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“outlying” questions are the Mars problems of medicine: they point to systematic flaws in our understanding, and therefore to potentially new ways of organizing the cosmos.
    Every outlier represents an opportunity to refine our understanding of illness. In 2009, a young cancer scientist named David Solit in New York set off on a research project that, at firstglance, might seem like a young scientist’s folly. It is a long-established fact in the world of cancer pharmacology that nine out of ten drugs in clinical development are doomed to fail. In pharmaceutical lingo, this phenomenon is called the valley of death: a new drug moves smoothly along in its early phase of clinical development, seemingly achieving all its scientific milestones, yet it inevitably falters and dies during an actual clinical trial. In some cases, a trial has to be stopped because of unanticipated toxicities. In other cases, the medicine provokes no response, or the response is not durable. Occasionally, a trial shows a striking response, but it is unpredictable and fleetingly rare. Only 1 woman in a trial of 1,000 women might experience a near complete disappearance of all the metastatic lesions of breast cancer—while 999 women experience no response. One patient with widely spread melanoma might live for fifteen years, while the rest of the cohort has died by the seventh month of the trial.
    The trouble with such “exceptional responders,” as Solit called them, was that they had traditionally been ignored, brushed off as random variations, attributed to errors in diagnosis or ascribed, simply, to extraordinary good fortune. The catchphrase attached to these case histories carried the stamp of ultimate scientific damnation: single patient anecdotes (of all words, scientists find the word anecdote particularly poisonous since it refers to a subjective memory). Medical journals have long refused to publish these reports. At scientific conferences when such cases were described, researchers generally rolled their eyes and avoided the topic. When the trials ended, theseresponders were formally annotated as “outliers,” and the drug was quietly binned.
    But Solit wanted to understand these rare responses. These “exceptional responders,” he reasoned, might have some peculiar combination of factors—genes, behaviors, risk factors, environmental exposures—that had made them respond so briskly and durably. He decided to use the latest medical tools to understand their responses as deeply and comprehensively as possible. He had inverted a paradigm: rather than spending an enormous effort trying to figure out why a drug had commonly failed, as most of his colleagues might have, he would try to understand why it had occasionally succeeded. He would try to map the landscape of the valley of death—not by querying all those who had fallen into it, but by asking the one or two patients who had clambered out.
    In 2012, Solit’s team published the first analysis of one such trial. Forty-four patients with advanced bladder cancer had been treated with a new drug called everolimus. The results had been uniformly disappointing. Some tumors may have shrunk a little, but none of the patients had showed a striking response. Then, in mid-April 2010, there was patient 45—a seventy-three-year-old woman with tumors filling her entire abdomen and invading her kidneys and lymph nodes. She started the medicine that month. Within weeks, her tumors had begun to involute. The mass invading the kidney necrosed and disappeared. Fifteen months later, when her CAT scans were checked again, her doctors had to squint hard to see any visible signs of tumor in her abdomen.
    Solit focused on just that case. Reasoning that genes were likely involved, he pulled out patient 45’s tumor sample from the freezer and sequenced every gene to find the ones that were mutated (in most human cancers, between 10 to 150 genes can be