The Emperor of All Maladies

by Siddhartha Mukherjee

I had a novice’s hunger for history, but also a novice’s inability to envision it.

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. That this seemingly simple mechanism—cell growth without barriers—can lie at the heart of this grotesque and multifaceted illness is a testament to the unfathomable power of cell growth. Cell division allows us as organisms to grow, to adapt, to recover, to repair—to live. And distorted and unleashed, it allows cancer cells to grow, to flourish, to adapt, to recover, and to repair—to live at the cost of our living. Cancer cells grow faster, adapt better. They are more perfect versions of ourselves. The secret to battling cancer, then, is to find means to prevent these mutations from occurring in susceptible cells, or to find means to eliminate the mutated cells without compromising normal growth. The conciseness of that statement belies the enormity of the task. Malignant growth and normal growth are so genetically intertwined that unbraiding the two might be one of the most significant scientific challenges faced by our species.

And cancer is imprinted in our society: as we extend our life span as a species, we inevitably unleash malignant growth (mutations in cancer genes accumulate with aging; cancer is thus intrinsically related to age). If we seek immortality, then so, too, in a rather perverse sense, does the cancer cell.

malignant growth remains a mystery. (“The universe,” the twentieth-century biologist6 J. B. S. Haldane liked to say, “is not only queerer than we suppose, but queerer than we can suppose”—

(More than a century later, in the early 1980s, another change in name18—from gay related immune disease (GRID) to acquired immuno deficiency syndrome (AIDS)—would signal an epic shift in the understanding of that disease.

When the heart muscle is forced to push against a blocked aortic outlet, it often adapts by making every muscle cell bigger to generate more force, eventually resulting in a heart so overgrown that it may be unable to function normally—pathological hypertrophy.

Cancer was a disease of pathological hyperplasia in which cells acquired an autonomous will to divide.

This aberrant, uncontrolled cell division created masses of tissue (tumors) that invaded organs and destroyed normal tissues.

These tumors could also spread from one site to another, causing outcroppings of the disease—called metastases—in distant sites, such as the bones, the brain, or the lungs. Cancer came in diverse forms—breast, stomach, skin, and cervical cancer, leukemias and lymphom...

To understand cancer as a whole, he reasoned, you needed to start at the bottom of its complexity, in its basement. And despite its many idiosyncrasies, leukemia possessed a singularly attractive feature: it could be measured.

Science begins with counting. To understand a phenomenon, a scientist must first describe it; to describe it objectively, he must first measure it. If cancer medicine was to be transformed into a rigorous science, then cancer would need to be counted somehow—measured in some reliable, reproducible way.

Cancer had certainly been present and noticeable in nineteenth-century America, but it had largely lurked in the shadow of vastly more common illnesses. In 1899, when Roswell Park46, a well-known Buffalo surgeon, had argued that cancer would someday overtake smallpox, typhoid fever, and tuberculosis to become the leading cause of death in the nation, his remarks had been perceived as a rather “startling prophecy,”

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.

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.

Translated in 1930, the papyrus is now thought to contain the collected teachings of Imhotep, a great Egyptian physician who lived around 2625 BC.

Imhotep, among the few nonroyal Egyptians known to us from the Old Kingdom, was a Renaissance man at the center of a sweeping Egyptian renaissance.

With a few notable exceptions, in the vast stretch of medical history there is no book or god for cancer. There are several reasons behind this absence. Cancer is an age-related disease—sometimes exponentially so. The risk of breast cancer113, for instance, is about 1 in 400 for a thirty-year-old woman and increases to 1 in 9 for a seventy-year-old. In most ancient societies, people didn’t live long enough to get cancer.

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

Our capacity to detect cancer earlier and earlier, and to attribute deaths accurately to it, has also dramatically increased in the last century.

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.

For cancer, Galen reserved the most malevolent and disquieting of the four humors: black bile. (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.”

But for the bleedings to be successful, they had to be performed at specific sites in the body. If the patient was to be bled prophylactically (that is, to prevent disease), then the purging was to be performed far away from the possible disease site, so that the humors could be diverted from it. But if the patient was being bled therapeutically—to cure an established disease—then the bleeding had to be done from nearby vessels leading into the site.

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

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.

This pattern—heroic, Olympian exertion to the brink of physical impossibility, often followed by a near collapse—was to become a hallmark of Halsted’s approach to nearly every challenge.

but the spectrum of damaged tissues—skin, lips, blood, gums, and nails—already provided an important clue: radium was attacking DNA. DNA is an inert molecule, exquisitely resistant to most chemical reactions, for its job is to maintain the stability of genetic information. 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—especi...

Grubbe had stumbled on another important observation: X-rays could only be used to treat cancer locally, with little effect on tumors that had already metastasized.

Like surgery, radiation was remarkably effective at obliterating locally confined cancers.

Grubbe’s fingers had been amputated199 one by one to remove necrotic and gangrenous bones, and his face was cut up in repeated operations to remove radiation-induced tumors and premalignant warts. In 1960, at the age of eighty-five, he died in Chicago, with multiple forms of cancer that had spread throughout his body.

In 1856, William Perkin, an eighteen-year-old student at one of these institutes, stumbled on what would soon become a Holy Grail of this industry: an inexpensive chemical dye that could be made entirely from scratch.

Moreover, this new chemical did not bleach or bleed.

Initially, the German textile chemists lived entirely in the shadow of the dye industry. But emboldened by their successes, the chemists began to synthesize not just dyes and solvents, but an entire universe of new molecules: phenols, alcohols, bromides, alkaloids, alizarins, and amides, chemicals never encountered in nature.

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.

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. The Wöhler experiment—seemingly trivial—had enormous implications. Urea was a “natural” chemical, while its precursor was an inorganic salt. That a chemical produced by natural organisms could be derived so easily in a flask threatened to overturn the entire conception of living organisms: for centuries, the chemistry of living organisms was thought to be imbued with some mystical property, a vital essence that could not be duplicated in a laboratory—a theory called vitalism. Wöhler’s experiment demolished vitalism. 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.

make physical contact with living cells. In 1878, in Leipzig, a twenty-four-year-old212 medical student, Paul Ehrlich, hunting for a thesis project, proposed using cloth dyes—aniline and its colored derivatives—to stain animal tissues. At best, Ehrlich hoped that the dyes might stain the tissues to make microscopy easier. But to his astonishment, the dyes were far from indiscriminate darkening agents. Aniline derivatives stained only parts of the cell, silhouetting certain structures and leaving others untouched.

The dyes seemed able to discriminate among chemicals hidden inside cells—binding some and sparing others. 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). He purified a potent serum against diphtheria toxin from the blood of horses, then moved to the Institute for Sera Research and Serum Testing in St...

The biological universe was full of molecules picking out their partners like clever locks designed to fit a key: toxins clinging inseparably to antitoxins, dyes that highlighted only particular parts of cells, chemical stains that could nimbly pick out one class of germs from a mixture of microbes.

biology was an elaborate mix-and-match game of chemicals, Ehrlich reasoned, what if some chemical could discriminate bacterial cells from animal cells—and kill the former without touching the host?

He began with a hunt for antimicrobial chemicals, in part because he already knew that chemical dyes could specifically bind microbial cells. He infected mice and rabbits with Trypanosoma brucei, the parasite responsible for the dreaded sleeping sickness, then injected the animals with chemical derivatives to determine if any of them could halt the infection. After several hundred chemicals, Ehrlich and his collaborators had their first antibiotic hit: a brilliant ruby-colored dye derivative that Ehrlich called Trypan Red. It was a name—a disease juxtaposed with a dye color—that captured nearly a century of medical history.

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. In Ehrlich’s era, syphilis—the “secret malady”217 of eighteenth-century Europe—was a sensational illness, a tabloid pestilence. Ehrlich218 knew that an antisyphilitic drug would be an instant sensation and he was prepared.

Compound 606 had secretly been tested in patients in the hospital wards of St. Petersburg, then retested in patients with neurosyphilis at the Magdeburg Hospital—each time with remarkable success. A gigantic factory, funded by Hoechst Chemical Works, was already being built to manufacture it for commercial use.

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.

In 1908, soon after Ehrlich won the Nobel Prize for his discovery of the principle of specific affinity, Kaiser Wilhelm of Germany invited him to a private audience in his palace. The Kaiser was seeking counsel: a noted hypochondriac afflicted by various real and imagined ailments, he wanted to know whether Ehrlich had an anticancer drug within reach.

1919, a pair of American pathologists220, Edward and Helen Krumbhaar, analyzed the effects of the Ypres bombing on the few men who had survived it. They found that the survivors had an unusual condition of the bone marrow. The normal blood-forming cells had dried up; the bone marrow, in a bizarre mimicry of the scorched and blasted battlefield, was markedly depleted. The men were anemic and needed transfusions of blood, often up to once a month. They were prone to infections. Their white cell counts often hovered persistently below normal.

The contract for investigating nitrogen mustard was issued to two scientists, Louis Goodman and Alfred Gilman, at Yale University.

Gilman and Goodman began with animal studies. Injected intravenously into rabbits and mice, the mustards made the normal white cells of the blood and bone marrow almost disappear, without producing all the nasty vesicant actions, dissociating the two pharmacological effects. Encouraged, Gilman and Goodman moved on to human studies, focusing on lymphomas—cancers of the lymph glands. In 1942, they persuaded a thoracic surgeon, Gustaf Lindskog, to treat a forty-eight-year-old New York silversmith with lymphoma with ten continuous doses of intravenous mustard. It was a one-off experiment but it worked. In men, as in mice, the drug produced miraculous remissions. The swollen glands disappeared. Clinicians described the phenomenon as an eerie “softening” of the cancer, as if the hard carapace of cancer that Galen had so vividly described nearly two thousand years ago had melted away. But the responses were followed, inevitably, by relapses.

Just a few hundred miles south of Yale, at the Burroughs Wellcome laboratory in New York, the biochemist George Hitchings had also227 turned to Ehrlich’s method to find molecules with a specific ability to kill cancer cells. Inspired by Yella Subbarao’s anti-folates, Hitchings focused on synthesizing decoy molecules that when taken up by cells killed them. His first targets were precursors of DNA and RNA. Hitchings’s approach was broadly disdained by academic scientists as a “fishing expedition.”