Siddhartha Mukherjee


American Physician, Biological Scientist and Author, Awarded Pulitzer Prize for his book, The Emperor Of All Maladies: A Biography of Cancer

Author Quotes

Hodgkin had just returned from his second visit to Paris, where he had learned to prepare and dissect cadaveric specimens. He was promptly recruited to collect specimens for Guy?s new museum. The job?s most inventive academic perk, perhaps, was his new title: the Curator of the Museum and the Inspector of the Dead. Hodgkin

I think the way we think about cancer, the way we treat cancer, has dramatically changed in the last century. There is an enormous amount of options that a physician can provide today, right down from curing patients, treating patients or providing patients with psychic solace or pain relief.

In 1997, the NCI director, Richard Klausner, responding to reports that cancer mortality had remained disappointingly static through the nineties, argued that the medical realities of one decade had little bearing on the realities of the next. ?There are far more good historians than there are good prophets,? Klausner wrote. ?It is extraordinarily difficult to predict scientific discovery, which is often propelled by seminal insights coming from unexpected directions. The classic example?Fleming?s discovery of penicillin on moldy bread and the monumental impact of that accidental finding?could not easily have been predicted, nor could the sudden demise of iron-lung technology when evolving techniques in virology allowed the growth of poliovirus and the preparation of vaccine. Any extrapolation of history into the future presupposes an environment of static discovery?an oxymoron.

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.

Indeed, like many of his epidemiologist peers, Graham was becoming exasperated with the exaggerated scrutiny of the word cause. That word, he believed, had outlived its original utily and turned into a liability. In 1884, the microbiologist Robert Koch had stipulated that for an agent to be defined as the cause of a disease, it would need to fulfill at least three criteria. The causal agent had to be present in diseased animals; it had to be isolated from diseased animals; and it had to be capable of transmitting the disease when introduced into a secondary host. But Koch?s postulates had arisen, crucially from the study of infectious diseases and infectious agents; they could not simply be repurposed for many noninfectious diseases. In lung cancer, for instance, it would be absurd to imagine a carcinogen being isolated from a cancerous lung after months, or years, of the original exposure.

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 immutable molecule, exquisitely 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, blood.

Memories sharpen the past; it is reality that decays.

New drugs appeared at an astonishing rate: by 1950, more than half the medicines in common medical use had been unknown merely a decade earlier. Perhaps even more significant than these miracle drugs, shifts in public health and hygiene had also drastically altered the national physiognomy of illness. Typhoid fever, a contagion whose deadly swirl could decimate entire districts in weeks, melted away as the putrid water supplies of several cities were cleansed by massive municipal efforts. Even tuberculosis, the infamous white plague of the nineteenth century, was vanishing, its incidence plummeting by more than half between 1910 and 1940, largely due to better sanitation and public hygiene efforts. The life expectancy of Americans rose from forty-seven to sixty-eight in half a century, a greater leap in longevity than had been achieved over several previous centuries.

Portions of this interview first appeared in OncNurse magazine in February 2011. We are grateful to Christin Melton for her questions.

Soot is a mixture of chemicals that would eventually be found to contain several carcinogens.

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.

The Italian memoirist Primo Levi, who survived a concentration camp and then navigated his way through a blasted Germany to his native Turin, often remarked that among the most fatal qualities of the camp was its ability to erase the idea of a life outside and beyond itself. A person?s past and his present were annihilated as a matter of course?to be in the camps was to abnegate history, identity, and personality?but it was the erasure of the future that was the most chilling. With that annihilation, Levi wrote, came a moral and spiritual death that perpetuated the status quo of imprisonment. If no life existed beyond the camp, then the distorted logic by which the camp operated became life as usual.

The smiling oncologist does not know whether his patients vomit or not.

This image?of cancer as our desperate, malevolent, contemporary doppelg„nger?is so haunting because it is at least partly true. A cancer cell is an astonishing perversion of the normal cell. Cancer is a phenomenally successful invader and colonizer in part because it exploits the very features that make us successful as a species or as an organism.

We hung our heads, ashamed. It was, I suspected, not the first time that a patient had consoled a doctor about the ineffectuality of his discipline.

Before the 1980s, the armamentarium of cancer therapy was largely built around two fundamental vulnerabilities of cancer cells. The first is that most cancers originate as local diseases before they spread systematically. Surgery and radiation therapy exploit this vulnerability. By physically excising locally restricted tumors before cancer cells can spread?or by searing cancer cells with localized bursts of powerful energy using X-rays?surgery and radiation attempt to eliminate cancer en bloc from the body. The second vulnerability is the rapid growth rate of cancer cells. Most chemotherapy drugs discovered before the 1980s target this second vulnerability. Anti-folates, such as Farber?s aminopteriin, interrupt the metabolism of folic acid and starve all cells of a crucial nutrient required for cell division. Nitrogen mustard and cisplatin chemically react with DNA, and DNA-damaged cells cannot replicate their genes and thus cannot divide. Vincristine, the periwinkle poison, thwarts the ability of a cell to construct the molecular ?scaffold? required for all cells to divide.

But what sort of experiment? An English statistician named Bradford Hill (a former victim of TB himself) proposed an extraordinary solution. Hill began by recognizing that doctors, of all people, could not be entrusted to perform such an experiment without inherent biases. Every biological experiment requires a control arm?untreated subjects against whom the efficacy of a treatment can be judged. But left to their own devices, doctors were inevitably likely (even if unconsciously so) to select certain types of patients upfront, then judge the effects of a drug on this highly skewed population using subjective criteria, piling bias on top of bias. Hill

Cancer is an expansionist disease; it invades through tissues, sets up colonies in hostile landscapes, seeking sanctuary in one organ and then immigrating to another. It lives desperately, inventively, fiercely, territorially, cannily, and defensively?at times, as if teaching us how to survive. To confront cancer is to encounter a parallel species, one perhaps more adapted to survival than even we are.

Consider the genesis of a single-celled embryo produced by the fertilization of an egg by a sperm. The genetic material of this embryo comes from two sources: paternal genes (from sperm) and maternal genes (from eggs). But the cellular material of the embryo comes exclusively from the egg; the sperm is no more than a glorified delivery vehicle for male DNA?a genome equipped with a hyperactive tail. Aside from proteins, ribosomes, nutrients, and membranes, the egg also supplies the embryo with specialized structures called mitochondria. These mitochondria are the energy-producing factories of the cell; they are so anatomically discrete and so specialized in their function that cell biologists call them organelles?i.e., mini-organs resident within cells. Mitochondria, recall, carry a small, independent genome that resides within the mitochondrion itself?not in the cell?s nucleus, where the twenty-three pairs of chromosomes (and the 21,000-odd human genes) can be found. The exclusively female origin of all the mitochondria in an embryo has an important consequence. All humans?male or female?must have inherited their mitochondria from their mothers, who inherited their mitochondria from their mothers, and so forth, in an unbroken line of female ancestry stretching indefinitely into the past. (A woman also carries the mitochondrial genomes of all her future descendants in her cells; ironically, if there is such a thing as a homunculus, then it is exclusively female in origin?technically, a femunculus?) Now imagine an ancient tribe of two hundred women, each of whom bears one child. If the child happens to be a daughter, the woman dutifully passes her mitochondria to the next generation, and, through her daughter?s daughter, to a third generation. But if she has only a son and no daughter, the woman?s mitochondrial lineage wanders into a genetic blind alley and becomes extinct (since sperm do not pass their mitochondria to the embryo, sons cannot pass their mitochondrial genomes to their children). Over the course of the tribe?s evolution, tens of thousands of such mitochondrial lineages will land on lineal dead ends by chance, and be snuffed out. And here is the crux: if the founding population of a species is small enough, and if enough time has passed, the number of surviving maternal lineages will keep shrinking, and shrinking further, until only a few are left. If half of the two hundred women in our tribe have sons, and only sons, then one hundred mitochondrial lineages will dash against the glass pane of male-only heredity and vanish in the next generation. Another half will dead-end into male children in the second generation, and so forth. By the end of several generations, all the descendants of the tribe, male or female, might track their mitochondrial ancestry to just a few women. For modern humans, that number has reached one: each of us can trace our mitochondrial lineage to a single human female who existed in Africa about two hundred thousand years ago. She is the common mother of our species. We do not know what she looked like, although her closest modern-day relatives are women of the San tribe from Botswana or Namibia. I find the idea of such a founding mother endlessly mesmerizing. In human genetics, she is known by a beautiful name?Mitochondrial Eve.

For years later, the NSABP proposed to test the operation using a systemized, randomized trial. It was, coincidentally, the eightieth ?anniversary? of Halsted?s original description of the radical mastectomy. The implicit, nearly devotional faith in a theory of cancer was finally to be put to a test. ?The clinician, no matter how venerable, must accept the fact that experience, voluminous as it might be, cannot be employed as a sensitive indicator of scientific validity,? Fisher wrote in an article. He was willing to have faith in divine wisdom, but not in Halsted as divine wisdom. ?In God we trust,? he brusquely told a journalist. ?All others [must] have data.?

How can one capture genes that behave like ghosts, Weinberg wrote, influencing cells from behind some dark curtain?

I think when we use 'stress', we are often using a kind of dummy word to try to fit many different things into one big category.

In 2004, a rash of early scientific reports suggested that cell phones, which produce radio frequency energy, might cause a fatal form of brain cancer called a glioma.

In New York in the 1910s, William B. Coley, James Ewing, and Ernest Codman had treated bone sarcomas with a mixture of bacterial toxins?the so-called Coley?s toxin.

Is g heritable? In a certain sense, yes. In the 1950s, a series of reports suggested a strong genetic component. Of these, twin studies were the most definitive. When identical twins who had been reared together ? i.e., with shared genes and shared environments ? were tested in the early fifties, psychologists had found a striking degree of concordance in their IQs, with a correlation value of 0.86. In the late eighties, when identical twins who were separated at birth and reared separately were tested, the correlation fell to 0.74 ? still a striking number.

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American Physician, Biological Scientist and Author, Awarded Pulitzer Prize for his book, The Emperor Of All Maladies: A Biography of Cancer