The Emperor of All Maladies

(#litres_trial_promo) 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.”

By then, the other inhabitants of Ehrlich’s train compartment had dozed off to sleep. But this rant in a train compartment was one of medicine’s most important ideas in its distilled, primordial form. “Chemotherapy,” the use of specific chemicals to heal the diseased body, was conceptually born in the middle of the night.

Ehrlich began looking for his “curative substances” in a familiar place: the treasure trove of dye-industry chemicals that had proved so crucial to his earlier biological experiments. His laboratory was now physically situated

(#litres_trial_promo) near the booming dye factories of Frankfurt—the Frankfurter Anilinfarben-Fabrik and the Leopold Cassella Company—and he could easily procure dye chemicals and derivatives via a short walk across the valley. With thousands of compounds available to him, Ehrlich embarked on a series of experiments to test their biological effects in animals.

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.

Galvanized by his discovery, Ehrlich unleashed volleys of chemical experiments. A universe of biological chemistry opened up before him: molecules with peculiar properties, a cosmos governed by idiosyncratic rules. Some compounds switched from precursors into active drugs in the bloodstream; others transformed backward from active drugs to inactive molecules. Some were excreted in the urine; others condensed in the bile or fell apart immediately in the blood. 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 packed

(#litres_trial_promo) 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”

(#litres_trial_promo) of eighteenth-century Europe—was a sensational illness, a tabloid pestilence. Ehrlich

(#litres_trial_promo) 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.

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’s magic bullets had one last target to fell: cancer. Syphilis and trypanosomiasis are microbial diseases. Ehrlich was slowly inching toward his ultimate goal: the malignant human cell. Between 1904 and 1908, he rigged several elaborate schemes to find an anticancer drug using his vast arsenal of chemicals. He tried amides, anilines, sulfa derivatives, arsenics, bromides, and alcohols to kill cancer cells. None of them worked. What was poison to cancer cells, he found, was inevitably poison to normal cells as well. Discouraged, he tried even more fantastical strategies. He thought of starving sarcoma cells of metabolites, or tricking them into death by using decoy molecules (a strategy that would presage Subbarao’s antifolate derivatives by nearly fifty years). But the search for the ultimate, discriminating anticancer drug proved fruitless. His pharmacological bullets, far from magical, were either too indiscriminate or too weak.

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.

Ehrlich hedged. The cancer cell, he explained, was a fundamentally different target from a bacterial cell. Specific affinity relied, paradoxically, not on “affinity,” but on its opposite—on difference. Ehrlich’s chemicals had successfully targeted bacteria because bacterial enzymes were so radically dissimilar to human enzymes. With cancer, it was the similarity of the cancer cell to the normal human cell that made it nearly impossible to target.

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.

Ehrlich’s thinking was lost on the Kaiser. Having little interest in this cheerless disquisition with no obvious end, he cut the audience short.

In 1915, Ehrlich fell ill with tuberculosis, a disease that he had likely acquired from his days in Koch’s laboratory. He went to recuperate in Bad Homburg, a spa town famous for its healing carbonic-salt baths. From his room, overlooking the distant plains below, he watched bitterly as his country pitched itself into the First World War. The dye factories that had once supplied his therapeutic chemicals—Bayer and Hoechst among them—were converted to massive producers of chemicals that would be turned into precursors for war gases. One particularly toxic gas was a colorless, blistering liquid produced by reacting the solvent thiodiglycol (a dye intermediate) with boiling hydrochloric acid. The gas’s smell was unmistakable, described alternatively as reminiscent of mustard, burnt garlic, or horseradishes ground on a fire. It came to be known as mustard gas.

On the foggy night of July 12, 1917, two years after Ehrlich’s death, a volley of artillery shells marked with small, yellow crosses rained down on British troops stationed near the small Belgian town of Ypres. The liquid in the bombs quickly vaporized, a “thick, yellowish green cloud

(#litres_trial_promo) veiling the sky,” as a soldier recalled, then diffused through the cool night air. The men in their barracks and trenches, asleep for the night, awoke to a nauseatingly sharp smell that they would remember for decades to come: the acrid whiff of horseradishes spreading through the chalk fields. Within seconds, soldiers ran for cover, coughing and sneezing in the mud, the blind scrambling among the dead. Mustard gas diffused through leather and rubber, and soaked through layers of cloth. It hung like a toxic mist over the battlefield for days until the dead smelled of mustard. On that night alone, mustard gas injured or killed two thousand soldiers. In a single year, it left thousands dead in its wake.

The acute, short-term effects of nitrogen mustard—the respiratory complications, the burnt skin, the blisters, the blindness—were so amply monstrous that its long-term effects were overlooked. In 1919, a pair of American pathologists

(#litres_trial_promo), 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.

In a world less preoccupied with other horrors, this news might have caused a small sensation among cancer doctors. Although evidently poisonous, this chemical had, after all, targeted the bone marrow and wiped out only certain populations of cells—a chemical with specific affinity. But Europe was full of horror stories in 1919, and this seemed no more remarkable than any other. The Krumbhaars published their paper in a second-tier medical journal and it was quickly forgotten in the amnesia of war.

The wartime chemists went back to their labs to devise new chemicals for other battles, and the inheritors of Ehrlich’s legacy went hunting elsewhere for his specific chemicals. They were looking for a magic bullet that would rid the body of cancer, not a toxic gas that would leave its victims half-dead, blind, blistered, and permanently anemic. That their bullet would eventually appear out of that very chemical weapon seemed like a perversion of specific affinity, a ghoulish distortion of Ehrlich’s dream.

Poisoning the Atmosphere (#ulink_5c77f29d-9215-52cd-8dd8-f9817215e59a)

What if this mixture do not work at all? . . .

(#litres_trial_promo)

What if it be a poison . . . ?

—Romeo and Juliet

We shall so poison the atmosphere

(#litres_trial_promo) of the first act that no one of decency shall want to see the play through to the end.

—James Watson, speaking about chemotherapy, 1977

Every drug, the sixteenth-century

(#litres_trial_promo) physician Paracelsus once opined, is a poison in disguise. Cancer chemotherapy, consumed by its fiery obsession to obliterate the cancer cell, found its roots in the obverse logic: every poison might be a drug in disguise.

On December 2, 1943

(#litres_trial_promo), more than twenty-five years after the yellow-crossed bombs had descended on Ypres, a fleet of Luftwaffe planes flew by a group of American ships huddled in a harbor just outside Bari in southern Italy and released a volley of shells. The ships were instantly on fire. Unbeknown even to its own crew, one of the ships in the fleet, the John Harvey, was stockpiled with seventy tons of mustard gas stowed away for possible use. As the Harvey blew up, so did its toxic payload. The Allies had, in effect, bombed themselves.

The German raid was unexpected and a terrifying success. Fishermen and residents around the Bari harbor began to complain of the whiff of burnt garlic and horseradishes in the breeze. Grimy, oil-soaked men, mostly young American sailors, were dragged out from the water seizing with pain and terror, their eyes swollen shut. They were given tea and wrapped in blankets, which only trapped the gas closer to their bodies. Of the 617 men rescued

(#litres_trial_promo), 83 died within the first week. The gas spread quickly over the Bari harbor, leaving an arc of devastation. Nearly a thousand men and women died of complications over the next months.

The Bari “incident,” as the media called it, was a terrible political embarrassment for the Allies. The injured soldiers and sailors were swiftly relocated to the States, and medical examiners were secretly flown in to perform autopsies on the dead civilians. The autopsies revealed what the Krumbhaars had noted earlier. In the men and women who had initially survived the bombing but succumbed later to injuries, white blood cells had virtually vanished in their blood, and the bone marrow was scorched and depleted. The gas had specifically targeted bone marrow cells—a grotesque molecular parody of Ehrlich’s healing chemicals.

The Bari incident set off a frantic effort to investigate war gases and their effects on soldiers. An undercover unit, called the Chemical Warfare Unit (housed within the wartime Office of Scientific Research and Development) was created to study war gases. Contracts for research on various toxic compounds were spread across research institutions around the nation. The contract for investigating nitrogen mustard was issued to two scientists, Louis Goodman and Alfred Gilman, at Yale University.

Goodman and Gilman weren’t interested

(#litres_trial_promo) in the “vesicant” properties of mustard gas—its capacity to burn skin and membranes. They were captivated by the Krumbhaar effect—the gas’s capacity to decimate white blood cells. Could this effect, or some etiolated cousin of it, be harnessed in a controlled setting, in a hospital, in tiny, monitored doses, to target malignant white cells?

To test this concept, 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. The softened tumors would harden again and recur—just as Farber’s leukemias had vanished then reappeared violently. Bound by secrecy during the war years, Goodman and Gilman eventually published their findings in 1946, several months before Farber’s paper on antifolates appeared in the press.

Just a few hundred miles south of Yale, at the Burroughs Wellcome laboratory in New York, the biochemist George Hitchings had also

(#litres_trial_promo) 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.” “Scientists in academia stood disdainfully

(#litres_trial_promo) apart from this kind of activity,” a colleague of Hitchings’s recalled. “[They] argued that it would be premature to attempt chemotherapy without sufficient basic knowledge about biochemistry, physiology, and pharmacology. In truth, the field had been sterile for thirty-five years or so since Ehrlich’s work.”

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.

Rescued from a life of pickles and mayonnaise, Gertrude Elion leapt into synthetic chemistry. 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 mounds

(#litres_trial_promo) 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.