Читать книгу The Emperor of All Maladies - Siddhartha Mukherjee, Siddhartha Mukherjee - Страница 20
ОглавлениеWhat if this mixture do not work at all? . . .221
What if it be a poison . . . ?
—Romeo and Juliet
We shall so poison the atmosphere222 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-century223 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, 1943224, 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 rescued225, 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 interested226 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 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.” “Scientists in academia stood disdainfully228 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 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.
6-MP failed some preliminary toxicological tests on animals (the drug is strangely toxic to dogs), and was nearly abandoned. But the success of mustard gas in killing cancer cells had boosted the confidence of early chemotherapists. In 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.
Predictably, the first target was acute lymphoblastic leukemia—the rare tumor that now occupied the limelight of oncology. In the early 1950s, two physician-scientists230, Joseph Burchenal and Mary Lois Murphy, launched a clinical trial at Memorial to use 6-MP on children with ALL.
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.
