The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

As one nurse on the wards often liked to remind her patients, with this disease “even a paper cut is an emergency.”

The isolation and rage of a thirty-six-year-old woman with stage III breast cancer had ancient echoes in Atossa, the Persian queen who swaddled her diseased breast in cloth to hide it and then, in a fit of nihilistic and prescient fury, possibly had a slave cut it off with a knife.

A patient’s desire to amputate her stomach, ridden with cancer—“sparing nothing,” as she put it to me—carried the memory of the perfection-obsessed nineteenth-century surgeon William Halsted, who had chiseled away at cancer with larger and more disfiguring surgeries, all in the hopes that cutting more would mean curing more.

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.

Cancer cells can 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.

That isn't true. They aren't more perfect versions because they kill the host and themselves. *That is not more perfect.*

If we seek immortality, then so, too, in a rather perverse sense, does the cancer cell.

Seek, perhaps. Succeed, no. Killing the host kills the cancer. They have no way to spread to a new host.

But the preliminary tests suggested that Carla had acute lymphoblastic leukemia. It is one of the most common forms of cancer in children, but rare in adults. And it is—I paused here for emphasis, lifting my eyes up—often curable.

In solving a problem of this sort, the grand thing is to be able to reason backwards. That is a very useful accomplishment, and a very easy one, but people do not practice it much. —Sherlock Holmes, in Sir Arthur Conan Doyle’s A Study in Scarlet

By the time Virchow died in 1902, a new theory of cancer had slowly coalesced out of all these observations. 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.

Leukemia was a malignant proliferation of white cells in the blood. It was cancer in a molten, liquid form.

But unlike Minot’s anemia, she found that the anemia in Bombay couldn’t be reversed by Minot’s concoctions or by vitamin B12. Astonishingly, she found she could cure it with Marmite, the dark, yeasty spread then popular among health fanatics in England and Australia. Wills could not determine the key chemical nutrient of Marmite. She called it the Wills factor. Wills factor turned out to be folic acid, or folate, a vitamin-like substance found in fruits and vegetables (and amply in Marmite). When

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.

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.

Indeed, cancer’s emergence in the world is the product of a double negative: it becomes common only when all other killers themselves have been killed. 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.

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

1884, at the prime of his career in New York, Halsted read a paper describing the use of a new surgical anesthetic called cocaine. At Halle, in Volkmann’s clinic, he had watched German surgeons perform operations using this drug; it was cheap, accessible, foolproof, and easy to dose—the fast food of surgical anesthesia. His experimental curiosity aroused, Halsted began to inject himself with the drug, testing it before using it to numb patients for his ambitious surgeries. He found that it produced much more than a transitory numbness: it amplified his instinct for tirelessness; it synergized with his already manic energy.

Halsted called this procedure the “radical mastectomy,” using the word radical in the original Latin sense to mean “root”; he was uprooting cancer from its very source.

As George Crile, one of the most fervent critics of radical surgery, later put it, “If the disease was so advanced 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.

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.

Röntgen whisked his wife, Anna, into the lab and placed her hand between the source of his rays and a photographic plate. The rays penetrated through her hand and left a silhouette of her finger bones and her metallic wedding ring on the photographic plate—the inner anatomy of a hand seen as if through a magical lens. “I have seen my death,” Anna said—but her husband saw something else: a form of energy so powerful that it could pass through most living tissues. Röntgen called his form of light X-rays.

At first, X-rays were thought to be an artificial quirk of energy produced by electron tubes. But in 1896, just a few months after Röntgen’s discovery, Henri Becquerel, the French chemist, who knew of Röntgen’s work, discovered that certain natural materials—uranium among them—autonomously...

In the mid-1880s, Pierre Curie had used minuscule quartz crystals to craft an instrument called an electrometer, capable of measuring exquisitely small doses of energy. Using this device, Marie had shown that even tiny amounts of radiation emitted by uranium ores could be quantified.

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

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.

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.

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. Radium workers soon began to complain of jaw pain, fatigue, and skin and tooth problems. In the late 1920s, medical investigations revealed that the bones in their jaws had necrosed, their tongues had been scarred by irradiation, and many had become chronically anemic (a sign of severe bone marrow damage).

In 1927, a group of five severely afflicted women in New Jersey—collectively termed “Radium girls” by the media—sued U.S. Radium.

The trouble lies in finding a selective poison—a drug that will kill cancer without annihilating the patient.

Scientists often study the past as obsessively as historians because few other professions depend so acutely on it. Every experiment is a conversation with a prior experiment, every new theory a refutation of the old.

(A paralyzed president trying to march a nation out of a depression was considered a disastrous image; Roosevelt’s public appearances were thus elaborately orchestrated to show him only from the waist up.)

Founded in 1927 in Philadelphia by a group of men in show business—producers, directors, actors, entertainers, and film-theater owners—the Variety Club had initially been modeled after the dining clubs of New York and London. But in 1928, just a year after its inception, the club had unwittingly acquired a more active social agenda. In the winter of 1928, with the city teetering on the abyss of the Depression, a woman had abandoned her child at the doorstep of the Sheridan Square Film Theater. A note pinned on the child read: Please take care of my baby. Her name is Catherine. I can no longer take care of her. I have eight others. My husband is out of work. She was born on Thanksgiving Day. I have always heard of the goodness of show business and I pray to God that you will look out for her. The cinematic melodrama of the episode, and the heartfelt appeal to the “goodness of show business,” made a deep impression on the members of the fledgling club. Adopting the orphan girl, the club paid for her upbringing and education. She was given the name Catherine Variety Sheridan—her middle name for the club and her last name for the theater outside which she had been found.

“Basic research leads to new knowledge. It provides scientific capital. It creates the fund from which the practical applications of knowledge must be drawn.… Basic research is the pacemaker of technological progress.

Hill’s randomized trial was a success. The streptomycin arm of the trial clearly showed an improved response over the placebo arm, enshrining the antibiotic as a new anti-TB drug. But perhaps more important, it was Hill’s methodological invention that was permanently enshrined. For medical scientists, the randomized trial became the most stringent means to evaluate the efficacy of any intervention in the most unbiased manner.

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.

I am not opposed to optimism, but I am fearful of the kind that comes from self-delusion. —Marvin Davis, in the New England Journal of Medicine, talking about the “cure” for cancer

Oft expectation fails, and most oft there Where most it promises; and oft it hits Where hope is coldest, and despair most sits —William Shakespeare, All’s Well That Ends Well

“In God we trust. All others [must] have data”

In science, ideology tends to corrupt; absolute ideology, [corrupts] absolutely. —Robert Nisbet

“The clinician, no matter how venerable, must accept the fact that experience, voluminous as it might be, cannot be employed as a sensitive indicator of scientific validity,” Fisher wrote in an article. He was willing to have faith in divine wisdom, but not in Halsted as divine wisdom. “In God we trust,” he brusquely told a journalist. “All others [must] have data.”

It is said that if you know your enemies and know yourself, you will not be imperiled in a hundred battles; if you do not know your enemies but do know yourself, you will win one and lose one; if you do not know your enemies nor yourself, you will be imperiled in every single battle. —Sun Tzu

In the winter of 1954, three years before his untimely death, Evarts Graham wrote a strikingly prescient essay in a book entitled Smoking and Cancer. At the end of the essay, Graham wondered about how the spread of tobacco in human societies might be combated in the future. Medicine, he concluded, was not powerful enough to restrict tobacco’s spread. Academic investigators could provide data about risks and argue incessantly about proof and causality, but the solution had to be political. “The obstinacy of [policymakers],” he wrote, “compels one to conclude that it is their own addiction… which blinds them. They have eyes to see, but see not

The biochemist Arthur Kornberg once joked that the discipline of modern biology in its early days often operated like the man in the proverbial story who is frantically searching for his keys under a streetlamp. When a passerby asks the man whether he lost his keys at that spot, the man says that he actually lost them at home—but he is looking for the keys under the lamp because “the light there is the brightest.”

Temin had suggested that an RNA virus could enter a cell, make a DNA copy of its genes, and attach itself to a cell’s genome. Spiegelman was convinced that this process, through a yet unknown mechanism, could activate a viral gene. That activated viral gene must induce the infected cell to proliferate—unleashing pathological mitosis, cancer.

Working fast and hard, Spiegelman found traces of retroviruses in human leukemia, in breast cancer, lymphomas, sarcomas, brain tumors, melanomas—in nearly every human cancer that he examined.

By analyzing the genes altered in these mutant viruses, these groups finally pinpointed RSV’s cancer-causing ability to a single gene in the virus. The gene was called src (pronounced “sarc”), a diminutive of sarcoma.

Rous’s sarcoma virus had likely picked up an activated src gene from a cancer cell and carried it in the viral genome, creating more cancer. 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.

“Nature,” Rous wrote in 1966, “sometimes seems possessed of a sardonic humor.”

“We have not slain our enemy, the cancer cell, or figuratively torn the limbs from his body,” Varmus said. “In our adventures, we have only seen our monster more clearly and described his scales and fangs in new ways—ways that reveal a cancer cell to be, like Grendel, a distorted version of our normal selves.”

The theory clarified why the same kind of cancer might arise in smokers and nonsmokers, albeit at different rates: both smokers and nonsmokers have the same proto-oncogenes in their cells, but smokers develop cancer at a higher rate because carcinogens in tobacco increase the mutation rate of these genes.