The Emperor of All Maladies

by Siddhartha Mukherjee

But with case forty-five, Imhotep fell atypically silent. Under the section titled “Therapy,” he offered only a single sentence: “There is none.”

More than two millennia pass after Imhotep’s description until we once more hear of cancer. And again, it is an illness cloaked in silence, a private shame.

Goaded by Democedes, who wanted to return to his native Greece, Atossa pleaded with her husband to turn his campaign westward—to invade Greece. That turn of the Persian empire from east to west, and the series of Greco-Persian wars that followed, would mark one of the definitive moments in the early history of the West. It was Atossa’s tumor, then, that quietly launched a thousand ships. Cancer, even as a clandestine illness, left its fingerprints on the ancient world.

In 1990, one such large desiccated gravesite containing about 140 bodies caught the attention of Arthur Aufderheide, a professor at the University of Minnesota in Duluth. Aufderheide is a pathologist by training but his specialty is paleopathology, a study of ancient specimens. His autopsies, unlike Farber’s, are not performed on recently living patients, but on the mummified remains found on archaeological sites. He stores these human specimens in small, sterile milk containers in a vaultlike chamber in Minnesota. There are nearly five thousand pieces of tissue, scores of biopsies, and hundreds of broken skeletons in his closet.

At the Chiribaya site108, Aufderheide rigged up a makeshift dissecting table and performed 140 autopsies over several weeks. One body revealed an extraordinary finding. The mummy was of a young woman in her midthirties, found sitting, with her feet curled up, in a shallow clay grave. When Aufderheide examined her, his fingers found a hard “bulbous mass” in her left upper arm. The papery folds of skin, remarkably preserved, gave way to that mass, which was intact and studded with spicules of bone. This, without question, was a malignant bone tumor, an osteosarcoma, a thousand-year-old cancer preserved inside of a mummy. Aufderheide suspects that the tumor had broken through the skin while she was still alive. Even small osteosarcomas can be unimaginably painful. The woman’s pain, he suggests, must have been blindingly intense.

Louis Leakey,110 the anthropologist who dug up some of the earliest known human skeletons, also discovered a jawbone dating from two million years ago from a nearby site that carried the signs of a peculiar form of lymphoma found endemically in southeastern Africa (although the origin of that tumor was never confirmed pathologically). If that finding does represent an ancient mark of malignancy, then cancer, far from being a “modern” disease, is one of the oldest diseases ever seen in a human specimen—quite possibly the oldest.

The link was correct, but the causality was not: civilization did not cause cancer, but by extending human life spans—civilization unveiled it.

The introduction of mammography to detect breast cancer early in its course sharply increased its incidence—a seemingly paradoxical result that makes perfect sense when we realize that the X-rays allow earlier tumors to be diagnosed.

But the rarity of ancient cancers notwithstanding, it is impossible to forget the tumor growing in the bone of Aufderheide’s mummy of a thirty-five-year-old. The woman must have wondered about the insolent gnaw of pain in her bone, and the bulge slowly emerging from her arm. It is hard to look at the tumor and not come away with the feeling that one has encountered a powerful monster in its infancy.

A patient, long before he becomes the subject of medical scrutiny, is, at first, simply a storyteller, a narrator of suffering—a traveler who has visited the kingdom of the ill. To relieve an illness, one must begin, then, by unburdening its story.

It was in the time of Hippocrates, around 400 BC, that a word for cancer first appeared in the medical literature: karkinos, from the Greek word for “crab.” The tumor, with its clutch of swollen blood vessels around it, reminded Hippocrates of a crab dug in the sand with its legs spread in a circle.

For some, the hardened, matted surface of the tumor was reminiscent of the tough carapace of a crab’s body.

Others felt a crab moving under the flesh as the disease spread stealthily throughout the body. For yet others, the sudden stab of pain produced by the disease was like being caught in the grip of a crab’s pincers.

Another Greek word would intersect with the history of cancer—onkos, a word used occasionally to describe tumors, from which the discipline ...

Onkos was the Greek term for a mass or a load, or more commonly a burden; cancer was imagined as a burden carried by the body. In Greek theater, the same word, onkos, would be used to denote a tragic mask that was often “burdened” with an unwieldy conical ...

The human body, Hippocrates proposed, was composed of four cardinal fluids called humors: blood, black bile, yellow bile, and phlegm. Each of these fluids had a unique color (red, black, yellow, and white), viscosity, and essential character. In the normal body, these four fluids were held in perfect, if somewhat precarious, balance. In illness, this balance was upset by the excess of one fluid.

(Only one other disease, replete with metaphors, would be attributed to an excess of this oily, viscous humor: depression. Indeed, melancholia, the medieval name for “depression,” would draw its name from the Greek melas, “black,” and khole, “bile.” Depression and cancer, the psychic and physical diseases of black bile, were thus intrinsically intertwined.)

Hunter had begun to classify tumors into “stages.” Movable tumors were typically early-stage, local cancers. Immovable tumors were advanced, invasive, and even metastatic. Hunter concluded that only movable cancers were worth removing surgically. For more advanced forms of cancer, he advised an honest, if chilling, remedy reminiscent of Imhotep’s: “remote sympathy.”*

Antisepsis and anesthesia were twin technological breakthroughs that released surgery from its constraining medieval chrysalis.

At the Allgemeines Krankenhaus, the teaching hospital in Vienna where he was appointed a professor, Billroth and his students now began to master and use a variety of techniques to remove tumors from the stomach, colon, ovaries, and esophagus, hoping to cure the body of cancer. The switch from exploration to cure produced an unanticipated challenge. A cancer surgeon’s task was to remove malignant tissue while leaving normal tissues and organs intact. But this task, Billroth soon discovered, demanded a nearly godlike creative spirit.

But what if the whole of cancer could be uprooted at its earliest stage using the most definitive surgery conceivable? What if cancer, incurable by means of conventional local surgery, could be cured by a radical, aggressive operation that would dig out its roots so completely, so exhaustively, that no possible trace was left behind? In an era captivated by the potency and creativity of surgeons, the idea of a surgeon’s knife extracting cancer by its roots was imbued with promise and wonder. It would land on the already brittle and combustible world of oncology like a firecracker thrown into gunpowder.

Halsted welcomed the technical challenges of his operation, often conflating the most difficult cases with the most curable: “I find myself inclined167 to welcome largeness [of a tumor],” he wrote—challenging cancer to duel with his knife.

The ultimate survival from breast cancer, in short, had little to do with how extensively a surgeon operated on the breast; it depended on how extensively the cancer had spread before surgery. As George Crile, one of the most fervent critics of radical surgery, later put it, “If the disease was so advanced172 that one had to get rid of the muscles in order to get rid of the tumor, then it had already spread through the system”—making the whole operation moot.

Surgeons often counted themselves lucky if their patients merely survived these operations. “There is an old Arabian proverb,”181 a group of surgeons wrote at the end of a particularly chilling discussion of stomach cancer in 1933, “that he is no physician who has not slain many patients, and the surgeon who operates for carcinoma of the stomach must remember that often.”

Halsted, Brunschwig, and Pack persisted with their mammoth operations because they genuinely believed that they could relieve the dreaded symptoms of cancer. But they lacked formal proof, and as they went further up the isolated promontories of their own beliefs, proof became irrelevant and trials impossible to run. The more fervently surgeons believed in the inherent good of their operations, the more untenable it became to put these to a formal scientific trial. Radical surgery thus drew the blinds of circular logic around itself for nearly a century.

Even so, obsessed with Halstedian theory and unable to see beyond its realm, surgeons sharply berated such attempts at nonradical surgery. A surgical procedure186 that did not attempt to obliterate cancer from the body was pooh-poohed as a “makeshift operation.” To indulge in such makeshift operations was to succumb to the old flaw of “mistaken kindness” that a generation of surgeons had tried so diligently to banish.

In late October 1895, a few months after Halsted had unveiled the radical mastectomy in Baltimore, Wilhelm Röntgen, a lecturer at the Würzburg Institute in Germany, was working with an electron tube—a vacuum tube that shot electrons from one electrode to another—when he noticed a strange leakage. The radiant energy was powerful and invisible, capable of penetrating layers of blackened cardboard and producing a white phosphorescent glow on a barium screen accidentally left on a bench in the room.

Radium, by virtue of its potency, revealed a new and unexpected property of X-rays: they could not only carry radiant energy through human tissues, but also deposit energy deep inside tissues.

Radiation would eventually burn into Marie Curie’s bone marrow, leaving her permanently anemic.

But X-rays can shatter strands of DNA or generate toxic chemicals that corrode DNA. Cells respond to this damage by dying or, more often, by ceasing to divide. X-rays thus preferentially kill the most rapidly proliferating cells in the body, cells in the skin, nails, gums, and blood.

This ability of X-rays to selectively kill rapidly dividing cells did not go unnoticed—especially by cancer researchers.

By the early 1900s, less than a decade after Röntgen’s discovery, doctors waxed ecstatic about the possibility of curing cancer with radiation. “I believe this treatment is an absolute cure192 for all forms of cancer,” a Chicago physician noted in 1901. “I do not know what its limitations are.”

Radiation therapy catapulted cancer medicine into its atomic age—an age replete with both promise and peril.

But like surgery, radiation medicine also struggled against its inherent limits. Emil Grubbe had already encountered the first of these limits with his earliest experimental treatments: since X-rays could only be directed locally, radiation was of limited use for cancers that had metastasized.

The second limit was far more insidious: radiation produced cancers. The very effect of X-rays killing rapidly dividing cells—DNA damage—also created cancer-causing mutations in genes. In the 1910s, soon after the Curies had discovered radium, a New Jersey corporation called U.S. Radium began to mix radium with paint to create a product called Undark—radium-infused paint that emitted a greenish white light at night. Although aware of the many injurious effects of radium, U.S. Radium promoted Undark for clock dials, boasting of glow-in-the-dark watches. Watch painting was a precise and artisanal craft, and young women with nimble, steady hands were commonly employed. These women were encouraged to use the paint without precautions, and to frequently lick the brushes with their tongues to produce sharp lettering on watches.

The Radium Girls

The complex intersection of radiation with cancer—cancer-curing at times, cancer-causing at others—dampened the initial enthusiasm of cancer scientists. Radiation was a powerful invisible knife—but still a knife. And a knife, no matter how deft or penetrating, could only reach so far in the battle against cancer. A more discriminating therapy was needed, especially for cancers that were nonlocalized.

Meyer had grasped a deep principle about cancer. Cancer, even when it begins locally, is inevitably waiting to explode out of its confinement. By the time many patients come to their doctor, the illness has often spread beyond surgical control and spilled into the body exactly like the black bile that Galen had envisioned so vividly nearly two thousand years ago.

Those who have not been trained in chemistry201 or medicine may not realize how difficult the problem of cancer treatment really is. It is almost—not quite, but almost—as hard as finding some agent that will dissolve away the left ear, say, and leave the right ear unharmed. So slight is the difference between the cancer cell and its normal ancestor.

Specificity refers to the ability of any medicine to discriminate between its intended target and its host. Killing a cancer cell in a test tube is not a particularly difficult task: the chemical world is packed with malevolent poisons that, even in infinitesimal quantities, can dispatch a cancer cell within minutes. The trouble lies in finding a selective poison—a drug that will kill cancer without annihilating the patient. Systemic therapy without specificity is an indiscriminate bomb. For an anticancer poison to become a useful drug, Meyer knew, it needed to be a fantastically nimble knife: sharp enough to kill cancer yet selective enough to spare the patient.

By the late 1870s, synthetic chemists in Germany had created more molecules than they knew what to do with. “Practical chemistry” had become almost a caricature of itself: an industry seeking a practical purpose for the products that it had so frantically raced to invent.

In 1828, a Berlin scientist named Friedrich Wöhler211 had sparked a metaphysical storm in science by boiling ammonium cyanate, a plain, inorganic salt, and creating urea, a chemical typically produced by the kidneys.

Organic and inorganic chemicals, he proved, were interchangeable. Biology was chemistry: perhaps even a human body was no different from a bag of busily reacting chemicals—a beaker with arms, legs, eyes, brain, and soul.

But such multifaceted chemicals already existed: the laboratories of the dye factories of Frankfurt were full of them. To build his interdisciplinary bridge between biology and chemistry, Wöhler only needed to take a short day-trip from his laboratory in Göttingen to the labs of Frankfurt. But neither Wöhler nor his students could make that last connection. The vast panel of molecules sitting idly on the shelves of the German textile chemists, the precursors of a revolution in medicine, may as well have been a continent away.

This molecular specificity, encapsulated so vividly in that reaction between a dye and a cell, began to haunt Ehrlich. In 1882, working with Robert Koch213, he discovered yet another novel chemical stain, this time for mycobacteria, the organisms that Koch had discovered as the cause of tuberculosis. A few years later, Ehrlich found that certain toxins, injected into animals, could generate “antitoxins,” which bound and inactivated poisons with extraordinary specificity (these antitoxins would later be identified as antibodies).

Returning from a conference late one evening, in the cramped compartment of a night train from Berlin to Frankfurt, Ehrlich animatedly described his idea to two fellow scientists, “It has occurred to me214 that . . . it should be possible to find artificial substances which are really and specifically curative for certain diseases, not merely palliatives acting favorably on one or another symptom. . . . Such curative substances—a priori—must directly destroy the microbes responsible for the disease; not by ‘action from a distance,’ but only when the chemical compound is fixed by the parasites. The parasites can only be killed if the chemical compound has a particular relation, a specific affinity for them.”

“Chemotherapy,” the use of specific chemicals to heal the diseased body, was conceptually born in the middle of the night.

One molecule might survive for days in an animal, but its chemical cousin—a variant by just a few critical atoms—might vanish from the body in minutes.

On April 19, 1910, at the densely packed216 Congress for Internal Medicine in Wiesbaden, Ehrlich announced that he had discovered yet another molecule with “specific affinity”—this one a blockbuster. The new drug, cryptically called compound 606, was active against a notorious microbe, Treponema pallidum, which caused syphilis.

Ehrlich’s successes with Trypan Red and compound 606 (which he named Salvarsan, from the word salvation) proved that diseases were just pathological locks waiting to be picked by the right molecules. The line of potentially curable illnesses now stretched endlessly before him. Ehrlich called his drugs “magic bullets”—bullets for their capacity to kill and magic for their specificity. It was a phrase with an ancient, alchemic ring that would sound insistently through the future of oncology.

Ehrlich went on in this vein, almost musing to himself. He was circling around something profound, an idea in its infancy: to target the abnormal cell, one would need to decipher the biology of the normal cell. He had returned, decades after his first encounter with aniline, to specificity again, to the bar codes of biology hidden inside every living cell.