The Emperor of All Maladies

by Siddhartha Mukherjee

The poet Jason Shinder wrote, “Cancer949 is a tremendous opportunity to have your face pressed right up against the glass of your mortality.” But what patients see through the glass is not a world outside cancer, but a world taken over by it—cancer reflected endlessly around them like a hall of mirrors.

As a medical procedure, childbirth is least likely to involve infectious complications and is thus the safest neighbor to a chemotherapy ward, where any infection can turn into a lethal rampage. As in so much in medicine, the juxtaposition between the two wards is purely functional and yet just as purely profound.)

I would like to see myself at my wife’s side awaiting the miraculous moment of my daughter’s birth as most fathers do. But in truth I was gowned and gloved like a surgeon, with a blue, sterile sheet spread out in front of me, and a long syringe in my hands, poised to harvest the maroon gush of blood cells from the umbilical cord. When I cut that cord, part of me was the father, but the other part an oncologist. Umbilical blood contains one of the richest known sources of blood-forming stem cells—cells that can be stored away in cryobanks and used for a bone marrow transplant to treat leukemia in the future, an intensely precious resource often flushed down a sink in hospitals after childbirth.

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 novelist Thomas Wolfe, recalling a lifelong struggle with illness, wrote in his last letter, “I’ve made a long voyage950 and been to a strange country, and I’ve seen the dark man very close.” I had not made the journey myself, and I had only seen the darkness reflected in the eyes of others. But surely, it was the most sublime moment of my clinical life to have watched that voyage in reverse, to encounter men and women returning from the strange country—to see them so very close, clambering back.

But these two traditional Achilles’ heels of cancer—local growth and rapid cell division—can only be targeted to a point. Surgery and radiation are intrinsically localized strategies, and they fail when cancer cells have spread beyond the limits of what can be surgically removed or irradiated. More surgery thus does not lead to more cures, as the radical surgeons discovered to their despair in the 1950s.

To target cancer cells with novel therapies, scientists and physicians needed new vulnerabilities that were unique to cancer. The discoveries of cancer biology in the 1980s offered a vastly more nuanced view of these vulnerabilities. Three new principles emerged, representing three new Achilles’ heels of cancer. First, cancer cells are driven to grow because of the accumulation of mutations in their DNA. These mutations activate internal proto-oncogenes and inactivate tumor suppressor genes, thus unleashing the “accelerators” and “brakes” that operate during normal cell division. Targeting these hyperactive genes, while sparing their modulated normal precursors, might be a novel means to attack cancer cells more discriminately.

In 1986, the discovery of the first oncogene-targeted drug would thus instantly galvanize cancer medicine. Although found largely serendipitously, the mere existence of such a molecule would set the stage for the vast drug-hunting efforts of the next decade.

The Ruijin discovery was remarkable: trans-retinoic acid represented the long-sought fantasy of molecular oncology—an oncogene-targeted cancer drug. But the discovery was a fantasy lived backward. Wang and Degos had first stumbled on trans-retinoic acid through inspired guesswork—and only later discovered that the molecule could directly target an oncogene.

Weinberg had an oncogene and possibly an oncogene-blocking drug, but the twain had never met (in human cells or bodies). In the neuroblastoma cells dividing in his incubators, neu rampaged on monomaniacally, single-mindedly, seemingly invincible. Yet its molecular foot still waved just outside the surface of the plasma membrane, exposed and vulnerable, like Achilles’ famous heel.

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.

“Cancer at the fin de siècle,”1038 as the oncologist Harold Burstein described it, “resides at the interface between society and science.” It poses not one but two challenges. The first, the “biological challenge” of cancer, involves “harnessing the fantastic rise in scientific knowledge . . . to conquer this ancient and terrible illness.” But the second, the “social challenge,” is just as acute: it involves forcing ourselves to confront our customs, rituals, and behaviors. These, unfortunately, are not customs or behaviors that lie at the peripheries of our society or selves, but ones that lie at their definitional cores: what we eat and drink, what we produce and exude into our environments, when we choose to reproduce, and how we age.

In July 2009, exactly five years after I had looked down the microscope into Carla’s bone marrow and confirmed her first remission, I drove to her house in Ipswich, Massachusetts, with a bouquet of flowers. It was an overcast morning, excruciatingly muggy, with a dun-colored sky that threatened rain but would not deliver any. Just before I left the hospital, I glanced quickly at the first note that I had written on Carla’s admission to the hospital in 2004. As I had written that note, I recalled with embarrassment, I had guessed that Carla would not even survive the induction phase of chemotherapy.

Oncologists and their patients are bound, it seems, by an intense subatomic force. So, albeit in a much smaller sense, this was a victory for me as well.

Rather than understand cancer gene by gene, the Cancer Genome Atlas will chart the entire territory of cancer: by sequencing the entire genome of several tumor types, every single mutated gene will be identified. It will represent the beginnings of the comprehensive “map” so hauntingly presaged by Maggie Jencks in her last essay.

If one compares two breast cancer specimens, the set of mutated genes is far from identical. “In the end,” as Vogelstein put it1048, “cancer genome sequencing validates a hundred years of clinical observations. Every patient’s cancer is unique because every cancer genome is unique. Physiological heterogeneity is genetic heterogeneity.” Normal cells are identically normal; malignant cells become unhappily malignant in unique ways.

But important preventable carcinogens might escape detection by either strategy. Subtle risk factors for cancer require enormous population studies; the subtler the effect, the larger the population needed. Such vast, unwieldy, and methodologically challenging studies are difficult to fund and launch.

“Traditional epidemiology,” Hunter reasoned, “is concerned with correlating exposures with cancer outcomes, and everything between the cause (exposure) and the outcome (a cancer) is treated as a ‘black box.’ . . . In molecular epidemiology, the epidemiologist [will] open up the ‘black box’ by examining the events intermediate between exposure and disease occurrence or progression.”

The third, and arguably most complex, new direction for cancer medicine is to integrate our understanding of aberrant genes and pathways to explain the behavior of cancer as a whole, thereby renewing the cycle of knowledge, discovery, and therapeutic intervention.

The entirety of human blood, for instance, can arise from a single, highly potent blood-forming stem cell (called a hematopoietic stem cell), which typically lives buried inside the bone marrow. Under normal conditions, only a fraction of these blood-forming stem cells are active; the rest are deeply quiescent—asleep. But if blood is suddenly depleted, by injury or chemotherapy, say, then the stem cells awaken and begin to divide with awe-inspiring fecundity, generating cells that generate thousands upon thousands of blood cells. In weeks, a single hematopoietic stem cell can replenish the entire human organism with new blood—and then, through yet unknown mechanisms, lull itself back to sleep.

Indeed, cancer stem cells have acquired the behavior of normal stem cells by activating the same genes and pathways that make normal stem cells immortal—except, unlike normal stem cells, they cannot be lulled back into physiological sleep. Cancer, then, is quite literally trying to emulate a regenerating organ—or perhaps, more disturbingly, the regenerating organism. Its quest for immortality mirrors our own quest, a quest buried in our embryos and in the renewal of our organs. Someday, if a cancer succeeds, it will produce a far more perfect being than its host—imbued with both immortality and the drive to proliferate. One might argue that the leukemia cells growing in my laboratory derived from the woman who died three decades earlier have already achieved this form of “perfection.”

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 creeps1059 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.

Here now in his triumph where all things falter, Stretched out on the spoils that his own hand spread, As a god self-slain on his own strange altar, Death lies dead.

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.

Above the door to Richard Peto’s office in Oxford hangs one of Doll’s favorite aphorisms: “Death in old age is inevitable, but death before old age is not.”

Move Atossa into the future now. In 2050, Atossa will arrive at her breast oncologist’s clinic with a thumb-size flash drive containing the entire sequence of her cancer’s genome, identifying every mutation in every gene. The mutations will be organized into key pathways. An algorithm might identify the pathways that are contributing to the growth and survival of her cancer. Therapies will be targeted against these pathways to prevent a relapse of the tumor after surgery. She will begin with one combination of targeted drugs, expect to switch to a second cocktail when her cancer mutates, and switch again when the cancer mutates again. She will likely take some form of medicine, whether to prevent, cure, or palliate her illness, for the rest of her life.

As Doll suggests, and as Atossa epitomizes, we might as well focus on prolonging life rather than eliminating death. This War on Cancer may best be “won” by redefining victory.

In a limited sense, Klausner is right. When truly radical discoveries appear, their impact is often not incremental but cataclysmic and paradigm-shifting. Technology dissolves its own past. The speculator who bought stock options in an iron-lung company before the discovery of the polio vaccine, or the scientist who deemed bacterial pneumonias incurable just as penicillin was being discovered, were soon shown to be history’s fools.

History repeats, but science reverberates.

The Greeks used an evocative word to describe tumors, onkos, meaning “mass” or “burden.” The word was more prescient than they might have imagined. Cancer is indeed the load built into our genome, the leaden counterweight to our aspirations for immortality. But if one looks back even further behind the Greek to the ancestral Indo-European language, the etymology of the word onkos changes. Onkos arises from the ancient word nek. And nek, unlike the static onkos, is the active form of the word load. It means to carry, to move the burden from one place to the next, to bear something across a long distance and bring it to a new place. It is an image that captures not just the cancer cell’s capacity to travel—metastasis—but also Atossa’s journey, the long arc of scientific discovery—and embedded in that journey, the animus, so inextricably human, to outwit, to outlive and survive.

(“Cancer breaks some families and makes some,” Germaine said. “In my case, it did both.”)

Two characters stand at the epicenter of this story—both contemporaries, both idealists, both children of the boom in postwar science and technology in America, and both caught in the swirl of a hypnotic, obsessive quest to launch a national “War on Cancer.” The first is Sidney Farber, the father of modern chemotherapy, who accidentally discovers a powerful anti-cancer chemical in a vitamin analogue and begins to dream of a universal cure for cancer. The second is Mary Lasker, the Manhattan socialite of legendary social and political energy, who joins Farber in his decades-long journey. But Lasker and Farber only exemplify the grit, imagination, inventiveness, and optimism of generations of men and women who have waged a battle against cancer for four thousand years. In a sense, this is a military history—one in which the adversary is formless, timeless, and pervasive. Here, too, there are victories and losses, campaigns upon campaigns, heroes and hubris, survival and resilience—and inevitably, the wounded, the condemned, the forgotten, the dead. In the end, cancer truly emerges, as a nineteenth-century surgeon once wrote in a book’s frontispiece, as “the emperor of all maladies, the king of terrors.”

One acknowledgment, though, cannot be left to the end. This book is not just a journey into the past of cancer, but also a personal journey of my coming-of-age as an oncologist. That second journey would be impossible without patients, who, above and beyond all contributors, continued to teach and inspire me as I wrote. It is in their debt that I stand forever.