The Emperor of All Maladies. Siddhartha Mukherjee
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Название: The Emperor of All Maladies
Автор: Siddhartha Mukherjee
Издательство: HarperCollins
Жанр: Прочая образовательная литература
isbn: 9780007435814
isbn:
It wasn’t a misspelling. When Freireich entered the office, he confronted a tall, thin young man who identified himself as Emil Frei. Freireich’s office, with the name correctly spelled, was next door.
Their names notwithstanding, the two Emils were vastly different characters. Freireich—just thirty-five years old and fresh out of a hematology fellowship at Boston University—was flamboyant, hot-tempered, and adventurous. He spoke quickly, often explosively, with a booming voice followed often by an even more expressive boom of laughter. He had been a medical intern at the fast-paced “Ward 55” of the Cook County Hospital in Chicago—and such a nuisance to the authorities that he had been released from his contract earlier than usual. In Boston, Freireich had worked with Chester Keefer, one of Minot’s colleagues who had subsequently spearheaded the production of penicillin during World War II. Antibiotics, folic acid, vitamins, and antifolates were stitched into Freireich’s soul. He admired Farber intensely—not just the meticulous, academic scientist, but the irreverent, impulsive, larger-than-life Farber who could antagonize his enemies as quickly as he could seduce his benefactors. “I have never seen Freireich in a moderate mood,”313 Frei would later say.
If Freireich had been a character in a film, he would have needed a cinematic foil, a Laurel to his Hardy or a Felix to his Oscar. The tall, thin man who confronted him at the door at the NCI that afternoon was that foil. Where Freireich was brusque and flamboyant, impulsive to a fault, and passionate about every detail, Frei was cool, composed, and cautious, a poised negotiator who preferred to work backstage. Emil Frei—known to most of his colleagues by his nickname, Tom—had been an art student in St. Louis in the thirties. He had attended medical school almost as an afterthought in the late 1940s, served in the navy in the Korean War, and returned to St. Louis as a resident in medicine. He was charming, soft-spoken, and careful—a man of few, chosen words. To watch him manage critically ill children and their testy, nervous parents was to watch a champion swimmer glide through water—so adept in the art that he made artistry vanish.
The person responsible for bringing the two Emils to Bethesda was Gordon Zubrod, the new director314 of the NCI’s Clinical Center. Intellectual, deliberate, and imposing, a clinician and scientist known for his regal composure, Zubrod had arrived at the NIH having spent nearly a decade developing antimalaria drugs during World War II, an experience that would deeply influence his early interests in clinical trials for cancer.
Zubrod’s particular interest was children’s leukemia—the cancer that Farber had plunged into the very forefront of clinical investigation. But to contend with leukemia, Zubrod knew, was to contend with its fieriness and brittleness, its moody, volcanic unpredictability. Drugs could be tested, but first, the children needed to be kept alive. A quintessential delegator—an “Eisenhower” of cancer research, as Freireich once called him—Zubrod quickly conscripted two young doctors to maintain the front lines of the wards: Freireich and Frei, fresh from their respective fellowships in Boston and St. Louis. Frei drove cross-country in a beat-up old Studebaker to join Zubrod. Freireich came just a few weeks later315, in a ramshackle Oldsmobile containing all his belongings, his pregnant wife, and his nine-month-old daughter.
It could easily have been a formula for disaster—but it worked. Right from the start, the two Emils found that they shared a unique synergy. Their collaboration was symbolic of a deep intellectual divide that ran through the front lines of oncology: the rift between overmoderated caution and bold experimentation. Each time Freireich pushed too hard on one end of the experimental fulcrum—often bringing himself and his patients to the brink of disaster—Frei pushed back to ensure that the novel, quixotic, and often deeply toxic therapies were mitigated by caution. Frei and Freireich’s battles soon became emblematic of the tussles within the NCI. “Frei’s job,” one researcher recalled316, “in those days was to keep Freireich from getting in trouble.”
Zubrod had his own schemes to keep leukemia research out of trouble. As new drugs, combinations, and trials proliferated, Zubrod worried that institutions would be caught at cross-purposes, squabbling over patients and protocols when they should really be battling cancer. Burchenal in New York, Farber in Boston, James Holland at Roswell Park, and the two Emils at the NCI were all chomping at the bit to launch clinical trials. And since ALL was a rare disease, every patient was a precious resource for a leukemia trial. To avert conflicts317, Zubrod proposed that a “consortium” of researchers be created to share patients, trials, data, and knowledge.
The proposal changed the field. “Zubrod’s cooperative group model galvanized cancer medicine,” Robert Mayer (who would later become the chair of one of these groups) recalls. “For the first time,318 an academic oncologist felt as if he had a community. The cancer doctor was not the outcast anymore, not the man who prescribed poisons from some underground chamber in the hospital.” The first group meeting, chaired by Farber, was a resounding success. The researchers agreed to proceed with a series of common trials, called protocols, as soon as possible.
Zubrod next set about organizing the process by which trials could be run. Cancer trials, he argued, had thus far been embarrassingly chaotic and disorganized. Oncologists needed to emulate the best trials in medicine. And to learn how to run objective, unbiased, state-of-the-art clinical trials, they would need to study the history of the development of antibiotics.
In the 1940s, as new antibiotics had begun to appear on the horizon, physicians had encountered an important quandary: how might one objectively test the efficacy of any novel drug? At the Medical Research Council in Britain, the question had taken on a particularly urgent and rancorous note. The discovery of streptomycin, a new antimicrobial drug in the early forties, had set off a flurry of optimism that tuberculosis could be cured. Streptomycin killed tuberculosis-causing mycobacteria in petri dishes, but its efficacy in humans was unknown. The drug was in critically short supply, with doctors parrying to use even a few milligrams of it to treat a variety of other infections. To ration streptomycin, an objective experiment to determine its efficacy in human tuberculosis was needed.
But what sort of experiment? An English statistician named Bradford Hill (a former victim of TB himself) proposed an extraordinary solution. Hill began by recognizing that doctors, of all people, could not be entrusted to perform such an experiment without inherent biases. Every biological experiment requires a “control” arm—untreated subjects against whom the efficacy of a treatment can be judged. But left to their own devices, doctors were inevitably likely (even if unconsciously so) to select certain types of patients upfront, then judge the effects of a drug on this highly skewed population using subjective criteria, piling bias on top of bias.
Hill’s319 proposed solution was to remove such biases by randomly assigning patients to treatment with streptomycin versus a placebo. By “randomizing” patients to each arm, any doctors’ biases in patient assignment would be dispelled. Neutrality would be enforced—and thus a hypothesis could be strictly tested.
Hill’s randomized trial was a success. The streptomycin arm of the trial clearly showed an improved response over the placebo arm, enshrining the antibiotic as a new anti-TB drug. But perhaps more important, it was Hill’s methodological invention that was permanently enshrined. For medical scientists, the randomized trial became the most stringent means to evaluate the efficacy of any intervention in the most unbiased СКАЧАТЬ