The Emperor of All Maladies

by Siddhartha Mukherjee

Both abnormalities, activated proto-oncogenes and inactivated tumor suppressors (“jammed accelerators” and “missing brakes”905), represent the core molecular defects in the cancer cell. Bishop, Knudson, and Varmus did not know how many such defects were ultimately needed to cause human cancers. But a confluence of them, they postulated, causes cancer.

The cancer cell was a broken, deranged machine. Oncogenes were its jammed accelerators and inactivated tumor suppressors its missing brakes.*

I do not wish to achieve immortality930 through my works. I wish to achieve immortality by not dying.

Cancer geneticists already knew two answers to this question. First, proto-oncogenes need to be activated through mutations, and mutations are rare events. Second, tumor suppressor genes need to be inactivated, but typically two copies exist of each tumor suppressor gene, and thus two independent mutations are needed to inactivate a tumor suppressor, an even rarer event. Vogelstein provided the third answer. Activating or inactivating any single gene, he postulated, produced only the first steps toward carcinogenesis. Cancer’s march was long and slow and proceeded though many mutations in many genes over many iterations. In genetic terms, our cells were not sitting on the edge of the abyss of cancer. They were dragged toward that abyss in graded, discrete steps.

Cancer, in short, was not merely genetic in its origin; it was genetic in its entirety. Abnormal genes governed all aspects of cancer’s behavior. Cascades of aberrant signals, originating in mutant genes, fanned out within the cancer cell, promoting survival, accelerating growth, enabling mobility, recruiting blood vessels, enhancing nourishment, drawing oxygen—sustaining cancer’s life.

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.

“With holistic clarity of mechanism,937 cancer prognosis and treatment will become a rational science, unrecognizable by current practitioners.”

The poet Jason Shinder wrote, “Cancer949 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.

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.)

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.

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.

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.

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.

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 dejected984, 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.

(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.)

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.

The success of Druker’s drug left a deep impression on the field of oncology. “When I was a youngster in Illinois1027 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?”

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.

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.

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?

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.

“In the end,” as Vogelstein put it1048, “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.

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?

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.”

“Death in old age is inevitable, but death before old age is not.”

Part of the unpredictability about the trajectory of cancer in the future is that we do not know the biological basis for this heterogeneity. We cannot yet fathom, for instance, what makes pancreatic cancer or gallbladder cancer so markedly different from CML or Atossa’s breast cancer. What is certain, however, is that even the knowledge of cancer’s biology is unlikely to eradicate cancer fully from our lives. As Doll suggests, and as Atossa epitomizes, we might as well focus on prolonging life rather than eliminating death. This War on Cancer may best be “won” by redefining victory.

“There are far more good historians than there are good prophets,”