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

I am a scientist and I am a physician. So I write papers.

If the history of medicine is told through the stories of doctors, it is because their contributions stand in place of the more substantive heroism of their patients.

In a particularly memorable exchange, Edell quizzed Liggett?s president about why the company had spent nearly $5 million to show that tobacco could cause tumors to sprout on the backs of mice, and then systematically chose to ignore any implications for carcinogenesis in humans: Edell: What was the purpose of this [experiment]? Dey: To try to reduce tumors on the backs of mice. Edell: It had nothing to do with the health and welfare of human beings? Is that correct? Dey: That?s correct. . . . Edell: And this was to save rats, right? Or mice?

In the early 1950s, Fanny Rosenow, a breast cancer survivor and cancer advocate, called the New York Times to post an advertisement for a support group for women with breast cancer. Rosenow was put through, puzzlingly, to the society editor of the newspaper. When she asked about placing her announcement, a long pause followed. I?m sorry, Ms. Rosenow, but the Times cannot publish the word breast or the word cancer in its pages. Perhaps, the editor continued, you could say there will be a meeting about diseases of the chest wall. Rosenow

It is an old complaint about the practice of medicine that it inures you to the idea of death. But when medicine inures you to the idea of life, to survival, then it has failed utterly.

Leukemia was a malignant proliferation of white cells in the blood. It was cancer in a molten, liquid form.

Most of the selected essays share a common thread: They describe how science happens.

Once again, Bradford Hill, the eminence grise of epidemiology, proposed a solution to this impasse. For studies on chronic and complex human diseases such as cancer, Hill suggested, the traditional understanding of causality needed to be broadened and revised. If lung cancer would not fit into Koch?s straitjacket, then the jacket needed to be relaxed. Hill acknowledged epidemiology?s infernal methodological struggle with causation?this was not an experimental discipline at its core?but he rose beyond it. At least in the case of lung cancer and smoking, he argued, the association possessed several additional features: It was strong: the increased risk of cancer was nearly five- or tenfold in smokers. It was consistent: Doll and Hill?s study, and Wynder and Graham?s study, performed in vastly different contexts on vastly different populations, had come up with the same link. It was specific: tobacco was linked to lung cancer?precisely the site where tobacco smoke enters the body. It was temporal: Doll and Hill had found that the longer one smoked, the greater was the increase in risk. It possessed a biological gradient: the more one smoked in quantity, the greater was the risk for lung cancer. It was plausible: a mechanistic link between an inhaled carcinogen and a malignant change in the lung was not implausible. It was coherent; it was backed by experimental evidence: the epidemiological findings and the laboratory findings, such as Graham?s tar-painting experiments in mice, were concordant. It behaved similarly in analogous situations: smoking had been correlated with lung cancer, and also with lip, throat, tongue, and esophageal cancer. Hill used these criteria to advance a radical proposition. Epidemiologists, he argued, could infer causality by using that list of nine criteria. No single item in that list proved a causal relationship. Rather, Hill?s list functioned as a sort of a la carte menu, from which scientists could pick and choose criteria to strengthen (or weak) the notion of a causal relationship. For scientific purists, this seemed rococo?and, like all things rococo, all too easy to mock: imagine a mathematician or physicist choosing from a menu of nine criteria to infer causality. Yet Hill?s list would charge epidemiological research with pragmatic clarity. Rather than fussing about the metaphysical idea about causality (what, in the purest sense, constitutes cause?), Hill changed its emphasis to a functional or operational idea. Cause is what cause does, Hill claimed. Often, like the weight of proof in a detective case, the preponderance of small bits of evidence, rather than a single definitive experiment, clinched cause.

Recombinant DNA technology allowed Genentech to synthesize human proteins de novo: rather than extracting proteins from animal and human organs, Genentech could ?engineer? a human gene into a bacterium, say, and use the bacterial cell as a bioreactor to produce vast quantities of that protein. The technology was transformative. In 1982, Genentech unveiled the first ?recombinant? human insulin; in 1984, it produced a clotting factor used to control bleeding in patients with hemophilia; in 1985, it created a recombinant version of human growth hormone?all created by engineering the production of human proteins in bacterial or animal cells.

Straining to see the world through triangle-shaped lenses, Pythagoreans argued that in heredity too a triangular harmony was at work. The mother and the father were two independent sides and the child was the third?the biological hypotenuse to the parents? two lines. And just as a triangle?s third side could arithmetically be derived from the two other sides using a strict mathematical formula, so was a child derived from the parents? individual contributions: nature from father and nurture from mother. A

The cure of even one solid cancer in adults, Farber knew, would singularly revolutionize oncology. It would provide the most concrete proof that this was a winnable war.

The moral and medical lessons from this story are even more relevant today. Medicine is in the midst of a vast reorganization of fundamental principles. Most of our models of illness are hybrid models; past knowledge is mish-mashed with present knowledge. These hybrid models produce the illusion of a systematic understanding of a disease?but the understanding is, in fact, incomplete. Everything seems to work spectacularly, until one planet begins to move backward on the horizon. We have invented many rules to understand normalcy?but we still lack a deeper, more unified understanding of physiology and pathology.

The word palliate comes from the Latin palliare, to cloak?and providing pain relief was perceived as cloaking the essence of the illness, smothering symptoms rather than attacking disease.

This was yet another colonial fascination: to create the conditions of misery in a population, then subject it to social or medical experimentation.

When you immerse yourself in medicine you realize that hope is not absolute. It's not that simple.

But cancer is not simply a clonal disease; it is a clonally evolving disease. If growth occured 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 of 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. This 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.

By the early 1940s, such tests had become accepted as an inherent part of American culture. IQ tests were used to rank job applicants, place children in school, and recruit agents for the Secret Service. In the 1950s, Americans commonly listed their IQs on their r‚sum‚s, submitted the results of a test for a job application, or even chose their spouses based on the test. IQ scores were pinned on the babies who were on display in Better Babies contests (although how IQ was measured in a two-year-old remained mysterious).

Cancer was not disorganized chromosomal chaos. It was organized chromosomal chaos.

Emblematic of this era was the prolific Viennese surgeon Theodor Billroth. Born in 1821, Billroth studied music and surgery with almost equal verve. (The professions still often go hand in hand. Both push manual skill to its limit; both mature with practice and age; both depend on immediacy, precision, and opposable thumbs.)

Gleevec, the commercial name, is used here because it is more familiar to patients. The scientific name for CGP57148 is imatinib. The drug was also called STI571.

I am not opposed to optimism, but I am fearful of the kind that comes from self-delusion.

If the history of the last century taught us the dangers of empowering governments to determine genetic fitness (i.e., which person fits within the triangle, and who lives outside it), then the question that confronts our current era is what happens when this power devolves to the individual. It is a question that requires us to balance the desires of the individual? to carve out a life of happiness and achievement, without undue suffering? with the desires of a society that, in the short term, may be interested only in driving down the burden of disease and the expense of disability. And operating silently in the background is a third set of actors: our genes themselves, which reproduce and create new variants oblivious of our desires and compulsions? but, either directly or indirectly, acutely or obliquely, influence our desires and compulsions. Speaking at the Sorbonne in 1975, the cultural historian Michel Foucault once proposed that a technology of abnormal individuals appears precisely when a regular network of knowledge and power has been established. Foucault was thinking about a regular network of humans. But it could just as easily be a network of genes.

In a piece published by the New York Times in the summer of 2009, James Watson, the co-discoverer 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.

In the era of non-targeted drugs, cancer cells were known to become drug-resistant through a variety of ingenious mechanisms. Some cells acquire mutations that activate molecular pumps. In normal cells, these pumps extrude natural poisons and waste products from a cell?s interior. In cancer cells, these activated pumps push chemotherapy drugs out from the interior of the cell. Spared by chemotherapy, the drug-resistant cells outgrow other cancer cells. Cancer cells can also activate proteins that destroy or neutralize drugs. Yet other cancers escape drugs by migrating into reservoirs of the body where drugs cannot penetrate?as in lymphoblastic leukemia relapsing in the brain.

It is easy to demonstrate an analogous effect in a lab: If you raise two plant strains ? one tall and one short ? in undernourished circumstances, then both plants grow short regardless of intrinsic genetic drive. In contrast, when nutrients are no longer limiting, the tall plant grows to its full height. Whether genes or environment ? nature or nurture ? dominates in influence depends on context. When environments are constraining, they exert a disproportionate influence. When the constraints are removed, genes become ascendant.

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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