Siddhartha Mukherjee - The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

  But most important, thirteen patients, about a third of the original cohort, had never relapsed. They were still alive, off chemotherapy. The children had come back to the clinic month after month. The longest remission was now in its sixth year, half the lifetime of that child.

  In 1979, Pinkel's team revisited the entire cohort of patients treated over several years with total therapy. Overall, 278 patients in eight consecutive trials had completed their courses of medicines and stopped chemotherapy. Of those, about one-fifth had relapsed. The rest, 80 percent--remained disease free after chemotherapy--"cured," as far as anyone could tell. "ALL in children cannot be considered an incurable disease," Pinkel wrote in a review article. "Palliation is no longer an acceptable approach to its initial treatment."

  He was writing to the future, of course, but in a more mystical sense he was writing back to the past, to the doctors who had been deeply nihilistic about therapy for leukemia and had once argued with Farber to let his children quietly "die in peace."

  * Although trained in Boston under Farber, Pinkel had spent several years at the Roswell Park Cancer Institute in Buffalo, New York, before moving to Memphis in 1961.

  + The Roswell Park group, led by James Holland, and Joseph Burchenal at the Memorial Hospital in New York continued to collaborate with Pinkel in developing the leukemia protocols.

  The Cart and the Horse

  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

  The iron is hot and this is the time to pound without cessation.

  --Sidney Farber to Mary Lasker,

  September 1965

  One swallow is a coincidence, but two swallows make summer. By the autumn of 1968, as the trials in Bethesda and in Memphis announced their noteworthy successes, the landscape of cancer witnessed a seismic shift. In the late fifties, as DeVita recalled, "it took plain old courage to be a chemotherapist . . . and certainly the courage of the conviction that cancer would eventually succumb to drugs. Clearly, proof was necessary."

  Just a decade later, the burden of proof had begun to shift dramatically. The cure of lymphoblastic leukemia with high-dose chemotherapy might have been dismissed as a biological fluke, but the success of the same strategy in Hodgkin's disease made it seem like a general principle. "A revolution [has been] set in motion," DeVita wrote. Kenneth Endicott, the NCI director, concurred: "The next step--the complete cure--is almost sure to follow."

  In Boston, Farber greeted the news by celebrating the way he knew best--by throwing a massive public party. The symbolic date for the party was not hard to come by. In September 1968, the Jimmy Fund turned twenty-one.* Farber recast the occasion as the symbolic twenty-first birthday of Jimmy, a coming-of-age moment for his "child with cancer." The Imperial Ballroom of the Statler Hotel, outside which the Variety Club had once positioned its baseball-shaped donation box for Jimmy in the 1950s, was outfitted for a colossal celebration. The guest list included Farber's typically glitzy retinue of physicians, scientists, philanthropists, and politicians. Mary Lasker couldn't attend the event, but she sent Elmer Bobst from the ACS. Zubrod flew up from the NCI. Kenneth Endicott came from Bethesda.

  Conspicuously missing from the list was the original Jimmy himself--Einar Gustafson. Farber knew of Jimmy's whereabouts (he was alive and well, Farber told the press opaquely) but deliberately chose to shroud the rest in anonymity. Jimmy, Farber insisted, was an icon, an abstraction. The real Jimmy had returned to a private, cloistered life on a farm in rural Maine where he now lived with his wife and three children--his restored normalcy a sign of victory against cancer. He was thirty-two years old. No one had seen or photographed him for nearly two decades.

  At the end of the evening, as the demitasse cups were being wheeled away, Farber rose to the stage in the full glare of the lights. Jimmy's Clinic, he said, now stood at "the most fortunate time in the history of science and medicine." Institutions and individuals across the nation--"the Variety Club, the motion picture industry, the Boston Braves . . . the Red Sox, the world of sports, the press, the television, the radio"--had come together around cancer. What was being celebrated in the ballroom that evening, Farber announced, was not an individual's birthday, but the birth of a once-beleaguered community that had clustered around a disease.

  That community now felt on the verge of a breakthrough. As DeVita described it, "The missing piece of the therapeutic puzzle, effective chemotherapy for systemic cancers," had been discovered. High-dose combination chemotherapy would cure all cancers--once the right combinations had been found. "The chemical arsenal," one writer noted, "now in the hands of prescribing physicians gives them every bit as much power . . . as the heroic surgeon wielding the knife at the turn of the century."

  The prospect of a systematic solution to a cure intoxicated oncologists. It equally intoxicated the political forces that had converged around cancer. Potent, hungry, and expansive, the word war captured the essence of the anticancer campaign. Wars demand combatants, weapons, soldiers, the wounded, survivors, bystanders, collaborators, strategists, sentinels, victories--and it was not hard to find a metaphorical analogue to each of these for this war as well.

  Wars also demand a clear definition of an enemy. They imbue even formless adversaries with forms. So cancer, a shape-shifting disease of colossal diversity, was recast as a single, monolithic entity. It was one disease. As Isaiah Fidler, the influential Houston oncologist, described it succinctly, cancer had to possess "one cause, one mechanism and one cure."

  If clinical oncologists had multidrug cytotoxic chemotherapy to offer as their unifying solution for cancer--"one cure"--then cancer scientists had their own theory to advance for its unifying cause: viruses. The grandfather of this theory was Peyton Rous, a stooping, white-haired chicken virologist who had been roosting quietly in a laboratory at the Rockefeller Institute in New York until he was dragged out of relative oblivion in the 1960s.

  In 1909 (note that date: Halsted had just wrapped up his study of the mastectomy; Neely was yet to advertise his "reward" for the cure for cancer), then a thirty-year-old scientist freshly launching his lab at the Rockefeller Institute, Peyton Rous had been brought a tumor growing on the back of a hen of a black-and-white species of chicken called Plymouth Rock. A rare tumor in a chicken might have left others unimpressed, but the indefatigable Rous secured a $200 grant to study the chicken cancer. Soon, he had categorized the tumor as a sarcoma, a cancer of the connective tissues, with sheet upon sheet of rhomboid, fox-eyed cells invading the tendons and muscle.

  Rous's initial work on the chicken sarcoma was thought to have little relevance to human cancers. In the 1920s, the only known causes of human cancer were environmental carcinogens such as radium (recall Marie Curie's leukemia) or organic chemicals, such as paraffin and dye by-products, that were known to cause solid tumors. In the late eighteenth century, an English surgeon named Percivall Pott had argued that cancer of the scrotum, endemic among chimney sweeps, was caused by chronic exposure to chimney soot and smoke. (We will meet Pott again in subsequent pages.)

  These observations had led to a theory called the somatic mutation hypothesis of cancer. The somatic theory of cancer argued that environmental carcinogens such as soot or radium somehow permanently altered the structure of the cell and thus caused cancer. But the precise nature of the alteration was unknown. Clearly, soot, paraffin, and radium possessed the capacity to alter a cell in some fundamental way to generate a malignant cell. But how could such a diverse range of insults all converge on the same pathological insult? Perhaps a more systematic explanation was missing--a deeper, more fundamental theory of carcinogenesis.

  In 1910, unwittingly, Rous threw the somatic theory into grave doubt. Experimenting with the spindle-cell sarcoma, Rous injected the tumor in one chicken into another chicken and found that the cancer could be transmitted from one bird to
another. "I have propagated a spindle-cell sarcoma of the common foul into its fourth generation," he wrote. "The neoplasm grows rapidly, infiltrates, metastasizes, and remains true to type."

  This was curious, but nonetheless still understandable--cancer was a disease of cellular origin, and transferring cells from one organism to another might have been expected to transmit the cancer. But then Rous stumbled on an even more peculiar result. Shuttling tumors from one bird to another, he began to pass the cells through a set of filters, a series of finer and finer cellular sieves, until the cells had been eliminated from the mix and all that was left was the filtrate derived from the cells. Rous expected the tumor transmission to stop, but instead, the tumors continued propagating with a ghostly efficacy--at times even increasing in transmissibility as the cells had progressively vanished.

  The agent responsible for carrying the cancer, Rous concluded, was not a cell or an environmental carcinogen, but some tiny particle lurking within a cell. The particle was so small that it could easily pass through most filters and keep producing cancer in animals. The only biological particle that had these properties was a virus. His virus was later called Rous sarcoma virus, or RSV for short.

  The discovery of RSV, the first cancer-causing virus, felled a deep blow to the somatic mutation theory and set off a frantic search for more cancer viruses. The causal agent for cancer, it seemed, had been found. In 1935, a colleague of Rous's named Richard Schope reported a papillomavirus that caused wartlike tumors in cottontail rabbits. Ten years later, in the mid-1940s, came news of a leukemia-causing virus in mice and then in cats--but still no sign of a bona fide cancer virus in humans.

  In 1958, after nearly a three-decade effort, the hunt finally yielded an important prize. An Irish surgeon, Denis Burkitt, discovered an aggressive form of lymphoma--now called Burkitt's lymphoma--that occurred endemically among children in the malaria-ridden belt of sub-Saharan Africa. The pattern of distribution suggested an infectious cause. When two British virologists analyzed the lymphoma cells from Africa, they discovered an infectious agent lodged inside them--not malaria parasites, but a human cancer virus. The new virus was named Epstein-Barr virus or EBV. (EBV is more familiar to us as the virus that causes infectious mononucleosis, or mono.)

  The grand total of cancer-causing viruses in humans now stood at one. But the modesty of that number aside, the cancer virus theory was in full spate now--in part because viruses were the new rage in all of medicine. Viral diseases, having been considered incurable for centuries, were now becoming potentially preventable: the polio vaccine, introduced in the summer of 1952, had been a phenomenal success, and the notion that cancer and infectious diseases could eventually collapse into a single pathological entity was simply too seductive to resist.

  "Cancer may be infectious," a Life magazine cover piece asserted in 1962. Rous received hundreds of letters from anxious men and women asking about exposures to cancer-causing bacteria or viruses. Speculation soon inched toward hysteria and fear. If cancer was infectious, some wondered, why not quarantine patients to prevent its spread? Why not send cancer patients to sanitation wards or isolation facilities, where TB and smallpox victims had once been confined? One woman who believed that she had been exposed to a coughing lung cancer patient wrote, "Is there something I can do to kill the cancer germ? Can the rooms be fumigated . . .? Should I give up my lease and move out?"

  If the "cancer germ" had infected one space most acutely, it was the imagination of the public--and, equally, the imagination of researchers. Farber turned into a particularly fervent believer. In the early 1960s, goaded by his insistence, the NCI inaugurated a Special Virus Cancer Program, a systematic hunt for human cancer viruses patterned explicitly after the chemotherapy discovery program. The project snowballed into public prominence, gathering enormous support. Hundreds of monkeys at the NCI-funded lab were inoculated with human tumors with the hopes of turning the monkeys into viral incubators for vaccine development. Unfortunately, the monkeys failed to produce even a single cancer virus, but nothing dimmed the optimism. Over the next decade, the cancer virus program siphoned away more than 10 percent of the NCI contract budget--nearly $500 million. (In contrast, the institute's cancer nutrition program, meant to evaluate the role of diet in cancer--a question of at least equal import--received one-twentieth of that allocation.)

  Peyton Rous was rehabilitated into the scientific mainstream and levitated into permanent scientific sainthood. In 1966, having been overlooked for a full fifty-five years, he was awarded the Nobel Prize for physiology and medicine. On the evening of December 10 at the ceremony in Stockholm, he rose to the podium like a resurrected messiah. Rous acknowledged in his talk that the virus theory of cancer still needed much more work and clarity. "Relatively few viruses have any connection with the production of neoplasms," Rous said. But bulldogish and unwilling to capitulate, Rous lambasted the idea that cancer could be caused by something inherent to the cells, such as a genetic mutation. "A favorite explanation has been that oncogenes cause alterations in the genes of the cells of the body, somatic mutations as these are termed. But numerous facts, when taken together, decisively exclude this supposition."

  He groused elsewhere: "What have been [the fruits] of this somatic mutation hypothesis? . . . Most serious of all the results of the somatic mutation hypothesis has been its effect on research workers. It acts as a tranquilizer on those who believe it."

  Rous had his own tranquilizer to offer: a unifying hypothesis that viruses caused cancer. And many in his audience, in no mood for caveats and complexities, were desperate to swallow his medicine. The somatic mutation theory of cancer was dead. The scientists who had studied environmental carcinogenesis needed to think of other explanations why radium or soot might cause cancer. (Perhaps, the virus theorists reasoned, these insults activated endogenous viruses.)

  Two superficial theories were thus stitched audaciously--and prematurely--into one comprehensive whole. One offered a cause: viruses caused cancer (although a vast majority of them were yet undiscovered). The second offered a cure: particular combinations of cytotoxic poisons would cure cancer (although specific combinations for the vast majority of cancers were yet undiscovered).

  Viral carcinogenesis clearly demanded a deeper explanation: how might viruses--elemental microbes floating from cell to cell--cause so profound a change in a cell's physiology as to create a malignant cell? The success of cytotoxic chemotherapy provoked equally fundamental questions: why had a series of rather general poisons cured some forms of cancer, while leaving other forms completely unscathed?

  Obviously, a more fundamental explanation lurked beneath all of this, an explanation that would connect cause and cure. So some researchers urged patience, diligence, and time. "The program directed by the National Cancer Institute has been derided as one that puts the cart before the horse by searching for a cure before knowing the cause," Kenneth Endicott, the NCI director, acknowledged in 1963. "We have certainly not found a cure for cancer. We have a dozen chemicals which are somewhat better than those known before the program began but none are dramatically better. They prolong the patient's life somewhat and make him more comfortable, but that is all."

  But the Laskerites had little time for such nuanced descriptions of progress; this cart would have to drag the horse. "The iron is hot and this is the time to pound without cessation," Farber wrote to Lasker. The groundwork for an all-out battle had already been laid. All that was necessary was to put pressure on Congress to release funds. "No large mission or goal-directed effort [against cancer], supported with adequate funds has ever been organized," Mary Lasker announced in an open letter to Congress in 1969.

  Lasker's thoughts were echoed by Solomon Garb, a little-known professor of pharmacology at the University of Missouri who shot to prominence by publishing the book Cure for Cancer: A National Goal in 1968. "The theme of this book," Garb began, "is that the time has come for a closer look at cancer research and for a new consolidation of effo
rt aimed at cure or control of cancer. . . . A major hindrance to cancer effort has been a chronic, severe shortage of funds--a situation that is not generally recognized. It is not enough, however, to point this out or to repeat it; it is also necessary to explain how additional funds would be used, what projects they would pay for, why such projects deserve support, and where the skilled scientists and technicians to do the work would come from."

  Garb's book was described as a "springboard to progress," and the Laskerites certainly sprang. As with Farber, a doctor's word was the ultimate prescription. That Garb had prescribed precisely the strategy advocated by the Laskerites instantly transformed him in their eyes into a messianic figure. His book became their bible.

  Religious movements and cults are often founded on a tetrad of elements: a prophet, a prophecy, a book, and a revelation. By the summer of 1969, the cancer crusade had acquired three of these four essential elements. Its prophet was Mary Lasker, the woman who had guided it out of the dark wilderness of the 1950s into national prominence just two decades later. Its prophecy was the cure for childhood leukemia, inaugurated by Farber's experiments in Boston and ending with Pinkel's astonishing successes in Memphis. Its book was Garb's Cure for Cancer. The final missing element was a revelation--a sign that would auger the future and capture the imagination of the public. In the spirit of all great revelations, this one would also appear unexpectedly and mystically out of the blue. It would apparition, quite literally, from the heavens.