The Emperor of All Maladies

by Siddhartha Mukherjee

By 1944, Hitchings’s fishing expedition had yet to yield a single chemical fish. Mounds of bacterial plates had grown around him like a molding, decrepit garden with still no sign of a promised drug. Almost on instinct, he hired a young assistant named Gertrude Elion, whose future seemed even more precarious than Hitchings’s. The daughter of Lithuanian immigrants, born with a precocious scientific intellect and a thirst for chemical knowledge, Elion had completed a master’s degree in chemistry from New York University in 1941 while teaching high school science during the day and performing her research for her thesis at night and on weekends. Although highly qualified, talented, and driven, she had been unable to find a job in an academic laboratory. Frustrated by repeated rejections, she had found a position as a supermarket product supervisor. When Hitchings found Trudy Elion, who would soon become one of the most innovative synthetic chemists of her generation (and a future Nobel laureate), she was working for a food lab in New York, testing the acidity of pickles and the color of egg yolk going into mayonnaise.

Like Hitchings, she started off by hunting for chemicals that could block bacterial growth by inhibiting DNA—but then added her own strategic twist. Instead of sifting through mounds229 of unknown chemicals at random, Elion focused on one class of compounds, called purines. Purines were ringlike molecules with a central core of six carbon atoms that were known to be involved in the building of DNA. She thought she would add various chemical side chains to each of the six carbon atoms, producing dozens of new variants of purine. Elion’s collection of new molecules was a strange merry-go-round of beasts. One molecule—2,6-diaminopurine—was too toxic at even low doses to give the drug to animals. Another molecule smelled like garlic purified a thousand times. Many were unstable, or useless, or both. But in 1951, Elion found a variant molecule called 6-mercaptopurine, or 6-MP.

1948, Cornelius “Dusty” Rhoads, a former army officer, left his position as chief of the army’s Chemical Warfare Unit to become the director of the Memorial Hospital (and its attached research institute), thus sealing the connection between the chemical warfare of the battlefields and chemical warfare in the body. Intrigued by the cancer-killing properties of poisonous chemicals, Rhoads actively pursued a collaboration between Hitchings and Elion’s lab at Burroughs Wellcome and Memorial Hospital. Within months of having been tested on cells in a petri dish, 6-MP was packaged off to be tested in human patients.

Burchenal and Murphy were astonished by the speedy remissions produced by 6-MP. Leukemia cells flickered and vanished in the bone marrow and the blood, often within a few days of treatment. But, like the remissions in Boston, these were disappointingly temporary, lasting only a few weeks. As with Farber’s anti-folates, there was only a fleeting glimpse of a cure.

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. Farber, too, studied the past compulsively—and the episode that pivotally fascinated him was the story of the national polio campaign. As a student at Harvard in the 1920s, Farber had witnessed polio epidemics sweeping through the city, leaving waves of paralyzed children in their wake. In the acute phase of polio, the virus can paralyze the diaphragm, making it nearly impossible to breathe. Even a decade later, in the mid-1930s, the only treatment available for this paralysis was an artificial respirator known as the iron lung

The influx of money and public attention also brought a search for other children’s charity projects. Koster’s visit to the Children’s Hospital in Boston was a scouting mission to find another such project. He was escorted around the hospital to the labs and clinics of prominent doctors. When Koster asked the chief of hematology at Children’s for suggestions for donations to the hospital, the chief was characteristically cautious: “Well, I need a new microscope,”237 he said. In contrast, when Koster stopped by Farber’s office, he found an excitable, articulate scientist with a larger-than-life vision—a messiah in a box. Farber didn’t want a microscope; he had an audacious telescopic plan that captivated Koster. Farber asked the club to help him create a new fund to build a massive research hospital dedicated to children’s cancer.

For Farber, the Jimmy Fund campaign was an early experiment—the building of another model. The campaign against cancer, Farber learned, was much like a political campaign: it needed icons, mascots, images, slogans—the strategies of advertising as much as the tools of science. For any illness to rise to political prominence, it needed to be marketed, just as a political campaign needed marketing. A disease needed to be transformed politically before it could be transformed scientifically.

Perhaps there is only one cardinal sin256: impatience. Because of impatience we were driven out of Paradise, because of impatience we cannot return. —Franz Kafka

the history of Medicine is replete with examples of cures obtained years, decades, and even centuries before the mechanism of action was understood for these cures.

In time, a variant of this idea, of advertising as a lubricant of information and of the need to distill information into elemental iconography would leave a deep and lasting impact on the cancer campaign.

In the third, she is a teenager in college, and is confined to an influenza ward during the epidemic of 1918. The lethal Spanish flu rages outside, decimating towns and cities. Lasker survives—but the flu will kill six hundred thousand Americans that year, and take nearly fifty million lives worldwide, becoming the deadliest pandemic in history.

Her first convert was her husband. Grasping Mary’s commitment to the idea, Albert Lasker became her partner, her adviser, her strategist, her coconspirator. “There are unlimited funds,” he told her. “I will show you how to get them.”

This idea—of transforming the landscape of American medical research using political lobbying and fund-raising at an unprecedented scale—electrified her.

The Laskers were professional socialites, in the same way that one can be a professional scientist or a professional athlete; they were extraordinary networkers, lobbyists, minglers, conversers, persuaders, letter writers, cocktail party–throwers, negotiators, name-droppers, deal makers. Fund-raising—and, more important, friend-raising—was instilled in their blood, and the depth and breadth of their social c...

“Doctors,” she wrote, “are not administrators271 of large amounts of money. They’re usually really small businessmen . . . small professional men”—men who clearly lacked a systematic vision for cancer. She made a $5,000 donation to the ASCC and promised to be back.

Farber and Mary Lasker met in Washington in late 1940s, not long after Farber had shot to national fame with his antifolates.

Burchenal in New York, Farber in Boston, James Holland at Roswell Park, and the two Emils at the NCI were all chomping at the bit to launch clinical trials. And since ALL was a rare disease, every patient was a precious resource for a leukemia trial.

The proposal changed the field. “Zubrod’s cooperative group model galvanized cancer medicine,” Robert Mayer (who would later become the chair of one of these groups) recalls. “For the first time,318 an academic oncologist felt as if he had a community. The cancer doctor was not the outcast anymore, not the man who prescribed poisons from some underground chamber in the hospital.” The first group meeting, chaired by Farber, was a resounding success. The researchers agreed to proceed with a series of common trials, called protocols, as soon as possible.

The NCI’s trials would be systematic: every trial would test a crucial piece of logic or hypothesis and produce yes and no answers. The trials would be sequential: the lessons of one trial would lead to the next and so forth—a relentless march of progress until leukemia had been cured. The trials would be objective, randomized if possible, with clear, unbiased criteria to assign patients and measure responses.

As Farber and Burchenal had discovered to their chagrin in Boston and New York, leukemia treated with a single drug would inevitably grow resistant to the drug, resulting in the flickering, transient responses followed by the devastating relapses.

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 decades that followed, trial after trial would prove this principle. But in 1960, oncology was not yet ready for this proposal. Not until several years later did it strike the board that had fired Li so hastily that the patients he had treated with the prolonged maintenance strategy would never relapse. This strategy—which cost Min Chiu Li his job—resulted in the first chemotherapeutic cure of cancer in adults.

Skipper learned that he could halt this effusive cell division by administering chemotherapy to the leukemia-engrafted mouse. By charting the life and death of leukemia cells as they responded to drugs in these mice, Skipper emerged with two pivotal findings341. First, he found that chemotherapy typically killed a fixed percentage of cells at any given instance no matter what the total number of cancer cells was. This percentage was a unique, cardinal number particular to every drug. In other words, if you started off with 100,000 leukemia cells in a mouse and administered a drug that killed 99 percent of those cells in a single round, then every round would kill cells in a fractional manner, resulting in fewer and fewer cells after every round of chemotherapy:

Second, Skipper found that by adding drugs in combination, he could often get synergistic effects on killing. Since different drugs elicited different resistance mechanisms, and produced different toxicities in cancer cells, using drugs in concert dramatically lowered the chance of resistance and increased cell killing.

Obituaries poured out from every corner of the world. Mary Lasker’s was possibly the most succinct and heartfelt, for she had lost not just her friend but a part of herself. “Surely,” she wrote, “the world will never be the same.”475

Oft expectation fails476,

Political revolutions, the writer Amitav Ghosh writes494, often occur in the courtyards of palaces, in spaces on the cusp of power, located neither outside nor inside. Scientific revolutions, in contrast, typically occur in basements, in buried-away places removed from mainstream corridors of thought. But a surgical revolution must emanate from within surgery’s inner sanctum—for surgery is a profession intrinsically sealed to outsiders. To even enter the operating theater, one must be soused in soap and water, and surgical tradition. To change surgery, one must be a surgeon.

The invention of that measure would have a profound influence on the history of oncology, a branch of medicine particularly suffused with hope (and thus particularly prone to unsubstantiated claims of success).

“Power,” in the colloquial sense of the word, thus collided with “power” in the statistical sense.

“The clinician, no matter how venerable,508 must accept the fact that experience, voluminous as it might be, cannot be employed as a sensitive indicator of scientific validity,”

“In God we trust,”509 he brusquely told a journalist. “All others [must] have data.”

Between 1891 and 1981, in the nearly one hundred years of the radical mastectomy, an estimated five hundred thousand women underwent the procedure to “extirpate” cancer. Many chose the procedure. Many were forced into it. Many others did not even realize that it was a choice. Many were permanently disfigured; many perceived the surgery as a benediction; many suffered its punishing penalties bravely, hoping that they had treated their cancer as aggressively and as definitively as possible. Halsted’s “cancer storehouse” grew far beyond its original walls at Hopkins. His ideas entered oncology, then permeated its vocabulary, then its psychology, its ethos, and its self-image. When radical surgery fell, an entire culture of surgery thus collapsed with it.

And it is solely by risking life513 that freedom is obtained.

Prostate cells were thus acutely dependent on the hormone testosterone for their growth and function. Female sexual hormones kept breast cells alive; male hormones had a similar effect on prostate cells.

Dogs, humans, and lions are the only animals known to develop prostate cancer,

If testosterone deprivation could shrink normal prostate cells, what might testosterone deprivation do to cancer cells?

The answer, as any self-respecting cancer biologist might have informed him, was almost certain: very little. Cancer cells, after all, were deranged, uninhibited, and altered—responsive only to the most poisonous combinations of drugs. The signals and hormones that regulated normal cells had long been flung aside; what remained was a cell driven to divide with such pathological and autonomous fecundity that it had erased all memory of normalcy.

In fact, if normal prostate cells were dependent on testosterone for survival, then malignant prostate cells were nearly addicted to the hormone—so much so that the acute withdrawal acted like the most powerful therapeutic drug conceivable.

“Cancer is not necessarily autonomous548 and intrinsically self-perpetuating,” Huggins wrote. “Its growth can be sustained and propagated549 by hormonal function in the host.” The link between the growth-sustenance of normal cells and of cancer cells was much closer than previously imagined: cancer could be fed and nurtured by our own bodies.

If male hormones were driving the growth of these cancer cells, Huggins reasoned, then rather than eliminate the male hormones, what if one tricked the cancer into thinking that the body was “female” by suppressing the effect of testosterone?

But for Huggins, the existence of synthetic estrogens suggested a markedly different use: he could inject them to “feminize” the male body553 and stop the production of testosterone in patients with prostate cancer. He called the method “chemical castration.” And once again, he found striking responses. As with surgical castration, patients with aggressive prostate cancer chemically castrated with feminizing hormones responded briskly to the therapy, often with minimal side effects. (The most prominent complaint among men was the occurrence of menopause-like hot flashes.)

But the remissions, which often stretched into several months, proved that hormonal manipulations could choke the growth of a hormone-dependent cancer. To produce a cancer remission, one did not need a toxic, indiscriminate cellular poison (such as cisplatin or nitrogen mustard).

softened. Like Huggins’s prostate cancer patients, many of the women who responded to the drug eventually relapsed. But the success of the trial was incontrovertible—and the proof of principle historic. A drug designed to target a specific pathway in a cancer cell—not a cellular poison discovered empirically by trial and error—had successfully driven metastatic tumors into remission.

The schema had a satisfying simplicity. For the first time in the history of cancer, a drug, its target, and a cancer cell had been conjoined by a core molecular logic.

Fisher reanalyzed the deviating curves of relapse and survival, the effect of tamoxifen treatment was even more dramatic. Among the five-hundred-odd women older than fifty assigned to each group, tamoxifen had prevented fifty-five relapses and deaths. Fisher had altered the biology of breast cancer after surgery using a targeted hormonal drug that had barely any significant side effects.

The word palliate comes from the Latin palliare, “to cloak”—and providing pain relief was perceived as cloaking the essence of the illness, smothering symptoms rather than attacking disease.

In the history of medicine, no significant disease had ever been eradicated by a treatment-related program alone. If one plotted the decline in deaths from tuberculosis, for instance, the decline predated the arrival of new antibiotics by several decades. Far more potently than any miracle medicine, relatively uncelebrated shifts in civic arrangements—better nutrition, housing, and sanitation, improved sewage systems and ventilation—had driven TB mortality down in Europe and America.

Polio and smallpox had also dwindled as a result of vaccinations.

Cairns wrote, “The death rates from malaria, cholera, typhus, tuberculosis, scurvy, pellagra and other scourges of the past have dwindled in the US because humankind has learned how to prevent these diseases. . . . To put ...

therapeutic intervention? The answer is immediately obvious: the increase in survival is, of course, an artifact. Survival rates seem to increase, although what has really increased is the time from diagnosis to death because of a screening test.

Bailar and Smith published their article in May 1986—and it shook the world of oncology by its roots.