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 aminotri
azole 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.
Atossa’s War
We aged a hundred years and this descended
In just one hour, as at a stroke
—Anna Akhmatova,
“In Memoriam, July 19, 1914”
It is time, it is time for me too to depart. Like an old man who has outlived his contemporaries and feels a sad inner emptiness, Kostoglotov felt that evening that the ward was no longer his home, even though . . . there were the same old patients asking the same old questions again and again as though they had never been asked before: . . . Will they cure me or won’t they? What other remedies are there that might help?
—Aleksandr Solzhenitsyn, Cancer Ward
On May 17, 1973, seven weeks after Sidney Farber’s death in Boston, Hiram Gans, an old friend, stood up at the memorial service to read some lines from Swinburne’s “A Forsaken Garden”:
Here now in his triumph where all things falter,
Stretched out on the spoils that his own hand spread,
As a god self-slain on his own strange altar,
Death lies dead.
It was—careful listeners might have noted—a peculiar and deliberate inversion of the moment. It was cancer that was soon to be dead—its corpus outstretched and spread-eagled ceremonially on the altar—death lying dead.
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br /> The image belongs very much to Farber and his era, but its essence still haunts us today. In the end, every biography must also confront the death of its subject. Is the end of cancer conceivable in the future? Is it possible to eradicate this disease from our bodies and our societies forever?
The answers to these questions are embedded in the biology of this incredible disease. Cancer, we have discovered, is stitched into our genome. Oncogenes arise from mutations in essential genes that regulate the growth of cells. Mutations accumulate in these genes when DNA is damaged by carcinogens, but also by seemingly random errors in copying genes when cells divide. The former might be preventable, but the latter is endogenous. Cancer is a flaw in our growth, but this flaw is deeply entrenched in ourselves. We can rid ourselves of cancer, then, only as much as we can rid ourselves of the processes in our physiology that depend on growth—aging, regeneration, healing, reproduction.
Science embodies the human desire to understand nature; technology couples that desire with the ambition to control nature. These are related impulses—one might seek to understand nature in order to control it—but the drive to intervene is unique to technology. Medicine, then, is fundamentally a technological art; at its core lies a desire to improve human lives by intervening on life itself. Conceptually, the battle against cancer pushes the idea of technology to its far edge, for the object being intervened upon is our genome. It is unclear whether an intervention that discriminates between malignant and normal growth is even possible. Perhaps cancer, the scrappy, fecund, invasive, adaptable twin to our own scrappy, fecund, invasive, adaptable cells and genes, is impossible to disconnect from our bodies. Perhaps cancer defines the inherent outer limit of our survival. As our cells divide and our bodies age, and as mutations accumulate inexorably upon mutations, cancer might well be the final terminus in our development as organisms.
The Emperor of All Maladies Page 55
