The Emperor of All Maladies

by Siddhartha Mukherjee

  The “wizards” had wrought astonishing technological magic. Physicists had created sonar, radar, radio-sensing bombs, and amphibious tanks. Chemists had produced intensely efficient and lethal chemical weapons, including the infamous war gases. Biologists had studied the effects of high-altitude survival and seawater ingestion. Even mathematicians, the archbishops of the arcane, had been packed off to crack secret codes for the military.

  The undisputed crown jewel of this targeted effort, of course, was the atomic bomb, the product of the OSRD-led Manhattan Project. On August 7, 1945, the morning after the Hiroshima bombing, the New York Times gushed about the extraordinary success of the project: “University professors who are opposed to organizing, planning and directing research after the manner of industrial laboratories . . . have something to think about now. A most important piece of research was conducted on behalf of the Army in precisely the means adopted in industrial laboratories. End result: an invention was given to the world in three years, which it would have taken perhaps half-a-century to develop if we had to rely on prima-donna research scientists who work alone. . . . A problem was stated, it was solved by teamwork, by planning, by competent direction, and not by the mere desire to satisfy curiosity.”

  The congratulatory tone of that editorial captured a general sentiment about science that had swept through the nation. The Manhattan Project had overturned the prevailing model of scientific discovery. The bomb had been designed, as the Times scoffingly put it, not by tweedy “prima-donna” university professors wandering about in search of obscure truths (driven by the “mere desire to satisfy curiosity”), but by a focused SWAT team of researchers sent off to accomplish a concrete mission. A new model of scientific governance emerged from the project—research driven by specific mandates, timelines, and goals (“frontal attack” science, to use one scientist’s description)—which had produced the remarkable technological boom during the war.

  But Vannevar Bush was not convinced. 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 plan had a deep and lasting influence in Washington. 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.

  For the Laskerites, this augured a profound conflict. A War on Cancer, they felt, demanded precisely the sort of focus and undiluted commitment that had been achieved so effectively at Los Alamos. World War II had clearly surcharged medical research with new problems and new solutions; it had prompted the development of novel resuscitation techniques, research on blood and frozen plasma, on the role of adrenal steroids in shock and on cerebral and cardiac blood flow. Never in the history of medicine, as A. N. Richards, the chairman of the Committee on Medical Research, put it, had there been “so great a coordination of medical scientific labor.”

  This sense of common purpose and coordination galvanized the Laskerites: they wanted a Manhattan Project for cancer. Increasingly, they felt that it was no longer necessary to wait for fundamental questions about cancer to be solved before launching an all-out attack on the problem. Farber had, after all, forged his way through the early leukemia trials with scarcely any foreknowledge of how aminopterin worked even in normal cells, let alone cancer cells. Oliver Heaviside, an English mathematician from the 1920s, once wrote jokingly about a scientist musing at a dinner table, “Should I refuse my dinner because I don’t understand the digestive system?” To Heaviside’s question, Farber might have added his own: should I refuse to attack cancer because I have not solved its basic cellular mechanisms?

  Other scientists echoed this frustration. The outspoken Philadelphia pathologist Stanley Reimann wrote, “Workers in cancer must make every effort to organize their work with goals in view not just because they are ‘interesting’ but because they will help in the solution of the cancer problem.” Bush’s cult of open-ended, curiosity-driven inquiry—“interesting” science—had ossified into dogma. To battle cancer, that dogma needed to be overturned.

  The first, and most seminal, step in this direction was the creation of a focused drug-discovery unit for anticancer drugs. In 1954, after a furious bout of political lobbying by Laskerites, the Senate authorized the NCI to build a program to find chemotherapeutic drugs in a more directed, targeted manner. By 1955, this effort, called the Cancer Chemotherapy National Service Center (CCNSC), was in full swing. Between 1954 and 1964, this unit would test 82,700 synthetic chemicals, 115,000 fermentation products, and 17,200 plant derivatives and treat nearly 1 million mice every year with various chemicals to find an ideal drug.

  Farber was ecstatic, but impatient. “The enthusiasm . . . of these new friends of chemotherapy is refreshing and seems to be on a genuine foundation,” he wrote to Lasker in 1955. “It nevertheless seems frightfully slow. It sometimes becomes monotonous to see more and more men brought into the program go through the joys of discovering America.”

  Farber had, meanwhile, stepped up his own drug-discovery efforts in Boston. In the 1940s, the soil microbiologist Selman Waksman had systematically scoured the world of soil bacteria and purified a diverse series of antibiotics. (Like the Penicillium mold, which produces penicillin, bacteria also produce antibiotics to wage chemical warfare on other microbes.) 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 la
ter 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. In the summer of 1954, Farber persuaded Waksman to send him a number of antibiotics, including actinomycin D, to repurpose them as antitumor agents by testing the drugs on a series of mouse tumors. Actinomycin D, Farber found, was remarkably effective in mice. Just a few doses melted away many mouse cancers, including leukemias, lymphomas, and breast cancers. “One hesitates to call them ‘cures,’” Farber wrote expectantly, “but it is hard to classify them otherwise.”

  Energized by the animal “cures,” in 1955 he launched a series of trials to evaluate the efficacy of the drug in humans. Actinomycin D had no effect on leukemias in children. Undeterred, Farber unleashed the drug on 275 children with a diverse range of cancers: lymphomas, kidney sarcomas, muscle sarcomas, and neuroblastic tumors. The trial was a pharmacist’s nightmare. Actinomycin D was so toxic that it had to be heavily diluted in saline; if even minute amounts leaked out of the veins, then the skin around the leak would necrose and turn black. In children with small veins, the drug was often given through an intravenous line inserted into the scalp.

  The one form of cancer that responded in these early trials was Wilms’ tumor, a rare variant of kidney cancer. Often detected in very young children, Wilms’ tumor was typically treated by surgical removal of the affected kidney. Surgical removal was followed by X-ray radiation to the affected kidney bed. But not all Wilms’ cases could be treated using local therapy. In a fraction of cases, by the time the tumor was detected, it had already metastasized, usually to the lungs. Recalcitrant to treatment there, Wilms’ tumors were usually bombarded with X-rays and assorted drugs but with little hopes of a sustained response.

  Farber found that actinomycin D, administered intravenously, potently inhibited the growth of these lung metastases, often producing remissions that lasted months. Intrigued, he pressed further. If X-rays and actinomycin D could both attack Wilms’ metastases independently, what if the agents could be combined? In 1958, he set a young radiologist couple named Giulio D’Angio and Audrey Evans and an oncologist named Donald Pinkel to work on the project. Within months, the team had confirmed that X-rays and actinomycin D were remarkably synergistic, each multiplying the toxic effect of the other. Children with metastatic cancer treated with the combined regimen often responded briskly. “In about three weeks lungs previously riddled with Wilms’ tumor metastasis cleared completely,” D’Angio recalled. “Imagine the excitement of those days when one could say for the first time with justifiable confidence, ‘We can fix that.’”

  The enthusiasm generated by these findings was infectious. Although combination X-ray and chemotherapy did not always produce long-term cures, Wilms’ tumor was the first metastatic solid tumor to respond to chemotherapy. Farber had achieved his long-sought leap from the world of liquid cancers to solid tumors.

  By the late 1950s, Farber was bristling with a fiery brand of optimism. Yet visitors to the Jimmy Fund clinic in the mid-1950s might have witnessed a more nuanced and complex reality. For Sonja Goldstein, whose two-year-old son, David, was treated with chemotherapy for Wilms’ tumor in 1956, the clinic seemed perpetually suspended between two poles—both “wonderful and tragic . . . unspeakably depressing and indescribably hopeful.” On entering the cancer ward, Goldstein would write later, “I sense an undercurrent of excitement, a feeling (persistent despite repeated frustrations) of being on the verge of discovery, which makes me almost hopeful.

  “We enter a large hall decorated with a cardboard train along one wall. Half way down the ward is an authentic-looking stop sign, which can flash green, red, and amber lights. The train’s engine can be climbed into and the bell pulled. At the other end of the ward is a life-size gasoline pump, registering amount sold and price. . . . My first impression is one of overweening activity, almost snake pit-like in its intensity.”

  It was a snake-pit—only of cancer, a seething, immersed box coiled with illness, hope, and desperation. A girl named Jenny, about four years old, played with a new set of crayons in the corner. Her mother, an attractive, easily excitable woman, kept Jenny in constant sight, holding her child with the clawlike intensity of her gaze as Jenny stooped to pick up the colors. No activity was innocent here; anything might be a sign, a symptom, a portent. Jenny, Goldstein realized, “has leukemia and is currently in the hospital because she developed jaundice. Her eyeballs are still yellow”—presaging fulminant liver failure. She, like many of the ward’s inhabitants, was relatively oblivious to the meaning of her illness. Jenny’s only concern was an aluminum teakettle to which she was deeply attached.

  “Sitting in a go-cart in the hall is a little girl, who, I think at first, has been given a black eye. . . . Lucy, a 2-year old, suffers from a form of cancer that spreads to the area behind the eye and causes hemorrhaging there. She is not a very attractive child, and wails almost incessantly that first day. So does Debbie, an angelic-looking 4-year old whose face is white and frowning with suffering. She has the same type of tumor as Lucy—a neuroblastoma. Alone in a room lies Teddy. It takes many days before I venture inside it, for, skeleton-thin and blinded, Teddy has a monstrosity for a face. His tumor, starting behind the ear, has engulfed one side of his head and obliterated his normal features. He is fed through a tube in the nostril, and is fully conscious.”

  Throughout the ward were little inventions and improvisations, often devised by Farber himself. Since the children were usually too exhausted to walk, tiny wooden go-carts were scattered about the room so that the patients could move around with relative freedom. IV poles for chemotherapy were strung up on the carts to allow chemo to be given at all times during the day. “To me,” Goldstein wrote, “one of the most pathetic sights of all that I have seen is the little go-cart, with the little child, leg or arm tightly bandaged to hold needle in vein, and a tall IV pole with its burette. The combined effect is that of a boat with mast but no sail, helplessly drifting alone in a rough, uncharted sea.”

  Every evening, Farber came to the wards, forcefully driving his own sail-less 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 promenade, we note another empty bed. Finish.”

  In the winter of 1956, after a prolonged and bruising battle, Sonja’s son, three-year-old David Goldstein, died of metastatic Wilms’ tumor at the Jimmy Fund clinic, having spent the last few hours of his life delirious and whimpering under an oxygen mask. Sonja Goldstein left the hospital carrying her own brown paper bag containing the remains of her child.

  But Farber was unfazed. The arsenal of cancer chemotherapy, having been empty for centuries, had filled up with new drug
s. The possibilities thrown open by these discoveries were enormous: permutations and combinations of medicines, variations in doses and schedules, trials containing two-, three-, and four-drug regimens. There was, at least in principle, the capacity to re-treat cancer with one drug if another had failed, or to try one combination followed by another. This, Farber kept telling himself with hypnotic conviction, was not the “finish.” This was just the beginning of an all-out attack.

  In her hospital bed on the fourteenth floor, Carla Reed was still in “isolation”—trapped in a cool, sterile room where even the molecules of air arrived filtered through dozens of sieves. The smell of antiseptic soap pervaded her clothes. A television occasionally flickered on and off. Food came on a tray labeled with brave, optimistic names—Chunky Potato Salad or Chicken Kiev—but everything tasted as if it had been boiled and seared almost to obliteration. (It had been; the food had to be sterilized before it could enter the room.) Carla’s husband, a computer engineer, came in every afternoon to sit by her bed. Ginny, her mother, spent the days rocking mechanically in a chair, exactly as I had found her the first morning. When Carla’s children stopped by, in masks and gloves, she wept quietly, turning her face toward the window.