Siddhartha Mukherjee has a powerful new metaphor in Emperor of All Maladies.

Reading between the lines.
Nov. 8 2010 6:50 AM

Is Cancer Our Evil, Smarter Twin?

A new metaphor may tell us what we need to know about the disease.

The Emperor of All Maladies by Siddhartha Mukherjee.

The metaphors of cancer have always multiplied like, well, hyperactive cells. The disease has taken shape as, variously, a crab, a black bile, a "demonic pregnancy." As Susan Sontag pointed out in the 1970s, it often inspires language that is topographical and military: Cancer is an invading enemy or, worse, a "barbarian within." Malignant cells have morphed, too, into a "disorganized autonomous mob of maladjusted adolescents, raging against the society from which it sprang," as surgeon and writer Sherwin Nuland described them in the early 1990s.

Now cancer's malevolence has acquired new imagery, even closer to home: Metastasizing cells are "more perfect versions of ourselves." This provocative idea comes from oncologist Siddhartha Mukherjee, who notes that cancer perverts normal cellular pathways to "grow faster, adapt better." Mukherjee acknowledges Sontag's warning against freighting cancer with metaphor. "But this is not a metaphor," he writes in The Emperor of All Maladies, an ambitious scientific, political, and cultural history of the disease. "Down to their innate molecular core, cancer cells are hyperactive, survival-endowed, scrappy, fecund, inventive copies of ourselves."

This imagery reflects a contemporary, molecularly sophisticated view of cancer cells as savvy, prolific, and immortal. It provides a unified way of thinking about a disease that has come to seem less like one problem with one potential solution than it ever has before. In fact, this imagery carries a more dire implication: If the enemy is ourselves, only better, there may be no solution. As Mukherjee himself wonders, if cancer cells are more wily and adaptable than we are, is it possible finally to defeat them—and if so, by what strategies? Maybe we must ultimately accept cancer, to some degree, as the "inherent outer limit of our survival"—an inevitable offshoot of growth and aging that we might learn to hold at bay but can never truly eradicate.

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Mukherjee is judicious in his assessment of historical anti-cancer efforts. He describes the earliest known reference to cancer, on a papyrus written by the ancient Egyptian thinker Imhotep, who compared the feel of breast tumors to "the unripe hemat fruit, which is hard and cool to the touch." As for therapy, wrote Imhotep, "there is none." Fast forward to the 20th century, and scientists had defined a few of cancer's calling cards, including unfettered, pathological cell division.

But lacking a molecular framework, their tools remained blunt, their strategies heroic. Around the turn of the century, surgeon William Halsted pioneered radical forms of mastectomy, which sought to avoid any "mistaken kindness" by removing not only the breast, but also the underlying muscle and, at times, part of the rib cage or even the shoulder. (For a description of the price of such kindness, you can't get much more vivid than this doctor's account of a patient who'd undergone an extended radical mastectomy in the 1950s: "I could practically see her heart pumping. It was separated from the outside world only by a layer of skin.") But such aggression was a mismatch both for patients whose disease remained local (it was too much) as well as for those in whom it had already spread widely (it was too little), as Mukherjee argues. Chemotherapies, which proliferated in the postwar period, were just as brutal, deploying all manner of toxins, including one derived from mustard gas.

Cold War metaphors of subversion, combat, and collateral damage often lurked behind radical treatment strategies. Mukjerhee perhaps underestimates how early the images of cancer as enemy infiltration or internal subversion took hold in the post-World War II period. But he nicely traces the activism that spurred a national war on cancer and rightly points out Richard Nixon's obsession with this fight, which, ironically, seemed to him more winnable than Vietnam. By the 1970s, the search for cellular poisons was turning the National Cancer Institute into "a factory of toxins," as Mukherjee puts it. In the 1980s and into the 1990s, the escalation continued with megadose chemotherapy for breast cancer, which exacted terrible suffering and did not cause patients to live longer.

At the same time, an explosion of basic research began to shed new light on cancer's cellular workings. Scientists found a host of crucial genes, which, when mutated, derail normal cell division, acting as "stuck accelerators" or "broken brakes." They learned how tumors avoid cellular death signals and how they start to metastasize, exploiting methods used by immune cells to become mobile and travel toward an infection. They showed  how tumors establish their own blood supplies, taking advantage of processes used for healing wounds. They even discovered that some cancerous mutations "speed up the acquisition of other mutations," as Mukjerkee puts it, ruthlessly exploiting natural selection, as we as a species also have done, but instead creating a cycle of "perfect madness." It's the accumulation of such findings that leads Mukherjee to see cancer as a warped version of ourselves, "an enigmatic, if somewhat deranged, image in the mirror."

Writing about tuberculosis, Susan Sontag argued that when the root cause was understood and effective treatment established, the mythology of the disease dissipated. She suggested that scientists might also find a clear and singular cause of cancer. But the more research has progressed, the less likely that seems—and the more useful imagery has become for understanding. In 2007, Johns Hopkins researcher Bert Vogelstein created a topographical map of the most common mutations in different types of cancer. On a bright green plane, a long winding path represents the human genome. Sharp purple spires rise from genes that are mutated in samples of breast and colon cancer. The maps are used to find patterns in genes turned on and off by cancer—to get beyond the sense of malignant cells as "disorganized mob," as Nuland put it. This is the old topographical language of cancer, turned on its head.

New maps have also given rise to new treatments, which suggest a narrow targeting of patients and should recalibrate our expectations of more than slow declines in cancer mortality. Mukherjee tells the inspiring tale of Gleevec, a highly-specific, nontoxic drug for chronic myeloid leukemia. First came the discovery of a chromosomal abnormality that is particular to this disease and that makes cells hyperactive. Then came tests of designer molecules to quell that hyperactivity. But this approach was never a sure thing: Chronic myeloid leukemia represents a "genetic tornado," as Mukherjee writes. Conceptually, it was never clear whether targeting the original abnormality would make a difference in the face of subsequent mutations.

And all along, there was the question of cost. The drug company Novartis, which owned the compound, hesitated to spend the hundreds of millions of dollars for clinical trials of a drug that might benefit only thousands of patients a year. The academic researcher Brian Drucker, who turned the drug into a personal mission, imagined that as a last resort, "I would make it in my own basement." Novartis did come around, though, in 1998, giving Drucker just enough for a small trial. The results were dramatic: Blood counts normalized, often rapidly. If, as Mukherjee imagines, cancer is our craftier, more clever doppelganger, Gleevec represents an even craftier, more clever response. Indeed today, chronic myeloid leukemia has gone from a fatal disease to a largely manageable and chronic one.

Yet Mukherjee is no Pollyanna when it comes to targeted treatments. Cancer's genetic signatures differ from one kind of cancer to the next, and even from one patient to another. "'Every patient's cancer is unique because every cancer genome is unique,'" he writes, quoting Vogelstein the mapmaker. To make a dent in cancer mortality, even in a best-case scenario, researchers would need a large number of customized molecules and long, expensive clinical trials. Meanwhile, cancers keep mutating. Some patients with chronic myeloid leukemia, for instance, have now developed resistance to Gleevec, and need new, updated treatments. It could be that cancer, "the scrappy, fecund, invasive, adaptable twin to our scrappy, fecund, invasive, adaptable cells and genes, is impossible to disconnect from our bodies," Mukherjee writes grimly.

Mukherjee does not discuss a new therapy, called Provenge, which the FDA approved in April. But it too seems a harbinger of things to come. Provenge relies on a patient's own immune cells to fight cancer. These cells are removed from the body, primed and fortified in a laboratory dish, then infused back in. Provenge has shown some success against advanced prostate cancer. But it also costs about $93,000. Gleevec can cost $4,500 per month. Revlimid, another cutting-edge treatment for multiple myeloma, can cost $10,000 per month. It's hard to see how these prices might come down when the market consists of patients increasingly fragmented not only by type of cancer but even by types of mutation. The answer to how well we manage at outsmarting our awful twin surely depends on our scientific maps and metaphors, but it may well have as much, or more, to do with money.

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Amanda Schaffer is a science and medical columnist for Slate.

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