PART SIX
We are really reaping the fruits of our long endeavors.
—Michael Gorman
to Mary Lasker, 1985
The National Cancer Institute, which has overseen American efforts on researching and combating cancers since 1971, should take on an ambitious new goal for the next decade: the development of new drugs that will provide lifelong cures for many, if not all, major cancers. Beating cancer now is a realistic ambition because, at long last, we largely know its true genetic and chemical characteristics.
—James Watson, 2009
The more perfect a power is, the more difficult it is to quell.
—Saint Aquinas, attributed
“No one had labored in vain”
Have you met Jimmy? . . . Jimmy is any one of thousands of children with leukemia or any other form of cancer, from the nation or from around the world.
—Pamphlet for the Jimmy Fund, 1963
In the summer of 1997, a woman named Phyllis Clauson, from Billerica, Massachusetts, posted a letter to the Dana-Farber Cancer Institute. She was writing on behalf of “Jimmy,” Farber’s mascot. It had been nearly fifty years since Jimmy had arrived at Farber’s clinic in Boston from upstate Maine with a diagnosis of lymphoma of the intestines. Like all his ward-mates from the 1950s, Jimmy was presumed long dead.
Not true, Clauson wrote; he was alive and well. Jimmy—Einar Gustafson—was her brother, a truck driver in Maine with three children. For five decades, his family had guarded the knowledge of Jimmy’s identity and his survival. Only Sidney Farber had known; Christmas cards from Farber had arrived each winter, until Farber himself had died in 1973. Every year, for decades, Clauson and her siblings had sent in modest donations to the Jimmy Fund, divulging to no one that the silhouetted face on the solicitation card for contributions was their brother’s. But with the passage of fifty years, Clauson felt she could no longer keep the secret in good conscience. “Jimmy’s story,” she recalled, “had become a story that I could not hold. I knew I had to write the letter while Einar was still alive.”
Clauson’s letter was nearly thrown into the trash. Jimmy “sightings,” like Elvis sightings, were reported often, but rarely taken seriously; all had turned out to be hoaxes. Doctors had informed the Jimmy Fund’s publicity department that the odds of Jimmy’s having survived were nil, and that all claims were to be treated with great skepticism. But Clauson’s letter contained details that could not be waved away. She wrote of listening to the radio in New Sweden, Maine, in the summer of 1948 to tune in to the Ralph Edwards broadcast. She recalled her brother’s midwinter trips to Boston that often took two days, with Jimmy in his baseball uniform lying patiently in the back of a truck.
When Clauson told her brother about the letter that she had sent, she found him more relieved than annoyed. “It was like an unburdening for him, too,” she recalled. “Einar was a modest man. He had kept to himself because he did not want to brag.” (“I would read in the papers that they had found me someplace,” he said, “and I would smile.”)
Clauson’s letter was spotted by Karen Cummings, an associate in the Jimmy Fund’s development office, who immediately understood its potential significance. She contacted Clauson, and then reached Gustafson.
A few weeks later, in January 1998, Cummings arranged to meet Jimmy at a truck stop outside a shopping center in a suburb of Boston. It was six in the morning on a bone-chilling winter day, and Gustafson and his wife piled into Cummings’s warm car. Cummings had brought a tape of Jimmy from 1948 singing his favorite song. She played it:
Take me out to the ball game,
Take me out with the crowd.
Buy me some peanuts and Cracker Jack,
I don’t care if I never get back.
Gustafson listened to his own voice with tears in his eyes. Cummings and Jimmy’s wife sat in the car, their eyes also welling with silent tears.
Later that month, Cummings drove up to New Sweden, a brutally beautiful town in northern Maine with austere angular houses set against an even more austere landscape. Old-timers in the town also recalled Gustafson’s trips to Boston for chemotherapy. He had hitchhiked to and from Boston in cars and trucks and delivery vans anytime someone from the town had driven up or down the coast; it had taken a village to save a child. As Cummings sat in Gustafson’s kitchen, he crept upstairs and returned with a cardboard box. Wrapped inside was the battered baseball uniform that the Boston Braves had given Jimmy on the night of the Edwards broadcast. Cummings needed no further proof.
And so it was in May 1998, almost exactly fifty years after he had journeyed from small-town Maine to the Children’s Hospital to meet the odd, formal doctor in a three-piece suit, that Jimmy returned with full fanfare to the Jimmy Fund. His wardmates from the hospital—the Sandler twin with his recalcitrant leukemia engorging his spleen, the blond girl in plaits by the television, little Jenny with leukemia—had long ago been buried in small graves in and around Boston. Gustafson walked into the Jimmy Fund Building,* up the low, long steps to the room where the clockwork train had run through the mountain tunnel. Patients, survivors, nurses, and doctors milled around him. Like a latter-day Rip van Winkle, he found the present unfathomable and unrecognizable. “Everything has changed,” Clauson recalled him saying. “The rooms, the patients, the drugs.” But more than anything, survivorship had changed. “Einar remembered the cancer ward as a place with many curtains,” she continued. “When the children were well, the curtains would be spread open. But they would soon close the curtains, and there would be no child when they were opened again.”
Here Gustafson was, fifty years later, back in those long hallways with the faded cartoon paintings on the walls, his curtains thrown apart. It is impossible to know whether Jimmy had survived because of surgery, or chemotherapy, or because his cancer had been inherently benign in its behavior. But the facts of his medical history are irrelevant; his return was symbolic. Jimmy had unwittingly been picked to become the icon of the child with cancer. But Einar Gustafson, now sixty-three years old, had returned as the icon of a man beyond cancer.
The Italian memoirist Primo Levi, who survived a concentration camp and then navigated his way through a blasted Germany to his native Turin, often remarked that among the most fatal qualities of the camp was its ability to erase the idea of a life outside and beyond itself. A person’s past and his present were annihilated as a matter of course—to be in the camps was to abnegate history, identity, and personality—but it was the erasure of the future that was the most chilling. With that annihilation, Levi wrote, came a moral and spiritual death that perpetuated the status quo of imprisonment. If no life existed beyond the camp, then the distorted logic by which the camp operated became life as usual.
Cancer is not a concentration camp, but it shares the quality of annihilation: it negates the possibility of life outside and beyond itself; it subsumes all living. The daily life of a patient becomes so intensely preoccupied with his or her illness that the world fades away. Every last morsel of energy is spent tending the disease. “How to overcome him became my obsession,” the journalist Max Lerner wrote of the lymphoma in his spleen. “If it was to be a combat then I had to engage it with everything I had—knowledge and guile, ways covert as well as overt.”
For Carla, in the midst of the worst phase of her chemotherapy, the day-to-day rituals of survival utterly blotted out any thought of survivorship in the long run. When I asked a woman with a rare form of muscle sarcoma about her life outside the hospital, she told me that she spent her days and nights scouring the Internet for news about the disease. “I am in the hospital,” she said, “even when I am outside the hospital.” The poet Jason Shinder wrote, “Cancer is a tremendous opportunity to have your face pressed right up against the glass of your mortality.” But what patients see through the glass is not a world outside cancer, but a world taken over by it—cancer reflected endlessly around them like a hall of mirrors.
I was not immune to this compulsive preoccupation either. In the summer of 2005, as my fellowship hurtled to its end, I experienced perhaps the singularly transformative event of my life: the birth of my daughter. Glowing, beautiful, and cherubic, Leela was born on a warm night at Massachusetts General Hospital, then swaddled in blankets and brought to the newborn unit on the fourteenth floor. The unit is directly across from the cancer ward. (The apposition of the two is hardly a coincidence. As a medical procedure, childbirth is least likely to involve infectious complications and is thus the safest neighbor to a chemotherapy ward, where any infection can turn into a lethal rampage. As in so much in medicine, the juxtaposition between the two wards is purely functional and yet just as purely profound.)
I would like to see myself at my wife’s side awaiting the miraculous moment of my daughter’s birth as most fathers do. But in truth I was gowned and gloved like a surgeon, with a blue, sterile sheet spread out in front of me, and a long syringe in my hands, poised to harvest the maroon gush of blood cells from the umbilical cord. When I cut that cord, part of me was the father, but the other part an oncologist. Umbilical blood contains one of the richest known sources of blood-forming stem cells—cells that can be stored away in cryobanks and used for a bone marrow transplant to treat leukemia in the future, an intensely precious resource often flushed down a sink in hospitals after childbirth.
The midwives rolled their eyes; the obstetrician, an old friend, asked jokingly if I ever stopped thinking about work. But I was too far steeped in the study of blood to ignore my instincts. In the bone-marrow-transplant rooms across that very hallway were patients for whom I had scoured tissue banks across the nation for one or two pints of these stem cells that might save their lives. Even in this most life-affirming of moments, the shadows of malignancy—and death—were forever lurking on my psyche.
But not everything was involuting into death. Something transformative was also happening in the fellows’ clinics in the summer of 2005: many of my patients, whose faces had so fixedly been pressed up against the glass of their mortality, began to glimpse an afterlife beyond cancer. February, as I said before, had marked the midpoint of an abysmal descent. Cancer had reached its full, lethal bloom that month. Nearly every week had brought news of a mounting toll, culminating chillingly with Steve Harmon’s arrival in the emergency room and his devastating spiral into death thereafter. Some days I dreaded walking by the fax machines outside my office, where a pile of death certificates would be waiting for my signature.
But then, like a poisonous tide receding, the bad news ebbed. The nightly phone calls from the hospitals or from ERs and hospice units around Boston bringing news of yet another death (“I’m calling to let you know that your patient arrived here this evening with dizziness and difficulty breathing”) suddenly ceased. It was as if the veil of death had lifted—and survivors had emerged from underneath.
Ben Orman had been definitively cured of Hodgkin’s lymphoma. It had not been an effortless voyage. His blood counts had dropped calamitously during the midcycle of chemotherapy. For a few weeks it had appeared that the lymphoma had ceased responding—a poor prognostic sign portending a therapy-resistant, fatal variant of the disease. But in the end the mass in his neck, and the larger archipelago of masses in his chest, had all melted away, leaving just minor remnants of scar tissue. The formality of his demeanor had visibly relaxed. When I last saw him in the summer of 2005, he spoke about moving away from Boston to Los Angeles to join a law firm. He assured me that he would visit to follow up, but I wasn’t convinced. Orman epitomized the afterlife of cancer—eager to forget the clinic and its bleak rituals, like a bad trip to a foreign country.
Katherine Fitz could also see a life beyond cancer. For Fitz, with the lung tumor wrapped ominously around her bronchus, the biggest hurdle had been the local control of her cancer. The mass had been excised in an incredibly meticulous surgery; she had then finished adjuvant chemotherapy and radiation. Nearly twelve months after the surgery, there was no sign of a local relapse. Nor was there any sign of the woman who had come to the clinic several months earlier, nearly folded over in fear. Tumor out, chemotherapy done, radiation behind her, Fitz’s effervescence poured out of every spigot of her soul. At times, watching her personality emerge as if through a nozzle, it seemed abundantly clear why the Greeks had thought of disease as pathological blockades of humors.
Carla returned to see me in July 2005, bringing pictures of her three growing children. She refused to let another doctor perform her bone marrow biopsy, so I walked over from the lab on a warm morning to perform the procedure. She looked relieved when she saw me, greeting me with her anxious half-smile. We had developed a ritualistic relationship; who was I to desecrate a lucky ritual? The biopsy revealed no leukemia in the bone marrow. Her remission, for now, was still intact.
I have chosen these cases not because they were “miraculous” but because of precisely the opposite reason. They represent a routine spectrum of survivors—Hodgkin’s disease cured with multidrug chemotherapy; locally advanced lung cancer controlled with surgery, chemotherapy, and radiation; lymphoblastic leukemia in a prolonged remission after intensive chemotherapy. To me, these were miracles enough. It is an old complaint about the practice of medicine that it inures you to the idea of death. But when medicine inures you to the idea of life, to survival, then it has failed utterly. The novelist Thomas Wolfe, recalling a lifelong struggle with illness, wrote in his last letter, “I’ve made a long voyage and been to a strange country, and I’ve seen the dark man very close.” I had not made the journey myself, and I had only seen the darkness reflected in the eyes of others. But surely, it was the most sublime moment of my clinical life to have watched that voyage in reverse, to encounter men and women returning from the strange country—to see them so very close, clambering back.
Incremental advances can add up to transformative changes. In 2005, an avalanche of papers cascading through the scientific literature converged on a remarkably consistent message—the national physiognomy of cancer had subtly but fundamentally changed. The mortality for nearly every major form of cancer—lung, breast, colon, and prostate—had continuously dropped for fifteen straight years. There had been no single, drastic turn but rather a steady and powerful attrition: mortality had declined by about 1 percent every year. The rate might sound modest, but its cumulative effect was remarkable: between 1990 and 2005, the cancer-specific death rate had dropped nearly 15 percent, a decline unprecedented in the history of the disease. The empire of cancer was still indubitably vast—more than half a million American men and women died of cancer in 2005—but it was losing power, fraying at its borders.
What precipitated this steady decline? There was no single answer but rather a multitude. For lung cancer, the driver of decline was primarily prevention—a slow attrition in smoking sparked off by the Doll-Hill and Wynder-Graham studies, fueled by the surgeon general’s report, and brought to its full boil by a combination of political activism (the FTC action on warning labels), inventive litigation (the Banzhaf and Cipollone cases), medical advocacy, and countermarketing (the antitobacco advertisements).
For colon and cervical cancer, the declines were almost certainly due to the successes of secondary prevention—cancer screening. Colon cancers were detected at earlier and earlier stages in their evolution, often in the premalignant state, and treated with relatively minor surgeries. Cervical cancer screening using Papanicolaou’s smearing technique was being offered at primary-care centers throughout the nation, and as with colon cancer, premalignant lesions were excised using relatively minor surgeries.
For leukemia, lymphoma, and testicular cancer, in contrast, the declining numbers reflected the successes of chemotherapeutic treatment. In childhood ALL, cure rates of 80 percent were routinely being achieved. Hodgkin’s disease was similarly curable, and so, too, were some large-cell aggressive lymphomas. Indeed, for Hodgkin’s disease, testicular cancer, and childhood leukemias, the burning question was not how much chemotherapy was curative, but how little: trials were addressing whether milder and less toxic doses of drugs, scaled back from the original protocols, could achieve equivalent cure rates.
Perhaps most symbolically, the decline in breast cancer mortality epitomized the cumulative and collaborative nature of these victories—and the importance of attacking cancer using multiple independent prongs. Between 1990 and 2005, breast cancer mortality had dwindled an unprecedented 24 percent. Three interventions had potentially driven down the breast cancer death rate—mammography (screening to catch early breast cancer and thereby prevent invasive breast cancer), surgery, and adjuvant chemotherapy (chemotherapy after surgery to remove remnant cancer cells). Donald Berry, a statistician in Houston, Texas, set out to answer a controversial question: How much had mammography and chemotherapy independently contributed to survival? Whose victory was this—a victory of prevention or of therapeutic intervention?*
Berry’s answer was a long-due emollient to a field beset by squabbles between the advocates of prevention and the proponents of chemotherapy. When Berry assessed the effect of each intervention independently using statistical models, it was a satisfying tie: both cancer prevention and chemotherapy had diminished breast cancer mortality equally—12 percent for mammography and 12 percent for chemotherapy, adding up to the observed 24 percent reduction in mortality. “No one,” as Berry said, paraphrasing the Bible, “had labored in vain.”
These were all deep, audacious, and meaningful victories borne on the backs of deep and meaningful labors. But, in truth, they were the victories of another generation—the results of discoveries made in the fifties and sixties. The core conceptual advances from which these treatment strategies arose predated nearly all the significant work on the cell biology of cancer. In a bewildering spurt over just two decades, scientists had unveiled a fantastical new world—of errant oncogenes and tumor suppressor genes that accelerated and decelerated growth to unleash cancer; of chromosomes that could be decapitated and translocated to create new genetic chimeras, of cellular pathways corrupted to subvert the death of cancer. But the therapeutic advances that had led to the slow attrition of cancer mortality made no use of this novel biology of cancer. There was new science on one hand and old medicine on the other. Mary Lasker had once searched for an epochal shift in cancer. But the shift that had occurred seemed to belong to another epoch.
Mary Lasker died of heart failure in 1994 in her carefully curated home in Connecticut—having removed herself physically from the bristling epicenters of cancer research and policymaking in Washington, New York, and Boston. She was ninety-three years old. Her life had nearly spanned the most transformative and turbulent century of biomedical science. Her potent ebullience had dimmed in her last decade. She spoke rarely about the achievements (or disappointments) of the War on Cancer. But she had expected cancer medicine to have achieved more during her lifetime—to have taken a more assertive step toward Farber’s “universal cure” for cancer and marked a more definitive victory in the war. The complexity, the tenacity—the sheer magisterial force of cancer—had made even its most committed and resolute opponent seem circumspect and humbled.
In 1994, a few months after Lasker’s death, the cancer geneticist Ed Harlow captured both the agony and the ecstasy of the era. At the end of a weeklong conference at the Cold Spring Harbor Laboratory in New York pervaded by a giddy sense of anticipation about the spectacular achievements of cancer biology, Harlow delivered a sobering assessment: “Our knowledge of . . . molecular defects in cancer has come from a dedicated twenty years of the best molecular biology research. Yet this information does not translate to any effective treatments nor to any understanding of why many of the current treatments succeed or why others fail. It is a frustrating time.”
More than a decade later, I could sense the same frustration in the clinic at Mass General. One afternoon, I watched Tom Lynch, the lung cancer clinician, masterfully encapsulate carcinogenesis, cancer genetics, and chemotherapy for a new patient, a middle-aged woman with bronchoalveolar cell cancer. She was a professor of history with a grave manner and a sharp, darting mind. He sat across from her, scribbling a picture as he spoke. The cells in her bronchus, he began, had acquired mutations in their genes that had allowed them to grow autonomously and uncontrollably. They had formed a local tumor. Their propensity was to acquire further mutations that might allow them to migrate, to invade tissues, to metastasize. Chemotherapy with Carboplatin and Taxol (two standard chemotherapy drugs), augmented with radiation, would kill the cells and perhaps prevent them from migrating to other organs to seed metastases. In the best-case scenario, the cells carrying the mutated genes would die, and her cancer would be cured.
She watched Lynch put his pen down with her quick, sharp eyes. The explanation sounded logical and organized, but she had caught the glint of a broken piece in the chain of logic. What was the connection between this explanation and the therapy being proposed? How, she wanted to know, would Carboplatin “fix” her mutated genes? How would Taxol know which cells carried the mutations in order to kill them? How would the mechanistic explanation of her illness connect with the medical interventions?
She had captured a disjunction all too familiar to oncologists. For nearly a decade, practicing cancer medicine had become like living inside a pressurized can—pushed, on one hand, by the increasing force of biological clarity about cancer, but then pressed against the wall of medical stagnation that seemed to have produced no real medicines out of this biological clarity. In the winter of 1945, Vannevar Bush had written to President Roosevelt, “The striking advances in medicine during the war have been possible only because we had a large backlog of scientific data accumulated through basic research in many scientific fields in the years before the war.”
For cancer, the “backlog of scientific data” had reached a critical point. The boil of science, as Bush liked to imagine it, inevitably produced a kind of steam—an urgent, rhapsodic pressure that could only find release in technology. Cancer science was begging to find release in a new kind of cancer medicine.
* Jimmy began chemo in the Children’s Hospital in 1948, but was later followed and treated in the Jimmy Fund Building in 1952.
* Surgery’s contribution could not be judged since surgery predated 1990, and nearly all women are treated surgically.
New Drugs for Old Cancers
In the story of Patroclus
No one survives, not even Achilles
Who was nearly a god.
Patroclus resembled him; they wore
The same armor
—Louise Glück
The perfect therapy has not been developed. Most of us believe that it will not involve toxic cytotoxic therapy, which is why we support the kinds of basic investigations that are directed towards more fundamental understanding of tumor biology. But . . . we must do the best with what we now have.
—Bruce Chabner to Rose Kushner
In the legend, Achilles was quickly dipped into the river Styx, held up only by the tendon of his heel. Touched by the dark sheath of water, every part of his body was instantly rendered impervious to even the most lethal weapon—except the undipped tendon. A simple arrow targeted to that vulnerable heel would eventually kill Achilles in the battlefields of Troy.
Before the 1980s, the armamentarium of cancer therapy was largely built around two fundamental vulnerabilities of cancer cells. The first is that most cancers originate as local diseases before they spread systemically. Surgery and radiation therapy exploit this vulnerability. By physically excising locally restricted tumors before cancer cells can spread—or by searing cancer cells with localized bursts of powerful energy using X-rays—surgery and radiation attempt to eliminate cancer en bloc from the body.
The second vulnerability is the rapid growth rate of cancer cells. Most chemotherapy drugs discovered before the 1980s target this second vulnerability. Antifolates, such as Farber’s aminopterin, interrupt the metabolism of folic acid and starve all cells of a crucial nutrient required for cell division. Nitrogen mustard and cisplatin chemically react with DNA, and DNA-damaged cells cannot duplicate their genes and thus cannot divide. Vincristine, the periwinkle poison, thwarts the ability of a cell to construct the molecular “scaffold” required for all cells to divide.
But these two traditional Achilles’ heels of cancer—local growth and rapid cell division—can only be targeted to a point. Surgery and radiation are intrinsically localized strategies, and they fail when cancer cells have spread beyond the limits of what can be surgically removed or irradiated. More surgery thus does not lead to more cures, as the radical surgeons discovered to their despair in the 1950s.
Targeting cellular growth also hits a biological ceiling because normal cells must grow as well. Growth may be the hallmark of cancer, but it is equally the hallmark of life. A poison directed at cellular growth, such as vincristine or cisplatin, eventually attacks normal growth, and cells that grow most rapidly in the body begin to bear the collateral cost of chemotherapy. Hair falls out. Blood involutes. The lining of the skin and gut sloughs off. More drugs produce more toxicity without producing cures, as the radical chemotherapists discovered to their despair in the 1980s.
To target cancer cells with novel therapies, scientists and physicians needed new vulnerabilities that were unique to cancer. The discoveries of cancer biology in the 1980s offered a vastly more nuanced view of these vulnerabilities. Three new principles emerged, representing three new Achilles’ heels of cancer.
First, cancer cells are driven to grow because of the accumulation of mutations in their DNA. These mutations activate internal proto-oncogenes and inactivate tumor suppressor genes, thus unleashing the “accelerators” and “brakes” that operate during normal cell division. Targeting these hyperactive genes, while sparing their modulated normal precursors, might be a novel means to attack cancer cells more discriminately.
Second, proto-oncogenes and tumor suppressor genes typically lie at the hubs of cellular signaling pathways. Cancer cells divide and grow because they are driven by hyperactive or inactive signals in these critical pathways. These pathways exist in normal cells but are tightly regulated. The potential dependence of a cancer cell on such permanently activated pathways is a second potential vulnerability of a cancer cell.
Third, the relentless cycle of mutation, selection, and survival creates a cancer cell that has acquired several additional properties besides uncontrolled growth. These include the capacity to resist death signals, to metastasize throughout the body, and to incite the growth of blood vessels. These “hallmarks of cancer” are not invented by the cancer cell; they are typically derived from the corruption of similar processes that occur in the normal physiology of the body. The acquired dependence of a cancer cell on these processes is a third potential vulnerability of cancer.
The central therapeutic challenge of the newest cancer medicine, then, was to find, among the vast numbers of similarities in normal cells and cancer cells, subtle differences in genes, pathways, and acquired capabilities—and to drive a poisoned stake into that new heel.
It was one thing to identify an Achilles’ heel—and quite another to discover a weapon that would strike it. Until the late 1980s, no drug had reversed an oncogene’s activation or a tumor suppressor’s inactivation. Even tamoxifen, the most specific cancer-targeted drug discovered to that date, works by attacking the dependence of certain breast cancer cells on estrogen, and not by directly inactivating an oncogene or oncogene-activated pathway. In 1986, the discovery of the first oncogene-targeted drug would thus instantly galvanize cancer medicine. Although found largely serendipitously, the mere existence of such a molecule would set the stage for the vast drug-hunting efforts of the next decade.
The disease that stood at the pivotal crossroads of oncology was yet another rare variant of leukemia called acute promyelocytic leukemia—APL. First identified as a distinct form of adult leukemia in the 1950s, the disease has a distinct characteristic: the cells in this form of cancer do not merely divide rapidly, they are also strikingly frozen in immature development. Normal white blood cells developing in the bone marrow undergo a series of maturational steps to develop into fully functional adult cells. One such intermediate cell is termed a promyelocyte, an adolescent cell on the verge of becoming functionally mature. APL is characterized by the malignant proliferation of these immature promyelocytes. Normal promyelocytes are loaded with toxic enzymes and granules that are usually released by adult white blood cells to kill viruses, bacteria, and parasites. In promyelocytic leukemia, the blood fills up with these toxin-loaded promyelocytes. Moody, mercurial, and jumpy, the cells of APL can release their poisonous granules on a whim—precipitating massive bleeding or simulating a septic reaction in the body. In APL, the pathological proliferation of cancer thus comes with a fiery twist. Most cancers contain cells that refuse to stop growing. In APL, the cancer cells also refuse to grow up.
Since the early 1970s, this maturation arrest of APL cells had prompted scientists to hunt for a chemical that might force these cells to mature. Scores of drugs had been tested on APL cells in test tubes, and only one had stood out—retinoic acid, an oxidized form of vitamin A. But retinoic acid, researchers had found, was a vexingly unreliable reagent. One batch of the acid might mature APL cells, while another batch of the same chemical might fail. Frustrated by these flickering, unfathomable responses, biologists and chemists had turned away after their initial enthusiasm for the maturation chemical.
In the summer of 1985, a team of leukemia researchers from China traveled to France to meet Laurent Degos, a hematologist at Saint Louis Hospital in Paris with a long-standing interest in APL. The Chinese team, led by Zhen Yi Wang, was also treating APL patients, at Ruijin Hospital, a busy, urban clinical center in Shanghai, China. Both Degos and Wang had tried standard chemotherapy agents—drugs that target rapidly growing cells—to promote remissions in APL patients, but the results had been dismal. Wang and Degos spoke of the need for a new strategy to attack this whimsical, lethal disease, and they kept circling back to the peculiar immaturity of APL cells and to the lapsed search for a maturation agent for the disease.
Retinoic acid, Wang and Degos knew, comes in two closely related molecular forms, called cis-retinoic acid and trans-retinoic acid. The two forms are compositionally identical, but possess a slight difference in their molecular structure, and they behave very differently in molecular reactions. (Cis-retinoic acid and trans-retinoic acid have the same atoms, but the atoms are arranged differently in the two chemicals.) Of the two forms, cis-retinoic acid had been the most intensively tested, and it had produced the flickering, transient responses. But Wang and Degos wondered if trans-retinoic acid was the true maturation agent. Had the unreliable responses in the old experiments been due to a low and variable amount of the trans-retinoic form present in every batch of retinoic acid?
Wang, who had studied at a French Jesuit school in Shanghai, spoke a lilting, heavily accented French. Linguistic and geographic barriers breached, the two hematologists outlined an international collaboration. Wang knew of a pharmaceutical factory outside Shanghai that could produce pure trans-retinoic acid—without the admixture of cis-retinoic acid. He would test the drug on APL patients at the Ruijin Hospital. Degos’s team in Paris would follow after the initial round of testing in China and further validate the strategy on French APL patients.
Wang launched his trial in 1986 with twenty-four patients. Twenty-three experienced a dazzling response. Leukemic promyelocytes in the blood underwent a brisk maturation into white blood cells. “The nucleus became larger,” Wang wrote, “and fewer primary granules were observed in the cytoplasm. On the fourth day of culture, these cells gave rise to myelocytes containing specific, or secondary, granules . . . [indicating the development of] fully mature granulocytes.”
Then something even more unexpected occurred: having fully matured, the cancer cells began to die out. In some patients, the differentiation and death erupted so volcanically that the bone marrow swelled up with differentiated promyelocytes and then emptied slowly over weeks as the cancer cells matured and underwent an accelerated cycle of death. The sudden maturation of cancer cells produced a short-lived metabolic disarray, which was controlled with medicines, but the only other side effects of trans-retinoic acid were dryness of lips and mouth and an occasional rash. The remissions produced by trans-retinoic acid lasted weeks and often months.
Acute promyelocytic leukemia still relapsed, typically about three to four months after treatment with trans-retinoic acid. The Paris and Shanghai teams next combined standard chemotherapy drugs with trans-retinoic acid—a cocktail of old and new drugs—and remissions were prolonged by several additional months. In about three-fourths of the patients, the leukemia remission began to stretch into a full year, then into five years. By 1993, Wang and Degos concluded that 75 percent of their patients treated with the combination of trans-retinoic acid and standard chemotherapy would never relapse—a percentage unheard of in the history of APL.
Cancer biologists would need another decade to explain the startling Ruijin responses at a molecular level. The key to the explanation lay in the elegant studies performed by Janet Rowley, the Chicago cytologist. In 1984, Rowley had identified a unique translocation in the chromosomes of APL cells—a fragment of a gene from chromosome fifteen fused with a fragment of a gene from chromosome seventeen. This created an activated “chimeric” oncogene that drove the proliferation of promyelocytes and blocked their maturation, thus creating the peculiar syndrome of APL.
In 1990, a full four years after Wang’s clinical trial in Shanghai, this culprit oncogene was isolated by independent teams of scientists from France, Italy, and America. The APL oncogene, scientists found, encodes a protein that is tightly bound by trans-retinoic acid. This binding immediately extinguishes the oncogene’s signal in APL cells, thereby explaining the rapid, powerful remissions observed in Shanghai.
The Ruijin discovery was remarkable: trans-retinoic acid represented the long-sought fantasy of molecular oncology—an oncogene-targeted cancer drug. But the discovery was a fantasy lived backward. Wang and Degos had first stumbled on trans-retinoic acid through inspired guesswork—and only later discovered that the molecule could directly target an oncogene.
But was it possible to make the converse journey—starting from oncogene and going to drug? Indeed, Robert Weinberg’s lab in Boston had already begun that converse journey, although Weinberg himself was largely oblivious of it.
By the early 1980s, Weinberg’s lab had perfected a technique to isolate cancer-causing genes directly out of cancer cells. Using Weinberg’s technique, researchers had isolated dozens of new oncogenes from cancer cells. In 1982, a postdoctoral scientist from Bombay working in Weinberg’s lab, Lakshmi Charon Padhy, reported the isolation of yet another such oncogene from a rat tumor called a neuroblastoma. Weinberg christened the gene neu, naming it after the type of cancer that harbored this gene.
Neu was added to the growing list of oncogenes, but it was an anomaly. Cells are bounded by a thin membrane of lipids and proteins that acts as an oily barrier against the entry of many drugs. Most oncogenes discovered thus far, such as ras and myc, are sequestered inside the cell (ras is bound to the cell membrane but faces into the cell), making them inaccessible to drugs that cannot penetrate the cell membrane. The product of the neu gene, in contrast, was a novel protein, not hidden deep inside the cell, but tethered to the cell membrane with a large fragment that hung outside, freely accessible to any drug.
Lakshmi Charon Padhy even had a “drug” to test. In 1981, while isolating his gene, he had created an antibody against the new neu protein. Antibodies are molecules designed to bind to other molecules, and the binding can occasionally block and inactivate the bound protein. But antibodies are unable to cross the cell membrane and need an exposed protein outside the cell to bind. Neu, then, was a perfect target, with a large portion, a long molecular “foot,” projected tantalizingly outside the cell membrane. It would have taken Padhy no more than an afternoon’s experiment to add the neu antibody to the neuroblastoma cells to determine the binding’s effect. “It would have been an overnight test,” Weinberg would later recall. “I can flagellate myself. If I had been more studious and more focused and not as monomaniacal about the ideas I had at that time, I would have made that connection.”
Despite the trail of seductive leads, Padhy and Weinberg never got around to doing their experiment. Afternoon upon afternoon passed. Introspective and bookish, Padhy shuffled through the lab in a threadbare coat in the winter, running his experiments privately and saying little about them to others. And although Padhy’s discovery was published in a high-profile scientific journal, few scientists noticed that he might have stumbled on a potential anticancer drug (the neu-binding antibody was buried in an obscure figure in the article). Even Weinberg, caught in the giddy upswirl of new oncogenes and obsessed with the basic biology of the cancer cell, simply forgot about the neu experiment.*
Weinberg had an oncogene and possibly an oncogene-blocking drug, but the twain had never met (in human cells or bodies). In the neuroblastoma cells dividing in his incubators, neu rampaged on monomaniacally, single-mindedly, seemingly invincible. Yet its molecular foot still waved just outside the surface of the plasma membrane, exposed and vulnerable, like Achilles’ famous heel.
* In 1986, Jeffrey Drebin and Mark Greene showed that treatment with an anti-neu antibody arrested the growth of cancer cells. But the prospect of developing this antibody into a human anticancer drug eluded all groups.
A City of Strings
In Ersilia, to establish the relationships that sustain the city’s life, inhabitants stretch strings from the corners of the houses, white or black or gray or black-and-white according to whether they mark a relationship of blood, of trade, authority, agency. When the strings become so numerous that you can no longer pass among them, the inhabitants leave: the houses are dismantled.
—Italo Calvino
Weinberg may briefly have forgotten about the therapeutic implication of neu, but oncogenes, by their very nature, could not easily be forgotten. In his book Invisible Cities, Italo Calvino describes a fictional metropolis in which every relationship between one household and the next is denoted by a piece of colored string stretched between the two houses. As the metropolis grows, the mesh of strings thickens and the individual houses blur away. In the end, Calvino’s city becomes no more than an interwoven network of colored strings.
If someone were to draw a similar map of relationships among genes in a normal human cell, then proto-oncogenes and tumor suppressors such as ras, myc, neu, and Rb would sit at the hub of this cellular city, radiating webs of colored strings in every direction. Proto-oncogenes and tumor suppressors are the molecular pivots of the cell. They are the gatekeepers of cell division, and the division of cells is so central to our physiology that genes and pathways that coordinate this process intersect with nearly every other aspect of our biology. In the laboratory, we call this the six-degrees-of-separation-from-cancer rule: you can ask any biological question, no matter how seemingly distant—what makes the heart fail, or why worms age, or even how birds learn songs—and you will end up, in fewer than six genetic steps, connecting with a proto-oncogene or tumor suppressor.
It should hardly come as a surprise, then, that neu was barely forgotten in Weinberg’s laboratory when it was resurrected in another. In the summer of 1984, a team of researchers, collaborating with Weinberg, discovered the human homolog of the neu gene. Noting its resemblance to another growth-modulating gene discovered previously—the Human EGF Receptor (HER)—the researchers called the gene Her-2.
A gene by any other name may still be the same gene, but something crucial had shifted in the story of neu. Weinberg’s gene had been discovered in an academic laboratory. Much of Weinberg’s attention had been focused on dissecting the molecular mechanism of the neu oncogene. Her-2, in contrast, was discovered on the sprawling campus of the pharmaceutical company Genentech. The difference in venue, and the resulting difference in goals, would radically alter the fate of this gene. For Weinberg, neu had represented a route to understanding the fundamental biology of neuroblastoma. For Genentech, Her-2 represented a route to developing a new drug.
Located on the southern edge of San Francisco, sandwiched among the powerhouse labs of Stanford, UCSF, and Berkeley and the burgeoning start-ups of Silicon Valley, Genentech—short for Genetic Engineering Technology—was born out of an idea imbued with deep alchemic symbolism. In the late 1970s, researchers at Stanford and UCSF had invented a technology termed “recombinant DNA.” This technology allowed genes to be manipulated—engineered—in a hitherto unimaginable manner. Genes could be shuttled from one organism to another: a cow gene could be transferred into bacteria, or a human protein synthesized in dog cells. Genes could also be spliced together to create new genes, creating proteins never found in nature. Genentech imagined leveraging this technology of genes to develop a pharmacopoeia of novel drugs. Founded in 1976, the company licensed recombinant DNA technology from UCSF, raised a paltry $200,000 in venture funds, and launched its hunt for these novel drugs.
A “drug,” in bare conceptual terms, is any substance that can produce an effect on the physiology of an animal. Drugs can be simple molecules; water and salt, under appropriate circumstances, can function as potent pharmacological agents. Or drugs can be complex, multifaceted chemicals—molecules derived from nature, such as penicillin, or chemicals synthesized artificially, such as aminopterin. Among the most complex drugs in medicine are proteins, molecules synthesized by cells that can exert diverse effects on human physiology. Insulin, made by pancreas cells, is a protein that regulates blood sugar and can be used to control diabetes. Growth hormone, made by the pituitary cells, augments growth by increasing the metabolism of muscle and bone cells.
Before Genentech, protein drugs, although recognizably potent, had been notoriously difficult to produce. Insulin, for instance, was produced by grinding up cow and pig innards into a soup and then extracting the protein from the mix—one pound of insulin from every eight thousand pounds of pancreas. Growth hormone, used to treat a form of dwarfism, was extracted from pituitary glands dissected out of thousands of human cadavers. Clotting drugs to treat bleeding disorders came from liters of human blood.
Recombinant DNA technology allowed Genentech to synthesize human proteins de novo: rather than extracting proteins from animal and human organs, Genentech could “engineer” a human gene into a bacterium, say, and use the bacterial cell as a bioreactor to produce vast quantities of that protein. The technology was transformative. In 1982, Genentech unveiled the first “recombinant” human insulin; in 1984, it produced a clotting factor used to control bleeding in patients with hemophilia; in 1985, it created a recombinant version of human growth hormone—all created by engineering the production of human proteins in bacterial or animal cells.
By the late 1980s, though, after an astonishing growth spurt, Genentech ran out of existing drugs to mass-produce using recombinant technology. Its early victories, after all, had been the result of a process and not a product: the company had found a radical new way to produce old medicines. Now, as Genentech set out to invent new drugs from scratch, it was forced to change its winning strategy: it needed to find targets for drugs—proteins in cells that might play a critical role in the physiology of a disease that might, in turn, be turned on or off by other proteins produced using recombinant DNA.
It was under the aegis of this “target discovery” program that Axel Ullrich, a German scientist working at Genentech, rediscovered Weinberg’s gene—Her-2/neu, the oncogene tethered to the cell membrane.* But having discovered the gene, Genentech did not know what to do with it. The drugs that Genentech had successfully synthesized thus far were designed to treat human diseases in which a protein or a signal was absent or low—insulin for diabetics, clotting factors for hemophiliacs, growth hormone for dwarfs. An oncogene was the opposite—not a missing signal, but a signal in overabundance. Genentech could fabricate a missing protein in bacterial cells, but it had yet to learn how to inactivate a hyperactive protein in a human cell.
In the summer of 1986, while Genentech was still puzzling over a method to inactivate oncogenes, Ullrich presented a seminar at the University of California in Los Angeles. Flamboyant and exuberant, dressed in a dark, formal suit, Ullrich was a riveting speaker. He floored his audience with the incredible story of the isolation of Her-2, and the serendipitous convergence of that discovery with Weinberg’s prior work. But he left his listeners searching for a punch line. Genentech was a drug company. Where was the drug?
Dennis Slamon, a UCLA oncologist, attended Ullrich’s talk that afternoon in 1986. The son of an Appalachian coal miner, Slamon had come to UCLA as a fellow in oncology after medical school at the University of Chicago. He was a peculiar amalgam of smoothness and tenacity, a “velvet jackhammer,” as one reporter described him. Early in his academic life he had acquired what he called “a murderous resolve” to cure cancer, but thus far, it was all resolve and no result. In Chicago, Slamon had performed a series of exquisite studies on a human leukemia virus called HTLV-1, the lone retrovirus shown to cause a human cancer. But HTLV-1 was a fleetingly rare cause of cancer. Murdering viruses, Slamon knew, would not cure cancer. He needed a method to kill an oncogene.
Slamon, hearing Ullrich’s story of Her-2, made a quick, intuitive connection. Ullrich had an oncogene; Genentech wanted a drug—but an intermediate was missing. A drug without a disease is a useless tool; to make a worthwhile cancer drug, both needed a cancer in which the Her-2 gene was hyperactive. Slamon had a panel of cancers that he could test for Her-2 hyperactivity. A compulsive pack rat, like Thad Dryja in Boston, Slamon had been collecting and storing samples of cancer tissues from patients who had undergone surgery at UCLA, all saved in a vast freezer. Slamon proposed a simple collaboration. If Ullrich sent him the DNA probes for Her-2 from Genentech, Slamon could test his collection of cancer cells for samples with hyperactive Her-2—thus bridging the gap between the oncogene and a human cancer.
Ullrich agreed. In 1986, he sent Slamon the Her-2 probe to test on cancer samples. In a few months, Slamon reported back to Ullrich that he had found a distinct pattern, although he did not fully understand it. Cancer cells that become habitually dependent on the activity of a gene for their growth can amplify that gene by making multiple copies of the gene in the chromosome. This phenomenon—like an addict feeding an addiction by ramping up the use of a drug—is called oncogene amplification. Her-2, Slamon found, was highly amplified in breast cancer samples, but not in all breast cancers. Based on the pattern of staining, breast cancers could neatly be divided into Her-2 amplified and Her-2 unamplified samples—Her-2 positive and Her-2 negative.
Puzzled by the “on-off” pattern, Slamon sent an assistant to determine whether Her-2 positive tumors behaved differently from Her-2 negative tumors. The search yielded yet another extraordinary pattern: breast tumors that amplified Ullrich’s gene tended to be more aggressive, more metastatic, and more likely to kill. Her-2 amplification marked the tumors with the worst prognosis.
Slamon’s data set off a chain reaction in Ullrich’s lab at Genentech. The association of Her-2 with a subtype of cancer—aggressive breast cancer—prompted an important experiment. What would happen, Ullrich wondered, if Her-2 activity could somehow be shut off? Was the cancer truly “addicted” to amplified Her-2? And if so, might squelching the addiction signal using an anti-Her-2 drug block the growth of the cancer cells? Ullrich was tiptoeing around the afternoon experiment that Weinberg and Padhy had forgotten to perform.
Ullrich knew where he might look for a drug to shut off Her-2 function. By the mid-1980s, Genentech had organized itself into an astonishing simulacrum of a university. The South San Francisco campus had departments, conferences, lectures, subgroups, even researchers in cutoff jeans playing Frisbee on the lawns. One afternoon, Ullrich walked to the Immunology Division at Genentech. The division specialized in the creation of immunological molecules. Ullrich wondered whether someone in immunology might be able to design a drug to bind Her-2 and possibly erase its signaling.
Ullrich had a particular kind of protein in mind—an antibody. Antibodies are immunological proteins that bind their targets with exquisite affinity and specificity. The immune system synthesizes antibodies to bind and kill specific targets on bacteria and viruses; antibodies are nature’s magic bullets. In the mid-1970s, two immunologists at Cambridge University, Cesar Milstein and George Kohler, had devised a method to produce vast quantities of a single antibody using a hybrid immune cell that had been physically fused to a cancer cell. (The immune cell secreted the antibody while the cancer cell, a specialist in uncontrolled growth, turned it into a factory.) The discovery had instantly been hailed as a potential route to a cancer cure. But to exploit antibodies therapeutically, scientists needed to identify targets unique to cancer cells, and such cancer-specific targets had proved notoriously difficult to identify. Ullrich believed that he had found one such target. Her-2, amplified in some breast tumors but barely visible in normal cells, was perhaps Kohler’s missing bull’s-eye.
At UCLA, meanwhile, Slamon had performed another crucial experiment with Her-2 expressing cancers. He had implanted these cancers into mice, where they had exploded into friable, metastatic tumors, recapitulating the aggressive human disease. In 1988, Genentech’s immunologists successfully produced a mouse antibody that bound and inactivated Her-2. Ullrich sent Slamon the first vials of the antibody, and Slamon launched a series of pivotal experiments. When he treated Her-2 overexpressing breast cancer cells in a dish with the antibody, the cells stopped growing, then involuted and died. More impressively, when he injected his living, tumor-bearing mice with the Her-2 antibody, the tumors also disappeared. It was as perfect a result as he or Ullrich could have hoped for. Her-2 inhibition worked in an animal model.
Slamon and Ullrich now had all three essential ingredients for a targeted therapy for cancer: an oncogene, a form of cancer that specifically activated that oncogene, and a drug that specifically targeted it. Both expected Genentech to leap at the opportunity to produce a new protein drug to erase an oncogene’s hyperactive signal. But Ullrich, holed away in his lab with Her-2, had lost touch with the trajectory of the company outside the lab. Genentech, he now discovered, was abandoning its interest in cancer. Through the 1980s, as Ullrich and Slamon had been hunting for a target specific to cancer cells, several other pharmaceutical companies had tried to develop anticancer drugs using the limited knowledge of the mechanisms driving the growth of cancer cells. Predictably, the drugs that had emerged were largely indiscriminate—toxic to both cancer cells and normal cells—and predictably, all had failed miserably in clinical trials. Ullrich and Slamon’s approach—an oncogene and an oncogene-targeted antibody—was vastly more sophisticated and specific, but Genentech was worried that pouring money into the development of another drug that failed would cripple the company’s finances. Chastened by the experience of others—“allergic to cancer,” as one Genentech researcher described it—Genentech pulled funding away from most of its cancer projects.
The decision created a deep rift in the company. A small cadre of scientists ardently supported the cancer program, but Genentech’s executives wanted to focus on simpler and more profitable drugs. Her-2 was caught in the cross fire. Drained and dejected, Ullrich left Genentech. He would eventually join an academic laboratory in Germany, where he could work on cancer genetics without the fickle pressures of a pharmaceutical company constraining his science.
Slamon, now working alone at UCLA, tried furiously to keep the Her-2 effort alive at Genentech, even though he wasn’t on the company’s payroll. “Nobody gave a shit except him,” John Curd, Genentech’s medical director, recalled. Slamon became a pariah at Genentech, a pushy, obsessed gadfly who would often jet up from Los Angeles and lurk in the corridors seeking to interest anyone he could in his mouse antibody. Most scientists had lost interest. But Slamon retained the faith of a small group of Genentech scientists, scientists nostalgic for the pioneering, early days of Genentech when problems had been taken on precisely because they were intractable. An MIT-educated geneticist, David Botstein, and a molecular biologist, Art Levinson, both at Genentech, had been strong proponents of the Her-2 project. (Levinson had come to Genentech from Michael Bishop’s lab at UCSF, where he had worked on the phosphorylating function of src; oncogenes were stitched into his psyche.) Pulling strings, resources, and connections, Slamon and Levinson convinced a tiny entrepreneurial team to push ahead with the Her-2 project.
Marginally funded, the work edged along, almost invisible to Genentech’s executives. In 1989, Mike Shepard, an immunologist at Genentech, improved the production and purification of the Her-2 antibody. But the purified mouse antibody, Slamon knew, was far from a human drug. Mouse antibodies, being “foreign” proteins, provoke a potent immune response in humans and make terrible human drugs. To circumvent that response, Genentech’s antibody needed to be converted into a protein that more closely resembled a human antibody. This process, evocatively called “humanizing” an antibody, is a delicate art, somewhat akin to translating a novel; what matters is not just the content, but the ineffable essence of the antibody—its form. Genentech’s resident “humanizer” was Paul Carter, a quiet, twenty-nine-year-old Englishman who had learned the craft at Cambridge from Cesar Milstein, the scientist who had first produced these antibodies using fused immune and cancer cells. Under Slamon’s and Shepard’s guidance, Carter set about humanizing the mouse antibody. In the summer of 1990, Carter proudly produced a fully humanized Her-2 antibody ready to be used in clinical trials. The antibody, now a potential drug, would soon be renamed Herceptin, fusing the words Her-2, intercept, and inhibitor.*
Such was the halting, traumatic birth of the new drug that it was easy to forget the enormity of what had been achieved. Slamon had identified Her-2 amplification in breast cancer tissue in 1987; Carter and Shepard had produced a humanized antibody against it by 1990. They had moved from cancer to target to drug in an astonishing three years, a pace unprecedented in the history of cancer.
In the summer of 1990, Barbara Bradfield, a forty-eight-year-old woman from Burbank, California, discovered a mass in her breast and a lump under her arm. A biopsy confirmed what she already suspected: she had breast cancer that had spread to her lymph nodes. She was treated with a bilateral mastectomy followed by nearly seven months of chemotherapy. “When I was finished with all that,” she recalled, “I felt as if I had crossed a river of tragedy.”
But there was more river to ford: Bradfield’s life was hit by yet another incommensurate tragedy. In the winter of 1991, driving on a highway not far from their house, her daughter, twenty-three years old and pregnant, was killed in a fiery accident. A few months later, sitting numbly in a Bible-study class one morning, Bradfield let her fingers wander up to the edge of her neck. A new grape-size mass had appeared just above her collarbone. Her breast cancer had relapsed and metastasized—almost certainly a harbinger of death.
Bradfield’s oncologist in Burbank offered her more chemotherapy, but she declined it. She enrolled in an alternative herbal-therapy program and bought a vegetable juicer and planned a trip to Mexico. When her oncologist asked if he could send samples of her breast cancer to Slamon’s lab at UCLA for a second opinion, she agreed reluctantly. A faraway doctor performing unfamiliar tests on her tumor sample, she knew, could not possibly affect her.
One afternoon in the summer of 1991, Bradfield received a phone call from Slamon. He introduced himself as a researcher who had been analyzing her slides. Slamon told Bradfield about Her-2. “His tone changed,” she recalled. Her tumor, he said, had one of the highest levels of amplified Her-2 that he had ever seen. Slamon told her that he was launching a trial of an antibody that bound Her-2 and that she would be the ideal candidate for the new drug. Bradfield refused. “I was at the end of my road,” she said, “and I had accepted what seemed inevitable.” Slamon tried to reason with her for a while, but found her unbending. He thanked her for her consideration and rang off.
Early the next morning, though, Slamon was back on the telephone. He apologized for the intrusion, but her decision had troubled him all night. Of all the variants of Her-2 amplification that he had encountered, hers had been truly extraordinary; Bradfield’s tumor was chock-full of Her-2, almost hypnotically drunk on the oncogene. He begged her once again to join his trial.
“Survivors look back and see omens, messages they missed,” Joan Didion wrote. For Bradfield, Slamon’s second phone call was an omen that was not missed; something in that conversation pierced through a shield that she had drawn around herself. On a warm August morning in 1992, Bradfield visited Slamon in his clinic at UCLA. He met her in the hallway and led her to a room in the back. Under the microscope, he showed her the breast cancer that had been excised from her body, with its dark ringlets of Her-2labeled cells. On a whiteboard, he drew a step-by-step picture of an epic scientific journey. He began with the discovery of neu, its rediscovery in Ullrich’s lab, the struggles to produce a drug, culminating in the antibody stitched together so carefully by Shepard and Carter. Bradfield considered the line that stretched from oncogene to drug. She agreed to join Slamon’s trial.
It was an extraordinarily fortunate decision. In the four months between Slamon’s phone call and the first infusion of Herceptin, Bradfield’s tumor had erupted, spraying sixteen new masses into her lung.
Fifteen women, including Bradfield, enrolled in Slamon’s trial at UCLA in 1992. (The number would later be expanded to thirty-seven.) The drug was given for nine weeks, in combination with cisplatin, a standard chemotherapy agent used to kill breast cancer cells, both delivered intravenously. As a matter of convenience, Slamon planned to treat all the women on the same day and in the same room. The effect was theatrical; this was a stage occupied by a beleaguered set of actors. Some women had begged and finagled their way into Slamon’s trial through friends and relatives; others, such as Bradfield, had been begged to join it. “All of us knew that we were living on borrowed time,” Bradfield said, “and so we felt twice as alive and lived twice as fiercely.” A Chinese woman in her fifties brought stash after stash of traditional herbs and salves that she swore had kept her alive thus far; she would take oncology’s newest drug, Herceptin, only if she could also take its most ancient drugs with it. A frail, thin woman in her thirties, recently relapsed with breast cancer after a bone marrow transplant, glowered silently and intensely in a corner. Some treated their illness reverentially. Some were bewildered, some too embittered to care. A mother from Boston in her midfifties cracked raunchy jokes about her cancer. The daylong drill of infusions and blood tests was exhausting. In the late evening, after all the tests, the women went their own ways. Bradfield went home and prayed. Another woman soused herself with martinis.
The lump on Bradfield’s neck—the only tumor in the group that could be physically touched, measured, and watched—became the compass for the trial. On the morning of the first intravenous infusion of the Her-2 antibody, all the women came up to feel the lump, one by one, running their hands across Bradfield’s collarbone. It was a peculiarly intimate ritual that would be repeated every week. Two weeks after the first dose of the antibody, when the group filed past Bradfield, touching the node again, the change was incontrovertible. Bradfield’s tumor had softened and visibly shrunk. “We began to believe that something was happening here,” Bradfield recalled. “Suddenly, the weight of our good fortune hit us.”
Not everyone was as fortunate as Bradfield. Exhausted and nauseous one evening, the young woman with relapsed metastatic cancer was unable to keep down the fluids needed to hydrate her body. She vomited through the night and then, too tired to keep drinking and too sick to understand the consequences, fell back into sleep. She died of kidney failure the next week.
Bradfield’s extraordinary response continued. When the CT scans were repeated two months into the trial, the tumor in her neck had virtually disappeared, and the lung metastases had also diminished both in number and size. The responses in many of the thirteen other women were more ambiguous. At the three-month midpoint of the trial, when Slamon reviewed the data with Genentech and the external trial monitors, tough decisions clearly needed to be made. Tumors had remained unchanged in size in some women—not shrunk, but static: was this to be counted as a positive response? Some women with bone metastasis reported diminished bone pain, but pain could not objectively be judged. After a prolonged and bitter debate, the trial coordinators suggested dropping seven women from the study because their responses could not be quantified. One woman discontinued the drug herself. Only five of the original cohort, including Bradfield, continued the trial to its six-month end point. Embittered and disappointed, the others returned to their local oncologists, their hopes for a miracle drug again dashed.
Barbara Bradfield finished eighteen weeks of therapy in 1993. She survives today. A gray-haired woman with crystalline gray-blue eyes, she lives in the small town of Puyallup near Seattle, hikes in the nearby woods, and leads discussion groups for her church. She vividly remembers her days at the Los Angeles clinic—the half-lit room in the back where the nurses dosed the drugs, the strangely intimate touch of the other women feeling the node in her neck. And Slamon, of course. “Dennis is my hero,” she said. “I refused his first phone call, but I have never, ever, refused him anything since that time.” The animation and energy in her voice crackled across the phone line like an electrical current. She quizzed me about my research. I thanked her for her time, but she, in turn, apologized for the distraction. “Get back to work,” she said, laughing. “There are people waiting for discoveries.”
* Ullrich actually found the human homolog of the mouse neu gene. Two other groups independently discovered the same gene.
* The drug is also known by its pharmacological name Trastuzumab; the “ab” suffix is used to denote the fact that this is an antibody.
Drugs, Bodies, and Proof
Dying people don’t have time or energy. We can’t keep doing this one woman, one drug, one company at a time.
—Gracia Buffleben
It seemed as if we had entered a brave new world of precisely targeted, less toxic, more effective combined therapies.
—Breast Cancer Action Newsletter, 2004
By the summer of 1993, news of Slamon’s early-phase trial had spread like wildfire through the community of breast cancer patients, fanning out through official and unofficial channels. In waiting rooms, infusion centers, and oncologists’ offices, patients spoke to other patients describing the occasional but unprecedented responses and remissions. Newsletters printed by breast cancer support groups whipped up a frenzy of hype and hope about Herceptin. Inevitably, a tinderbox of expectations was set to explode.
The issue was “compassionate use.” Her-2 positive breast cancer is one of the most fatal and rapidly progressive variants of the disease, and patients were willing to try any therapy that could produce a clinical benefit. Breast cancer activists pounded on Genentech’s doors to urge the release of the drug to women with Her-2 positive cancer who had failed other therapies. These patients, the activists argued, could not wait for the drug to undergo interminable testing; they wanted a potentially lifesaving medicine now. “True success happens,” as one writer put it in 1995, “only when these new drugs actually enter bodies.”
For Genentech, though, “true success” was defined by vastly different imperatives. Herceptin had not been approved by the FDA; it was a molecule in its infancy. Genentech wanted carefully executed early-phase trials—not just new drugs entering bodies, but carefully monitored drugs entering carefully monitored bodies in carefully monitored trials. For the next phase of Herceptin trials launched in 1993, Genentech wanted to stay small and focused. The number of women enrolled in these trials had been kept to an absolute minimum: twenty-seven patients at Sloan-Kettering, sixteen at UCSF, and thirty-nine at UCLA, a tiny cohort that the company intended to follow deeply and meticulously over time. “We do not provide . . . compassionate use programs,” Curd curtly told a journalist. Most doctors involved in the early-phase trials agreed. “If you start making exceptions and deviating from your protocol,” Debu Tripathy, one of the leaders of the UCSF trial, said, “then you get a lot of patients whose results are not going to help you understand whether a drug works or not. All you’re doing is delaying . . . being able to get it out into the public.”
Outside the cloistered laboratories of Genentech, the controversy ignited a firestorm. San Francisco, of course, was no stranger to this issue of compassionate use versus focused research. In the late 1980s, as AIDS had erupted in the city, filling up Paul Volberding’s haunted Ward 5B with scores of patients, gay men had coalesced into groups such as ACT UP to demand speedier access to drugs, in part through compassionate use programs. Breast cancer activists saw a grim reflection of their own struggle in these early battles. As one newsletter put it, “Why do women dying of breast cancer have such trouble getting experimental drugs that could extend their lives? For years, AIDS activists have been negotiating with drug companies and the FDA to obtain new HIV drugs while the therapies were still in clinical trials. Surely women with metastatic breast cancer for whom standard treatments have failed should know about, and have access to, compassionate use programs for experimental drugs.”
Or, as another writer put it, “Scientific uncertainty is no excuse for inaction. . . . We cannot wait for ‘proof.’”
Marti Nelson, for one, certainly could not afford to wait for proof. An outgoing, dark-haired gynecologist in California, Nelson had discovered a malignant mass in her breast in 1987, when she was just thirty-three. She had had a mastectomy and multiple cycles of chemo, then returned to practicing medicine in a San Francisco clinic. The tumor had disappeared. The scars had healed. Nelson thought that she might have been cured.
In 1993, six years after her initial surgery, Nelson noticed that the scar in her breast had begun to harden. She waved it away. But the hardened line of tissue outlining her breast was relapsed breast cancer, worming its way insidiously along the scar lines and coalescing into small, matted masses in her chest. Nelson, who compulsively followed the clinical literature on breast cancer, had heard of Her-2. Reasoning presciently that her tumor might be Her-2 positive, she tried to have her own specimen tested for the gene.
But Nelson soon found herself inhabiting a Kafkaesque nightmare. Her HMO insisted that because Herceptin was in investigational trials, testing the tumor for Her-2 was useless. Genentech insisted that without Her-2 status confirmed, giving her access to Herceptin was untenable.
In the summer of 1993, with Nelson’s cancer advancing daily and spewing out metastases into her lungs and bone marrow, the struggle took an urgent, political turn. Nelson contacted the Breast Cancer Action project, a local San Francisco organization connected with ACT UP, to help her get someone to test her tumor and obtain Herceptin for compassionate use. BCA, working through its activist networks, asked several laboratories in and around San Francisco to test Nelson’s tumor. In October 1994, the tumor was finally tested for Her-2 expression at UCSF. It was strikingly Her-2 positive. She was an ideal candidate for the drug. But the news came too late. Nine days later, still awaiting Herceptin approval from Genentech, Marti Nelson drifted into a coma and died. She was forty-one years old.
For BCA activists, Nelson’s death was a watershed event. Livid and desperate, a group of women from the BCA stormed through the Genentech campus on December 5, 1994, to hold a fifteen-car “funeral procession” for Nelson with placards showing Nelson in her chemo turban before her death. The women shouted and honked their horns and drove their cars through the manicured lawns. Gracia Buffleben, a nurse with breast cancer and one of the most outspoken leaders of the BCA, parked her car outside one of the main buildings and handcuffed herself to the steering wheel. A furious researcher stumbled out of one of the lab buildings and shouted, “I’m a scientist working on the AIDS cure. Why are you here? You are making too much noise.” It was a statement that epitomized the vast and growing rift between scientists and patients.
Marti Nelson’s “funeral” woke Genentech up to a new reality. Outrage, rising to a crescendo, threatened to spiral into a public relations disaster. Genentech had a narrow choice: unable to silence the activists, it was forced to join them. Even Curd admitted, if somewhat begrudgingly, that the BCA was “a tough group [and] their activism is not misguided.”
In 1995, a small delegation of Genentech scientists and executives thus flew to Washington to meet Frances Visco, the chair of the National Breast Cancer Coalition (NBCC), a powerful national coalition of cancer activists, hoping to use the NBCC as a neutral intermediary between the company and the local breast cancer activists in San Francisco. Pragmatic, charismatic, and savvy, Visco, a former attorney, had spent nearly a decade immersed in the turbulent politics of breast cancer. Visco had a proposal for Genentech, but her terms were inflexible: Genentech had to provide an expanded access program for Herceptin. This program would allow oncologists to treat patients outside clinical trials. In return, the National Breast Cancer Coalition would act as a go-between for Genentech and its embittered and alienated community of cancer patients. Visco offered to join the planning committee of the phase III trials of Herceptin, and to help recruit patients for the trial using the NBCC’s extensive network. For Genentech, this was a long-overdue education. Rather than running trials on breast cancer patients, the company learned to run trials with breast cancer patients. (Genentech would eventually outsource the compassionate-access program to a lottery system run by an independent agency. Women applied to the lottery and “won” the right to be treated, thus removing the company from any ethically difficult decision-making.)
It was an uneasy triangle of forces—academic researchers, the pharmaceutical industry, and patient advocates—united by a deadly disease. Genentech’s next phase of trials involved large-scale, randomized studies on thousands of women with metastatic Her-2positive cancer, comparing Herceptin treatment against placebo treatment. Visco sent out newsletters from the NBCC to patients using the coalition’s enormous Listservs. Kay Dickersin, a coalition member and an epidemiologist, joined the Data Safety and Monitoring board of the trial, underscoring the new partnership between Genentech and the NBCC, between academic medicine and activism. And an all-star team of breast oncologists was assembled to run the trial: Larry Norton from Sloan-Kettering, Karen Antman from Columbia, Daniel Hayes from Harvard, and, of course, Slamon from UCLA.
In 1995, empowered by the very forces that it had resisted for so long, Genentech launched three independent phase III trials to test Herceptin. The most pivotal of the three was a trial labeled 648, randomizing women newly diagnosed with metastatic breast cancer to standard chemotherapy alone versus chemotherapy with Herceptin added. Trial 648 was launched in 150 breast cancer clinics around the world. The trial would enroll 469 women and cost Genentech $15 million to run.
In May 1998, eighteen thousand cancer specialists flocked to Los Angeles to attend the thirty-fourth meeting of the American Society of Clinical Oncology, where Genentech would unveil the data from the Herceptin trials, including trial 648. On Sunday, May 17, the third day of the meeting, an expectant audience of thousands piled into the stuffy central amphitheater at the convention center to attend a special session dedicated to Her-2/neu in breast cancer. Slamon was slated to be the last speaker. A coil of nervous energy, with the characteristic twitch in his mustache, he stood up at the podium.
Clinical presentations at ASCO are typically sanitized and polished, with blue-and-white PowerPoint slides depicting the bottom-line message using survival curves and statistical analyses. But Slamon began—relishing this pivotal moment—not with numbers and statistics, but with forty-nine smudgy bands on a gel run by one of his undergraduate students in 1987. Oncologists slowed down their scribbling. Reporters squinted their eyes to see the bands on the gel.
That gel, he reminded his audience, had identified a gene with no pedigree—no history, no function, no mechanism. It was nothing more than an isolated, amplified signal in a fraction of breast cancer cases. Slamon had gambled the most important years of his scientific life on those bands. Others had joined the gamble: Ullrich, Shepard, Carter, Botstein and Levinson, Visco and the activists, pharma executives and clinicians and Genentech. The trial results to be announced that afternoon represented the result of that gamble. But Slamon wouldn’t—he couldn’t—rush to the end point of the journey without reminding everyone in the room of the fitful, unsanitized history of the drug.
Slamon paused for a theatrical moment before revealing the results of the trial. In the pivotal 648 study, 469 women had received standard cytotoxic chemotherapy (either Adriamycin and Cytoxan in combination, or Taxol) and were randomized to receive either Herceptin or a placebo. In every conceivable index of response, women treated with the addition of Herceptin had shown a clear and measurable benefit. Response rates to standard chemotherapy had moved up 150 percent. Tumors had shrunk in half the women treated with Herceptin compared to a third of women in the control arm. The progression of breast cancer had been delayed from four to seven and a half months. In patients with tumors heavily resistant to the standard Adriamycin and Cytoxan regimen, the benefit had been the most marked: the combination of Herceptin and Taxol had increased response rates to nearly 50 percent—a rate unheard of in recent clinical experience. The survival rate would also follow this trend. Women treated with Herceptin lived four or five months longer than women in the control group.
At face value, some of these gains might have seemed small in absolute terms—life extended by only four months. But the women enrolled in these initial trials were patients with late-stage, metastatic cancers, often heavily pretreated with standard chemotherapies and refractory to all drugs—women carrying the worst and most aggressive variants of breast cancer. (This pattern is typical: in cancer medicine, trials often begin with the most advanced and refractory cases, where even small benefits of a drug might outweigh risks.) The true measure of Herceptin’s efficacy would lie in the treatment of treatment-naive patients—women diagnosed with early-stage breast cancer who had never received any prior treatment.
In 2003, two enormous multinational studies were launched to test Herceptin in early-stage breast cancer in treatment-naive patients. In one of the studies, Herceptin treatment increased breast cancer survival at four years by a striking 18 percent over the placebo group. The second study, although stopped earlier, showed a similar magnitude of benefit. When the trials were statistically combined, overall survival in women treated with Herceptin was increased by 33 percent—a magnitude unprecedented in the history of chemotherapy for Her-2 positive cancer. “The results,” one oncologist wrote, were “simply stunning . . . not evolutionary, but revolutionary. The rational development of molecularly targeted therapies points the direction toward continued improvement in breast cancer therapy. Other targets and other agents will follow.”
On the evening of May 17, 1998, after Slamon had announced the results of the 648 study to a stunned audience at the ASCO meeting, Genentech threw an enormous cocktail party at the Hollywood Terrace, an open-air restaurant nestled in the hills of Los Angeles. Wine flowed freely, and the conversation was light and breezy. Just a few days earlier, the FDA had reviewed the data from the three Herceptin trials, including Slamon’s study, and was on the verge of “fast-tracking” the approval of Herceptin. It was a poignant posthumous victory for Marti Nelson: the drug that would likely have saved her life would become accessible to all breast cancer patients—no longer reserved for clinical trials or compassionate use alone.
“The company,” Robert Bazell, the journalist, wrote, “invited all the investigators, as well as most of Genentech’s Her-2 team. The activists came too: Marilyn McGregor and Bob Erwin [Marti Nelson’s husband] from San Francisco and Fran Visco from the National Breast Cancer Coalition.”
The evening was balmy, clear, and spectacular. “The warm orange glow of the setting sun over the San Fernando Valley set the tone of the festivities. Everyone at the party would celebrate an enormous success. Women’s lives would be saved and a huge fortune would be made.”
Only one person was conspicuously missing from the party—Dennis Slamon. Having spent the afternoon planning the next phase of Herceptin trials with breast oncologists at ASCO, Slamon had jumped into his run-down Nissan and driven home.
A Four-Minute Mile
The nontoxic curative compound remains undiscovered but not undreamt.
—James F. Holland
Why, it is asked, does the supply of new miracle drugs lag so far behind, while biology continues to move from strength to strength . . .? There is still the conspicuous asymmetry between molecular biology and, say, the therapy of lung cancer.
—Lewis Thomas,
The Lives of a Cell, 1978
In the summer of 1990, as Herceptin entered its earliest trials, another oncogene-targeted drug began its long journey toward the clinic. More than any other medicine in the history of cancer, more even than Herceptin, the development of this drug—from cancer to oncogene to a targeted therapy and to successive human trials—would signal the arrival of a new era in cancer medicine. Yet to arrive at this new era, cancer biologists would again need to circle back to old observations—to the peculiar illness that John Bennett had called a “suppuration of blood,” that Virchow had reclassified as weisses Blut in 1847, and that later researchers had again reclassified as chronic myeloid leukemia or CML.
For more than a century, Virchow’s weisses Blut had lived on the peripheries of oncology. In 1973, CML was suddenly thrust center stage. Examining CML cells, Janet Rowley identified a unique chromosomal aberration that existed in all the leukemia cells. This abnormality, the so-called Philadelphia chromosome, was the result of a translocation in which the “head” of chromosome twenty-two and the “tail” of chromosome nine had been fused to create a novel gene. Rowley’s work suggested that CML cells possess a distinct and unique genetic abnormality—possibly the first human oncogene.
Rowley’s observation launched a prolonged hunt for the mysterious chimeric gene produced by the 9:22 fusion. The identity of the gene emerged piece by piece over a decade. In 1982, a team of Dutch researchers in Amsterdam isolated the gene on chromosome nine. They called it abl.* In 1984, working with American collaborators in Maryland, the same team isolated abl’s partner on chromosome twenty-two—a gene called Bcr. The oncogene created by the fusion of these two genes in CML cells was named Bcr-abl.In 1987, David Baltimore’s laboratory in Boston “engineered” a mouse containing the activated Bcr-abl oncogene in its blood cells. The mouse developed the fatal spleen-choking leukemia that Bennett had seen in the Scottish slate-layer and Virchow in the German cook more than a century earlier—proving that Bcr-abl drove the pathological proliferation of CML cells.
As with the study of any oncogene, the field now turned from structure to function: what did Bcr-abl do to cause leukemia? When Baltimore’s lab and Owen Witte’s lab investigated the function of the aberrant Bcr-abl oncogene, they found that, like src, it was yet another kinase—a protein that tagged other proteins with a phosphate group and thus unleashed a cascade of signals in a cell. In normal cells, the Bcr and abl genes existed separately; both were tightly regulated during cell division. In CML cells, the translocation created a new chimera—Bcr-abl, a hyperactive, overexuberant kinase that activated a pathway that forced cells to divide incessantly.
In the mid-1980s, with little knowledge about the emerging molecular genetics of CML, a team of chemists at Ciba-Geigy, a pharmaceutical company in Basel, Switzerland, was trying to develop drugs that might inhibit kinases. The human genome has about five hundred kinases (of which, about ninety belong to the subclass that contains src and Bcr-abl). Every kinase attaches phosphate tags to a unique set of proteins in the cell. Kinases thus act as molecular master-switches in cells—turning “on” some pathways and turning “off” others—thus providing the cell a coordinated set of internal signals to grow, shrink, move, stop, or die. Recognizing the pivotal role of kinases in cellular physiology, the Ciba-Geigy team hoped to discover drugs that could activate or inhibit kinases selectively in cells, thus manipulating the cell’s master-switches. The team was led by a tall, reserved, acerbic Swiss physician-biochemist, Alex Matter. In 1986, Matter was joined in his hunt for selective kinase inhibitors by Nick Lydon, a biochemist from Leeds, England.
Pharmaceutical chemists often think of molecules in terms of faces and surfaces. Their world is topological; they imagine touching molecules with the tactile hypersensitivity of the blind. If the surface of a protein is bland and featureless, then that protein is typically “undruggable”; flat, poker-faced topologies make for poor targets for drugs. But if a protein’s surface is marked with deep crevices and pockets, then that protein tends to make an attractive target for other molecules to bind—and is thereby a possible “druggable” target.
Kinases, fortuitously, possess at least one such deep druggable pocket. In 1976, a team of Japanese researchers looking for poisons in sea bacteria had accidentally discovered a molecule called staurosporine, a large molecule shaped like a lopsided Maltese cross that bound to a pocket present in most kinases. Staurosporine inhibited dozens of kinases. It was an exquisite poison, but a terrible drug—possessing virtually no ability to discriminate between any kinase, active or inactive, good or bad, in most cells.
The existence of staurosporine inspired Matter. If sea bacteria could synthesize a drug to block kinases nonspecifically, then surely a team of chemists could make a drug to block only certain kinases in cells. In 1986, Matter and Lydon found a critical lead. Having tested millions of potential molecules, they discovered a skeletal chemical that, like staurosporine, could also lodge itself into a kinase protein’s cleft and inhibit its function. Unlike staurosporine, though, this skeletal structure was a much simpler chemical. Matter and Lydon could make dozens of variants of this chemical to determine if some might bind better to certain kinases. It was a self-conscious emulation of Paul Ehrlich, who had, in the 1890s, gradually coaxed specificity from his aniline dyes and thus created a universe of novel medicines. History repeats itself, but chemistry, Matter and Lydon knew, repeats itself more insistently.
It was a painstaking, iterative game—chemistry by trial and error. Jürg Zimmermann, a talented chemist on Matter’s team, created thousands of variants of the parent molecule and handed them off to a cell biologist, Elisabeth Buchdunger. Buchdunger tested these new molecules on cells, weeding out those that were insoluble or toxic, then bounced them back to Zimmermann for resynthesis, resetting the relay race toward more and more specific and nontoxic chemicals. “[It was] what a locksmith does when he has to make a key fit,” Zimmermann said. “You change the shape of the key and test it. Does it fit? If not, you change it again.”
By the early nineties, this fitting and refitting had created dozens of new molecules that were structurally related to Matter’s original kinase inhibitor. When Lydon tested this panel of inhibitors on various kinases found in cells, he discovered that these molecules possessed specificity: one molecule might inhibit src and spare every other kinase, while another might block abl and spare src. What Matter and Lydon now needed was a disease in which to apply this collection of chemicals—a form of cancer driven by a locked, overexuberant kinase that they could kill using a specific kinase inhibitor.
In the late 1980s, Nick Lydon traveled to the Dana-Farber Cancer Institute in Boston to investigate whether one of the kinase inhibitors synthesized in Basel might inhibit the growth of a particular form of cancer. Lydon met Brian Druker, a young faculty member at the institute fresh from his oncology fellowship and about to launch an independent laboratory in Boston. Druker was particularly interested in chronic myelogenous leukemia—the cancer driven by the Bcr-abl kinase.
Druker heard of Lydon’s collection of kinase-specific inhibitors, and he was quick to make the logical leap. “I was drawn to oncology as a medical student because I had read Farber’s original paper on aminopterin and it had had a deep influence on me,” he recalled. “Farber’s generation had tried to target cancer cells empirically, but had failed because the mechanistic understanding of cancer was so poor. Farber had had the right idea, but at the wrong time.”
Druker had the right idea at the right time. Once again, as with Slamon and Ullrich, two halves of a puzzle came together. Druker had a cohort of CML patients afflicted by a tumor driven by a specific hyperactive kinase. Lydon and Matter had synthesized an entire collection of kinase inhibitors now stocked in Ciba-Geigy’s freezer in Basel. Somewhere in that Ciba collection, Druker reasoned, was lurking his fantasy drug—a chemical kinase inhibitor with specific affinity for Bcr-abl. Druker proposed an ambitious collaboration between Ciba-Geigy and the Dana-Farber Cancer Institute to test the kinase inhibitors in patients. But the agreement fell apart; the legal teams in Basel and Boston could not find agreeable terms. Drugs could recognize and bind kinases specifically, but scientists and lawyers could not partner with each other to bring these drugs to patients. The project, having generated an interminable trail of legal memos, was quietly tabled.
But Druker was persistent. In 1993, he left Boston to start his own laboratory at the Oregon Health and Science University (OHSU) in Portland. Unyoked, at last, from the institution that had forestalled his collaboration, he immediately called Lydon to reestablish a connection. Lydon informed him that the Ciba-Geigy team had synthesized an even larger collection of inhibitors and had found a molecule that might bind Bcr-abl with high specificity and selectivity. The molecule was called CGP57148. Summoning all the nonchalance that he could muster—having learned his lessons in Boston—Druker walked over to the legal department at OHSU and, revealing little about the potential of the chemicals, watched as the lawyers absentmindedly signed on the dotted line. “Everyone just humored me,” he recalled. “No one thought even faintly that this drug might work.” In two weeks, he received a package from Basel with a small collection of kinase inhibitors to test in his lab.
The clinical world of CML was, meanwhile, reeling from disappointment to disappointment. In October 1992, just a few months before CGP57148 crossed the Atlantic from Lydon’s Basel lab into Druker’s hands in Oregon, a fleet of leukemia experts descended on the historic town of Bologna in Italy for an international conference on CML. The location was resplendent and evocative—Vesalius had once lectured and taught in these quadrangles and amphitheaters, dismantling Galen’s theory of cancer piece by piece. But the news at the meeting was uninspiring. The principal treatment for CML in 1993 was allogeneic bone marrow transplantation, the protocol pioneered in Seattle by Donnall Thomas in the sixties. Allo-transplantation, in which a foreign bone marrow was transplanted into a patient’s body, could increase the survival of CML patients, but the gains were often so modest that massive trials were needed to detect them. At Bologna, even transplanters glumly acknowledged the meager benefits: “Although freedom from leukemia could be obtained only with BMT,” one study concluded, “a beneficial effect of BMT on overall survival could be detected only in a patients’ subset, and . . . many hundreds of cases and a decade could be necessary to evaluate the effect on survival.”
Like most leukemia experts, Druker was all too familiar with this dismal literature. “Cancer is complicated, everyone kept telling me patronizingly—as if I had suggested that it was not complicated.” The growing dogma, he knew, was that CML was perhaps intrinsically a chemotherapy-resistant disease. Even if the leukemia was initiated by that single translocation of the Bcr-abl gene, by the time the disease was identified in full bloom in real patients, it had accumulated a host of additional mutations, creating a genetic tornado so chaotic that even transplantation, the chemotherapist’s bluntest weapon, was of no consequence. The inciting Bcr-abl kinase had likely long been overwhelmed by more powerful driver mutations. Using a kinase inhibitor to try to control the disease, Druker feared, would be like blowing hard on a matchstick long after it had ignited a forest fire.
In the summer of 1993, when Lydon’s drug arrived in Druker’s hands, he added it to CML cells in a petri dish, hoping, at best, for a small effect. But the cell lines responded briskly. Overnight, the drug-treated CML cells died, and the tissue-culture flasks filled up with floating husks of involuted leukemia cells. Druker was amazed. He implanted CML cells into mice to form real, living tumors and treated the mice with the drug. As with the first experiment, the tumors regressed in days. The response suggested specificity as well: normal mouse blood cells were left untouched. Druker performed a third experiment. He drew out samples of bone marrow from a few human patients with CML and applied CGP57148 to the cells in a petri dish. The leukemia cells in the marrow died immediately. The only cells remaining in the dish were normal blood cells. He had cured leukemia in the dish.
Druker described the findings in the journal Nature Medicine. It was a punchy, compact study—just five clean, well-built experiments—driving relentlessly toward a simple conclusion: “This compound may be useful in the treatment of Bcr-abl positive leukemias.” Druker was the first author and Lydon the senior author, with Buchdunger and Zimmermann as key contributors.
Druker expected Ciba-Geigy to be ecstatic about these results. This, after all, was the ultimate dream child of oncology—a drug with exquisite specificity for an oncogene in a cancer cell. But in Basel, Ciba-Geigy was in internal disarray. The company had fused with its archrival across the river, the pharma giant Sandoz, into a pharmaceutical behemoth called Novartis. For Novartis, it was the exquisite specificity of CGP57148 that was precisely its fatal undoing. Developing CGP57148 into a clinical drug for human use would involve further testing—animal studies and clinical trials that would cost $100 to $200 million. CML afflicts a few thousand patients every year in America. The prospect of spending millions on a molecule to benefit thousands gave Novartis cold feet.
Druker now found himself inhabiting an inverted world in which an academic researcher had to beg a pharmaceutical company to push its own products into clinical trials. Novartis had a plethora of predictable excuses: “The drug . . . would never work, would be too toxic, would never make any money.” Between 1995 and 1997 Druker flew back and forth between Basel and Portland trying to convince Novartis to continue the clinical development of its drug. “Either get [the drug] into clinical trials or license it to me. Make a decision,” Druker insisted. If Novartis would not make the drug, Druker thought he could have another chemist take it on. “In the worst case,” he recalled, “I thought I would make it in my own basement.”
Planning ahead, he assembled a team of other physicians to run a potential clinical trial of the drug on CML patients: Charles Sawyers from UCLA, Moshe Talpaz, a hematologist from Houston, and John Goldman from the Hammersmith Hospital in London, all highly regarded authorities on CML. Druker said, “I had patients in my clinic with CML with no effective treatment options remaining. Every day, I would come home from the clinic and promise to push Novartis a little.”
In early 1998, Novartis finally relented. It would synthesize and release a few grams of CGP57148, just about enough to run a trial on about a hundred patients. Druker would have a shot—but only one shot. To Novartis, CGP57148, the product of its most ambitious drug-discovery program to date, was already a failure.
I first heard of Druker’s drug in the fall of 2002. I was a medical resident triaging patients in the emergency room at Mass General when an intern called me about a middle-aged man with a history of CML who had come in with a rash. I heard the story almost instinctively, drawing quick conclusions. The patient, I surmised, had been transplanted with foreign bone marrow, and the rash was the first blush of a cataclysm to come. The immune cells in the foreign marrow were attacking his own body—graft-versus-host disease. His prognosis was grim. He would need steroids, immunosuppressives, and immediate admission to the transplant floor.
But I was wrong. Glancing at the chart in the red folder, I saw no mention of a transplant. Under the stark neon light of the examining room when he held out his hand to be examined, the rash was just a few scattered, harmless-looking papules—nothing like the dusky, mottled haze that is often the harbinger of a graft reaction. Searching for an alternative explanation, I quickly ran my eye through his list of medicines. Only one drug was listed: Gleevec, the new name for Druker’s drug, CGP57148.*
The rash was a minor side effect of the drug. The major effect of the drug, though, was less visible but far more dramatic. Smeared under the microscope in the pathology lab on the second floor, his blood cells looked extraordinarily ordinary—“normal red cells, normal platelets, normal white blood cells,” I whispered under my breath as I ran my eyes slowly over the three lineages. It was hard to reconcile this field of blood cells in front of my eyes with the diagnosis; not a single leukemic blast was to be seen. If this man had CML, he was in a remission so deep that the disease had virtually vanished from sight.
By the winter of 1998, Druker, Sawyers, and Talpaz had witnessed dozens of such remissions. Druker’s first patient to be treated with Gleevec was a sixty-year-old retired train conductor from the Oregon coast. The patient had read about the drug in an article about Druker in a local newspaper. He had called Druker immediately and offered to be a “guinea pig.” Druker gave him a small dose of the drug, then stood by his bedside for the rest of the afternoon, nervously awaiting any signs of toxicity. By the end of the day there were no adverse effects; the man was still alive. “It was the first time that the molecule had entered a human body, and it could easily have created havoc, but it didn’t,” Druker recalled. “The sense of relief was incredible.”
Druker edged into higher and higher doses—25, 50, 85, and 140 mg. His cohort of patients grew as well. As the dose was escalated in patients, Gleevec’s effect became even more evident. One patient, a Portland woman, had come to his clinic with a blood count that had risen to nearly thirtyfold the normal number; her blood vessels were engorged with leukemia, her spleen virtually heaving with leukemic cells. After a few doses of the drug, Druker found her counts dropping precipitously, then normalizing within one week. Other patients, treated by Sawyers at UCLA and Talpaz in Houston, responded similarly, with blood counts normalizing within a few weeks.
News of the drug spread quickly. The development of Gleevec paralleled the birth of the patient chat room on the Internet; by 1999, patients were exchanging information about trials online. In many cases, it was patients who informed their doctors about Druker’s drug and then, finding their own doctors poorly informed and incredulous, flew to Oregon or Los Angeles to enroll themselves in the Gleevec trial.
Of the fifty-four patients who received high doses of the drug in the initial phase I study, fifty-three showed a complete response within days of starting Gleevec. Patients continued the medicine for weeks, then months, and the malignant cells did not visibly return in the bone marrow. Left untreated, chronic myeloid leukemia is only “chronic” by the standards of leukemia: as the disease accelerates, the symptoms run on a tighter, faster arc and most patients live only three to five years. Patients on Gleevec experienced a palpable deceleration of their disease. The balance between normal and malignant cells was restored. It was an unsuppuration of blood.
By June 1999, with many of the original patients still in deep remissions, Gleevec was evidently a success. This success continues; Gleevec has become the standard of care for patients with CML. Oncologists now use the phrases “pre-Gleevec era” and “post-Gleevec era” when discussing this once-fatal disease. Hagop Kantarjian, the leukemia physician at the MD Anderson Cancer Center in Texas, recently summarized the impact of the drug on CML: “Before the year 2000, when we saw patients with chronic myeloid leukemia, we told them that they had a very bad disease, that their course was fatal, their prognosis was poor with a median survival of maybe three to six years, frontline therapy was allogeneic transplant . . . and there was no second-line treatment. . . . Today when I see a patient with CML, I tell them that the disease is an indolent leukemia with an excellent prognosis, that they will usually live their functional life span provided they take an oral medicine, Gleevec, for the rest of their lives.”
CML, as Novartis noted, is hardly a scourge on public health, but cancer is a disease of symbols. Seminal ideas begin in the far peripheries of cancer biology, then ricochet back into more common forms of the disease. And leukemia, of all forms of cancer, is often the seed of new paradigms. This story began with leukemia in Sidney Farber’s clinic in 1948, and it must return to leukemia. If cancer is in our blood, as Varmus reminded us, then it seems only appropriate that we keep returning, in ever-widening circles, to cancer of the blood.
The success of Druker’s drug left a deep impression on the field of oncology. “When I was a youngster in Illinois in the 1950s,” Bruce Chabner wrote in an editorial, “the world of sport was shocked by the feat of Roger Bannister. . . . On May 6, 1954, he broke the four-minute barrier in the mile. While improving upon the world record by only a few seconds, he changed the complexion of distance running in a single afternoon. . . . Track records fell like ripe apples in the late 50s and 60s. Will the same happen in the field of cancer treatment?”
Chabner’s analogy was carefully chosen. Bannister’s mile remains a touchstone in the history of athletics not because Bannister set an unbreachable record—currently, the fastest mile is a good fifteen seconds under Bannister’s. For generations, four minutes was thought to represent an intrinsic physiological limit, as if muscles could inherently not be made to move any faster or lungs breathe any deeper. What Bannister proved was that such notions about intrinsic boundaries are mythical. What he broke permanently was not a limit, but the idea of limits.
So it was with Gleevec. “It proves a principle. It justifies an approach,” Chabner continued. “It demonstrates that highly specific, non-toxic therapy is possible.” Gleevec opened a new door for cancer therapeutics. The rational synthesis of a molecule to kill cancer cells—a drug designed to specifically inactivate an oncogene—validated Ehrlich’s fantasy of “specific affinity.” Targeted molecular therapy for cancer was possible; one only needed to hunt for it by studying the deep biology of cancer cells.
A final note: I said CML was a “rare” disease, and that was true in the era before Gleevec. The incidence of CML remains unchanged from the past: only a few thousand patients are diagnosed with this form of leukemia every year. But the prevalence of CML—the number of patients presently alive with the disease—has dramatically changed with the introduction of Gleevec. As of 2009, CML patients treated with Gleevec survive an average of thirty years after their diagnosis. Based on that survival figure, Hagop Kantarjian estimates that within the next decade, 250,000 people will be living with CML in America, all of them on targeted therapy. Druker’s drug will alter the national physiognomy of cancer, converting a once-rare disease into a relatively common one. (Druker jokes that he has achieved the perfect inversion of the goals of cancer medicine: his drug has increased the prevalence of cancer in the world.) Given that most of our social networks typically extend to about one thousand individuals, each of us, on average, will know one person with this leukemia who is being kept alive by a targeted anticancer drug.
*Abl, too, was first discovered in a virus, and later found to be present in human cells—again recapitulating the story of ras and src. Once more, a retrovirus had “pirated” a human cancer gene and turned into a cancer-causing virus.
* Gleevec, the commercial name, is used here because it is more familiar to patients. The scientific name for CGP57148 is imatinib. The drug was also called STI571.
The Red Queen’s Race
“Well, in our country,” said Alice, still panting a little, “you’d generally get to somewhere else—if you ran very fast for a long time, as we’ve been doing.”
“A slow sort of country!” said the Queen. “Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!”
—Lewis Carroll,
Through the Looking-Glass
In August 2000, Jerry Mayfield, a forty-one-year-old Louisiana policeman diagnosed with CML, began treatment with Gleevec. Mayfield’s cancer responded briskly at first. The fraction of leukemic cells in his bone marrow dropped over six months. His blood count normalized and his symptoms improved; he felt rejuvenated—“like a new man [on] a wonderful drug.” But the response was short-lived. In the winter of 2003, Mayfield’s CML stopped responding. Moshe Talpaz, the oncologist treating Mayfield in Houston, increased the dose of Gleevec, then increased it again, hoping to outpace the leukemia. But by October of that year, there was no response. Leukemia cells had fully recolonized his bone marrow and blood and invaded his spleen. Mayfield’s cancer had become resistant to targeted therapy.
Now in the fifth year of their Gleevec trial, Talpaz and Sawyers had seen several cases like Mayfield’s. They were rare. The vast proportion of CML patients maintained deep, striking remissions on the drug, requiring no other therapy. But occasionally, a patient’s leukemia stopped responding to Gleevec, and Gleevec-resistant leukemia cells grew back. Sawyers, having just entered the world of targeted therapy, swiftly entered a molecular world beyond targeted therapy: how might a cancer cell become resistant to a drug that directly inhibits its driving oncogene?
In the era of nontargeted drugs, cancer cells were known to become drug-resistant through a variety of ingenious mechanisms. Some cells acquire mutations that activate molecular pumps. In normal cells, these pumps extrude natural poisons and waste products from a cell’s interior. In cancer cells, these activated pumps push chemotherapy drugs out from the interior of the cell. Spared by chemotherapy, the drug-resistant cells outgrow other cancer cells. Other cancer cells activate proteins that destroy or neutralize drugs. Yet other cancers escape drugs by migrating into reservoirs of the body where drugs cannot penetrate—as in lymphoblastic leukemia relapsing in the brain.
CML cells, Sawyers discovered, become Gleevec-resistant through an even wilier mechanism: the cells acquire mutations that specifically alter the structure of Bcr-abl, creating a protein still able to drive the growth of the leukemia but no longer capable of binding to the drug. Normally, Gleevec slips into a narrow, wedgelike cleft in the center of Bcr-abl—like “an arrow pierced through the center of the protein’s heart,” as one chemist described it. Gleevec-resistant mutations in Bcr-abl change the molecular “heart” of the Bcr-abl protein so that the drug can no longer access the critical cleft in the protein, thus rendering the drug ineffective. In Mayfield’s case, a single alteration in the Bcr-abl protein had rendered it fully resistant to Gleevec, resulting in the sudden relapse of leukemia. To escape targeted therapy, cancer had changed the target.
To Sawyers, these observations suggested that overcoming Gleevec resistance with a second-generation drug would require a very different kind of attack. Increasing the dose of Gleevec, or inventing closely related molecular variants of the drug, would be useless. Since the mutations changed the structure of Bcr-abl, a second-generation drug would need to block the protein through an independent mechanism, perhaps by gaining another entry point into its crucial central cleft.
In 2005, working with chemists at Bristol-Myers Squibb, Sawyers’s team generated another kinase inhibitor to target Gleevec-resistant Bcr-abl. As predicted, this new drug, dasatinib, was not a simple structural analogue of Gleevec; it accessed Bcr-abl’s “heart” through a separate molecular crevice on the protein’s surface. When Sawyers and Talpaz tested dasatinib on Gleevec-resistant patients, the effect was remarkable: the leukemia cells involuted again. Mayfield’s leukemia, fully resistant to Gleevec, was forced back into remission in 2005. His blood count normalized again. Leukemia cells dissipated out of his bone marrow gradually. In 2009, Mayfield still remains in remission, now on dasatinib.
Even targeted therapy, then, was a cat-and-mouse game. One could direct endless arrows at the Achilles’ heel of cancer, but the disease might simply shift its foot, switching one vulnerability for another. We were locked in a perpetual battle with a volatile combatant. When CML cells kicked Gleevec away, only a different molecular variant would drive them down, and when they outgrew that drug, then we would need the next-generation drug. If the vigilance was dropped, even for a moment, then the weight of the battle would shift. In Lewis Carroll’s Through the Looking-Glass, the Red Queen tells Alice that the world keeps shifting so quickly under her feet that she has to keep running just to keep her position. This is our predicament with cancer: we are forced to keep running merely to keep still.
In the decade since the discovery of Gleevec, twenty-four novel drugs have been listed by the National Cancer Institute as cancer-targeted therapies. Dozens more are in development. The twenty-four drugs have been shown to be effective against lung, breast, colon, and prostate cancers, sarcomas, lymphomas, and leukemias. Some, such as dasatinib, directly inactivate oncogenes. Others target oncogene-activated pathways—the “hallmarks of cancer” codified by Weinberg. The drug Avastin interrupts tumor angiogenesis by attacking the capacity of cancer cells to incite blood-vessel growth. Bortezomib, or Velcade, blocks an internal waste-dispensing mechanism for proteins that is particularly hyperactive in cancer cells.
More than nearly any other form of cancer, multiple myeloma, a cancer of immune-system cells, epitomizes the impact of these newly discovered targeted therapies. In the 1980s, multiple myeloma was treated by high doses of standard chemotherapy—old, hard-bitten drugs that typically ended up decimating patients about as quickly as they decimated the cancer. Over a decade, three novel targeted therapies have emerged for myeloma—Velcade, thalidomide, and Revlimid—all of which interrupt activated pathways in myeloma cells. Treatment of multiple myeloma today involves mixing and matching these drugs with standard chemotherapies, switching drugs when the tumor relapses, and switching again when the tumor relapses again. No single drug or treatment cures myeloma outright; myeloma is still a fatal disease. But as with CML, the cat-and-mouse game with cancer has extended the survival of myeloma patients—strikingly in some cases. In 1971, about half the patients diagnosed with multiple myeloma died within twenty-four months of diagnosis; the other half died by the tenth year. In 2008, about half of all myeloma patients treated with the shifting armamentarium of new drugs will still be alive at five years. If the survival trends continue, the other half will continue to be alive well beyond ten years.
In 2005, a man diagnosed with multiple myeloma asked me if he would be alive to watch his daughter graduate from high school in a few months. In 2009, bound to a wheelchair, he watched his daughter graduate from college. The wheelchair had nothing to do with his cancer. The man had fallen down while coaching his youngest son’s baseball team.
In a broader sense, the Red Queen syndrome—moving incessantly just to keep in place—applies equally to every aspect of the battle against cancer, including cancer screening and cancer prevention. In the early winter of 2007, I traveled to Framingham in Massachusetts to visit a study site that will likely alter the way we imagine cancer prevention. A small, nondescript Northeastern town bound by a chain of frozen lakes in midwinter, Framingham is nonetheless an iconic place writ large in the history of medicine. In 1948, epidemiologists identified a cohort of about five thousand men and women living in Framingham. The behavior of this cohort, its habits, its interrelationships, and its illnesses, has been documented year after year in exquisite detail, creating an invaluable longitudinal corpus of data for hundreds of epidemiological studies. The English mystery writer Agatha Christie often used a fictional village, St. Mary Mead, as a microcosm of all mankind. Framingham is the American epidemiologist’s English village. Under sharp statistical lenses, its captive cohort has lived, reproduced, aged, and died, affording a rare glimpse of the natural history of life, disease, and death.
The Framingham data set has spawned a host of studies on risk and illness. The link between cholesterol and heart attacks was formally established here, as was the association of stroke and high blood pressure. But recently, a conceptual transformation in epidemiological thinking has also been spearheaded here. Epidemiologists typically measure the risk factors for chronic, noninfectious illnesses by studying the behavior of individuals. But recently, they have asked a very different question: what if the real locus of risk lies not in the behaviors of individual actors, but in social networks?
In May 2008, two Harvard epidemiologists, Nicholas Christakis and James Fowler, used this notion to examine the dynamics of cigarette smoking. First, Fowler and Christakis plotted a diagram of all known relationships in Framingham—friends, neighbors, and relatives, siblings, ex-wives, uncles, aunts—as a densely interconnected web. Viewed abstractly, the network began to assume familiar and intuitive patterns. A few men and women (call them “socializers”) stood at the epicenter of these networks, densely connected to each other through multiple ties. In contrast, others lingered on the outskirts of the social web—“loners”—with few and fleeting contacts.
When the epidemiologists juxtaposed smoking behavior onto this network and followed the pattern of smoking over decades, a notable phenomenon emerged: circles of relationships were found to be more powerful predictors of the dynamics of smoking than nearly any other factor. Entire networks stopped smoking concordantly, like whole circuits flickering off. A family that dined together was also a family that quit together. When highly connected “socializers” stopped smoking, the dense social circle circumscribed around them also slowly stopped as a group. As a result, smoking gradually became locked into the far peripheries of all networks, confined to the “loners” with few social contacts, puffing away quietly in the distant and isolated corners of the town.
The smoking-network study offers, to my mind, a formidable challenge to simplistic models of cancer prevention. Smoking, this model argues, is entwined into our social DNA just as densely and as inextricably as oncogenes are entwined into our genetic material. The cigarette epidemic, we might recall, originated as a form of metastatic behavior—one site seeding another site seeding another. Soldiers brought smoking back to postwar Europe; women persuaded women to smoke; the tobacco industry, sensing opportunity, advertised cigarettes as a form of social glue that would “stick” individuals into cohesive groups. The capacity of metastasis is thus built into smoking. If entire networks of smokers can flicker off with catalytic speed, then they can also flicker on with catalytic speed. Sever the ties that bind the nonsmokers of Framingham (or worse, nucleate a large social network with a proselytizing smoker), and then, cataclysmically, the network might alter as a whole.
This is why even the most successful cancer-prevention strategies can lapse so swiftly. When the Red Queen’s feet stop spinning even temporarily, she does not maintain her position; the world around her, counter-spinning, pushes her off-balance. So it is with cancer prevention. When antitobacco campaigns lose their effectiveness or penetrance—as has recently happened among teens in America or in Asia—smoking often returns like an old plague. Social behavior metastasizes, eddying out from its center toward the peripheries of social networks. Mini-epidemics of smoking-related cancers are sure to follow.
The landscape of carcinogens is not static either. We are chemical apes: having discovered the capacity to extract, purify, and react molecules to produce new and wondrous molecules, we have begun to spin a new chemical universe around ourselves. Our bodies, our cells, our genes are thus being immersed and reimmersed in a changing flux of molecules—pesticides, pharmaceutical drugs, plastics, cosmetics, estrogens, food products, hormones, even novel forms of physical impulses, such as radiation and magnetism. Some of these, inevitably, will be carcinogenic. We cannot wish this world away; our task, then, is to sift through it vigilantly to discriminate bona fide carcinogens from innocent and useful bystanders.
This is easier said than done. In 2004, a rash of early scientific reports suggested that cell phones, which produce radio frequency energy, might cause a fatal form of brain cancer called a glioma. Gliomas appeared on the same side of the brain that the phone was predominantly held, further tightening the link. An avalanche of panic ensued in the media. But was this a falsely perceived confluence of a common phenomenon and a rare disease—phone usage and glioma? Or had epidemiologists missed the “nylon stockings” of the digital age?
In 2004, an enormous British study was launched to confirm these ominous early reports. “Cases”—patients with gliomas—were compared to “controls”—men and women with no gliomas—in terms of cell phone usage. The study, reported in 2006, appeared initially to confirm an increased risk of right-sided brain cancers in men and women who held their phone on their right ear. But when researchers evaluated the data meticulously, a puzzling pattern emerged: right-sided cell phone use reduced the risk of left-sided brain cancer. The simplest logical explanation for this phenomenon was “recall bias”: patients diagnosed with tumors unconsciously exaggerated the use of cell phones on the same side of their head, and selectively forgot the use on the other side. When the authors corrected for this bias, there was no detectable association between gliomas and cell phone use overall. Prevention experts, and phone-addicted teenagers, may have rejoiced—but only briefly. By the time the study was completed, new phones had entered the market and swapped out old phones—making even the negative results questionable.
The cell phone case is a sobering reminder of the methodological rigor needed to evaluate new carcinogens. It is easy to fan anxiety about cancer. Identifying a true preventable carcinogen, estimating the magnitude of risk at reasonable doses and at reasonable exposures, and reducing exposure through scientific and legislative intervention—keeping the legacy of Percivall Pott alive—is far more complex.
“Cancer at the fin de siècle,” as the oncologist Harold Burstein described it, “resides at the interface between society and science.” It poses not one but two challenges. The first, the “biological challenge” of cancer, involves “harnessing the fantastic rise in scientific knowledge . . . to conquer this ancient and terrible illness.” But the second, the “social challenge,” is just as acute: it involves forcing ourselves to confront our customs, rituals, and behaviors. These, unfortunately, are not customs or behaviors that lie at the peripheries of our society or selves, but ones that lie at their definitional cores: what we eat and drink, what we produce and exude into our environments, when we choose to reproduce, and how we age.
Thirteen Mountains
“Every sickness
is a musical problem,”
so said Novalis,
“and every cure
a musical solution.”
—W. H. Auden
The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease.
—Bert Vogelstein
When I began writing this book, in the early summer of 2004, I was often asked how I intended to end it. Typically, I would dodge the question or brush it away. I did not know, I would cautiously say. Or I was not sure. In truth, I was sure, although I did not have the courage to admit it to myself. I was sure that it would end with Carla’s relapse and death.
I was wrong. In July 2009, exactly five years after I had looked down the microscope into Carla’s bone marrow and confirmed her first remission, I drove to her house in Ipswich, Massachusetts, with a bouquet of flowers. It was an overcast morning, excruciatingly muggy, with a dun-colored sky that threatened rain but would not deliver any. Just before I left the hospital, I glanced quickly at the first note that I had written on Carla’s admission to the hospital in 2004. As I had written that note, I recalled with embarrassment, I had guessed that Carla would not even survive the induction phase of chemotherapy.
But she had made it; a charring, private war had just ended. In acute leukemia, the passage of five years without a relapse is nearly synonymous with a cure. I handed her the azaleas and she stood looking at them speechlessly, almost numb to the enormity of her victory. Once, earlier this year, preoccupied with clinical work, I had waited two days before calling her about a negative bone marrow biopsy. She had heard from a nurse that the results were in, and my delay had sent her into a terrifying spiral of depression: in twenty-four hours she had convinced herself that the leukemia had crept back and my hesitation was a signal of impending doom.
Oncologists and their patients are bound, it seems, by an intense subatomic force. So, albeit in a much smaller sense, this was a victory for me as well. I sat at Carla’s table and watched her pour a glass of water for herself, unpurified and straight from the sink. She glowed radiantly, her eyes half-closed, as if the compressed autobiography of the last five years were flashing through a private and internal cinema screen. Her children played with their Scottish terrier in the next room, blissfully oblivious of the landmark date that had just passed for their mother. All of this was for the best. “The purpose of my book,” Susan Sontag concluded in Illness as Metaphor, “was to calm the imagination, not to incite it.” So it was with my visit. Its purpose was to declare her illness over, to normalize her life—to sever the force that had locked us together for five years.
I asked Carla how she thought she had survived her nightmare. The drive to her house from the hospital that morning had taken me an hour and a half through a boil of heavy traffic. How had she managed, through the long days of that dismal summer, to drive to the hospital, wait in the room for hours as her blood tests were run, and then, told that her blood counts were too low for her to be given chemotherapy safely, turn back and return the next day for the same pattern to be repeated?
“There was no choice,” she said, motioning almost unconsciously to the room where her children were playing. “My friends often asked me whether I felt as if my life was somehow made abnormal by my disease. I would tell them the same thing: for someone who is sick, this is their new normal.”
Until 2003, scientists knew that the principal distinction between the “normalcy” of a cell and the “abnormalcy” of a cancer cell lay in the accumulation of genetic mutations—ras, myc, Rb, neu, and so forth—that unleashed the hallmark behaviors of cancer cells. But this description of cancer was incomplete. It provoked an inevitable question: how many such mutations does a real cancer possess in total? Individual oncogenes and tumor suppressors had been isolated, but what was the comprehensive set of such mutated genes that exists in any true human cancer?
The Human Genome Project, the full sequence of the normal human genome, was completed in 2003. In its wake comes a far less publicized but vastly more complex project: fully sequencing the genomes of several human cancer cells. Once completed, this effort, called the Cancer Genome Atlas, will dwarf the Human Genome Project in its scope. The sequencing effort involves dozens of teams of researchers across the world. The initial list of cancers to be sequenced includes brain, lung, pancreatic, and ovarian cancer. The Human Genome Project will provide the normal genome, against which cancer’s abnormal genome can be juxtaposed and contrasted.
The result, as Francis Collins, the leader of the Human Genome Project describes it, will be a “colossal atlas” of cancer—a compendium of every gene mutated in the most common forms of cancer: “When applied to the 50 most common types of cancer, this effort could ultimately prove to be the equivalent of more than 10,000 Human Genome Projects in terms of the sheer volume of DNA to be sequenced. The dream must therefore be matched with an ambitious but realistic assessment of the emerging scientific opportunities for waging a smarter war.” The only metaphor that can appropriately describe this project is geological. Rather than understand cancer gene by gene, the Cancer Genome Atlas will chart the entire territory of cancer: by sequencing the entire genome of several tumor types, every single mutated gene will be identified. It will represent the beginnings of the comprehensive “map” so hauntingly presaged by Maggie Jencks in her last essay.
Two teams have forged ahead in their efforts to sequence the cancer genome. One, called the Cancer Genome Atlas consortium, has multiple interconnected teams spanning several labs in several nations. The second is Bert Vogelstein’s group at Johns Hopkins, which has assembled its own cancer genome sequencing facility, raised private funding for the effort, and raced ahead to sequence the genomes of breast, colon, and pancreatic tumors. In 2006, the Vogelstein team revealed the first landmark sequencing effort by analyzing thirteen thousand genes in eleven breast and colon cancers. (Although the human genome contains about twenty thousand genes in total, Vogelstein’s team initially had tools to assess only thirteen thousand.) In 2008, both Vogelstein’s group and the Cancer Genome Atlas consortium extended this effort by sequencing hundreds of genes of several dozen specimens of brain tumors. As of 2009, the genomes of ovarian cancer, pancreatic cancer, melanoma, lung cancer, and several forms of leukemia have been sequenced, revealing the full catalog of mutations in each tumor type.
Perhaps no one has studied the emerging cancer genome as meticulously or as devotionally as Bert Vogelstein. A wry, lively, irreverent man in blue jeans and a rumpled blazer, Vogelstein recently began a lecture on the cancer genome in a packed auditorium at Mass General Hospital by attempting to distill the enormous array of discoveries in a few slides. Vogelstein’s challenge was that of the landscape artist: How does one convey the gestalt of a territory (in this case, the “territory” of a genome) in a few broad strokes of a brush? How can a picture describe the essence of a place?
Vogelstein’s answer to these questions borrows beautifully from an insight long familiar to classical landscape artists: negative space can be used to convey expanse, while positive space conveys detail. To view the landscape of the cancer genome panoramically, Vogelstein splayed out the entire human genome as if it were a piece of thread zigzagging across a square sheet of paper. (Science keeps eddying into its past: the word mitosis—Greek for “thread”—is resonant here again.) In Vogelstein’s diagram, the first gene on chromosome one of the human genome occupies the top left corner of the sheet of paper, the second gene is below it, and so forth, zigzagging through the page, until the last gene of chromosome twenty-three occupies the bottom right corner of the page. This is the normal, unmutated human genome stretched out in its enormity—the “background” out of which cancer arises.
Against the background of this negative space, Vogelstein placed mutations. Every time a gene mutation was encountered in a cancer, the mutated gene was demarcated as a dot on the sheet. As the frequency of mutations in any given gene increased, the dots grew in height into ridges and hills and then mountains. The most commonly mutated genes in breast cancer samples were thus represented by towering peaks, while genes rarely mutated were denoted by small hills or flat dots.
Viewed thus, the cancer genome is at first glance a depressing place. Mutations litter the chromosomes. In individual specimens of breast and colon cancer, between fifty to eighty genes are mutated; in pancreatic cancers, about fifty to sixty. Even brain cancers, which often develop at earlier ages and hence may be expected to accumulate fewer mutations, possess about forty to fifty mutated genes.
Only a few cancers are notable exceptions to this rule, possessing relatively few mutations across the genome. One of these is an old culprit, acute lymphoblastic leukemia: only five or ten genetic alterations cross its otherwise pristine genomic landscape.*Indeed, the relative paucity of genetic aberrancy in this leukemia may be one reason that this tumor is so easily felled by cytotoxic chemotherapy. Scientists speculate that genetically simple tumors (i.e., those carrying few mutations) might inherently be more susceptible to drugs, and thus intrinsically more curable. If so, the strange discrepancy between the success of high-dose chemotherapy in curing leukemia and its failure to cure most other cancers has a deep biological explanation. The search for a “universal cure” for cancer was predicated on a tumor that, genetically speaking, is far from universal.
In contrast to leukemia, the genomes of the more common forms of cancer, Vogelstein finds, are filled with genetic bedlam—mutations piled upon mutations upon mutations. In one breast cancer sample from a forty-three-year-old woman, 127 genes were mutated—nearly one in every two hundred genes in the human genome. Even within a single type of tumor, the heterogeneity of mutations is daunting. If one compares two breast cancer specimens, the set of mutated genes is far from identical. “In the end,” as Vogelstein put it, “cancer genome sequencing validates a hundred years of clinical observations. Every patient’s cancer is unique because every cancer genome is unique. Physiological heterogeneity is genetic heterogeneity.” Normal cells are identically normal; malignant cells become unhappily malignant in unique ways.
Yet, characteristically, where others see only daunting chaos in the littered genetic landscape, Vogelstein sees patterns coalescing out of the mess. Mutations in the cancer genome, he believes, come in two forms. Some are passive. As cancer cells divide, they accumulate mutations due to accidents in the copying of DNA, but these mutations have no impact on the biology of cancer. They stick to the genome and are passively carried along as the cell divides, identifiable but inconsequential. These are “bystander” mutations or “passenger” mutations. (“They hop along for the ride,” as Vogelstein put it.)
Other mutations are not passive players. Unlike the passenger mutations, these altered genes directly goad the growth and the biological behavior of cancer cells. These are “driver” mutations, mutations that play a crucial role in the biology of a cancer cell.
Every cancer cell possesses some set of driver and passenger mutations. In the breast cancer sample from the forty-three-year-old woman with 127 mutations, only about ten might directly be contributing to the actual growth and survival of her tumor, while the rest may have been acquired due to gene-copying errors in cancer cells. But while functionally different, these two forms of mutations cannot easily be distinguished. Scientists can identify some driver genes that directly goad cancer’s growth using the cancer genome. Since passenger mutations occur randomly, they are randomly spread throughout the genome. Driver mutations, on the other hand, strike key oncogenes and tumor suppressors, and only a limited number of such genes exist in the genome. These mutations—in genes such as ras, myc, and Rb—recur in sample upon sample. They stand out as tall mountains in Vogelstein’s map, while passenger mutations are typically represented by the valleys. But when a mutation occurs in a previously unknown gene, it is impossible to predict whether that mutation is consequential or inconsequential—driver or passenger, barnacle or engine.
The “mountains” in the cancer genome—i.e., genes most frequently mutated in a particular form of cancer—have another property. They can be organized into key cancer pathways. In a recent series of studies, Vogelstein’s team at Hopkins reanalyzed the mutations present in the cancer genome using yet another strategy. Rather than focusing on individual genes mutated in cancers, they enumerated the number of pathways mutated in cancer cells. Each time a gene was mutated in any component of the Ras-Mek-Erk pathway, it was classified as a “Ras pathway” mutation. Similarly, if a cell carried a mutation in any component of the Rb signaling pathway, it was classified as “Rb pathway mutant,” and so forth, until all driver mutations had been organized into pathways.
How many pathways are typically dysregulated in a cancer cell? Typically, Vogelstein found, between eleven and fifteen, with an average of thirteen. The mutational complexity on a gene-by-gene level was still enormous. Any one tumor bore scores of mutations pockmarked throughout the genome. But the same core pathways were characteristically dysregulated in any tumor type, even if the specific genes responsible for each broken pathway differed from one tumor to the next. Ras may be activated in one sample of bladder cancer; Mek in another; Erk in the third—but in each case, some vital piece of the Ras-Mek-Erk cascade was dysregulated.
The bedlam of the cancer genome, in short, is deceptive. If one listens closely, there are organizational principles. The language of cancer is grammatical, methodical, and even—I hesitate to write—quite beautiful. Genes talk to genes and pathways to pathways in perfect pitch, producing a familiar yet foreign music that rolls faster and faster into a lethal rhythm. Underneath what might seem like overwhelming diversity is a deep genetic unity. Cancers that look vastly unlike each other superficially often have the same or similar pathways unhinged. “Cancer,” as one scientist recently put it, “really is a pathway disease.”
This is either very good news or very bad news. The cancer pessimist looks at the ominous number thirteen and finds himself disheartened. The dysregulation of eleven to fifteen core pathways poses an enormous challenge for cancer therapeutics. Will oncologists need thirteen independent drugs to attack thirteen independent pathways to “normalize” a cancer cell? Given the slipperiness of cancer cells, when a cell becomes resistant to one combination of thirteen drugs, will we need an additional thirteen?
The cancer optimist, however, argues that thirteen is a finite number. It is a relief: until Vogelstein identified these core pathways, the mutational complexity of cancers seemed nearly infinite. In fact, the hierarchical organization of genes into pathways in any given tumor type suggests that even deeper hierarchies might exist. Perhaps not all thirteen need to be targeted to attack complex cancers such as breast or pancreatic cancer. Perhaps some of the core pathways may be particularly responsive to therapy. The best example of this might be Barbara Bradfield’s tumor, a cancer so hypnotically addicted to Her-2 that targeting this key oncogene melted the tumor away and forced a decades-long remission.
Gene by gene, and now pathway by pathway, we have an extraordinary glimpse into the biology of cancer. The complete maps of mutations in many tumor types (with their hills, valleys, and mountains) will soon be complete, and the core pathways that are mutated fully defined. But as the old proverb runs, there are mountains beyond mountains. Once the mutations have been identified, the mutant genes will need to be assigned functions in cellular physiology. We will need to move through a renewed cycle of knowledge that recapitulates a past cycle—from anatomy to physiology to therapeutics. The sequencing of the cancer genome represents the genetic anatomy of cancer. And just as Virchow made the crucial leap from Vesalian anatomy to the physiology of cancer in the nineteenth century, science must make a leap from the molecular anatomy to the molecular physiology of cancer. We will soon know what the mutant genes are. The real challenge is to understand what the mutant genes do.
This seminal transition from descriptive biology to the functional biology of cancer will provoke three new directions for cancer medicine.
The first is a direction for cancer therapeutics. Once the crucial driver mutations in any given cancer have been identified, we will need to launch a hunt for targeted therapies against these genes. This is not an entirely fantastical hope: targeted inhibitors of some of the core thirteen pathways mutated in many cancers have already entered the clinical realm. As individual drugs, some of these inhibitors have thus far had only moderate response rates. The challenge now is to determine which combinations of such drugs might inhibit cancer growth without killing normal cells.
In a piece published in the New York Times in the summer of 2009, James Watson, the codiscoverer of the structure of DNA, made a remarkable turnabout in opinion. Testifying before Congress in 1969, Watson had lambasted the War on Cancer as ludicrously premature. Forty years later, he was far less critical: “We shall soon know all the genetic changes that underlie the major cancers that plague us. We already know most, if not all, of the major pathways through which cancer-inducing signals move through cells. Some 20 signal-blocking drugs are now in clinical testing after first being shown to block cancer in mice. A few, such as Herceptin and Tarceva, have Food and Drug Administration approval and are in widespread use.”
The second new direction is for cancer prevention. To date, cancer prevention has relied on two disparate and polarized methodologies to try to identify preventable carcinogens. There have been intensive, often massive, human studies that have connected a particular form of cancer with a risk factor, such as Doll and Hill’s study identifying smoking as a risk factor for lung cancer. And there have been laboratory studies to identify carcinogens based on their ability to cause mutations in bacteria or incite precancer in animals and humans, such as Bruce Ames’s experiment to capture chemical mutagens, or Marshall and Warren’s identification of H. pylori as a cause for stomach cancer.
But important preventable carcinogens might escape detection by either strategy. Subtle risk factors for cancer require enormous population studies; the subtler the effect, the larger the population needed. Such vast, unwieldy, and methodologically challenging studies are difficult to fund and launch. Conversely, several important cancer-inciting agents are not easily captured by laboratory experiments. As Evarts Graham discovered to his dismay, even tobacco smoke, the most common human carcinogen, does not easily induce lung cancer in mice. Bruce Ames’s bacterial test does not register asbestos as a mutagen.*
Two recent controversies have starkly highlighted such blind spots in epidemiology. In 2000, the so-called Million Women Study in the United Kingdom identified estrogen and progesterone, prescribed in hormone-replacement therapy to women to ease menopausal symptoms, as major risk factors for the incidence and fatality from estrogen-positive breast cancer. Scientifically speaking, this is an embarrassment. Estrogen is not identified as a mutagen in Bruce Ames’s test; nor does it cause cancer in animals at low doses. But the two hormones have been known as pathological activators of the ER-positive subtype of breast cancer since the 1960s. Beatson’s surgery and tamoxifen induce remissions in breast cancer by blocking estrogen, and so it stands to reason that exogenous estrogen might incite breast cancer. A more integrated approach to cancer prevention, incorporating the prior insights of cancer biology, might have predicted this cancer-inducing activity, preempted the need for a million-person association study, and potentially saved the lives of thousands of women.
The second controversy also has its antecedents in the 1960s. Since the publication of Rachel Carson’s Silent Spring in 1962, environmental activists have stridently argued that the indiscriminate overuse of pesticides is partially responsible for the rising incidence of cancer in America. This theory has spawned intense controversy, activism, and public campaigns over the decades. But although the hypothesis is credible, large-scale human-cohort experiments directly implicating particular pesticides as carcinogens have emerged slowly, and animal studies have been inconclusive. DDT and aminotriazole have been shown to cause cancer in animals at high doses, but thousands of chemicals proposed as carcinogens remain untested. Again, an integrated approach is needed. The identification of key activated pathways in cancer cells might provide a more sensitive detection method to discover carcinogens in animal studies. A chemical may not cause overt cancer in animal studies, but may be shown to activate cancer-linked genes and pathways, thus shifting the burden of proof of its potential carcinogenicity.
In 2005, the Harvard epidemiologist David Hunter argued that the integration of traditional epidemiology, molecular biology, and cancer genetics will generate a resurgent form of epidemiology that is vastly more empowered in its ability to prevent cancer. “Traditional epidemiology,” Hunter reasoned, “is concerned with correlating exposures with cancer outcomes, and everything between the cause (exposure) and the outcome (a cancer) is treated as a ‘black box.’ . . . In molecular epidemiology, the epidemiologist [will] open up the ‘black box’ by examining the events intermediate between exposure and disease occurrence or progression.”
Like cancer prevention, cancer screening will also be reinvigorated by the molecular understanding of cancer. Indeed, it has already been. The discovery of the BRCA genes for breast cancer epitomizes the integration of cancer screening and cancer genetics. In the mid-1990s, building on the prior decade’s advances, researchers isolated two related genes, BRCA-1 and BRCA-2, that vastly increase the risk of developing breast cancer. A woman with an inherited mutation in BRCA-1 has a 50 to 80 percent chance of developing breast cancer in her lifetime (the gene also increases the risk for ovarian cancer), about three to five times the normal risk. Today, testing for this gene mutation has been integrated into prevention efforts. Women found positive for a mutation in the two genes are screened more intensively using more sensitive imaging techniques such as breast MRI. Women with BRCA mutations might choose to take the drug tamoxifen to prevent breast cancer, a strategy shown effective in clinical trials. Or, perhaps most radically, women with BRCA mutations might choose a prophylactic mastectomy of both breasts and ovaries before cancer develops, another strategy that dramatically decreases the chances of developing breast cancer. An Israeli woman with a BRCA-1 mutation who chose this strategy after developing cancer in one breast told me that at least part of her choice was symbolic. “I am rejecting cancer from my body,” she said. “My breasts had become no more to me than a site for my cancer. They were of no more use to me. They harmed my body, my survival. I went to the surgeon and asked him to remove them.”
The third, and arguably most complex, new direction for cancer medicine is to integrate our understanding of aberrant genes and pathways to explain the behavior of cancer as a whole, thereby renewing the cycle of knowledge, discovery, and therapeutic intervention.
One of the most provocative examples of a cancer cell’s behavior, inexplicable by the activation of any single gene or pathway, is its immortality. Rapid cellular proliferation, or the insensitivity to growth-arresting signals, or tumor angiogenesis, can all largely be explained by aberrantly activated and inactivated pathways such as ras, Rb, or myc in cancer cells. But scientists cannot explain how cancers continue to proliferate endlessly. Most normal cells, even rapidly growing normal cells, will proliferate over several generations and then exhaust their capacity to keep dividing. What allows a cancer cell to keep dividing endlessly without exhaustion or depletion generation upon generation?
An emerging, although highly controversial, answer to this question is that cancer’s immortality, too, is borrowed from normal physiology. The human embryo and many of our adult organs possess a tiny population of stem cells that are capable of immortal regeneration. Stem cells are the body’s reservoir of renewal. The entirety of human blood, for instance, can arise from a single, highly potent blood-forming stem cell (called a hematopoietic stem cell), which typically lives buried inside the bone marrow. Under normal conditions, only a fraction of these blood-forming stem cells are active; the rest are deeply quiescent—asleep. But if blood is suddenly depleted, by injury or chemotherapy, say, then the stem cells awaken and begin to divide with awe-inspiring fecundity, generating cells that generate thousands upon thousands of blood cells. In weeks, a single hematopoietic stem cell can replenish the entire human organism with new blood—and then, through yet unknown mechanisms, lull itself back to sleep.
Something akin to this process, a few researchers believe, is constantly occurring in cancer—or at least in leukemia. In the mid-1990s, John Dick, a Canadian biologist working in Toronto, postulated that a small population of cells in human leukemias also possess this infinite self-renewing behavior. These “cancer stem cells” act as the persistent reservoir of cancer—generating and regenerating cancer infinitely. When chemotherapy kills the bulk of cancer cells, a small remnant population of these stem cells, thought to be intrinsically more resistant to death, regenerate and renew the cancer, thus precipitating the common relapses of cancer after chemotherapy. Indeed, cancer stem cells have acquired the behavior of normal stem cells by activating the same genes and pathways that make normal stem cells immortal—except, unlike normal stem cells, they cannot be lulled back into physiological sleep. Cancer, then, is quite literally trying to emulate a regenerating organ—or perhaps, more disturbingly, the regenerating organism. Its quest for immortality mirrors our own quest, a quest buried in our embryos and in the renewal of our organs. Someday, if a cancer succeeds, it will produce a far more perfect being than its host—imbued with both immortality and the drive to proliferate. One might argue that the leukemia cells growing in my laboratory derived from the woman who died three decades earlier have already achieved this form of “perfection.”
Taken to its logical extreme, the cancer cell’s capacity to consistently imitate, corrupt, and pervert normal physiology thus raises the ominous question of what “normalcy” is. “Cancer,” Carla said, “is my new normal,” and quite possibly cancer is our normalcy as well, that we are inherently destined to slouch towards a malignant end. Indeed, as the fraction of those affected by cancer creeps inexorably in some nations from one in four to one in three to one in two, cancer will, indeed, be the new normal—an inevitability. The question then will not be if we will encounter this immortal illness in our lives, but when.
* Thus far, the full sequencing of ALL genomes has not been completed. The alterations described are deletions or amplifications of genes. Detailed sequencing may reveal an increase in the number of mutated genes.
* Mice filter out many of the carcinogenic components of tar. Asbestos incites cancer by inducing a scar-forming, inflammatory reaction in the body. Bacteria don’t generate this reaction and are thus “immune” to asbestos.