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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