The Emperor of All Maladies. Siddhartha Mukherjee
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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 1950,299 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 research300 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.”301
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 dinner302 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 Reimann303 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 Center304 (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 impatient305. “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 microbe306 called Actinomyces. Waksman called it actinomycin D307. 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. 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