The Emperor of All Maladies

by Siddhartha Mukherjee

  She watched Lynch put his pen down with her quick, sharp eyes. The explanation sounded logical and organized, but she had caught the glint of a broken piece in the chain of logic. What was the connection between this explanation and the therapy being proposed? How, she wanted to know, would Carboplatin “fix” her mutated genes? How would Taxol know which cells carried the mutations in order to kill them? How would the mechanistic explanation of her illness connect with the medical interventions?

  She had captured a disjunction all too familiar to oncologists. For nearly a decade, practicing cancer medicine had become like living inside a pressurized can—pushed, on one hand, by the increasing force of biological clarity about cancer, but then pressed against the wall of medical stagnation that seemed to have produced no real medicines out of this biological clarity. In the winter of 1945, Vannevar Bush had written to President Roosevelt, “The striking advances in medicine during the war have been possible only because we had a large backlog of scientific data accumulated through basic research in many scientific fields in the years before the war.”

  For cancer, the “backlog of scientific data” had reached a critical point. The boil of science, as Bush liked to imagine it, inevitably produced a kind of steam—an urgent, rhapsodic pressure that could only find release in technology. Cancer science was begging to find release in a new kind of cancer medicine.

  * Jimmy began chemo in the Children’s Hospital in 1948, but was later followed and treated in the Jimmy Fund Building in 1952.

  * Surgery’s contribution could not be judged since surgery predated 1990, and nearly all women are treated surgically.

  New Drugs for Old Cancers

  In the story of Patroclus

  No one survives, not even Achilles

  Who was nearly a god.

  Patroclus resembled him; they wore

  The same armor

  —Louise Glück

  The perfect therapy has not been developed. Most of us believe that it will not involve toxic cytotoxic therapy, which is why we support the kinds of basic investigations that are directed towards more fundamental understanding of tumor biology. But . . . we must do the best with what we now have.

  —Bruce Chabner to Rose Kushner

  In the legend, Achilles was quickly dipped into the river Styx, held up only by the tendon of his heel. Touched by the dark sheath of water, every part of his body was instantly rendered impervious to even the most lethal weapon—except the undipped tendon. A simple arrow targeted to that vulnerable heel would eventually kill Achilles in the battlefields of Troy.

  Before the 1980s, the armamentarium of cancer therapy was largely built around two fundamental vulnerabilities of cancer cells. The first is that most cancers originate as local diseases before they spread systemically. Surgery and radiation therapy exploit this vulnerability. By physically excising locally restricted tumors before cancer cells can spread—or by searing cancer cells with localized bursts of powerful energy using X-rays—surgery and radiation attempt to eliminate cancer en bloc from the body.

  The second vulnerability is the rapid growth rate of cancer cells. Most chemotherapy drugs discovered before the 1980s target this second vulnerability. Antifolates, such as Farber’s aminopterin, interrupt the metabolism of folic acid and starve all cells of a crucial nutrient required for cell division. Nitrogen mustard and cisplatin chemically react with DNA, and DNA-damaged cells cannot duplicate their genes and thus cannot divide. Vincristine, the periwinkle poison, thwarts the ability of a cell to construct the molecular “scaffold” required for all cells to divide.

  But these two traditional Achilles’ heels of cancer—local growth and rapid cell division—can only be targeted to a point. Surgery and radiation are intrinsically localized strategies, and they fail when cancer cells have spread beyond the limits of what can be surgically removed or irradiated. More surgery thus does not lead to more cures, as the radical surgeons discovered to their despair in the 1950s.

  Targeting cellular growth also hits a biological ceiling because normal cells must grow as well. Growth may be the hallmark of cancer, but it is equally the hallmark of life. A poison directed at cellular growth, such as vincristine or cisplatin, eventually attacks normal growth, and cells that grow most rapidly in the body begin to bear the collateral cost of chemotherapy. Hair falls out. Blood involutes. The lining of the skin and gut sloughs off. More drugs produce more toxicity without producing cures, as the radical chemotherapists discovered to their despair in the 1980s.

  To target cancer cells with novel therapies, scientists and physicians needed new vulnerabilities that were unique to cancer. The discoveries of cancer biology in the 1980s offered a vastly more nuanced view of these vulnerabilities. Three new principles emerged, representing three new Achilles’ heels of cancer.

  First, cancer cells are driven to grow because of the accumulation of mutations in their DNA. These mutations activate internal proto-oncogenes and inactivate tumor suppressor genes, thus unleashing the “accelerators” and “brakes” that operate during normal cell division. Targeting these hyperactive genes, while sparing their modulated normal precursors, might be a novel means to attack cancer cells more discriminately.

  Second, proto-oncogenes and tumor suppressor genes typically lie at the hubs of cellular signaling pathways. Cancer cells divide and grow because they are driven by hyperactive or inactive signals in these critical pathways. These pathways exist in normal cells but are tightly regulated. The potential dependence of a cancer cell on such permanently activated pathways is a second potential vulnerability of a cancer cell.

  Third, the relentless cycle of mutation, selection, and survival creates a cancer cell that has acquired several additional properties besides uncontrolled growth. These include the capacity to resist death signals, to metastasize throughout the body, and to incite the growth of blood vessels. These “hallmarks of cancer” are not invented by the cancer cell; they are typically derived from the corruption of similar processes that occur in the normal physiology of the body. The acquired dependence of a cancer cell on these processes is a third potential vulnerability of cancer.

  The central therapeutic challenge of the newest cancer medicine, then, was to find, among the vast numbers of similarities in normal cells and cancer cells, subtle differences in genes, pathways, and acquired capabilities—and to drive a poisoned stake into that new heel.

  It was one thing to identify an Achilles’ heel—and quite another to discover a weapon that would strike it. Until the late 1980s, no drug had reversed an oncogene’s activation or a tumor suppressor’s inactivation. Even tamoxifen, the most specific cancer-targeted drug discovered to that date, works by attacking the dependence of certain breast cancer cells on estrogen, and not by directly inactivating an oncogene or oncogene-activated pathway. In 1986, the discovery of the first oncogene-targeted drug would thus instantly galvanize cancer medicine. Although found largely serendipitously, the mere existence of such a molecule would set the stage for the vast drug-hunting efforts of the next decade.

  The disease that stood at the pivotal crossroads of oncology was yet another rare variant of leukemia called acute promyelocytic leukemia—APL. First identified as a distinct form of adult leukemia in the 1950s, the disease has a distinct characteristic: the cells in this form of cancer do not merely divide rapidly, they are also strikingly frozen in immature development. Normal white blood cells developing in the bone marrow undergo a series of maturational steps to develop into fully functional adult cells. One such intermediate cell is termed a promyelocyte, an adolescent cell on the verge of becoming functionally mature. APL is characterized by the malignant proliferation of these immature promyelocytes. Normal promyelocytes are loaded with toxic enzymes and granules that are usually released by adult white blood cells to kill viruses, bacteria, and parasites. In promyelocytic leukemia, the blood fills up with these toxin-loaded promyelocytes. Moody, mercurial, and jumpy, the cells of APL can release their poisonous granu
les on a whim—precipitating massive bleeding or simulating a septic reaction in the body. In APL, the pathological proliferation of cancer thus comes with a fiery twist. Most cancers contain cells that refuse to stop growing. In APL, the cancer cells also refuse to grow up.

  Since the early 1970s, this maturation arrest of APL cells had prompted scientists to hunt for a chemical that might force these cells to mature. Scores of drugs had been tested on APL cells in test tubes, and only one had stood out—retinoic acid, an oxidized form of vitamin A. But retinoic acid, researchers had found, was a vexingly unreliable reagent. One batch of the acid might mature APL cells, while another batch of the same chemical might fail. Frustrated by these flickering, unfathomable responses, biologists and chemists had turned away after their initial enthusiasm for the maturation chemical.

  In the summer of 1985, a team of leukemia researchers from China traveled to France to meet Laurent Degos, a hematologist at Saint Louis Hospital in Paris with a long-standing interest in APL. The Chinese team, led by Zhen Yi Wang, was also treating APL patients, at Ruijin Hospital, a busy, urban clinical center in Shanghai, China. Both Degos and Wang had tried standard chemotherapy agents—drugs that target rapidly growing cells—to promote remissions in APL patients, but the results had been dismal. Wang and Degos spoke of the need for a new strategy to attack this whimsical, lethal disease, and they kept circling back to the peculiar immaturity of APL cells and to the lapsed search for a maturation agent for the disease.

  Retinoic acid, Wang and Degos knew, comes in two closely related molecular forms, called cis-retinoic acid and trans-retinoic acid. The two forms are compositionally identical, but possess a slight difference in their molecular structure, and they behave very differently in molecular reactions. (Cis-retinoic acid and trans-retinoic acid have the same atoms, but the atoms are arranged differently in the two chemicals.) Of the two forms, cis-retinoic acid had been the most intensively tested, and it had produced the flickering, transient responses. But Wang and Degos wondered if trans-retinoic acid was the true maturation agent. Had the unreliable responses in the old experiments been due to a low and variable amount of the trans-retinoic form present in every batch of retinoic acid?

  Wang, who had studied at a French Jesuit school in Shanghai, spoke a lilting, heavily accented French. Linguistic and geographic barriers breached, the two hematologists outlined an international collaboration. Wang knew of a pharmaceutical factory outside Shanghai that could produce pure trans-retinoic acid—without the admixture of cis-retinoic acid. He would test the drug on APL patients at the Ruijin Hospital. Degos’s team in Paris would follow after the initial round of testing in China and further validate the strategy on French APL patients.

  Wang launched his trial in 1986 with twenty-four patients. Twenty-three experienced a dazzling response. Leukemic promyelocytes in the blood underwent a brisk maturation into white blood cells. “The nucleus became larger,” Wang wrote, “and fewer primary granules were observed in the cytoplasm. On the fourth day of culture, these cells gave rise to myelocytes containing specific, or secondary, granules . . . [indicating the development of] fully mature granulocytes.”

  Then something even more unexpected occurred: having fully matured, the cancer cells began to die out. In some patients, the differentiation and death erupted so volcanically that the bone marrow swelled up with differentiated promyelocytes and then emptied slowly over weeks as the cancer cells matured and underwent an accelerated cycle of death. The sudden maturation of cancer cells produced a short-lived metabolic disarray, which was controlled with medicines, but the only other side effects of trans-retinoic acid were dryness of lips and mouth and an occasional rash. The remissions produced by trans-retinoic acid lasted weeks and often months.

  Acute promyelocytic leukemia still relapsed, typically about three to four months after treatment with trans-retinoic acid. The Paris and Shanghai teams next combined standard chemotherapy drugs with trans-retinoic acid—a cocktail of old and new drugs—and remissions were prolonged by several additional months. In about three-fourths of the patients, the leukemia remission began to stretch into a full year, then into five years. By 1993, Wang and Degos concluded that 75 percent of their patients treated with the combination of trans-retinoic acid and standard chemotherapy would never relapse—a percentage unheard of in the history of APL.

  Cancer biologists would need another decade to explain the startling Ruijin responses at a molecular level. The key to the explanation lay in the elegant studies performed by Janet Rowley, the Chicago cytologist. In 1984, Rowley had identified a unique translocation in the chromosomes of APL cells—a fragment of a gene from chromosome fifteen fused with a fragment of a gene from chromosome seventeen. This created an activated “chimeric” oncogene that drove the proliferation of promyelocytes and blocked their maturation, thus creating the peculiar syndrome of APL.

  In 1990, a full four years after Wang’s clinical trial in Shanghai, this culprit oncogene was isolated by independent teams of scientists from France, Italy, and America. The APL oncogene, scientists found, encodes a protein that is tightly bound by trans-retinoic acid. This binding immediately extinguishes the oncogene’s signal in APL cells, thereby explaining the rapid, powerful remissions observed in Shanghai.

  The Ruijin discovery was remarkable: trans-retinoic acid represented the long-sought fantasy of molecular oncology—an oncogene-targeted cancer drug. But the discovery was a fantasy lived backward. Wang and Degos had first stumbled on trans-retinoic acid through inspired guesswork—and only later discovered that the molecule could directly target an oncogene.

  But was it possible to make the converse journey—starting from oncogene and going to drug? Indeed, Robert Weinberg’s lab in Boston had already begun that converse journey, although Weinberg himself was largely oblivious of it.

  By the early 1980s, Weinberg’s lab had perfected a technique to isolate cancer-causing genes directly out of cancer cells. Using Weinberg’s technique, researchers had isolated dozens of new oncogenes from cancer cells. In 1982, a postdoctoral scientist from Bombay working in Weinberg’s lab, Lakshmi Charon Padhy, reported the isolation of yet another such oncogene from a rat tumor called a neuroblastoma. Weinberg christened the gene neu, naming it after the type of cancer that harbored this gene.

  Neu was added to the growing list of oncogenes, but it was an anomaly. Cells are bounded by a thin membrane of lipids and proteins that acts as an oily barrier against the entry of many drugs. Most oncogenes discovered thus far, such as ras and myc, are sequestered inside the cell (ras is bound to the cell membrane but faces into the cell), making them inaccessible to drugs that cannot penetrate the cell membrane. The product of the neu gene, in contrast, was a novel protein, not hidden deep inside the cell, but tethered to the cell membrane with a large fragment that hung outside, freely accessible to any drug.

  Lakshmi Charon Padhy even had a “drug” to test. In 1981, while isolating his gene, he had created an antibody against the new neu protein. Antibodies are molecules designed to bind to other molecules, and the binding can occasionally block and inactivate the bound protein. But antibodies are unable to cross the cell membrane and need an exposed protein outside the cell to bind. Neu, then, was a perfect target, with a large portion, a long molecular “foot,” projected tantalizingly outside the cell membrane. It would have taken Padhy no more than an afternoon’s experiment to add the neu antibody to the neuroblastoma cells to determine the binding’s effect. “It would have been an overnight test,” Weinberg would later recall. “I can flagellate myself. If I had been more studious and more focused and not as monomaniacal about the ideas I had at that time, I would have made that connection.”

  Despite the trail of seductive leads, Padhy and Weinberg never got around to doing their experiment. Afternoon upon afternoon passed. Introspective and bookish, Padhy shuffled through the lab in a threadbare coat in the winter, running his experiments privately and saying little about them to others. And although P
adhy’s discovery was published in a high-profile scientific journal, few scientists noticed that he might have stumbled on a potential anticancer drug (the neu-binding antibody was buried in an obscure figure in the article). Even Weinberg, caught in the giddy upswirl of new oncogenes and obsessed with the basic biology of the cancer cell, simply forgot about the neu experiment.*

  Weinberg had an oncogene and possibly an oncogene-blocking drug, but the twain had never met (in human cells or bodies). In the neuroblastoma cells dividing in his incubators, neu rampaged on monomaniacally, single-mindedly, seemingly invincible. Yet its molecular foot still waved just outside the surface of the plasma membrane, exposed and vulnerable, like Achilles’ famous heel.

  * In 1986, Jeffrey Drebin and Mark Greene showed that treatment with an anti-neu antibody arrested the growth of cancer cells. But the prospect of developing this antibody into a human anticancer drug eluded all groups.

  A City of Strings

  In Ersilia, to establish the relationships that sustain the city’s life, inhabitants stretch strings from the corners of the houses, white or black or gray or black-and-white according to whether they mark a relationship of blood, of trade, authority, agency. When the strings become so numerous that you can no longer pass among them, the inhabitants leave: the houses are dismantled.