The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

The virus, in effect, was no more than an accidental courier for a gene that had originated in a cancer cell—a parasite parasitized by cancer.

The theory made sense of Bruce Ames’s peculiar correlation between carcinogens and mutagens: chemicals that cause mutations in DNA produce cancers because they alter cellular proto-oncogenes.

Cancer was not disorganized chromosomal chaos. It was organized chromosomal chaos: specific and identical mutations existed in particular forms of cancer.

Chromosomal translocations can create new genes called chimeras by fusing two genes formerly located on two different chromosomes—the

For certain cancer-causing genes, two mutational “hits” were needed to provoke cell division and thus produce cancer.

“Two classes of genes are apparently critical in the origin of the cancers of children,” he wrote. “One class, that of oncogenes, acts by virtue of abnormal or elevated activity.… The other class, that of anti-oncogenes [or tumor suppressors], is recessive in oncogenesis; cancer results when both normal copies have been mutated or deleted.

Cancer genes, Knudson proposed, came in two flavors. “Positive” genes, such as src, are mutant activated versions of normal cellular genes. In normal cells, these genes accelerate cell division, but only when the cell receives an appropriate growth signal. In their mutant form, these genes are driven into perpetual hyperactivity, unleashing cell division beyond control. An activated proto-oncogene, to use Bishop’s analogy, is “a jammed accelerator” in a car. A cell with such a jammed accelerator careens down the path of cell division, unable to cease mitosis, dividing and dividing again relentlessly. “Negative” genes, such as Rb, suppress cell division. In normal cells, these anti-oncogenes, or tumor suppressor genes, provide the “brakes” to cellular proliferation, shutting down cell division when the cell receives appropriate signals. In cancer cells, these brakes have been inactivated by mutations. In cells with missing brakes, to use Bishop’s analogy again, the “stop” signals for mitosis can no longer be registered. Again, the cell divides and keeps dividing, defying all signals to stop.

The philosopher of science Karl Popper coined the term risky prediction to describe the process by which scientists verify untested theories. Good theories, Popper proposed, generate risky predictions. They presage an unanticipated fact or event that runs a real risk of not occurring or being proven incorrect. When this unanticipated fact proves true or the event does occur, the theory gains credibility and robustness. Newton’s understanding of gravitation was most spectacularly validated when it accurately presaged the return of Halley’s comet in 1758.

It was the simplest of strategies: to hunt the gene with absent function, Dryja would look for absence in structure.

Cancer cells did not activate or inactivate genes at random. Instead, the shift from a premalignant state to an invasive cancer could precisely be correlated with the activation and inactivation of genes in a strict and stereotypical sequence.

First, proto-oncogenes need to be activated through mutations, and mutations are rare events. Second, tumor suppressor genes need to be inactivated, but typically two copies exist of each tumor suppressor gene, and thus two independent mutations are needed to inactivate a tumor suppressor, an even rarer event. Vogelstein provided the third answer. Activating or inactivating any single gene, he postulated, produced only the first steps toward carcinogenesis. Cancer’s march was long and slow and proceeded though many mutations in many genes over many iterations. In genetic terms, our cells were not sitting on the edge of the abyss of cancer. They were dragged toward that abyss in graded, discrete steps.

Cancer, in short, was not merely genetic in its origin; it was genetic in its entirety. Abnormal genes governed all aspects of cancer’s behavior. Cascades of aberrant signals, originating in mutant genes, fanned out within the cancer cell, promoting survival, accelerating growth, enabling mobility, recruiting blood vessels, enhancing nourishment, drawing oxygen—sustaining cancer’s life.

Cancer’s life is a recapitulation of the body’s life, its existence a pathological mirror of our own.

“We suggest that the vast catalog of cancer cell genotypes is a manifestation of six essential alterations in cell physiology that collectively dictate malignant growth.”

Self-sufficiency in growth signals: cancer cells acquire an autonomous drive to proliferate—pathological mitosis—by virtue of the activation of oncogenes such as ras or myc. 2. Insensitivity to growth-inhibitory (antigrowth) signals: cancer cells inactivate tumor suppressor genes, such as retinoblastoma (Rb), that normally inhibit growth 3. Evasion of programmed cell death (apoptosis): cancer cells suppress and inactivate genes and pathways that normally enable cells to die. 4. Limitless replicative potential: cancer cells activate specific gene pathways that render them immortal even after generations of growth. 5. Sustained angiogenesis: cancer cells acquire the capacity to draw out their own supply of blood and blood vessels—tumor angiogenesis. 6. Tissue invasion and metastasis: cancer cells acquire the capacity to migrate to other organs, invade other tissues, and colonize these organs, resulting in their spread throughout the body.

The Italian memoirist Primo Levi, who survived a concentration camp and then navigated his way through a blasted Germany to his native Turin, often remarked that among the most fatal qualities of the camp was its ability to erase the idea of a life outside and beyond itself. A person’s past and his present were annihilated as a matter of course—to be in the camps was to abnegate history, identity, and personality—but it was the erasure of the future that was the most chilling. With that annihilation, Levi wrote, came a moral and spiritual death that perpetuated the status quo of imprisonment. If no life existed beyond the camp, then the distorted logic by which the camp operated became life as usual.

Cancer is not a concentration camp, but it shares the quality of annihilation: it negates the possibility of life outside and beyond itself; it subsumes all living. The daily life of a patient becomes so intensely preoccupied with his or her illness that the world fades away. Every last morsel of energy is spent tending the disease.

It is an old complaint about the practice of medicine that it inures you to the idea of death. But when medicine inures you to the idea of life, to survival, then it has failed utterly.

The central therapeutic challenge of the newest cancer medicine, then, was to find, among the vast numbers of similarities in normal cells and cancer cells, subtle differences in genes, pathways, and acquired capabilities—and to drive a poisoned stake into that new heel.

In the mid-1970s, two immunologists at Cambridge University, Cesar Milstein and George Kohler, had devised a method to produce vast quantities of a single antibody using a hybrid immune cell that had been physically fused to a cancer cell. (The immune cell secreted the antibody while the cancer cell, a specialist in uncontrolled growth, turned it into a factory.)

Slamon and Ullrich now had all three essential ingredients for a targeted therapy for cancer: an oncogene, a form of cancer that specifically activated that oncogene, and a drug that specifically targeted it.

where he could work on cancer genetics without the fickle pressures of a pharmaceutical company constraining his science.