Friday, August 5, 2016

Our Malevolent Doppelganger

When I first heard of Siddartha Mukerjee’s prize-winning book, The Emperor of All Maladies, I decided I wanted no part of it. Why read a book about cancer when we already hear far too much about this insidious horror of a disease? But then I read Mukerjee’s second book, The Gene, and realized that he is the latest in that enduring trend of physicians (William Carlos Williams, Lewis Thomas, Abraham Verghese) who are also brilliantly accomplished writers. So I decided to take a look at The Emperor of All Maladies (Scribner: 2010). I’m truly glad I did. Mukerjee is the real thing—a physician who seems to have maintained his humanity, his soul, his sensitivity to words, even as he maintains a killing schedule as an oncologist. Both aspects of his persona give him the necessary insights to write the book he has: a ‘biography of cancer’ that crackles with the suspense of a good mystery. The mystery, of course, involves finding the biology and genesis of cancer as a disease—the scientific pursuit—and ferreting out the medications that might promise a cure—the therapeutic pursuit. Both, though with a heavy emphasis on finding the cure, comprise what came to be known as The War on Cancer. It was a public-relations ploy designed to raise money to pay for research: money for trials for new procedures such as drugs for chemotherapy, surgery for tumor removal, X-rays to kill the offending cells; and also for the pure research into the fundamental biology of cancer cells to finally discover what, in fact, was causing cancer. What was the cellular malady that turned normally functioning cells into maniac proliferators of the tumors that were choking the body—always more and more bodies, it seemed—to death? And though the War on Cancer succeeded in raising an astonishing amount of money for cancer research and therapy, both from the U.S. Government and from private foundations, it never quite lived up to its promise. This is because the metaphor of war automatically implies taking aim and destroying an outside enemy—a virus or a bacterium that invades the body. But what Mukerjee leads us to in the end is the discovery, made gradually over the years, that the enemy is not something external to the human body. The enemy is within. Within the body. Deep within the cell. As Pogo once famously said, “we have met the enemy and it is us.”
            This is really the main thrust of Mukerjee’s book for me: cancer is not something that invades the body from without; cancer is a relentless and sometimes beautiful (Mukerjee actually uses this word) perversion of the most basic process of the human body: cell division or mitosis. The body must reproduce its cells constantly in order to live, to survive (blood cells are produced in our bone marrow at the astonishing rate of 300 billion per day!). And cancer hijacks this process in a way that makes it a virtual duplicate of ourselves. Here is how Mukerjee puts it early on:

To confront cancer is to encounter a parallel species, one perhaps more adapted to survival than even we are….This image—of cancer as our desperate, malevolent, contemporary doppelganger—is so haunting because it is at least partly true. A cancer cell is an astonishing perversion of the normal cell…Like the normal cell, the cancer cell relies on growth in the most basic, elemental sense: the division of one cell to form two (38).

What is even more mind-boggling is that cancer is not simply a fierce replica of our own ability to produce cells; the resultant cells also have the ability to evolve, to change in response to our attempts to kill or halt them. Mukerjee again:

Every generation of cancer cells creates a small number of cells that is genetically different from its parents. When a chemotherapeutic drug or the immune system attacks cancer, mutant clones that can resist the attack grow out. The fittest cancer cell survives (39).

So though we might want to think of cancer as simply a “dumb” result of basic chemical processes, we are forced to realize that cancer, like all “dumb” life, possesses a deep and deeply-ingrained intelligence. It recognizes attempts to extirpate it, bides its time, and works out strategies that allow it to survive and thrive (though here, as elsewhere in contemplating disease, I have never been able to quite figure out how “survival” fits a disease whose end game seems to be to destroy its host, and thereby, itself). Leukemia cells under attack from poisonous chemicals (combination chemotherapy), for example, seem to know enough to be able to migrate (metastasize) to the brain, where these chemicals are helpless to cross the blood-brain barrier. Mukerjee calls the brain, in this instance, “a natural ‘sanctuary’ for cancer within the body,” for a leukemia that seems almost conscious: “sensing an opportunity in that sanctuary, [it] had furtively climbed in, colonizing the one place that is fundamentally unreachable by chemotherapy” (147).
            Mukerjee gives us a detailed history of how cancer came to be recognized as a specific disease (as far back as ancient Egypt), and the many therapies developed to combat it: surgery (his description of mastectomies to extirpate breast cancer leaves us fascinated, and horrified at the more and more radical excisions that surgeons like William S. Halsted recommended in their mania to cut out every bit of a remaining cancer—all this mutilation, in the end, to no avail); chemotherapy, which found drugs almost by chance, by trial and error, and evolved to include higher and higher doses of more and more drugs, often leaving the patient half-dead from nausea (combination drug, X-ray and spinal-tap therapy was called, at St. Jude’s, “total hell”); to radiation therapy from higher and higher doses of X-rays, which themselves led to mutations; all in the effort to make the War on Cancer pay off with what was hopefully referred to as a “moon shot.” Mukerjee describes each of these phases in detail, often animated with case histories of some of his patients—the most memorable being Carla Reed. In her quest to stop her leukemia, we are told, Carla in 2004 entered “total hell,” visiting the clinic 66 times, with 58 blood tests, seven spinal taps, and several bone-marrow biopsies, in addition to multiple chemotherapies and radiations. Mukerjee cites a writer, a former nurse, describing a typical course of this “total therapy” at St. Jude’s hospital:

“From the time of his diagnosis, Eric’s illness had lasted 628 days. He had spent one quarter of these days either in a hospital bed or visiting the doctors. He had received more than 800 blood tests, numerous spinal and bone marrow taps, 30 X-rays, 120 biochemical tests, and more than 200 transfusions. No fewer than twenty doctors—hematologists, pulmonologists, neurologists, surgeons, specialists and so on—were involved in his treatment, not including the psychologist and a dozen nurses” (169).

But at least some of the patients suffering these agonies earned extensions of their lives. Mukerjee is harder on the results of the radical surgeries that were, and still, though rarely, are, the preferred treatment for breast cancer: 

Between 1891 and 1981, in the nearly 100 years of the radical mastectomy, an estimated 500,000 women underwent the procedure to “extirpate” cancer….Many were permanently disfigured; many perceived the surgery as a benediction…When radical surgery fell, an entire culture of surgery thus collapsed with it. The radical mastectomy is rarely, if ever, performed by surgeons today (201).

            The good news (if one can call it that) in Mukerjee’s story has to do with the long process of discovery about cancer biology, and the linking, finally, of these discoveries with therapies and drugs designed to match that knowledge. First, the discoveries (and it should be noted that all I can do here is provide a truncated sketch of what was and is a very complicated process). Beginning with a hunch by an Italian scientist named Boveri, biologists began to hone in on the mechanisms whereby the tightly regulated process of mitosis (cell division) in normal cells became chaotic in cancer cells. Bruce Ames, with his famous test on Salmonella bacteria in the late 1960s, found that a gene mutation would allow Salmonella to grow on sugar (galactose). He then saw that chemicals that scored high as mutagens (causing mutations) also tended to be carcinogens (causing cancer). Carcinogens, in short, had a common property: they could alter genes (mutation). One of the first carcinogens to be identified in the lab was a virus: the Rous Sarcoma Virus that could insert a viral gene into cells and make them cancerous. Though many scientists then became convinced that all cancer was caused by viruses, Howard Temin soon saw that it wasn’t the virus but what it had done that was key. By examining the Sarcoma virus, several scientists next found a specific gene, a single gene, that had done the damage. The gene was called src (pron. “sarc”), and it became one of a class called “oncogenes”—genes capable of causing cancer. It was then found how the src gene functioned: it encoded a protein whose main function was to modify other proteins by attaching a chemical, a phosphate group, to these proteins. Such protein enzymes were already known as kinases, and they acted as “molecular master switches,” often switching a cell “on” which then turned another “on” until with many cells turned “on” the target cell switched from a non-dividing to a dividing state, all under tight control. Src, by contrast, was a kinase on hyperdrive, turning normal cells into endlessly-dividing machines, the hallmark of cancer.
            One final mystery remained: how did src evolve into an oncogene? Two scientists at UCFS (University of California at San Francisco), J. Michael Bishop and Harold Varmus in the 1970s began to study src and came up with the solution. They discovered that src was not some foreign gene that had infiltrated normal cells; src was everywhere in normal cells from ducks to mice to fish to humans. But these normal src genes were not identical to the ones in the Rous virus. They were kinases, but not hyperactive ones; they were tightly regulated to act only during normal cell division. In short, they did not have the mutation that the viral genes had that made them permanently activated. Out of this, Varmus and Bishop developed a theory: normal src was a precursor to the cancer-causing viral src. It was a normal part of the cell, endogenous to the cell, that needed a mutation to turn it into a cancer-causer, an oncogene. Here is how Mukerjee sums up this vital discovery and insight:

The crucial implication of the Varmus and Bishop experiments was that a precursor of a cancer-causing gene—the “proto-oncogene,” as Bishop and Varmus called it—was a normal cellular gene. Mutations induced by chemicals or X-rays caused cancer not by “inserting” foreign genes into cells, but by activating such endogenous proto-oncogenes (362).

Mukerjee goes on to put this in historical perspective: “The Greeks had been prescient with their name for cancer, onkos (meaning load or burden). Cancer was intrinsically ‘loaded’ in our genome, awaiting activation” (362)—often by an environmental insult like cigarette smoke or radiation. He also cites a wonderful image from Harold Varmus’ speech when he and Bishop received the Nobel Prize in 1989, revealing the cancer cell to be “like Grendel (the monster in Beowulf), a distorted version of our normal selves” (363). 
            With many modifications and extensions (further research found that there were two “flavors” of cancer genes: positive ones like src that drive cell growth into hyperactivity [Bishop compared these to a “jammed accelerator”]; and negative genes, like Rb, that normally suppress cell division, but, with mutations, lose their suppressing function so that cell division goes on unhindered [as in “brakes” that don’t work]), this has become the dominant theory in cancer research. It has also, finally, led to targeted therapies that have allowed drugs to be specifically targeted to a specific kind of cancer-causing gene. Among these new targeted drugs was one called Herceptin, which targeted a breast-cancer oncogene labeled Her-2. In 1991, a patient named Bradfield was given Herceptin in combination with an older chemical, cisplatin, designed to kill breast cancer cells. Two months into her therapy, Bradfield’s neck tumor disappeared, and after 18 months of therapy, she was in full remission and survives today. Another is known as Gleevec, a drug developed by Ciba-Geigy (now Novartis) for Chronic Myeloid Leukemia or CML. Though it at first refused to spend money for drug trials for Gleevec (not enough patients would use it for Novartis to make money), Novartis finally relented and agreed to a few trials. As of 2009, CML patients treated with Gleevec were surviving an average of thirty years after diagnosis, proving that targeted cancer therapy really does work.
            But lest we forget, Mukerjee reminds us that cancer is the wiliest of all diseases. Soon, doctors were noticing that some cancers were demonstrating Gleevec resistance (similar to bacteria that become resistant to antibiotics). It is worth trying to describe this Gleevec resistance to demonstrate the phenomenal intelligence Mukerjee is at pains to make us see. I have already described cancers that migrate into the brain to escape drugs; but there is another, a cancer cell mutation that, almost fiendishly, activates the cellular pumps that normally rid the cell of natural poisons—to get rid of the chemotherapy drugs! Gleevec-resistant cells did something more astonishing: they acquired mutations that precisely altered the structure of the leukemia-causing oncogene Bcr-abl, “creating a protein still able to drive the growth of leukemia but no longer capable of binding to the drug” (442). That is, where normally Gleevec slips precisely into a “narrow, wedgelike cleft in the center of Bcr-abl” to literally pierce its heart and kill it, the mutations altered this molecular “heart” so that the drug could no longer penetrate it (it no longer fit), thus making the mutated cancer immune. As Mukerjee puts it, “To escape targeted therapy, cancer had changed the target” (442).
            I don’t know about you, but this kind of (apparently) non-cognitive intelligence, even in a form that most of us would not hesitate to call “evil,” leaves me gasping for words. It does the same to Mukerjee, though he is quite adept at providing brilliant phrases and sentences in this captivating book. But let me give you some of the thoughts that it has evoked in me, and then end with Mukerjee again. It occurred to me today that if cancer is a perversion of our normal selves, our normal processes, as Mukerjee says, then we might say that it is a perversion because it is uniquely and brilliantly concerned only with its own survival. I have always had a problem with those who insist that the only thing that matters in life is survival. Because if survival is the end game, then cancer does it even better than we do. Cancer, as we see countless times in Mukerjee’s story, is the ultimate survivor. He even says, at one point, “Some day, if a cancer succeeds (in finding immortality), it will produce a far more perfect being than its host—imbued with both immortality and the drive to proliferate” (459). Cancer, that is, is better than we humans are at survival. The question becomes, is that all we are? Are we simply here to survive? Designed to outlast everything and everyone else? If that is the case, then we are on the “right” path, moving ourselves and the planet towards destruction as we do so. In this way, we are indeed just like cancer. Our monomaniacal drive for survival moves inevitably towards the destruction of our host, the only home we know. Which is why it is here that I part company with the survivalists. Though it is difficult to say how, and to what degree, humans, human being, is/are more than simply the number of years we survive or the sum of those who survive. Human being involves others, involves all other being. It matters to humans if others survive. It must matter, as we know from the cases where such mattering is thrust aside—and we see the horrors that have marked our century, and the horrors that may yet be coming if we do nothing but look out for our own survival, either as individuals, as a country, as a continent, as a hemisphere. We can easily predict the outcome of that kind of survivalism; we are already getting a taste of it today. No. Human being, again, is more than mere survival, and that is how we differ from cancer.
            So though Mukerjee ends with a reiteration of his overall theme (“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”), when he says this he is speaking strictly as a scientist, as someone looking at cancer, at humans, as strictly physical processes. Though I have nothing but admiration for his ability to do this, and for his ability to make us see how elegant and intertwined this dread disease is with our own fate, I part company with him here. For here, after all, is where we as humans have the capacity to look deeply into this flaw in our being, contemplate it, even come to terms with it, perhaps accept it (at least in the abstract)—and in so doing, comprehend it. We, that is, comprehend it; it does not comprehend us, other than as obstacles to its survival. And that makes all the difference.

Lawrence DiStasi

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