The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

Bannister’s mile remains a touchstone in the history of athletics not because Bannister set an unbreachable record—currently, the fastest mile is a good fifteen seconds under Bannister’s. For generations, four minutes was thought to represent an intrinsic physiological limit, as if muscles could inherently not be made to move any faster or lungs breathe any deeper. What Bannister proved was that such notions about intrinsic boundaries are mythical. What he broke permanently was not a limit, but the idea of limits. So it was with Gleevec. “It proves a principle. It justifies an approach,” Chabner continued. “It demonstrates that highly specific, non-toxic therapy is possible.” Gleevec opened a new door for cancer therapeutics. The rational synthesis of a molecule to kill cancer cells—a drug designed to specifically inactivate an oncogene—validated Ehrlich’s fantasy of “specific affinity.” Targeted molecular therapy for cancer was possible; one only needed to hunt for it by studying the deep biology of cancer cells.

When the epidemiologists juxtaposed smoking behavior onto this network and followed the pattern of smoking over decades, a notable phenomenon emerged: circles of relationships were found to be more powerful predictors of the dynamics of smoking than nearly any other factor. Entire networks stopped smoking concordantly, like whole circuits flickering off. A family that dined together was also a family that quit together. When highly connected “socializers” stopped smoking, the dense social circle circumscribed around them also slowly stopped as a group. As a result, smoking gradually became locked into the far peripheries of all networks, confined to the “loners” with few social contacts, puffing away quietly in the distant and isolated corners of the town.

The cell phone case is a sobering reminder of the methodological rigor needed to evaluate new carcinogens. It is easy to fan anxiety about cancer. Identifying a true preventable carcinogen, estimating the magnitude of risk at reasonable doses and at reasonable exposures, and reducing exposure through scientific and legislative intervention—keeping the legacy of Percivall Pott alive—is far more complex.

Until 2003, scientists knew that the principal distinction between the “normalcy” of a cell and the “abnormalcy” of a cancer cell lay in the accumulation of genetic mutations—ras, myc, Rb, neu, and so forth—that unleashed the hallmark behaviors of cancer cells. But this description of cancer was incomplete. It provoked an inevitable question: how many such mutations does a real cancer possess in total? Individual oncogenes and tumor suppressors had been isolated, but what was the comprehensive set of such mutated genes that exists in any true human cancer?

Every cancer cell possesses some set of driver and passenger mutations. In the breast cancer sample from the forty-three-year-old woman with 127 mutations, only about ten might directly be contributing to the actual growth and survival of her tumor, while the rest may have been acquired due to gene-copying errors in cancer cells. But while functionally different, these two forms of mutations cannot easily be distinguished. Scientists can identify some driver genes that directly goad cancer’s growth using the cancer genome. Since passenger mutations occur randomly, they are randomly spread throughout the genome. Driver mutations, on the other hand, strike key oncogenes and tumor suppressors, and only a limited number of such genes exist in the genome. These mutations—in genes such as ras, myc, and Rb—recur in sample upon sample. They stand out as tall mountains in Vogelstein’s map, while passenger mutations are typically represented by the valleys. But when a mutation occurs in a previously unknown gene, it is impossible to predict whether that mutation is consequential or inconsequential—driver or passenger, barnacle or engine.

The dysregulation of eleven to fifteen core pathways poses an enormous challenge for cancer therapeutics. Will oncologists need thirteen independent drugs to attack thirteen independent pathways to “normalize” a cancer cell? Given the slipperiness of cancer cells, when a cell becomes resistant to one combination of thirteen drugs, will we need an additional thirteen? The cancer optimist, however, argues that thirteen is a finite number. It is a relief: until Vogelstein identified these core pathways, the mutational complexity of cancers seemed nearly infinite.

Since the publication of Rachel Carson’s Silent Spring in 1962, environmental activists have stridently argued that the indiscriminate overuse of pesticides is partially responsible for the rising incidence of cancer in America. This theory has spawned intense controversy, activism, and public campaigns over the decades. But although the hypothesis is credible, large-scale human-cohort experiments directly implicating particular pesticides as carcinogens have emerged slowly, and animal studies have been inconclusive. DDT and aminotriazole have been shown to cause cancer in animals at high doses, but thousands of chemicals proposed as carcinogens remain untested. Again, an integrated approach is needed. The identification of key activated pathways in cancer cells might provide a more sensitive detection method to discover carcinogens in animal studies. A chemical may not cause overt cancer in animal studies, but may be shown to activate cancer-linked genes and pathways, thus shifting the burden of proof of its potential carcinogenicity. Similarly, we now know there is a link between nutrition and the risk of particular forms of cancer, but this field remains in its infancy. Low fiber, red meat rich diets increase the risks of colon cancer, and obesity is linked to breast cancer, but much more about these links remain unknown, especially in molecular terms.

One of the most provocative examples of a cancer cell’s behavior, inexplicable by the activation of any single gene or pathway, is its immortality. Rapid cellular proliferation, or the insensitivity to growth-arresting signals, or tumor angiogenesis, can all largely be explained by aberrantly activated and inactivated pathways such as ras, Rb, or myc in cancer cells. But scientists cannot explain how cancers continue to proliferate endlessly. Most normal cells, even rapidly growing normal cells, will proliferate over several generations and then exhaust their capacity to keep dividing. What allows a cancer cell to keep dividing endlessly without exhaustion or depletion generation upon generation?

Is the end of cancer conceivable in the future? Is it possible to eradicate this disease from our bodies and our societies forever? The answers to these questions are embedded in the biology of this incredible disease. Cancer, we have discovered, is stitched into our genome. Oncogenes arise from mutations in essential genes that regulate the growth of cells. Mutations accumulate in these genes when DNA is damaged by carcinogens, but also by seemingly random errors in copying genes when cells divide. The former might be preventable, but the latter is endogenous. Cancer is a flaw in our growth, but this flaw is deeply entrenched in ourselves. We can rid ourselves of cancer, then, only as much as we can rid ourselves of the processes in our physiology that depend on growth—aging, regeneration, healing, reproduction.

“Death in old age is inevitable, but death before old age is not.”