The Emperor of All Maladies

by Siddhartha Mukherjee

Diseases desperate grown2 By desperate appliance are relieved, Or not at all.

Cancer begins and ends with people3. In the midst of scientific abstraction, it is sometimes possible to forget this one basic fact. . . . Doctors treat diseases, but they also treat people, and this precondition of their professional existence sometimes pulls them in two directions at once.

Leukemia is cancer of the white blood cells—cancer in one of its most explosive, violent incarnations. As one nurse on the wards often liked to remind her patients, with this disease “even a paper cut is an emergency.”

To be diagnosed with cancer, Rusanov discovers, is to enter a borderless medical gulag, a state even more invasive and paralyzing than the one that he has left behind. (Solzhenitsyn may have intended his absurdly totalitarian cancer hospital to parallel the absurdly totalitarian state outside it, yet when I once asked a woman with invasive cervical cancer about the parallel, she said sardonically, “Unfortunately, I did not need any metaphors to read the book. The cancer ward was my confining state, my prison.”)

Immersed in the day-to-day management of cancer, I could only see the lives and fates of my patients played out in color-saturated detail, like a television with the contrast turned too high. I could not pan back from the screen. I knew instinctively that these experiences were part of a much larger battle against cancer, but its contours lay far outside my reach. I had a novice’s hunger for history, but also a novice’s inability to envision it.

The isolation and rage of a thirty-six-year-old woman with stage III breast cancer had ancient echoes in Atossa, the Persian queen5 who swaddled her diseased breast in cloth to hide it and then, in a fit of nihilistic and prescient fury, had a slave cut it off with a knife.

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.

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.

How, precisely, a future generation might learn to separate the entwined strands of normal growth from malignant growth remains a mystery. (“The universe,” the twentieth-century biologist6 J. B. S. Haldane liked to say, “is not only queerer than we suppose, but queerer than we can suppose”—and so is the trajectory of science.) But this much is certain: the story, however it plays out, will contain indelible kernels of the past. It will be a story of inventiveness, resilience, and perseverance against what one writer called the most “relentless and insidious enemy” among human diseases. But it will also be a story of hubris, arrogance, paternalism, misperception, false hope, and hype, all leveraged against an illness that was just three decades ago widely touted as being “curable” within a few years.

In solving a problem of this sort7, the grand thing is to be able to reason backwards. That is a very useful accomplishment, and a very easy one, but people do not practice it much.

Its palliation is a daily task9, its cure a fervent hope.

Virchow ultimately settled for weisses Blut—white blood—no more than a literal description of the millions of white cells he had seen under his microscope. In 1847, he changed the name to the more academic-sounding “leukemia”—from leukos, the Greek word for “white.”

As a young professor at the University of Würzburg, Virchow’s work soon extended far beyond naming leukemia. A pathologist by training, he launched a project that would occupy him for his life: describing human diseases in simple cellular terms.

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. Borrowing and extending this idea, Virchow set out to create a “cellular theory” of human biology, basing it on two fundamental tenets. 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. In hypertrophy, the number of cells did not change; instead, each individual cell merely grew in size—like a balloon being blown up. Hyperplasia, in contrast, was growth by virtue of cells increasing in number.

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.

Conversely, and importantly for this story, Virchow soon stumbled upon the quintessential disease of pathological hyperplasia—cancer. Looking at cancerous growths through his microscope, Virchow discovered an uncontrolled growth of cells—hyperplasia in its extreme form. As Virchow examined the architecture of cancers, the growth often seemed to have acquired a life of its own, as if the cells had become possessed by a new and mysterious drive to grow.

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 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.

This second version of the disease, called acute leukemia, came in two further subtypes, based on the type of cancer cell involved. Normal white cells in the blood can be broadly divided into two types of cells—myeloid cells or lymphoid cells. Acute myeloid leukemia (AML) was a cancer of the myeloid cells. Acute lymphoblastic leukemia (ALL) was cancer of immature lymphoid cells. (Cancers of more mature lymphoid cells are called lymphomas.)

Her treatment would require extraordinary finesse. She would need chemotherapy to kill her leukemia, but the chemotherapy would collaterally decimate any remnant normal blood cells. We would push her deeper into the abyss to try to rescue her. For Carla, the only way out would be the way through.

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.

The idea mesmerized Farber. In the 1940s and ’50s, young biologists were galvanized by the idea of using simple models to understand complex phenomena. Complexity was best understood by building from the ground up. Single-celled organisms such as bacteria would reveal the workings of massive, multicellular animals such as humans. What is true for E. coli24 [a microscopic bacterium], the French biochemist Jacques Monod would grandly declare in 1954, must also be true for elephants.

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.

But the fact remains that the cancer ‘cure’ still includes only two principles—the removal and destruction of diseased tissue [the former by surgery; the latter by X-rays]. No other means have been proved.”

“Cancer: The Great Darkness” wasn’t alone in building a case for a coordinated national response to cancer. In May that year,50 Life carried its own dispatch on cancer research, which conveyed the same sense of urgency. The New York Times published two reports on rising cancer rates, in April and June. When cancer appeared51 in the pages of Time in July 1937, interest in what was called the “cancer problem” was like a fierce contagion in the media.

If leukemia “belonged” anywhere66, it was within hematology, the study of normal blood. If a cure for it was to be found, Farber reasoned, it would be found by studying blood. If he could uncover how normal blood cells were generated, he might stumble backward into a way to block the growth of abnormal leukemic cells. His strategy, then, was to approach the disease from the normal to the abnormal—to confront cancer in reverse.

—Minot and his team of researchers70 conclusively demonstrated in 192671 that pernicious anemia was caused by the lack of a critical micronutrient, a single molecule later identified as vitamin B12. In 1934, Minot and two of his colleagues72 won the Nobel Prize for this pathbreaking work.

Eight thousand miles away, in the cloth mills of Bombay73 (owned by English traders and managed by their cutthroat local middlemen), wages had been driven to such low levels that the mill workers lived in abject poverty, malnourished and without medical care. When English physicians tested these mill workers in the 1920s to study the effects of this chronic malnutrition, they discovered that many of them, particularly women after childbirth, were severely anemic. (This was yet another colonial fascination: to create the conditions of misery in a population, then subject it to social or medical experimentation.)

Since blood cells are produced by arguably the most fearsome rate of cell division in the human body—more than 300 billion cells a day—the genesis of blood is particularly dependent on folic acid. In its absence (in men and women starved of vegetables, as in Bombay) the production of new blood cells in the bone marrow halts. Millions of half-matured cells spew out, piling up like half-finished goods bottlenecked in an assembly line. The bone marrow becomes a dysfunctional mill, a malnourished biological factory oddly reminiscent of the cloth factories of Bombay.

If folic acid accelerated the leukemia cells in children, what if he could cut off its supply with some other drug—an antifolate? Could a chemical that blocked the growth of white blood cells stop leukemia?

If the bone marrow was a busy cellular factory to begin with, then a marrow occupied with leukemia was that factory in overdrive, a deranged manufacturing unit for cancer cells.

Minot and Wills had turned the production lines of the bone marrow on by adding nutrients to the body. But could the malignant marrow be shut off by choking the supply of nutrients? Could the anemia of the mill workers in Bombay be re-created therapeutically in the medical units of Boston?

The word chemotherapy, in the sense we understand it today, had never been used for anticancer medicines.* The elaborate armamentarium of “antivitamins” that Farber had dreamed up so vividly in his fantasies did not exist.

The chemical reactions to make folic acid brought a serendipitous bonus. Since the reactions had several intermediate steps, Subbarao and Kiltie could create variants of folic acid through slight alterations in the recipe. These variants of folic acid—closely related molecular mimics—possessed counterintuitive properties. Enzymes and receptors in cells typically work by recognizing molecules using their chemical structure. But a “decoy” molecular structure—one that nearly mimics the natural molecule—can bind to the receptor or enzyme and block its action, like a false key jamming a lock. Some of Yella’s molecular mimics could thus behave like antagonists to folic acid. These were precisely the antivitamins that Farber had been fantasizing about. Farber wrote to Kiltie and Subbarao asking them if he could use their folate antagonists on patients with leukemia. Subbarao consented. In the late summer of 1947, the first package of antifolate left Lederle’s labs in New York and arrived in Farber’s laboratory.

Throughout the centuries81 the sufferer from this disease has been the subject of almost every conceivable form of experimentation. The fields and forests, the apothecary shop and the temple, have been ransacked for some successful means of relief from this intractable malady. Hardly any animal has escaped making its contribution, in hair or hide, tooth or toenail, thymus or thyroid, liver or spleen, in the vain search by man for a means of relief.

When one clinician suggested that Farber’s novel “chemicals” be reserved only as a last resort for leukemic children, Farber, recalling his prior life as a pathologist, shot back, “By that time, the only chemical88 that you will need will be embalming fluid.”

And case by case, an incredible pattern emerged: the antifolates could drive leukemia cell counts down, occasionally even resulting in their complete disappearance—at least for a while. There were other remissions as dramatic as Sandler’s. Two boys treated with aminopterin91 returned to school. Another child, a two-and-a-half-year-old92 girl, started to “play and run about” after seven months of lying in bed. The normalcy of blood almost restored a flickering, momentary normalcy to the childhood.

Yet the remissions, even if temporary, were still genuine remissions—and historic. By April 1948, there was just enough data93 to put together a preliminary paper for the New England Journal of Medicine. The team had treated sixteen patients. Of the sixteen, ten had responded. And five children—about one-third of the initial group—remained alive four or even six months after their diagnosis. In leukemia, six months of survival was an eternity.

But for Farber, the study carried a tantalizing message: cancer, even in its most aggressive form, had been treated with a medicine, a chemical. In six months between 1947 and 1948, Farber thus saw a door open—briefly, seductively—then close tightly shut again. And through that doorway, he glimpsed an incandescent possibility. The disappearance of an aggressive systemic cancer via a chemical drug was virtually unprecedented in the history of cancer. In the summer of 1948, when one of Farber’s assistants performed a bone marrow biopsy on a leukemic child after treatment with aminopterin, the assistant could not believe the results. “The bone marrow looked so normal,”95 he wrote, “that one could dream of a cure.”

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. It was then up to an entire generation of doctors and scientists to pick it up.

Now it is cancer’s turn98 to be the disease that doesn’t knock before it enters.

The cancer cell is a desperate individualist, “in every possible sense, a nonconformist,”101 as the surgeon-writer Sherwin Nuland wrote. The word metastasis, used to describe the migration of cancer from one site to another, is a curious mix of meta and stasis—“beyond stillness” in Latin—an unmoored, partially unstable state that captures the peculiar instability of modernity.

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.

This image—of cancer as our desperate, malevolent, contemporary doppelgänger—is so haunting because it is at least partly true. 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.

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 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.

But the surprising feature of the Smith papyrus is not magic and religion but the absence of magic and religion. In a world immersed in spells, incantations, and charms, Imhotep wrote about broken bones and dislocated vertebrae with a detached, sterile scientific vocabulary, as if he were writing a modern surgical textbook.

Describing case forty-five103, Imhotep advises, “If you examine [a case] having bulging masses on [the] breast and you find that they have spread over his breast; if you place your hand upon [the] breast [and] find them to be cool, there being no fever at all therein when your hand feels him; they have no granulations, contain no fluid, give rise to no liquid discharge, yet they feel protuberant to your touch, you should say concerning him: ‘This is a case of bulging masses I have to contend with. . . . Bulging tumors of the breast mean the existence of swellings on the breast, large, spreading, and hard; touching them is like touching a ball of wrappings, or they may be compared to the unripe hemat fruit, which is hard and cool to the touch.’ ”