The Emperor Of All Maladies

My initial intention was to read The Philadelphia Chromosome by Jessica Wapner, but as I was browsing for this book, another one grabbed my attention within the “Customers Who Bought This Item Also Bought” section at Amazon and that was The Emperor of All Maladies – A Biography of Cancer – by Siddharta Mukherjee – with its stellar reviews. So I decided to buy and read the latter and below is my summary/review of this must read “literary thriller”. I have subsequently learned that this book was awarded the Pulitzer prize in 2011 in the General Nonfiction category.

First a morbid statistical reminder about the fatality of cancer and its pervasiveness:

In 2010, about six hundred thousand Americans, and more than 7 million humans around the world, will die of cancer. In the United States, one in three women and one in two men will develop cancer during their lifetime. A quarter of all American deaths, and about 75 percent of all deaths worldwide, will be attributed to cancer. In some nations, cancer will surpass heart disease to become the most common cause of death.

The author then proceeds with outlining the premise of this book – a biography of cancer:

This book is a history of cancer. It is a chronicle of an ancient disease— a clandestine, “whispered-about” illness—that has metamorphosed into a lethal shape-shifting entity imbued with such penetrating metaphorical, medical, scientific, and political potency that cancer is often described as the defining plague of our generation. This book is a “biography” in the truest sense of the word—an attempt to enter the mind of this immortal illness, to understand its personality, to demystify its behavior. But my ultimate aim is to raise a question beyond biography: Is cancer’s end conceivable in the future? Is it possible to eradicate this disease from our bodies and societies forever?…Two characters stand at the epicenter of this story—both contemporaries, both idealists, both children of the boom in postwar science and technology in America, and both caught in the swirl of a hypnotic, obsessive quest to launch a national “War on Cancer.” The first is Sidney Farber, the father of modern chemotherapy, who accidentally discovers a powerful anti-cancer chemical in a vitamin analogue and begins to dream of a universal cure for cancer. The second is Mary Lasker, the Manhattan socialite of legendary social and political energy, who joins Farber in his decades-long journey But Lasker and Farber only exemplify the grit, imagination, inventiveness, and optimism of generations of men and women who have waged a battle against cancer for four thousand years. In a sense, this is a military history—one in which the adversary is formless, timeless, and pervasive. Here, too, there are victories and losses, campaigns upon campaigns, heroes and hubris, survival and resilience—and inevitably, the wounded, the condemned, the forgotten, the dead. In the end, cancer truly emerges, as a nineteenth-century surgeon once wrote in a books frontispiece, as “the emperor of all maladies, the king of terrors.’

So what exactly is cancer?

Roiling underneath these medical, cultural, and metaphorical interceptions of cancer over the centuries was the biological understanding of the illness—an understanding that had morphed, often radically, from decade to decade. Cancer, we now know, is a disease caused by the uncontrolled growth of a single cell. This growth is unleashed by mutations—changes in DNA that specifically affect genes that incite unlimited cell growth. In a normal cell, powerful genetic circuits regulate cell division and cell death. In a cancer cell, these circuits have been broken, unleashing a cell that cannot stop growing. That this seemingly simple mechanism—cell growth without barriers—can lie at the heart of this grotesque and multifaceted illness is a testament to the unfathomable power of cell growth. Cell division allows us as organisms to grow, to adapt, to recover, to repair—to live. And distorted and unleashed, it allows cancer cells to grow, to flourish, to adapt, to recover, and to repair—to live at the cost of our living. Cancer cells grow faster, adapt better. They are more perfect versions of ourselves. The secret to battling cancer, then, is to find means to prevent these mutations from occurring in susceptible cells, or to find means to eliminate the mutated cells without compromising normal growth.

Following the post-war medical progress man-kind presumed that all illnesses could be cured – not so:

The sweeping victories of postwar medicine illustrated the potent and transformative capacity of science and technology in American life. Hospitals proliferated—between 1945 and 1960, nearly one thousand new hospitals were launched nationwide; between 1935 and 1952, the number of patients admitted more than doubled from 7 million to 17 million per year. And with the rise in medical care came the concomitant expectation of medical cure. As one student observed, “When a doctor has to tell a patient that there is no specific remedy for his condition, [the patient] is apt to feel affronted, or to wonder whether the doctor is keeping abreast of the times.”

Farber, is the father of chemotherapy:

Farber’s paper, published on June 3, 1948, was seven pages long, jampacked with tables, figures, microscope photographs, laboratory values, and blood counts. Its language was starched, formal, detached, and scientific…The paper was received, as one scientist recalls, “with skepticism, disbelief, and outrage.”…In the summer of 1948, when one of Farber’s assistants performed a bone marrow biopsy on a leukemic child after treatment with aminopterin, the assistant could not believe the results. “The bone marrow looked so normal,” he wrote, “that one could dream of a cure.” And so Farber did dream. He dreamed of malignant cells being killed by Specific anticancer drugs, and of normal cells regenerating and reclaiming their physiological spaces; of a whole gamut of such systemic antagonists to decimate malignant cells; of curing leukemia with chemicals, then applying his experience with chemicals and leukemia to more common cancers. He was throwing down a gauntlet for cancer medicine. It was then up to an entire generation of doctors and scientists to pick it up.

A reminder however of why treating cancer is particularly difficult – it evolves:

But cancer is not simply a clonal disease; it is a clonally evolving disease. If growth occurred without evolution, cancer cells would not be imbued with their potent capacity to invade, survive, and metastasize. 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. This mirthless, relentless cycle of mutation, selection, and overgrowth generates cells that are more and more adapted to survival and growth. In some cases, the mutations speed up the acquisition of other mutations The genetic instability, like a perfect madness, only provides more impetus to generate mutant clones. Cancer thus exploits the fundamental logic of evolution unlike any other illness. If we, as a species, are the ultimate product of Darwinian selection, then so, too, is this incredible disease that lurks inside us.

Is cancer a new disease? Why does it seem to occur more now than it did in the past?

The most striking finding, though, is not that cancer existed in the distant past, but that it was fleetingly rare. When I asked Aufderheide about this he laughed. “The early history of cancer,” he said, “is that there is very little early history of cancer.”…There are several reasons behind this absence. Cancer is an age-related disease—sometimes exponentially so…Our capacity to detect cancer earlier and earlier, and to attribute deaths accurately to it, has also dramatically increased in the last century…Finally changes in the structure of modern life have radically shifted the spectrum of cancers—increasing the incidence of some, decreasing the incidence of others.

How radiation therapy came to be:

It would take biologists decades to fully decipher the mechanism that lay behind these effects, but the spectrum of damaged tissues—skin, lips. blood, gums, and nails—already provided an important clue: radium was attacking DNA. DNA is an inert molecule, exhaustively resistant to most chemical reactions, for its job is to maintain the stability of genetic information. But X-rays can shatter strands of DNA or generate toxic chemicals that corrode DNA. Cells respond to this damage by dying or, more often, by ceasing to divide. X-rays thus preferentially kill the most rapidly proliferating cells in the body, cells in the skin, nails, gums, and blood. This ability of X-rays to selectively kill rapidly dividing cells did not go unnoticed—especially by cancer researchers. In 1896, barely a year after Rontgen had discovered his X-rays, a twenty-one-year-old Chicago medical student, Emil Grubbe. had the inspired notion of using X-rays to treat cancer…Radiation therapy catapulted cancer medicine into its atomic age—an age replete with both promise and peril. Certainly, the vocabulary, the images, and the metaphors bore the potent symbolism of atomic power unleashed on cancer.

A key component of the war against cancer was funding for research – how was that to be unlocked?

But to measure the genius of the Jimmy campaign in dollars and cents is to miss its point. For Farber, the Jimmy Fund campaign was an early experiment—the building of another model. The campaign against cancer, Farber learned, was much like a political campaign: it needed icons, mascots, images, slogans—the strategies of advertising as much as the tools of science. For any illness to rise to political prominence, it needed to be marketed, just as a political campaign needed marketing. A disease needed to be transformed politically before it could be transformed scientifically. If Farber’s antifolates were his first discovery in oncology, then this critical truth was his second. It set off a seismic transformation in his career that would far outstrip his transformation from a pathologist to a leukemia doctor. This second transformation—from a clinician into an advocate for cancer research—reflected the transformation of cancer itself. The emergence of cancer from its basement into the glaring light of publicity would change the trajectory of this story. It is a metamorphosis that he’s at the heart of this book.

This is where Mary Lasker played an instrumental role:

“If a toothpaste … deserved advertising at the rate of two or three or four million dollars a year,” Mary Lasker reasoned, “then research against diseases maiming and crippling people in the United States and in the rest of the world deserved hundreds of millions of dollars.” Within just a few years, she transformed, as BusinessWeek magazine once put it, into “the fairy godmother of medical research.”…To Farber’s evangelistic tambourine, Lasker added her own drumbeats of enthusiasm. She spoke and wrote passionately and confidently about her cause, emphasizing her points with quotes and questions. Back in New York, she employed a retinue of assistants to scour newspapers and magazines and clip out articles containing even a passing reference to cancer— all of which she read, annotated on the margins with questions in small, precise script, and distributed to the other Laskerites every week.

While it was important from a campaigning perspective to have one enemy cancer, the reality is cancer was of many types and forms (and thus each required a different cure):

But naive or not, it was this lumping—this emphatic, unshakable faith in the underlying singularity of cancer more than its pluralities—that galvanized the Laskerites in the 1960s. Oncology was on a quest for cohesive truths—a “universal cure,” as Farber put it in 1962. And if the oncologists of the 1960s imagined a common cure for all forms of cancer, it was because they imagined a common disease called cancer. Curing one form, the belief ran, would inevitably Iead to the cure, of another, and so forth like a chain reaction, until the whole malignant edifice had crumbled like a set of dominoes. That assumption—that a monolithic hammer would eventually demolish a monolithic disease—surcharged physicians, scientists, and cancer lobbyists with vitality and energy. For the Laskerites, it was an organizing principle, a matter of faith, the only certain beacon toward which they all gravitated. Indeed, the Political consolidation of cancer that the Laskerites sought in Washington (a single institute, a single source of funds, led by a single physician or scientist) relied on a deeper notion of a medical consolidation of cancer into a single disease, a monolith, a single, central narrative. Without this grand, embracing narrative, neither Mary Lasker nor Sidney Farber could have envisioned a systematic, targeted war.

A key element of the progress of the battle against cancer was defining how that progress was to be measured:

The measurement of illness, Breslow was arguing, is an inherently subjective activity: it inevitably ends up being a measure of ourselves. Objective decisions come to rest on normative ones. Cairns or Bailar could tell us how many absolute lives were being saved or lost by cancer therapeutics. But to decide whether the investment in cancer research was “worth it,” one needed to start by questioning the notion of “worth” itself: was the life extension of a five-year-old “worth” more than the life extension of a sixty-year-old? Even Bailar and Smiths “most fundamental measure of clinical outcome”—death—was far from fundamental. Death (or at least the social meaning of death) could be counted and recounted with other gauges, often resulting in vastly different conclusions. The appraisal of diseases depends, Breslow argued, on our self-appraisal. Society and illness often encounter each other in parallel mirrors, each holding up a Rorschach test for the other.

One cannot talk about cancer and not mention smoking and the impact the tobacco industry has had on smokers developing lung cancer:

Yet the real legacy of the Cipollone case had little to do with legal victories or losses. Lampooned in court as a weak-willed, ill-informed, and dim-witted addict unaware of the “obvious” dangers of tobacco, Rose Cipollone nonetheless turned into a heroic icon of a cancer victim battling her disease—even from her grave…Yet, old sins have long shadows, and carcinogenic sins especially so. The lag time between tobacco exposure and lung cancer is nearly three decades, and the lung cancer epidemic in America will have an afterlife long after smoking incidence has dropped. Among men, the age-adjusted incidence of lung adenocarcinoma, having peaked at 102 per 100,000 in 1984, dropped to 77 in 2002. Among women, though, the epidemic still runs unabated. The stratospheric rise of smoking among women in Rose Cipollone’s generation is still playing itself out in the killing fields of lung cancer…Yet despite the evident seriousness of this addiction and its long-term consequences, tobacco consumption continues relatively unfettered even today Smoking rates, having plateaued for decades, have begun to rise again in certain demographic pockets, and lackluster antismoking campaigns have lost their grip on public imagination. The disjunction between the threat and the response is widening. It remains an astonishing, disturbing fact that in America—a nation where nearly every new drug is subjected to rigorous scrutiny as a potential carcinogen, and even the bare hint of a substances link to cancer ignites a firestorm of public hysteria and media anxiety—one of the most potent and common carcinogens known to humans can be freely bought and sold at every corner store for a few dollars.

A reminder about the realities of scientific research:

Science is often described as an iterative and cumulative process, a puzzle solved piece by piece, with each piece contributing a few hazy pixels of a much larger picture. But the arrival of a truly powerful new theory in science often feels far from iterative. Rather than explain one observation or phenomenon in a single, pixelated step, an entire field of observations suddenly seems to crystallize into a perfect whole. The effect is almost like watching a puzzle solve itself. Varmus and Bishops experiments had precisely such a crystalizing, zippering effect on cancer genetics. The crucial implication of the Varmus and Bishop experiment 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.

And also, the fact that we are surrounded by an evolving list of potential carcinogens:

The landscape of carcinogens is not static either. We are chemical apes: laving discovered the capacity to extract, purify, and react molecules to produce new and wondrous molecules, we have begun to spin a new chemical universe around ourselves. Our bodies, our cells, our genes are thus being immersed and reimmersed in a changing flux of molecules—pesticides, pharmaceutical drugs, plastics, cosmetics, estrogens, food products, hormones, even novel forms of physical impulses, such as radiation and magnetism. Some of these, inevitably, will be carcinogenic. We cannot wish this world away; our task, then, is to sift through it vigilantly to discriminate bona fide carcinogens from innocent and useful bystanders.

The future might not bring a cure that eradicates cancer, but treatments that prolong the life of those affected:

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 Atossas 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.

On a concluding note:

Germaine seemed, that evening, to have captured something essential about our struggle against cancer: that, to keep pace with this malady, you needed to keep inventing and reinventing, learning and unlearning strategies. Germaine fought cancer obsessively, cannily, desperately, fiercely, madly, brilliantly, and zealously—as if channeling all the fierce, inventive energy of generations of men and women who had fought cancer in the past and would fight it in the future. Her quest for a cure had taken her on a strange and limitless journey, through Internet blogs and teaching hospitals, chemotherapy and clinical trials halfway across the country, through a landscape more desolate, desperate, and disquieting than she had ever imagined. She had deployed every morsel of energy to the quest, mobilizing and remobilizing the last dregs of her courage, summoning her will and wit and imagination, until, that final evening, she had stared into the vault of her resourcefulness and resilience and found it empty. In that haunted last night, hanging on to her life by no more than a tenuous thread, summoning all her strength and dignity as she wheeled herself to the privacy of her bathroom, it was as if she had encapsulated the essence of a four-thousand-year-old war.

A highly recommended read, about a subject that unfortunately touches most of us whether directly or indirectly. I dedicate this post to my grandmother, Aida, who passed away from cancer in 2000.

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