The Emperor of All Maladies

A Biography of Cancer

Siddhartha Mukherjee

Summary: Cancer seems to be an inevitable part of our biology

Score: 80 / 100

Leukemia is cancer of the white blood cells—cancer in one of its most explosive, violent incarnations.

disease. In Aleksandr Solzhenitsyn’s novel Cancer Ward,

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.

(mutations in cancer genes accumulate with aging; cancer is thus intrinsically related to age).

In 1838, Matthias Schleiden, a botanist, and Theodor Schwann, a physiologist, both working in Germany, had claimed that all living organisms were built out of fundamental building blocks called cells.

In adult animals, fat and muscle usually grow by hypertrophy. In contrast, the liver, blood, the gut, and the skin all grow through hyperplasia—cells becoming cells becoming more cells, omnis cellula e cellula e cellula.

quintessential disease of pathological hyperplasia—cancer.

Nuremberg code for human experimentation, requiring explicit voluntary consent from patients, was drafted on August 9, 1947, less than a month before the PAA trial.

To confront cancer is to encounter a parallel species, one perhaps more adapted to survival than even we are.

Nearly every known cancer originates from one ancestral cell that, having acquired the capacity of limitless cell division and survival, gives rise to limitless numbers of descendants—Virchow’s omnis cellula e cellula e cellula repeated ad infinitum.

Cancer is an age-related disease—sometimes exponentially so. The risk of breast cancer, for instance, is about 1 in 400 for a thirty-year-old woman and increases to 1 in 9 for a seventy-year-old.

civilization did not cause cancer, but by extending human life spans—civilization unveiled it.

lung cancer incidence in men increased dramatically in the 1950s as a result of an increase in cigarette smoking during the early twentieth century.

the most rapidly proliferating cells in the body, cells in the skin, nails, gums, and blood.

Life is . . . a chemical incident. —Paul Ehrlich as a schoolboy, 1870

Scientists often study the past as obsessively as historians because few other professions depend so acutely on it. Every experiment is a conversation with a prior experiment, every new theory a refutation of the old.

“Basic research,” Bush wrote, “is performed without thought of practical ends. It results in general knowledge and an understanding of nature and its laws. This general knowledge provides the means of answering a large number of important practical problems, though it may not give a complete specific answer to any one of them. . . .

(CCNSC), was in full swing. Between 1954 and 1964, this unit would test 82,700 synthetic chemicals, 115,000 fermentation products, and 17,200 plant derivatives and treat nearly 1 million mice every year with various chemicals to find an ideal drug.

At the NCI, you didn’t expect. You just waited and watched and took surprises as they came.”

flabbergasted:

Li had stumbled on a deep and fundamental principle of oncology: cancer needed to be systemically treated long after every visible sign of it had vanished.

A model is a lie that helps you see the truth. —Howard Skipper

chemotherapy typically killed a fixed percentage of cells at any given instance no matter what the total number of cancer cells was. This percentage was a unique, cardinal number particular to every drug.

Second, Skipper found that by adding drugs in combination, he could often get synergistic effects on killing.

Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing. —Voltaire

The pain is that a lot of love affairs end.”

absentmindedly

Religious movements and cults are often founded on a tetrad of elements: a prophet, a prophecy, a book, and a revelation.

In 1928, four years after Keynes had begun his lumpectomies in London, two statisticians, Jerzy Neyman and Egon Pearson, provided a systematic method to evaluate a negative statistical claim.

In autopsies of men over sixty years old, nearly one in every three specimens will bear some evidence of prostatic malignancy.

Dogs, humans, and lions are the only animals known to develop prostate cancer, and dogs with sizable prostate tumors kept appearing in his lab during his studies.

tamoxifen. Originally invented as a birth control pill, tamoxifen had been synthesized by a team led by the hormone biologist Arthur Walpole and a synthetic chemist, Dora Richardson, both members of the “fertility control program” at the ICI.

“The death rates from malaria, cholera, typhus, tuberculosis, scurvy, pellagra and other scourges of the past have dwindled in the US because humankind has learned how to prevent these diseases.

(“Syphilis,” as the saying ran, “was one night with Venus, followed by a thousand nights with mercury.”)

In 1870, the per capita consumption in America was less than one cigarette per year. A mere thirty years later, Americans were consuming 3.5 billion cigarettes and 6 billion cigars every year. By 1953, the average annual consumption of cigarettes had reached thirty-five hundred per person.

By the early 1970s, working with a team of collaborators, his lab had purified particles of a new virus, which he called hepatitis B virus, or HBV. The virus was structurally simple—“roughly circular . . . about forty-two nanometers in diameter, one of the smallest DNA viruses that infect humans”—but the simple structure belied extraordinarily complex behavior.

smears. A Japanese fish and bird painter named Hashime Murayama,

In primary prevention, a disease is prevented by attacking its cause—smoking cessation for lung cancer or a vaccine against hepatitis B for liver cancer. In secondary prevention (also called screening), a disease is prevented by screening for its early, presymptomatic stage.

The risk of not having a mammogram until after age 50 is about the same as riding a bicycle for 15 hours without a helmet.”

We are a visual species. Seeing is believing, and to see cancer in its early, incipient form, we believe, must be the best way to prevent it.

“All photographs are accurate,” the artist Richard Avedon liked to say, “[but] none of them is the truth.”

Cancer therapy is like beating the dog with a stick to get rid of his fleas. —Anna Deavere Smith, Let Me Down Easy

“‘Cancer’ is, in truth, a variety of diseases.

The cells, technically speaking, are immortal. The woman from whose body they were once taken has been dead for thirty years.

chronic inflammation, smoldering over decades, does cause cancer (chronic hepatitis virus infection in the liver precipitates liver cancer),

Two hundred miles south of Virchow’s Berlin laboratory, Walther Flemming, a biologist working in Prague, tried to uncover the cause of abnormal cell division, although using salamander eggs rather than human cells as his subject.

chromosomes—“colored bodies.”

diseases. In 1909, a year before Rous isolated his cancer-causing virus, Karl Landsteiner implicated a virus as the cause for polio.

Beadle and Tatum found that a gene “works” by providing the blueprint to build a protein.

RNA is the working copy of the genetic blueprint. It is through RNA that a gene is translated into a protein.

This unidirectional flow of genetic information—DNA → RNA → protein—was found to be universal in living organisms, from bacteria to slime molds to fruit flies to humans. In the mid-1950s, biologists termed this the “central dogma” of molecular biology.

Rous sarcoma virus was no ordinary virus. It could write genetic information backward: it was a retrovirus.

human retrovirus called HIV.

RSV possesses only four genes in its genome.

Src, Erikson discovered, was an unusual gene. It encoded a protein whose most prominent function was to modify other proteins by attaching a small chemical, a phosphate group, to these proteins—in essence, playing an elaborate game of molecular tag.

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.

“Negative” genes, such as Rb, suppress cell division. In normal cells, these anti-oncogenes, or tumor suppressor genes, provide the “brakes” to cellular proliferation, shutting down cell division when the cell receives appropriate signals. In cancer cells, these brakes have been inactivated by mutations.

Good theories, Popper proposed, generate risky predictions.

In genetic terms, our cells were not sitting on the edge of the abyss of cancer. They were dragged toward that abyss in graded, discrete steps.

Ras, for instance, activates a protein called Mek. Mek in turn activates Erk, which, through several intermediary steps, ultimately accelerates cell division. This cascade of steps, called the Ras-Mek-Erk pathway—is tightly regulated in normal cells, thereby ensuring tightly regulated cell division. In cancer cells, activated “Ras” chronically and permanently activates Mek, which permanently activates Erk, resulting in uncontrolled cell division—pathological mitosis.

A “drug,” in bare conceptual terms, is any substance that can produce an effect on the physiology of an animal.

The Framingham data set has spawned a host of studies on risk and illness. The link between cholesterol and heart attacks was formally established here, as was the association of stroke and high blood pressure.

Smoking, this model argues, is entwined into our social DNA just as densely and as inextricably as oncogenes are entwined into our genetic material.

The Human Genome Project, the full sequence of the normal human genome, was completed in 2003.

the human genome contains about twenty thousand genes in total,

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.

Cancer, we have discovered, is stitched into our genome. Oncogenes arise from mutations in essential genes that regulate the growth of cells. Mutations accumulate in these genes when DNA is damaged by carcinogens, but also by seemingly random errors in copying genes when cells divide. The former might be preventable, but the latter is endogenous.

Science embodies the human desire to understand nature; technology couples that desire with the ambition to control nature.

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.