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

An emerging, though highly controversial, answer to this question is that cancer?s immortality, too, is borrowed from normal physiology. The human embryo and many of our adult organs possess a tiny population of stem cells that are capable of immortal regeneration. Stem cells are the body?s reservoir of renewal. The entirety of human blood, for instance, can arise from a single, highly potent blood-forming stem cell (call a hematopoietic stem cell), which typically lives buried inside the bone marrow. Under normal conditions, only a fraction of these blood-forming stem cells are active; the rest are deeply quiescent?asleep. But if blood is suddenly depleted, by injury or chemotherapy say, then the stem cells awaken and begin to divide with awe-inspiring fecundity, generating cells that generate thousands upon thousands of blood cells. In weeks, a single hematopoietic stem cell can replenish the entire human organism with new blood?and then, through yet unknown mechanisms, lull itself back to sleep.

But the activated ras pathway (Ras?>Mek?>Erk) does not merely cause accelerated cell division; the pathway also intersects with other pathways to enable several other ?behaviors? of cancer cells. At Children?s Hospital in Boston in the 1990s, the surgeon-scientist Judah Folkman demonstrated that certain activated signaling pathways within cancer cells, Ras among them, could also induce neighboring blood vessels to grow. A tumor could thus ?acquire? its own blood supply by insidiously inciting a network of blood vessels around itself and then growing, in grapelike clusters, around those vessels, a phenomenon that folkman called tumor angiogenesis.

By the time Virchow died in 1902, a new theory of cancer had slowly coalesced out of all these observations. Cancer was a disease of pathological hyperplasia in which cells acquired an autonomous will to divide. This aberrant, uncontrolled cell division created masses of tissue (tumors) that invaded organs and destroyed normal tissues. These tumors could also spread from one site to another, causing outcroppings of the disease?called metastasis?in distant sites, such as the bones, the brain, or the lungs. Cancer came in diverse forms?breast, stomach, skin, and cervical cancer, leukemias and lymphomas. But all these diseases were deeply connected at the cellular level. In every case, cells had acquired the same characteristic: uncontrollable pathological cell division.

Cancer, perhaps, is an ultimate perversion of genetics?a genome that becomes pathologically obsessed with replicating itself.

Etymologically, patient means sufferer. It is not suffering as such that is most deeply feared but suffering that degrades. ?Susan Sontag, Illness as Metaphor

Great science emerges out of great contradiction.

I believe the biggest breakthroughs on cancer could come from brilliant researchers based in India.

In 1788, the Chimney Sweepers Act was passed in Parliament, preventing master sweeps from employing children under eight (children over eight were allowed to be apprenticed).

In August 1867, a thirteen-year-old boy who had severely cut his arm while operating a machine at a fair in Glasgow was admitted to Lister?s infirmary. The boy?s wound was open and smeared with grime?a setup for gangrene. But rather than amputating the arm, Lister tried a salve of carbolic acid, hoping to keep the arm alive and uninfected. The wound teetered on the edge of a terrifying infection, threatening to become an abscess. But Lister persisted, intensifying his application of carbolic acid paste. For a few weeks, the whole effort seemed hopeless. But then, like a fire running to the end of a rope, the wound began to dry up. A month later, when the poultices were removed, the skin had completely healed underneath.

In the laboratory, we call this the six-degrees-of-separation-from-cancer rule: you can ask any biological question, no matter how seemingly distant?what makes the heart fail, or why worms age, or even how birds learn songs?and you will end up, in fewer than six genetic steps, connecting with a proto-oncogene or tumor suppressor.

It is not what you have, as a certain Brazilian samba instructor once told me, it is what you do with it.

Like so many doctors, Rieff recalls, he spoke to us as if we were children but without the care that a sensible adult takes in choosing what words to use with a child. The sheer inflexibility of that approach

My book is an attempt to answer her question by going back to the origin of the disease and showing its development through history. I called it a biography of cancer, because it draws a portrait of an illness over time.

Other cancer-causing viruses, such as SV40 and human papillomavirus (HPV), would eventually be discovered in 1960 and 1983, respectively.

Science embodies the human desire to understand nature; technology couples that desire with the ambition to control nature. These are related impulses?one might seek to understand nature in order to control it?but the drive to intervene is unique to technology. Medicine, then, is fundamentally a technological art; at its core lies a desire to improve human lives by intervening on life itself. Conceptually, the battle against cancer pushes the idea of technology to its far edge, for the object being intervened upon is our genome. It is unclear whether an intervention that discriminates between malignant and normal growth is even possible. Perhaps cancer, the scrappy, fecund, invasive, adaptable twin to our own scrappy, fecund, invasive, adaptable cells and genes, is impossible to disconnect from our bodies. Perhaps cancer defines the inherent outer limit of our survival. As our cells divide and our bodies age, and as mutants accumulate inexorably upon mutations, cancer might well be the final terminus in our development as organisms. But our goals could be more modest. Above the door to Richard Peto?s office in Oxford hangs one of Doll?s favorite aphorisms: Death in old age is inevitable, but death before old age is not. Doll?s idea represents a far more reasonable proximal goal to define success in the war on cancer. It is possible that we are fatally conjoined to this ancient illness, forced to play its cat-and-mouse game for the foreseeable future of our species. But if cancer deaths can be prevented before old age, if the terrifying game of treatment, resistance, recurrence and more treatment can be stretched out longer and longer, then it will transform the way we imagine this ancient illness. Given what we know about cancer, even this modest goal would represent a technological victory unlike any other in our history. It will be a victory over our own inevitability?a victory over our genomes.

Technological innovations do not define a science; they merely prove that medicine is scientific.

The evolution of Rous sarcoma virus, then, was purely an accident. Retroviruses, Temin had shown, shuttle constantly out of the cell?s genome: RNA to DNA to RNA. During this cycling, they can pick up pieces of the cell?s genes and carry them, like barnacles, from one cell to another. Rous sarcoma virus had likely picked up an activated src gene from a cancer cell and carried it around, creating more cancer. The virus was no more than an accidental courier for a cancer-causing gene that had originated in a cancer cell?a parasite parasitized by cancer.

The philosopher of science Karl Popper coined the term ?risky prediction? to describe the process by which scientists verify untested theories. Good theories, Popper proposed, generate risky predictions. They presage a unanticipated fact or event that runs a real risk of not occurring or being proven incorrect. When this unanticipated fact proves true or the event does occur, the theory gains credibility and robustness. Newton?s understanding of gravitation was most spectacularly validated when it accurately presaged the return of Halley?s comet in 1758. Einstein?s theory of relativity was vindicated in 1919 by the demonstration that light from distant stars is ?bent? by the mass of the sun, just as predicted by the theory?s equations.

There is a very moving and ancient connection between cancer and depression.

Today when I see a patient with CML, I tell them that the disease is an indolent leukemia with an excellent prognosis, that they will usually live their functional life span provided they take an oral medicine, Gleevec, for the rest of their lives.

Yet the hunger to treat patients still drove Farber. And sitting in his basement laboratory in the summer of 1947, Farber had a single inspired idea: he chose, among all cancers, to focus his attention on one of its oddest and most hopeless variants?childhood leukemia. To understand cancer as a whole, he reasoned, you needed to start at the bottom of its complexity, in its basement. And despite its many idiosyncrasies, leukemia possessed a singularly attractive feature: it could be measured. Science begins with counting. To understand a phenomenon, a scientist must first describe it; to describe it objectively, he must first measure it. If cancer medicine was to be transformed into a rigorous science, then cancer would need to be counted somehow?measured in some reliable, reproducible way. In this, leukemia was different from nearly every other type of cancer. In a world before CT scans and MRIs, quantifying the change in size of an internal solid tumor in the lung or the breast was virtually impossible without surgery: you could not measure what you could not see. But leukemia, floating freely in the blood, could be measured as easily as blood cells?by drawing a sample of blood or bone marrow and looking at it under a microscope. If leukemia could be counted, Farber reasoned, then any intervention?a chemical sent circulating through the blood, say?could be evaluated for its potency in living patients. He could watch cells grow or die in the blood and use that to measure the success or failure of a drug. He could perform an experiment on cancer.

An Irish surgeon, Denis Burkitt, discovered an aggressive form of lymphoma?now called Burkitt?s lymphoma?

But the heritability of a trait, no matter how strong, may be the result of multiple genes, each exerting a relatively minor effect. If that was the case, identical twins would show strong correlations in g, but parents and children would be far less concordant. IQ followed this pattern. The correlation between parents and children living together, for instance, fell to 0.42. With parents and children living apart, the correlation collapsed to 0.22. Whatever the IQ test was measuring, it was a heritable factor, but one also influenced by many genes and possibly strongly modified by environment ? part nature and part nurture.

Cancer at the fin de siecle, as the oncologist Harold Burstein describes it, resides at the interface between society and science. It poses not one but two challenges. The first, the biological challenge of cancer, involves harnessing the fantastic rise in scientific knowledge?to conquer this ancient and terrible illness. But the second, the social challenge, is just as acute: it involves forcing ourselves to confront our customs, rituals, and behaviors. These, unfortunately, are not customs or behaviors that lie at the peripheries of our society or selves, but ones that lie at their definitional cores: what we eat and drink, what we produce and excrete into our environments, when we choose to reproduce, and how we age.

Cancer, then, is quite literally trying to emulate a regenerating organ?or perhaps, more disturbingly, the regenerating organism. Its quest for immortality mirrors our own quest, a quest buried in our embryos and in the renewal of our organs. Someday, if a cancer succeeds, it will produce a far more perfect being than its host?imbued with both immortality and the drive to proliferate. One might argue that the leukemia cells growing in my laboratory derived from the woman who died three decades earlier have already achieved this form of perfection.

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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