The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

Illness is the night-side of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the kingdom of the well and in the kingdom of the sick. Although we all prefer to use only the good passport, sooner or later each of us is obliged, at least for a spell, to identify ourselves as citizens of that other place. —Susan Sontag

Cancer, we now know, is a disease caused by the uncontrolled growth of a single cell. This growth is unleashed by mutations—changes in DNA that specifically affect genes that incite unlimited cell growth. In a normal cell, powerful genetic circuits regulate cell division and cell death. In a cancer cell, these circuits have been broken, unleashing a cell that cannot stop growing.

The cancer cell is a desperate individualist, “in every possible sense, a nonconformist,” as the surgeon-writer Sherwin Nuland wrote. The word metastasis, used to describe the migration of cancer from one site to another, is a curious mix of meta and stasis—“beyond stillness” in Latin—an unmoored, partially unstable state that captures the peculiar instability of modernity. If consumption once killed its victims by pathological evisceration (the tuberculosis bacillus gradually hollows out the lung), then cancer asphyxiates us by filling bodies with too many cells; it is consumption in its alternate meaning—the pathology of excess. Cancer is an expansionist disease; it invades through tissues, sets up colonies in hostile landscapes, seeking “sanctuary” in one organ and then immigrating to another. It lives desperately, inventively, fiercely, territorially, cannily, and defensively—at times, as if teaching us how to survive. To confront cancer is to encounter a parallel species, one perhaps more adapted to survival than even we are.

Every generation of cancer cells creates a small number of cells that is genetically different from its parents. When a chemotherapeutic drug or the immune system attacks cancer, mutant clones that can resist the attack grow out. The fittest cancer cell survives. This mirthless, relentless cycle of mutation, selection, and overgrowth generates cells that are more and more adapted to survival and growth. In some cases, the mutations speed up the acquisition of other mutations. The genetic instability, like a perfect madness, only provides more impetus to generate mutant clones. Cancer thus exploits the fundamental logic of evolution unlike any other illness. If we, as a species, are the ultimate product of Darwinian selection, then so, too, is this incredible disease that lurks inside us.

Nineteenth-century doctors often linked cancer to civilization: cancer, they imagined, was caused by the rush and whirl of modern life, which somehow incited pathological growth in the body. The link was correct, but the causality was not: civilization did not cause cancer, but by extending human life spans—civilization unveiled it.

Etymologically, patient means sufferer. It is not suffering as such that is most deeply feared but suffering that degrades. —Susan Sontag, Illness as Metaphor

Li had stumbled on a deep and fundamental principle of oncology: cancer needed to be systemically treated long after every visible sign of it had vanished. The hcg level—the hormone secreted by choriocarcinoma—had turned out to be its real fingerprint, its marker.

In the folklore of science, there is the often-told story of the moment of discovery: the quickening of the pulse, the spectral luminosity of ordinary facts, the overheated, standstill second when observations crystallize and fall together into patterns, like pieces of a kaleidoscope. The apple drops from the tree. The man jumps up from a bathtub; the slippery equation balances itself.

But there is another moment of discovery—its antithesis—that is rarely recorded: the discovery of failure. It is a moment that a scientist often encounters alone. A patient’s CT scan shows a relapsed lymphoma. A cell once killed by a drug begins to grow back. A child returns to the NCI with a headache.

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.

These gene cascades, notably, were perversions of signaling pathways used by the body under normal circumstances. The “motility genes” activated by cancer cells, for instance, are the very genes that normal cells use when they require movement through the body, such as when immuno-logical cells need to move toward sites of infection. Tumor angiogenesis exploits the same pathways that are used when blood vessels are created to heal wounds. Nothing is invented; nothing is extraneous. Cancer’s life is a recapitulation of the body’s life, its existence a pathological mirror of our own. Susan Sontag warned against overburdening an illness with metaphors. But this is not a metaphor. Down to their innate molecular core, cancer cells are hyperactive, survival-endowed, scrappy, fecund, inventive copies of ourselves.

“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.” 1. 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.

Taken to its logical extreme, the cancer cell’s capacity to consistently imitate, corrupt, and pervert normal physiology thus raises the ominous question of what “normalcy” is. “Cancer,” Carla said, “is my new normal,” and quite possibly cancer is our normalcy as well, that we are inherently destined to slouch towards a malignant end. Indeed, as the fraction of those affected by cancer creeps inexorably in some nations from one in four to one in three to one in two, cancer will, indeed, be the new normal—an inevitability. The question then will not be if we will encounter this immortal illness in our lives, but when.