The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

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.

And distorted and unleashed, it allows cancer cells to grow, to flourish, to adapt, to recover, and to repair—to live at the cost of our living. Cancer cells can grow faster, adapt better. They are more perfect versions of ourselves.

The secret to battling cancer, then, is to find means to prevent these mutations from occurring in susceptible cells, or to find means to eliminate the mutated cells without compromising normal growth. The conciseness of that statement belies the enormity of the task. Malignant growth and normal growth are so genetically intertwined that unbraiding the two might be one of the most significant scientific challenges faced by our species. Cancer is built into our genomes: the genes that unmoor normal cell division are not foreign to our bodies, but rather mutated, distorted versions of the very genes that perform vital cellular functions. And cancer is imprinted in our society: as we extend our life span as a species, we inevitably unleash malignant growth (mutations in cancer genes accumulate with aging; cancer is thus intrinsically related to age). If we seek immortality, then so, too, in a rather perverse sense, does the cancer cell.

(More than a century later, in the early 1980s, another change in name—from gay related immune disease (GRID) to acquired immuno deficiency syndrome (AIDS)—would signal an epic shift in the understanding of that disease.*)

First, that human bodies (like the bodies of all animals and plants) were made up of cells. Second, that cells only arose from other cells—omnis cellula e cellula, as he put it.

If cells only arose from other cells, then growth could occur in only two ways: either by increasing cell numbers or by increasing cell size. Virchow called these two modes hyperplasia and hypertrophy.

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 metastases—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 all acquired the same characteristic: uncontrollable pathological cell division.

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

Lymphoid cells are thus produced in vast excess, but, unable to mature, they cannot fulfill their normal function in fighting microbes. Carla had immunological poverty in the face of plenty.

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.

A solitary malignant lump in the breast, say, could be removed via a radical mastectomy pioneered by the great surgeon William Halsted at Johns Hopkins in the 1890s. With the discovery of X-rays in the early 1900s, radiation could also be used to kill tumor cells at local sites.

But scientifically, cancer still remained a black box, a mysterious entity that was best cut away en bloc rather than treated by some deeper medical insight. To cure cancer (if it could be cured at all), doctors had only two strategies: excising the tumor surgically or incinerating it with radiation—a choice between the hot ray and the cold knife.

In the months that passed, Farber found that folic acid, far from stopping the progression of leukemia, actually accelerated it. In one patient, the white cell count nearly doubled. In another, the leukemia cells exploded into the bloodstream and sent fingerlings of malignant cells to infiltrate the skin. Farber stopped the experiment in a hurry. He called this phenomenon acceleration, evoking some dangerous object in free fall careering toward its end.

And so Farber did dream. He dreamed of malignant cells being killed by specific anticancer drugs, and of normal cells regenerating and reclaiming their physiological spaces; of a whole gamut of such systemic antagonists to decimate malignant cells; of curing leukemia with chemicals, then applying his experience with chemicals and leukemia to more common cancers. He was throwing down a gauntlet for cancer medicine.

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.

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.

Like the normal cell, the cancer cell relies on growth in the most basic, elemental sense: the division of one cell to form two. In normal tissues, this process is exquisitely regulated, such that growth is stimulated by specific signals and arrested by other signals. In cancer, unbridled growth gives rise to generation upon generation of cells. Biologists use the term clone to describe cells that share a common genetic ancestor. Cancer, we now know, is a clonal disease. 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.

But cancer is not simply a clonal disease; it is a clonally evolving disease. If growth occurred 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 or 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. The genetic instability, like a perfect madness, only provides more impetus to generate mutant clones. Cancer t...

Louis Leakey, the anthropologist who dug up some of the earliest known human skeletons, also discovered a jawbone dating from two million years ago from a nearby site that carried the signs of a peculiar form of lymphoma found endemically in southeastern Africa (although the origin of that tumor was never confirmed pathologically). If that finding does represent an ancient mark of malignancy, then cancer, far from being a “modern” disease, is one of the oldest diseases ever seen in a human specimen—quite possibly the oldest.

There are several reasons behind this absence. 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. In most ancient societies, people didn’t live long enough to get cancer. Men and women were long consumed by tuberculosis, dropsy, cholera, smallpox, leprosy, plague, or pneumonia. If cancer existed, it remained submerged under the sea of other illnesses. Indeed, cancer’s emergence in the world is the product of a double negative: it becomes common only when all other killers themselves have been killed. Nineteenth-century doctors often linked cancer to civilization: cancer, they imagined, was caused by the rush and whirl of modern life, which somehow incited pathological growth in the body. The link was correct, but the causality was not: civilization did not cause cancer, but by extending human life spans—civilization unveiled it.

Longevity, although certainly the most important contributor to the prevalence of cancer in the early twentieth century, is probably not the only contributor. Our capacity to detect cancer earlier and earlier, and to attribute deaths accurately to it, has also dramatically increased in the last century. The death of a child with leukemia in the 1850s would have been attributed to an abscess or infection (or, as Bennett would have it, to a “suppuration of blood”). And surgery, biopsy, and autopsy techniques have further sharpened our ability to diagnose cancer. The introduction of mammography to detect breast cancer early in its course sharply increased its incidence—a seemingly paradoxical result that makes perfect sense when we realize that the X-rays allow earlier tumors to be diagnosed.

Finally, changes in the structure of modern life have radically shifted the spectrum of cancers—increasing the incidence of some, decreasing the incidence of others. Stomach cancer, for instance, was highly prevalent in certain populations until the late nineteenth century, likely the result of several carcinogens found in pickling reagents and preservatives and exacerbated by endemic and contagious infection with a bacterium that causes stomach cancer. With the introduction of modern refrigeration (and possibly changes in public hygiene that have diminished the rate of endemic infection), the stomach cancer epidemic seems to have abated. In contrast, lung cancer incidence in men increased dramatically in the 1950s ...

Antisepsis and anesthesia were twin technological breakthroughs that released surgery from its constraining medieval chrysalis.

These procedures represented pivotal advances in the treatment of cancer. By the early twentieth century, many locally restricted cancers (i.e., primary tumors without metastatic lesions) could be removed by surgery. These included uterine and ovarian cancer, breast and prostate cancer, colon cancer, and lung cancer. If these tumors were removed before they had invaded other organs, these operations produced cures in a significant fraction of patients. Surgery remains the mainstay in the treatment of localized tumors.

But despite these remarkable advances, some cancers—even seemingly locally restricted ones—still relapsed after surgery, prompting second and often third attempts to resect tumors. Surgeons returned to the operating table and cut and cut again, as if caught in a cat-and-mouse game, as cancer was slowly excavated out of the human body piece by piece.

What caused this relapse? At St. Luke’s Hospital in London in the 1860s, the English surgeon Charles Moore had also noted these vexing local recurrences. Frustrated by repeated failures, Moore had begun to record the anatomy of each relapse, denoting the area of the original tumor, the precise margin of the surgery, and the site of cancer recurrence by drawing tiny black dots on a diagram of a breast—creating a sort of historical dartboard of cancer recurrence. And to Moore’s surprise, dot by dot, a pattern had emerged. The recurrences had accumulated precisely around the margins of the original surgery, as if minute remnants of cancer had been left behind by incomplete surgery and grown back. “Mammary cancer requires the careful extirpation of the entire organ,”

Moore concluded. “Local recurrence of cancer after operations is due to the continuous growth of fragments of the principal tumor.”

Moore’s hypothesis had an obvious corollary. If breast cancer relapsed due to the inadequacy of the original surgical excisions, then even more breast tissue should be removed during the initial operation. Since the margins of e...

Halsted would almost certainly have been right in his theory of radical surgery: that attacking even small cancers with aggressive local surgery was the best way to achieve a cure. But there was a deep conceptual error. Imagine a population in which breast cancer occurs at a fixed incidence, say 1 percent per year. The tumors, however, demonstrate a spectrum of behavior right from their inception. In some women, by the time the disease has been diagnosed the tumor has already spread beyond the breast: there is metastatic cancer in the bones, lungs, and liver. In other women, the cancer is confined to the breast, or to the breast and a few nodes; it is truly a local disease.

Halsted’s ability to cure patients with breast cancer obviously depends on the sort of cancer—the stage of breast cancer—that he confronts. The woman with the metastatic cancer is not going to be cured by a radical mastectomy, no matter how aggressively and meticulously Halsted extirpates the tumor in her breast: her cancer is no longer a local problem. In contrast, the woman with the small, confined cancer does benefit from the operation—but for her, a far less aggressive procedure, a local mastectomy, would have done just as well. Halsted’s mastectomy is thus a peculiar misfit in both cases; it underestimates its target in the first case and overestimates it in the second. In both cases, women are forced to undergo indiscriminate, disfiguring, and morbid operations—too much, too early for the woman with local breast cancer, and too little, too late, for the woman with metastatic cancer.

The ultimate survival from breast cancer, in short, had little to do with how extensively a surgeon operated on the breast; it depended on how extensively the cancer had spread before surgery.

Indeed Cushing found radical operations on brain tumors not just difficult, but inconceivable: even if he desired it, a surgeon could not extirpate the entire organ.

DNA is an inert 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, and blood.

But like surgery, radiation medicine also struggled against its inherent limits. Emil Grubbe had already encountered the first of these limits with his earliest experimental treatments:

since X-rays could only be directed locally, radiation was of limited use for cancers that had metasta-sized.* One could double and quadruple the doses of radiant energy, but this did not translate into more cures. Instead, indiscriminate irradiation left patients scarred, blinded, and scalded by doses that had far exceeded tolerability.

The second limit was far more insidious: radiation produced cancers. The very effect of X-rays killing rapidly dividing cells—DNA damage—also cr...

watches. Radium workers soon began to complain of jaw pain, fatigue, and skin and tooth problems. In the late 1920s, medical investigations revealed that the bones in their jaws had necrosed, their tongues had been scarred by irradiation, and many had become chronically anemic (a sign of severe bone marrow damage). Some women, tested with radioactivity counters, were found to be glowing with radioactivity. Over the next decades, dozens of radium-induced tumors sprouted in these radium-exposed workers—sarcomas and leukemias, and bone, tongue, neck, and jaw tumors.

Radiation was a powerful invisible knife—but still a knife. And a knife, no matter how deft or penetrating, could only reach so far in the battle against cancer. A more discriminating therapy was needed, especially for cancers that were nonlocalized.

There is, in that letter, an unfailing recognition that cancer medicine had reached some terminus, that a new direction was needed.

Meyer had grasped a deep principle about cancer. Cancer, even when it begins locally, is inevitably waiting to explode out of its confinement. By the time many patients come to their doctor, the illness has often spread beyond surgical control and spilled into the body exactly like the black bile that

Galen had envisioned so vividly nearly two thousand years ago.

Ehrlich’s successes with Trypan Red and compound 606 (which he named Salvarsan, from the word salvation) proved that diseases were just pathological locks waiting to be picked by the right molecules.

“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.… “Basic research leads to new knowledge. It provides scientific capital. It creates the fund from which the practical applications of knowledge must be drawn.… Basic research is the pacemaker of technological progress. In the nineteenth century, Yankee mechanical ingenuity, building largely upon the basic discoveries of European scientists, could greatly advance the technical arts. Now the situation is different. A nation which depends upon others for its new basic scientific knowledge will be slow in its industrial progress and weak in its competitive position in world trade, regardless of its mechanical skill.”

As Bush perceived it, even the widely lauded Manhattan Project epitomized the virtues of basic inquiry. True, the bomb was the product of Yankee “mechanical ingenuity.” But that mechanical ingenuity stood on the shoulders of scientific discoveries about the fundamental nature of the atom and the energy locked inside it—research performed, notably, with no driving mandate to produce anything resembling the atomic bomb. While the bomb might have come to life physically in Los Alamos, intellectually speaking it was the product of prewar physics and chemistry rooted deeply in Europe. The iconic homegrown product of wartime American science was, at least philosophically speaking, an import.

A lesson Bush had learned from all of this was that goal-directed strategies, so useful in wartime, would be of limited use during periods of peace. “Frontal attacks” were useful on the war front, but postwar science could not be produced by fiat. So Bush had pushed for a radically inverted model of scientific development, in which researchers were allowed full autonomy over their explorations and open-ended inquiry was prioritized.

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’s proposed solution was to remove such biases by randomly assigning patients to treatment with streptomycin versus a placebo. By “randomizing” patients to each arm, any doctors’ biases in patient assignment would be dispelled. Neutrality would be enforced—and thus a hypothesis could be strictly tested.

Trial methodology was not the only powerful lesson that Zubrod, Frei, and Freireich learned from the antimicrobial world. “The analogy of drug resistance to antibiotics was given deep thought,” Freireich remembered. As Farber and Burchenal had discovered to their chagrin in Boston and New York, leukemia treated with a single drug would inevitably grow resistant to the drug, resulting in the flickering, transient responses followed by the devastating relapses.

The situation was reminiscent of TB. Like cancer cells, mycobacteria—the germs that cause tuberculosis—also became resistant to antibiotics if the drugs were used singly. Bacteria that survived a single-drug regimen divided, mutated, and acquired drug resistance, thus making that original drug useless. To thwart this resistance, doctors treating TB had used a blitzkrieg of antibiotics—two or three used together like a dense pharmaceutical blanket meant to smother all cell division and stave off bacterial resistance, thus extinguishing the infection as definitively as possible.

But could two or three drugs be tested simultaneously against cancer—or would the toxicities be so forbidding that they would instantly kill patients? As Freireich, Frei, and Zubrod studied the growing list of anti-leukemia drugs, the notion of combining drugs emerged with growing clarity: toxicities notwithstan...