s enthusiasm. But he didn’t know what it was or what to call it. The word chemotherapy, in the sense we understand it today, had never been used for anticancer medicines.* The elaborate armamentarium of “antivitamins” that Farber had dreamed up so vividly in his fantasies did not exist.

  Farber’s supply of folic acid for his disastrous first trial had come from the laboratory of an old friend, a chemist, Yellapragada Subbarao—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 cell), and another molecule called creatine, the energy carrier in muscle cells. Any one of these achievements should have been enough to guarantee him a professorship at Harvard. But Subbarao was a foreigner, a reclusive, nocturnal, heavily accented vegetarian who lived in a one-room apartment downtown, befriended only by other nocturnal recluses such as Farber. In 1940, denied tenure and recognition, Yella huffed off to join Lederle Labs, a pharmaceutical laboratory in upstate New York, owned by the American Cyanamid Corporation, where he had been asked to run a group on chemical synthesis.

  At Lederle, Yella Subbarao quickly reformulated his old strategy and focused on making synthetic versions of the natural chemicals that he had found within cells, hoping to use them as nutritional supplements. In the 1920s, another drug company, Eli Lilly, had made a fortune selling a concentrated form of vitamin B12, the missing nutrient in pernicious anemia. Subbarao decided to focus his attention on the other anemia, the neglected anemia of folate deficiency. But in 1946, after many failed attempts to extract the chemical from pigs’ livers, he switched tactics and started to synthesize folic acid from scratch, with the help of a team of scientists including Harriet Kiltie, a young chemist at Lederle.

  The chemical reactions to make folic acid brought a serendipitous bonus. Since the reactions had several intermediate steps, Subbarao and Kiltie 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 Kiltie and Subbarao asking them 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.

  * In 1944, the NCI would become a subsidiary component of the National Institutes of Health (NIH). This foreshadowed the creation of other disease-focused institutes over the next decades.

  *In 1946–47, Neely and Senator Claude Pepper launched a third national cancer bill. This was defeated in Congress by a small margin in 1947.

  * In New York in the 1910s, William B. Coley, James Ewing, and Ernest Codman had treated bone sarcomas with a mixture of bacterial toxins—the so-called Coley’s toxin. Coley had observed occasional responses, but the unpredictable responses, likely caused by immune stimulation, never fully captured the attention of oncologists or surgeons.

  Farber’s Gauntlet

  Throughout the centuries the sufferer from this disease has been the subject of almost every conceivable form of experimentation. The fields and forests, the apothecary shop and the temple, have been ransacked for some successful means of relief from this intractable malady. Hardly any animal has escaped making its contribution, in hair or hide, tooth or toenail, thymus or thyroid, liver or spleen, in the vain search by man for a means of relief.

  —William Bainbridge

  The search for a way to eradicate this scourge . . . is left to inci
dental dabbling and uncoordinated research.

  —The Washington Post, 1946

  Seven miles southwest of the Longwood hospitals in Boston, the town of Dorchester is a typical sprawling New England suburb, a triangle wedged between the sooty industrial settlements to the west and the gray-green bays of the Atlantic to its east. In the late 1940s, waves of Jewish and Irish immigrants—shipbuilders, iron casters, railway engineers, fishermen, and factory workers—settled in Dorchester, occupying rows of brick-and-clapboard houses that snaked their way up Blue Hill Avenue. Dorchester reinvented itself as the quintessential suburban family town, with parks and playgrounds along the river, a golf course, a church, and a synagogue. On Sunday afternoons, families converged at Franklin Park to walk through its leafy pathways or to watch ostriches, polar bears, and tigers at its zoo.

  On August 16, 1947, in a house across from the zoo, the child of a ship worker in the Boston yards fell mysteriously ill with a low-grade fever that waxed and waned over two weeks without pattern, followed by increasing lethargy and pallor. Robert Sandler was two years old. His twin, Elliott, was an active, cherubic toddler in perfect health.

  Ten days after his first fever, Robert’s condition worsened significantly. His temperature climbed higher. His complexion turned from rosy to a spectral milky white. He was brought to Children’s Hospital in Boston. His spleen, a fist-size organ that stores and makes blood (usually barely palpable underneath the rib cage), was visibly enlarged, heaving down like an overfilled bag. A drop of blood under Farber’s microscope revealed the identity of his illness; thousands of immature lymphoid leukemic blasts were dividing in a frenzy, their chromosomes condensing and uncondensing, like tiny clenched and unclenched fists.