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

by Siddhartha Mukherjee

  By the early 1990s, cancer biologists could begin to model the genesis of cancer in terms of molecular changes in genes. To understand that model, let us begin with a normal cell, say a lung cell that resides in the left lung of a forty-year-old fire-safety-equipment installer. One morning in 1968, a minute sliver of asbestos from his equipment wafts through the air and lodges in the vicinity of that cell. His body reacts to the sliver with an inflammation. The cells around the sliver begin to divide furiously, like a minuscule wound trying to heal, and a small clump of cells derived from the original cell arises at the site.

  In one cell in that clump an accidental mutation occurs in the ras gene. The mutation creates an activated version of ras. The cell containing the mutant gene is driven to grow more swiftly than its neighbors and creates a clump within the original clump of cells. It is not yet a cancer cell, but a cell in which uncontrolled cell division has partly been unleashed--cancer's primordial ancestor.

  A decade passes. The small collection of ras-mutant cells continues to proliferate, unnoticed, in the far periphery of the lung. The man smokes cigarettes, and a carcinogenic chemical in tar reaches the periphery of the lung and collides with the clump of ras-mutated cells. A cell in this clump acquires a second mutation in its genes, activating a second oncogene.

  Another decade passes. Yet another cell in that secondary mass of cells is caught in the path of an errant X-ray and acquires yet another mutation, this time inactivating a tumor suppressor gene. This mutation has little effect since the cell possesses a second copy of that gene. But in the next year, another mutation inactivates the second copy of the tumor suppressor gene, creating a cell that possesses two activated oncogenes and an inactive tumor suppressor gene.

  Now a fatal march is on; an unraveling begins. The cells, now with four mutations, begin to outgrow their brethren. As the cells grow, they acquire additional mutations and they activate pathways, resulting in cells even further adapted for growth and survival. One mutation in the tumor allows it to incite blood vessels to grow; another mutation within this blood-nourished tumor allows the tumor to survive even in areas of the body with low oxygen.

  Mutant cells beget cells beget cells. A gene that increases the mobility of the cells is activated in a cell. This cell, having acquired motility, can migrate through the lung tissue and enter the bloodstream. A descendant of this mobile cancer cell acquires the capacity to survive in the bone. This cell, having migrated through the blood, reaches the outer edge of the pelvis, where it begins yet another cycle of survival, selection, and colonization. It represents the first metastasis of a tumor that originated in the lung.

  The man is occasionally short of breath. He feels a tingle of pain in the periphery of his lung. Occasionally, he senses something moving under his rib cage when he walks. Another year passes, and the sensations accelerate. The man visits a physician and a CT scan is performed, revealing a rindlike mass wrapped around a bronchus in the lung. A biopsy reveals lung cancer. A surgeon examines the man and the CT scan of the chest and deems the cancer inoperable. Three weeks after that visit, the man returns to the medical clinic complaining of pain in his ribs and his hips. A bone scan reveals metastasis to the pelvis and the ribs.

  Intravenous chemotherapy is initiated. The cells in the lung tumor respond. The man soldiers through a punishing regimen of multiple cell-killing drugs. But during the treatment, one cell in the tumor acquires yet another mutation that makes it resistant to the drug used to treat the cancer. Seven months after his initial diagnosis, the tumor relapses all over the body--in the lungs, the bones, the liver. On the morning of October, 17, 2004, deeply narcotized on opiates in a hospital bed in Boston and surrounded by his wife and his children, the man dies of metastatic lung cancer, a sliver of asbestos still lodged in the periphery of his lung. He is seventy-six years old.

  I began this as a hypothetical story of cancer. The genes, carcinogens, and the sequence of mutations in this story are all certainly hypothetical. But the body at its center is real. This man was the first patient to die in my care during my fellowship in cancer medicine at Massachusetts General Hospital.

  Medicine, I said, begins with storytelling. Patients tell stories to describe illness; doctors tell stories to understand it. Science tells its own story to explain diseases. This story of one cancer's genesis--of carcinogens causing mutations in internal genes, unleashing cascading pathways in cells that then cycle through mutation, selection, and survival--represents the most cogent outline we have of cancer's birth.

  In the fall of 1999, Robert Weinberg attended a conference on cancer biology in Hawaii. Late one afternoon, he and Douglas Hanahan, another cancer biologist, trekked through the lava beds of the low, black mountains until they found themselves at the mouth of a volcano, staring in. Their conversation was tinged with frustration. For too long, it seemed, cancer had been talked about as if it were a bewildering hodgepodge of chaos. The biological characteristics of tumors were described as so multifarious as to defy any credible organization. There seemed to be no organizing rules.

  Yet, Weinberg and Hanahan knew, the discoveries of the prior two decades had suggested deep rules and principles. Biologists looking directly into cancer's maw now recognized that roiling beneath the incredible heterogeneity of cancer were behaviors, genes, and pathways. In January 2000, a few months after their walk to the volcano's mouth, Weinberg and Hanahan published an article titled "The Hallmarks of Cancer" to summarize these rules. It was an ambitious and iconic work that marked a return, after nearly a century's detour, to Boveri's original notion of a "unitary cause of carcinoma":

  "We discuss . . . rules that govern the transformation of normal human cells into malignant cancers. We suggest that research over the past decades has revealed a small number of molecular, biochemical, and cellular traits--acquired capabilities--shared by most and perhaps all types of human cancer."

  How many "rules," then, could Weinberg and Hanahan evoke to explain the core behavior of more than a hundred distinct types and subtypes of tumors? The question was audacious in its expansiveness; the answer even more audacious in its economy: six. "We suggest that the vast catalog of cancer cell genotypes is a manifestation of six essential alterations in cell physiology that collectively dictate malignant growth."

  1. Self-sufficiency in growth signals: cancer cells acquire an autonomous drive to proliferate--pathological mitosis--by virtue of the activation of oncogenes such as ras or myc.

  2. Insensitivity to growth-inhibitory (antigrowth) signals: cancer cells inactivate tumor suppressor genes, such as retinoblastoma (Rb), that normally inhibit growth

  3. Evasion of programmed cell death (apoptosis): cancer cells suppress and inactivate genes and pathways that normally enable cells to die.

  4. Limitless replicative potential: cancer cells activate specific gene pathways that render them immortal even after generations of growth.

  5. Sustained angiogenesis: cancer cells acquire the capacity to draw out their own supply of blood and blood vessels--tumor angiogenesis.

  6. Tissue invasion and metastasis: cancer cells acquire the capacity to migrate to other organs, invade other tissues, and colonize these organs, resulting in their spread throughout the body.

  Notably, Weinberg and Hanahan wrote, these six rules were not abstract descriptions of cancer's behavior. Many of the genes and pathways that enabled each of these six behaviors had concretely been identified--ras, myc, Rb, to name just a few. The task now was to connect this causal understanding of cancer's deep biology to the quest for its cure:

  "Some would argue that the search for the origin and treatment of this disease will continue over the next quarter century in much the same manner as it has in the recent past, by adding further layers of complexity to a scientific literature that is already complex almost beyond measure. But we anticipate otherwise: those researching the cancer problem will be practicing a dramatically different type of science than we have experienced over the past 25 years.
"

  The mechanistic maturity of cancer science would create a new kind of cancer medicine, Weinberg and Hanahan posited: "With holistic clarity of mechanism, cancer prognosis and treatment will become a rational science, unrecognizable by current practitioners." Having wandered in the darkness for decades, scientists had finally reached a clearing in their understanding of cancer. Medicine's task was to continue that journey toward a new therapeutic attack.

  * In 1988, the precise identity of only one gene--ras--was known. The other three were suspected human anti-oncogenes, although their identity would only become known later.

  PART SIX

  THE FRUITS OF

  LONG ENDEAVORS

  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 r
un. 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.)