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

How many ?rules?, then, could Weinberg and Hanahan evoke to explain the core behavior of more than a hundred distinct types and subtypes of tumors? The question was audacious in its expansiveness; the answer even more audacious in its economy: six. ?We suggest that the vast catalog of cancer cell genotypes is a manifestation of six essential alterations in cell physiology that collectively dictate malignant growth.? 1. Self-sufficiency in growth signals: cancer cells acquire an autonomous drive to proliferate?pathological mitosis?by virtue of the activation of oncogenes such as ras or myc. 2. Insensitivity to growth-inhibitory (antigrowth) signals: cancer cells inactivate tumor-suppressor genes, such as retinoblastoma (Rb), that normally inhibit growth. 3. Evasion of programmed cell death (apoptosis): cancer cells suppress and inactivate genes and pathways that normally enable cells to die. 4. Limitless replicative potential: cancer cells activate specific gene pathways that render them immortal even after generations of growth. 5. Sustained angiogenesis: Cancer cells acquire the capacity to draw out their own supply of blood and blood vessels?tumor angiogenesis. 6. Tissue invasion and metastasis: cancer cells acquire the capacity to migrate to other organs, invade other tissues, and colonize these organs, resulting in their spread throughout the body.

I wanted to explore cancer not just biologically, but metaphorically. The idea that tuberculosis in the 19th century possessed the same kind of frightening and decaying quality was very interesting to me, and it seemed that one could explore the idea that every age defined its own illness.

In 2005, a man diagnosed with multiple myeloma asked me if he would be alive to watch his daughter graduate from high school in a few months. In 2009, bound to a wheelchair, he watched his daughter graduate from college. The wheelchair had nothing to do with his cancer. The man had fallen down while coaching his youngest son's baseball team.

In Paris, friend of Bequerel?s, a young physicist-chemist couple named Pierre and Marie Curie, began to scour the natural world for even more powerful chemical sources of X-rays. Pierre and Marie (then Maria Sklodowska, a penniless Polish immigrant living in a garret in Paris) had met at the Sorbonne and been drawn to each other because of a common interest in magnetism.

Is medicine a science?

Its false-positive and false-negative rates make it far from an ideal screening test. But the fatal flaw in mammography lies in that these rates are not absolute: they depend on age. For women above fifty-five, the incidence of breast cancer is high enough that even a relatively poor screening tool can detect an early baseline tumor and provide a survival benefit. For women between forty and fifty years, though, the incidence of breast cancer sinks to a point that a mass detected on a mammogram, more often than not, turns out to be a false positive. To use a visual analogy: a magnifying lens designed to make small script legible does perfectly well when the font size is ten or even six points. But then it hits a limit. At a certain size font, chances of reading a letter correctly become about the same as reading a letter incorrectly.

Modesty is a virtue, he would later write, yet one gets further without it.

Normalcy is the antithesis of evolution.

Probably the most important reason we are seeing more cancers than before is because the population is ageing overall. And cancer is an age-related disease.

Src was a prototypical kinase?although a kinase on hyperdrive. The protein made by the viral src gene was so potent and hyperactive that it reflexively phosphorylated anything and everything around it, including the antibody that Erikson had used to bind it. Src worked by unleashing a volley of phosphorylation?throwing on dozens of molecular switches. In src?s case, the activated series of proteins eventually impinged on proteins that controlled cell division. Src thus forcibly induced a cell to change its state from non-dividing to dividing, ultimately inducing accelerated mitosis, the hallmark of cancer.

The children and grandchildren of famine-starved individuals tended to develop metabolic illnesses, as if their genomes carried some recollection of their grandparents? metabolic travails.

The landscape of carcinogens is not static either. We are chemical apes: having 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 re-immersed 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 trial designed to bring the most rigorous statistical analysis to the cause of lung cancer barely required elementary mathematics to prove its point.

This seminal transition from descriptive biology to the functional biology of cancer will provoke three new directions for cancer medicine. The first is a direction for cancer therapeutics. Once the crucial driver mutations in any given cancer have been identified, we will need to launch a hunt for targeted therapies against these genes. This is not an entirely fantastical hope: targeted inhibitors of some of the core thirteen pathways mutated in many cancers have already entered the clinical realm. As individual drugs, some of these inhibitors have thus far had only mild response rates. The challenge now is to determine which combinations of such drugs might inhibit cancer growth without killing normal cells.

We tend to think of cancer as a modern illness because its metaphors are so modern. It is a disease of overproduction, of fulminant growth?growth unstoppable growth, tipped into the abyss of no control. Modern biology encourages us to imagine the cell as a molecular machine. Cancer is that machine unable to quench its initial demand (to grow) and thus transformed into an indestructible, self-propelled automation. The notion of cancer as an affliction that belongs paradigmatically to the twentieth century is reminiscent, as Susan Sontag argued so magisterially in her book Illness as Metaphor, of another disease once considered paradigmatic of another era: tuberculosis in the nineteenth century. Both diseases, as Sontag pointedly noted, were similarly obscene?in the original meaning of that word: ill-omened, abominable, repugnant to the senses. Both drain vitality; both stretch out the encounter with death; in both cases, dying, even more than death, defines the illness.

How many of us have asked the question, ?If this great country of ours can put a man on the moon why can?t we find a cure for cancer?

If someone were to draw a similar map of relationships among genes in a normal human cell, then proto-oncogenes and tumor suppressors such as ras, myc, neu, and Rb would sit at the hub of this cellular city, radiating webs of colored strings in every direction. Proto-oncogenes and tumor suppressors are the molecular pivots of the cell. They are the gatekeepers of cell division, and the division of cells is so central to our physiology that genes and pathways that coordinate this process intersect with nearly every other aspect of our biology. 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 a tumor suppressor.

In 2006, the Vogelstein team revealed the first landmark sequencing effort by analyzing thirteen thousand genes in eleven breast and colon cancers. (Although the human genome contains about twenty thousand genes in total, Vogelstein?s team initially had tools to assess only thirteen thousand.) In 2008, both Vogelstein?s group and the Cancer Genome Atlas consortium extended this effort by sequencing hundreds of genes of several dozen specimens of brain tumors. As of 2009, the genomes of ovarian cancer, pancreatic cancer, melanoma, lung cancer, and several forms of leukemia have been sequenced, revealing the full catalog of mutations in each tumor type. Perhaps

In some nations, cancer will surpass heart disease to become the most common cause of death.

Is there something I can do to kill the cancer germ? Can the rooms be fumigated?? Should I give up my lease and move out?

Labs, too, can become machines. In science, it is more often a pejorative description than a complimentary one: an efficient, thrumming, technically accomplished laboratory is like a robot orchestra that produces perfectly pitched tunes but no music.

Most days, I go home and I feel rejuvenated. I feel ebullient.

On August 7, 1945, the morning after the Hiroshima bombing, the New York Times gushed about the extraordinary success of the Project: ?University professors who are opposed to organizing, planning, and directing research after the manner of industrial laboratories? have something to think now. A most important piece of research was conducted on behalf of the Army in precisely the means adopted in industrial laboratories. End result: an invention was given to the world in three years, which it would have taken perhaps half-a-century to develop if we had to rely on prima-donna research scientists who work alone?. A problem was stated, it was solved by teamwork, by planning, by competent direction, and not by the mere desire to satisfy curiosity.

Prostate cancer represents a full third of all cancer incidence in men?sixfold that of leukemia and lymphoma.

Statistics, the journalist Paul Brodeur once wrote, are human beings with the tears wiped off.

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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