It is in vain to speak of cures, or think of remedies, until such time as we have considered of the causes . . . cures must be imperfect, lame, and to no purpose, wherein the causes have not first been searched.

—Robert Burton,

The Anatomy of Melancholy, 1893

You can’t do experiments to see what causes cancer. It’s not an accessible problem and it’s not the sort of thing scientists can afford to do.

—I. Hermann,

cancer researcher, 1978

What can be the “why” of these happenings?

—Peyton Rous,

1966, on the mystery

of the origin of cancer

“A unitary cause”

It is the spring of 2005—a pivot point in the medical oncology fellowship. Our paths are about to divide. Three of us will continue in the clinic, with a primary focus in clinical research and in the day-to-day care of patients. Four will explore cancer in the laboratory, retaining just a minor presence in the clinic, seeing just a handful of patients every week.

The choice between the two paths is instinctual. Some of us inherently perceive ourselves as clinicians; others primarily as scientists. My own inclinations have changed little since the first day of my internship. Clinical medicine moves me viscerally. But I am a lab rat, a nocturnal, peripatetic creature drawn to the basic biology of cancer. I mull over the type of cancer to study in the laboratory, and I find myself gravitating toward leukemia. I may be choosing the laboratory, but my subject of research is governed by a patient. Carla’s disease has left its mark on my life.

Even so, in the fading twilight of my full-time immersion in the hospital, there are disquieting moments that remind me how deeply clinical medicine can surprise and engage me. It is late one evening in the fellows’ room, and the hospital around us has fallen silent save for the metallic clink of cutlery being brought up for meals. The air outside is heavy with impending rain. The seven of us, close friends by now, are compiling lists of patients to pass on to the next class of fellows when Lauren begins to read her list aloud, calling out the names of those in her care who have died over our two-year fellowship. Suddenly inspired, she pauses and adds a sentence to each name as a sort of epitaph.

It is an impromptu memorial service, and it stirs something in the room. I join in, calling out names of my patients who have died and appending a sentence or two in memory.

Kenneth Armor, sixty-two, an internist with stomach cancer. In his final days, all he wished for was a vacation with his wife and time to play with his cats.

Oscar Fisher, thirty-eight, had small-cell lung cancer. Cognitively impaired since birth, he was his mother’s favorite child. When he died, she was threading rosaries through his fingers.

That night I sit alone with my list, remembering the names and faces late into the evening. How does one memorialize a patient? These men and women have been my friends, my interlocutors, my teachers—a surrogate family. I stand up at my desk, as if at a funeral, my ears hot with emotion, my eyes full of tears. I look around the room at the empty desks and note how swiftly the last two years have reshaped all seven of us. Eric, cocksure, ambitious, and smart, is humbler and more introspective. Edwin, preternaturally cheerful and optimistic in his first month, talks openly about resignation and grief. Rick, an organic chemist by training, has become so infatuated with clinical medicine that he doubts that he will return to the laboratory. Lauren, guarded and mature, enlivens her astute assessments with jokes about oncology. Our encounter with cancer has rounded us off; it has smoothed and polished us like river rocks.


A few days later, I meet Carla in the infusion room. She is casually chatting with the nurses, as if catching up with old friends. From a distance, she is barely recognizable. The sheet-white complexion I recall from her first visit to the hospital has warmed up several degrees of red. The bruises in her arm from repeated infusions have vanished. Her children are back in their routine, her husband has returned to work, her mother is home in Florida. Carla’s life is nearly normal. She tells me that her daughter occasionally wakes up crying from a nightmare. When I ask her if this reflects some remnant trauma from Carla’s yearlong ordeal with illness, she shakes her head assertively: “No. It’s just monsters in the dark.”

It has been a little more than a year since her original diagnosis. She is still taking pills of 6-mercaptopurine and methotrexate—Burchenal’s drug and Farber’s drug, a combination intended to block the growth of any remnant cancer cells. When she recalls the lowest points of her illness, she shudders in disgust. But something is normalizing and healing inside her. Her own monsters are vanishing, like old bruises.

When her blood counts return from the lab, they are stone-cold normal. Her remission continues. I am astonished and exalted by the news, but I bring it to her cautiously, as neutrally as I can. Like all patients, Carla smells overenthusiasm with deep suspicion: a doctor who raves disproportionately about small victories is the same doctor who might be preparing his patient for some ultimate defeat. But this time there is no reason to be suspicious. I tell her that her counts look perfect, and that no more tests are required today. In leukemia, she knows, no news is the best kind of news.


Late that evening, having finished my notes, I return to the laboratory. It is a beehive of activity. Postdocs and graduate students hover around the microscopes and centrifuges. Medical words and phrases are occasionally recognizable here, but the dialect of the lab bears little resemblance to the dialect of medicine. It is like traveling to a neighboring country—one that has similar mannerisms but speaks a different language:

“But the PCR on the leukemia cells should pick up the band.”

“What conditions did you use to run this gel?”

“Agarose, four percent.”

“Was the RNA degraded in the centrifugation step?”

I retrieve a plate of cells from the incubator. The plate has 384 tiny wells, each barely large enough to hold two grains of rice. In each well, I have placed two hundred human leukemia cells, then added a unique chemical from a large collection of untested chemicals. In parallel, I have its “twin” plate—containing two hundred normal human blood-forming stem cells, with the same panel of chemicals added to every well.

Several times each day, an automated microscopic camera will photograph each well in the two plates, and a computerized program will calculate the number of leukemia cells and normal stem cells. The experiment is seeking a chemical that can kill leukemia cells but spare normal stem cells—a specifically targeted therapy against leukemia.

I aspirate a few microliters containing the leukemia cells from one well and look at them under the microscope. The cells look bloated and grotesque, with a dilated nucleus and a thin rim of cytoplasm, the sign of a cell whose very soul has been co-opted to divide and to keep dividing with pathological, monomaniacal purpose. These leukemia cells have come into my laboratory from the National Cancer Institute, where they were grown and studied for nearly three decades. That these cells are still growing with obscene fecundity is a testament to the terrifying power of this disease.

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


As early as 1858, Virchow recognized this power of proliferation. Looking at cancer specimens under the microscope, Virchow understood that cancer was cellular hyperplasia, the disturbed, pathological growth of cells. But although Virchow recognized and described the core abnormality, he could not fathom its cause. He argued that inflammation—the body’s reaction to a harmful injury, characterized by redness, swelling, and immune-system activation—caused cells to proliferate, leading to the outgrowth of malignant cells. He was almost right: chronic inflammation, smoldering over decades, does cause cancer (chronic hepatitis virus infection in the liver precipitates liver cancer), but Virchow missed the essence of the cause. Inflammation makes cells divide in response to injury, but this cell division is driven as a reaction to an external agent such as a bacteria or a wound. In cancer, the cell acquires autonomous proliferation; it is driven to divide by an internal signal. Virchow attributed cancer to the disturbed physiological milieu around the cell. He failed to fathom that the true disturbance lay within the cancer cell itself.

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. To understand cell division, Flemming had to visualize the inner anatomy of the cell. In 1879, Flemming thus stained dividing salamander cells with aniline, the all-purpose chemical dye used by Paul Ehrlich. The stain highlighted a blue, threadlike substance located deep within the cell’s nucleus that condensed and brightened to a cerulean shade just before cell division. Flemming called his blue-stained structures chromosomes—“colored bodies.” He realized that cells from every species had a distinct number of chromosomes (humans have forty-six; salamanders have fourteen). Chromosomes were duplicated during cell division and divided equally between the two daughter cells, thus keeping the chromosome number constant from generation to generation of cell division. But Flemming could not assign any further function to these mysterious blue “colored bodies” in the cell.

Had Flemming moved his lens from salamander eggs to Virchow’s human specimens, he might have made the next crucial conceptual leap in understanding the root abnormality in cancer cells. It was Virchow’s former assistant David Paul von Hansemann, following Flemming’s and Virchow’s trails, who made a logical leap between the two. Examining cancer cells stained with aniline dyes with a microscope, von Hansemann noticed that Flemming’s chromosomes were markedly abnormal in cancer. The cells had split, frayed, disjointed chromosomes, chromosomes broken and rejoined, chromosomes in triplets and quadruplets.

Von Hansemann’s observation had a profound corollary. Most scientists continued to hunt for parasites in cancer cells. (Bennett’s theory of spontaneous suppuration still held a macabre fascination for some pathologists.) But von Hansemann proposed that the real abnormality lay in the structure of these bodies internal to cancer cells—in chromosomes—and therefore in the cancer cell itself.

But was it cause or effect? Had cancer altered the structure of chromosomes? Or had chromosomal changes precipitated cancer? Von Hansemann had observed a correlation between chromosomal change and cancer. What he needed was an experiment to causally connect the two.

The missing experimental link emerged from the lab of Theodor Boveri, yet another former assistant of Virchow’s. Like Flemming, who worked with salamander cells, Boveri chose to study simple cells in simple organisms, eggs from sea urchins, which he collected on the windswept beaches near Naples. Urchin eggs, like most eggs in the animal kingdom, are strictly monogamous; once a single sperm has entered the egg, the egg puts up an instant barrier to prevent others from entering. After fertilization, the egg divides, giving rise to two, then four cells—each time duplicating the chromosomes and splitting them equally between the two daughter cells. To understand this natural chromosomal separation, Boveri devised a highly unnatural experiment. Rather than allowing the urchin egg to be fertilized by just one sperm, he stripped the outer membrane of the egg with chemicals and forcibly fertilized the egg with two sperms.

The multiple fertilization, Boveri found, precipitated chromosomal chaos. Two sperms fertilizing an egg results in three of each chromosome—a number impossible to divide evenly. The urchin egg, unable to divide the number of chromosomes appropriately among its daughter cells, was thrown into frantic internal disarray. The rare cell that got the right combination of all thirty-six sea urchin chromosomes developed normally. Cells that got the wrong combinations of chromosomes failed to develop or aborted development and involuted and died. Chromosomes, Boveri concluded, must carry information vital for the proper development and growth of cells.

This conclusion allowed Boveri to make a bold, if far-fetched, conjecture about the core abnormality in cancer cells. Since cancer cells possessed striking aberrations in chromosomes, Boveri argued that these chromosomal abnormalities might be the cause of the pathological growth characteristic of cancer.

Boveri found himself circling back to Galen—to the age-old notion that all cancers were connected by a common abnormality—the “unitary cause of carcinoma,” as Boveri called it. Cancer was not “an unnatural group of different maladies,” Boveri wrote. Instead, a common feature lurked behind all cancers, a uniform abnormality that emanated from abnormal chromosomes—and was therefore internal to the cancer cell. Boveri could not put his finger on the nature of this deeper internal abnormality. But the “unitary cause” of carcinoma lay in this disarray—not a chaos of black bile, but a chaos of blue chromosomes.

Boveri published his chromosomal theory of cancer in an elegant scientific pamphlet entitled “Concerning the Origin of Malignant Tumors” in 1914. It was a marvel of fact, fantasy, and inspired guesswork that stitched sea urchins and malignancy into the same fabric. But Boveri’s theory ran into an unanticipated problem, a hard contradictory fact that it could not explain away. In 1910, four years before Boveri had published his theory, Peyton Rous, working at the Rockefeller Institute, had demonstrated that cancer in chickens could be caused by a virus, soon to be named the Rous sarcoma virus, or RSV.

The central problem was this: as causal agents, Rous’s virus and Boveri’s chromosomes were incompatible. A virus is a pathogen, an external agent, an invader exogenous to the cell. A chromosome is an internal entity, an endogenous structure buried deep inside the cell. The two opposites could not both claim to be the “unitary cause” of the same disease. How could an internal structure, a chromosome, and an external infectious agent, a virus, both create cancer?

In the absence of concrete proof for either theory, a viral cause for cancer seemed far more attractive and believable. Viruses, initially isolated in 1898 as minuscule infectious microbes that caused plant diseases, were becoming increasingly recognized as causes for a variety of animal and human diseases. In 1909, a year before Rous isolated his cancer-causing virus, Karl Landsteiner implicated a virus as the cause for polio. By the early 1920s, viruses that caused cowpox and human herpes infections had been isolated and grown in laboratories, further cementing the connection between viruses and human and animal diseases.

Undeniably, the belief in cause was admixed with the hope for a cure. If the causal agent was exogenous and infectious, then a cure for cancer seemed more likely. Vaccination with cowpox, as Jenner had shown, prevented the much more lethal smallpox infection, and Rous’s discovery of a cancer-causing virus (albeit in chickens) had immediately provoked the idea of a therapeutic cancer vaccine. In contrast, Boveri’s theory that cancer was caused by a mysterious problem lurking in the threadlike chromosomes, stood on thin experimental evidence and offered no prospect for a cure.


While the mechanistic understanding of the cancer cell remained suspended in limbo between viruses and chromosomes, a revolution in the understanding of normal cells was sweeping through biology in the early twentieth century. The seeds of this revolution were planted by a retiring, nearsighted monk in the isolated hamlet of Brno, Austria, who bred pea plants as a hobby. In the early 1860s, working alone, Gregor Mendel had identified a few characteristics in his purebred plants that were inherited from one generation to the next—the color of the pea flower, the texture of the pea seed, the height of the pea plant. When Mendel intercrossed short and tall, or blue-flowering and green-flowering, plants using a pair of minute forceps, he stumbled on a startling phenomenon. Short plants bred with tall plants did not produce plants of intermediate height; they produced tall plants. Wrinkle-seeded peas crossed with smooth-seeded peas produced only wrinkled peas.

The implication of Mendel’s experiment was far-reaching: inherited traits, Mendel proposed, are transmitted in discrete, indivisible packets. Biological organisms transmit “instructions” from one cell to its progeny by transferring these packets of information.

Mendel could only visualize these traits or properties in a descriptive sense—as colors, texture, or height moving from generation to generation; he could not see or fathom what conveyed this information from one plant to its progeny. His primitive lamplit microscope, with which he could barely peer into the interior of cells, had no power to reveal the mechanism of inheritance. Mendel did not even have the name for this unit of inheritance; decades later, in 1909, botanists would christen it a gene. But the name was still just a name; it offered no further explanation about a gene’s structure or function. Mendel’s studies left a provocative question hanging over biology for half a century: in what corporal, physical form was a “gene”—the particle of inheritance—carried inside the cell?


In 1910, Thomas Hunt Morgan, an embryologist at Columbia University in New York, discovered the answer. Like Mendel, Morgan was a compulsive breeder, but of fruit flies, which he raised by the thousands on rotting bananas in the Fly Room on the far edge of the Columbia campus. Again, like Mendel, Morgan discovered heritable traits moving indivisibly through his fruit flies generation upon generation—eye colors and wing patterns that were conveyed from parents to offspring without blending.

Morgan made another observation. He noted that an occasional rare trait, such as white eye color, was intrinsically linked to the gender of the fly: white eyes were found only in male flies. But “maleness”—the inheritance of sex—Morgan knew, was linked to chromosomes. So genes had to be carried on chromosomes—the threadlike structures identified by Flemming three decades earlier. Indeed, a number of Flemming’s initial observations on the properties of chromosomes began to make sense to Morgan. Chromosomes were duplicated during cell division, and genes were duplicated as well and thus transmitted from one cell to the next, and from one organism to the next. Chromosomal abnormalities precipitated abnormalities in the growth and development of sea urchins, and so abnormal genes must have been responsible for this dysfunction. In 1915, Morgan proposed a crucial advance to Mendel’s theory of inheritance: genes were borne on chromosomes. It was the transmission of chromosomes during cell division that allowed genes to move from a cell to its progeny.


The third vision of the “gene” emerged from the work of Oswald Avery, a bacteriologist at the Rockefeller University in New York. Mendel had found that genes could move from one generation to the next; Morgan had proved that they did so by being carried on chromosomes. In 1926, Avery found that in certain species of bacteria, genes could also be transmitted laterally between two organisms—from one bacterium to its neighbor. Even dead, inert bacteria—no more than a conglomeration of chemicals—could transmit genetic information to live bacteria. This implied that an inert chemical was responsible for carrying genes. Avery separated heat-killed bacteria into their chemical components. And by testing each chemical component for its capacity to transmit genes, Avery and his colleagues reported in 1944 that genes were carried by one chemical, deoxyribonucleic acid, or DNA. What scientists had formerly disregarded as a form of cellular stuffing with no real function—a “stupid molecule,” as the biologist Max Delbruck once called it dismissively—turned out to be the central conveyor of genetic information between cells, the least stupid of all molecules in the chemical world.

By the mid-1940s, three decades after biologists had coined the word, the molecular nature of the gene had come into focus. Functionally, a gene was a unit of inheritance that carried a biological trait from one cell to another or from one generation to the next. Physically, genes were carried within the cell in the form of chromosomes. Chemically, genes were composed of DNA, deoxyribonucleic acid.


But a gene only carries information. The functional, physical, and chemical understanding of the gene begged a mechanistic understanding: How did genetic information become manifest inside the cell? What did a gene “do”—and how?

George Beadle, Thomas Morgan’s student, switched from Morgan’s fruit flies to an even more primitive organism, the slime mold, to answer these questions. Collaborating with the biochemist Edward Tatum at Stanford University in California, Beadle discovered that genes carried instructions to build proteins—complex, multidimensional macromolecules that were the workhorses of the cell.

Proteins, researchers found in the 1940s, carry out the bulk of cellular functions. They form enzymes, catalysts that speed up biochemical reactions vital to the life of the cell. Proteins are receptors for other proteins or molecules, responsible for transmitting signals from one cell to the next. They can create structural components of the cell, such as the molecular scaffolding that allows a cell to exist in a particular configuration in space. They can regulate other proteins, thus creating minuscule circuits inside the cell responsible for coordinating the life cycle of the cell.

Beadle and Tatum found that a gene “works” by providing the blueprint to build a protein. A protein is a gene realized—the machine built from a gene’s instructions. But proteins are not created directly out of genes. In the late 1950s, Jacques Monod and François Jacob, working in Paris, Sydney Brenner and Matthew Meselson at Caltech, and Francis Crick in Cambridge, discovered that the genesis of proteins from genes requires an intermediary step—a molecule called ribonucleic acid, or RNA.

RNA is the working copy of the genetic blueprint. It is through RNA that a gene is translated into a protein. This intermediary RNA copy of a gene is called a gene’s “message.” Genetic information is transmitted from a cell to its progeny through a series of discrete and coordinated steps. First, genes, located in chromosomes, are duplicated when a cell divides and are transmitted into progeny cells. Next, a gene, in the form of DNA, is converted into its RNA copy. Finally, this RNA message is translated into a protein. The protein, the ultimate product of genetic information, carries out the function encoded by the gene.

An example, borrowed from Mendel and Morgan, helps illustrate the process of cellular information transfer. Red-eyed flies have glowering, ruby-colored eyes because they possess a gene that bears the information to build a red pigment protein. A copy of this gene is created every time a cell divides and it thus moves from a fly to its egg cells, and then into the cells of the offspring fly. In the eye cells of the progeny fly, this gene is “deciphered”—i.e., converted into an intermediate RNA message. The RNA message, in turn, instructs the eye cells to build the red pigment protein, thus giving rise to red-eyed flies of the next generation. Any interruption in this information flow might disrupt the transmission of the red eye trait—producing flies with colorless eyes.

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.


An incandescent century of biological discovery—spanning from Mendel’s discovery of genes in 1860 to Monod’s identification of the RNA copy of genes in the late 1950s—illuminated the inner workings of a normal cell. But it did little to illuminate the workings of a cancer cell or the cause of cancer—except in two tantalizing instances.

The first came from human studies. Nineteenth-century physicians had noted that some forms of cancer, such as breast and ovarian cancer, tended to run in families. This in itself could not prove a hereditary cause: families share not just genes, but also habits, viruses, foods, exposures to chemicals, and neurotic behaviors—all factors, at some time or another, implicated as causes of cancer. But occasionally, a family history was so striking that a hereditary cause (and, by extension, a genetic cause) could not be ignored. In 1872, Hilário de Gouvêa, a Brazilian ophthalmologist practicing in Rio, treated a young boy with a rare cancer of the eye called a retinoblastoma by removing the eye surgically. The boy had survived, grown up, and married a woman with no family history of cancer. The couple had several children, and two of the daughters developed their father’s retinoblastoma in both eyes—and died. De Gouvêa reported this case as a puzzling enigma. He did not possess the language of genetics, but to later observers, the case suggested an inherited factor that “lived” in genes and caused cancer. But such cases were so rare that it was hard to test this hypothesis experimentally, and de Gouvêa’s report was largely ignored.

The second time scientists circled around the cause of cancer—almost hitting the nerve spot of carcinogenesis—came several decades after the strange Brazilian case. In the 1910s, Thomas Hunt Morgan, the fruit fly geneticist at Columbia, noticed that mutant flies occasionally appeared within his flock of flies. In biology, mutants are defined as organisms that differ from the normal. Morgan noticed that an enormous flock of flies with normal wings might occasionally give birth to a “monster” with rough or scalloped wings. These mutations, Morgan discovered, were the results of alterations in genes and the mutations could be carried from one generation to the next.

But what caused mutations? In 1928, Hermann Joseph Muller, one of Morgan’s students, discovered that X-rays could vastly increase the rate of mutation in fruit flies. At Columbia, Morgan had produced mutant flies spontaneously. (When DNA is copied during cell division, a copying error occasionally generates an accidental change in genes, thus causing mutations.) Muller found that he could accelerate the incidence of these accidents. Using X-rays to bombard flies, he found that he could produce hundreds of mutant flies over a few months—more than Morgan and his colleagues had produced using their vast breeding program over nearly two decades.

The link between X-rays and mutations nearly led Morgan and Muller to the brink of a crucial realization about cancer. Radiation was known to cause cancer. (Recall Marie Curie’s leukemia, and the tongue cancers of the radium-watch makers.) Since X-rays also caused mutations in fruit fly genes, could cancer be a disease of mutations? And since mutations were changes in genes, could genetic alterations be the “unitary cause” of cancer?

Had Muller and Morgan, student and mentor, pitched their formidable scientific skills together, they might have answered this question and uncovered this essential link between mutations and malignancy. But once close colleagues, they became pitted and embittered rivals. Cantankerous and rigid with old age, Morgan refused to give Muller full recognition for his theory of mutagenesis, which he regarded as a largely derivative observation. Muller, in turn, was sensitive and paranoid; he felt that Morgan had stolen his ideas and taken an undue share of credit. In 1932, having moved his lab to Texas, Muller walked into the nearby woods and swallowed a roll of sleeping pills in an attempted suicide. He survived, but haunted by anxiety and depression, his scientific productivity lapsed in his later years.

Morgan, in turn, remained doggedly pessimistic about the relevance of the fruit fly work in understanding human diseases. In 1933, Morgan received the Nobel Prize in Physiology or Medicine for his far-reaching work on fruit fly genetics. (Muller would receive the Nobel Prize independently in 1946.) But Morgan wrote self-deprecatingly about the medical relevance of his work, “The most important contribution to medicine that genetics has made is, in my opinion, intellectual.” At some point far in the future, he imagined a convergence between medicine and genetics. “Possibly,” he speculated, “the doctor may then want to call in his geneticist friends for consultation!”

But to oncologists in the 1940s, such a “consultation” seemed far-fetched. The hunt for an internal, genetic cause of cancer had stalled since Boveri. Pathological mitosis was visible in cancerous tissue. But both geneticists and embryologists failed to answer the key question: what caused mitosis to turn so abruptly from such an exquisitely regulated process to chaos?

More deeply, what had failed was a kind of biological imagination. Boveri’s mind had so acrobatically leapt from sea urchins to carcinomas, or Morgan’s from pea plants to fruit flies, in part because biology itself was leaping from organism to organism, finding systematic cellular blueprints that ran deeply through all the living world. But extending that same blueprint to human diseases had turned out to be a much more challenging task. At Columbia, Morgan had assembled a fair collection of fruit fly monsters, but none that even remotely resembled a real human affliction. The notion that the cancer doctor might call in a “genetic friend” to help understand the pathophysiology of cancer seemed laughable.

Cancer researchers would return to the language of genes and mutations again in the 1970s. But the journey back to this language—and to the true “unitary” cause of cancer—would take a bewildering detour through the terrain of new biology, and a further fifty years.

Under the Lamps of Viruses

Unidentified flying objects, abominable snowmen, the Loch Ness monster and human cancer viruses.

Medical World News, 1974,

on four “mysteries” widely reported

and publicized but never seen

The biochemist Arthur Kornberg once joked that the discipline of modern biology in its early days often operated like the man in the proverbial story who is frantically searching for his keys under a streetlamp. When a passerby asks the man whether he lost his keys at that spot, the man says that he actually lost them at home—but he is looking for the keys under the lamp because “the light there is the brightest.”

In the predawn of modern biology, experiments were so difficult to perform on biological organisms, and the results of manipulations so unpredictable, that scientists were severely constrained in their experimental choices. Experiments were conducted on the simplest model organisms—fruit flies, sea urchins, bacteria, slime molds—because the “light” there was the brightest.

In cancer biology, Rous’s sarcoma virus represented the only such lamplit spot. Admittedly, it was a rare virus that produced a rare cancer in a species of chicken.* But it was the most reliable way to produce a real cancer in a living organism. Cancer researchers knew that X-rays, soot, cigarette smoke, and asbestos represented vastly more common risk factors for human cancers. They had heard of the odd Brazilian case of a family that seemed to carry retinoblastoma cancer in its genes. But the capacity to manipulatecancer in an experimental environment was unique to the Rous virus, and so it stood center stage, occupying all the limelight.

The appeal of studying Rous virus was further compounded by the formidable force of Peyton Rous’s personality. Bulldogish, persuasive, and inflexible, Rous had acquired a near paternal attachment to his virus, and he was unwilling to capitulate to any other theory of cause. He acknowledged that epidemiologists had shown that exogenous carcinogens were correlated with cancer (Doll and Hill’s study, published in 1950, had clearly shown that smoking was associated with an increase in lung cancer), but this had not offered any mechanistic explanation of cancer causation. Viruses, Rous felt, were the only answer.

By the early 1950s, cancer researchers had thus split into three feuding camps. The virologists, led by Rous, claimed that viruses caused cancer, although no such virus had been found in human studies. Epidemiologists, such as Doll and Hill, argued that exogenous chemicals caused cancer, although they could not offer a mechanistic explanation for their theory or results. The third camp, of Theodor Boveri’s successors, stood at the farthest periphery. They possessed weak, circumstantial evidence that genes internal to the cell might cause cancer, but had neither the powerful human data of the epidemiologists nor the exquisite experimental insights of the chicken virologists. Great science emerges out of great contradiction, and here was a gaping rift slicing its way through the center of cancer biology. Was human cancer caused by an infectious agent? Was it caused by an exogenous chemical? Was it caused by an internal gene? How could the three groups of scientists have examined the same elephant and returned with such radically variant opinions about its essential anatomy?


In 1951, a young virologist named Howard Temin, then a postdoctoral researcher, arrived at the California Institute of Technology in Pasadena, California, to study the genetics of fruit flies. Restless and imaginative, Temin soon grew bored with fruit flies. Switching fields, he chose to study Rous sarcoma virus in Renato Dulbecco’s laboratory. Dulbecco, a suave, exquisitely mannered Calabrian aristocrat, ran his lab at Caltech with a distant and faintly patrician air. Temin was a perfect fit: if Dulbecco wanted distance, Temin wanted independence. Temin found a house in Pasadena with several other young scientists (including John Cairns, the future author of the Scientific American article on the War on Cancer) and spent his time cooking up unusual meals in heavy communal pots and talking volubly about biological riddles late into the night.

In the laboratory, too, Temin was cooking up an unusual experiment that was virtually guaranteed to fail. Until the late fifties, Rous sarcoma virus had been shown to cause tumors only in live chickens. Temin, working closely with Harry Rubin, wanted to study how the virus converted normal cells into cancer cells. To do this, they needed a vastly simplified system—a system free of chickens and tumors, and analogous to bacteria in a petri dish. And so Temin imagined creating cancer in a petri dish. In 1958, in his seventh year in Dulbecco’s lab, Temin succeeded. He added Rous sarcoma virus to a layer of normal cells in a petri dish. The infection of the cells incited them to grow uncontrollably, forcing them to form tiny distorted heaps containing hundreds of cells that Temin called foci (the plural of focus). The foci, Temin reasoned, represented cancer distilled into its essential, elemental form: cells growing uncontrollably, unstoppably—pathological mitosis. It was the sheer, driving power of Temin’s imagination that allowed him to look at a tiny heap of cells and reimagine that heap as the essence of the diffuse systemic disease that kills humans. But Temin believed that the cell, and its interaction with the virus, had all the biological components necessary to drive the malignant process. The ghost was out of the organism.

Temin could now use his cancer-in-a-dish to perform experiments that would have been nearly impossible using whole animals. One of his first experiments with this system, performed in 1959, produced an unexpected result. Normally, viruses infect cells, produce more viruses, and infect more cells, but they do not directly affect the genetic makeup, the DNA, of the cell. Influenza virus, for instance, infects lung cells and produces more influenza virus, but it does not leave a permanent fingerprint in our genes; when the virus goes away, our DNA is left untouched. But Rous’s virus behaved differently. Rous sarcoma virus, having infected the cells, had physically attached itself to the cell’s DNA and thereby altered the cell’s genetic makeup, its genome. “The virus, in some structural as well as functional sense, becomes part of the genome of the cell,” Temin wrote.*

This observation—that a DNA copy of a virus’s genes could structurally attach itself to a cell’s genes—intrigued Temin and Dulbecco. But it raised an even more intriguing conceptual problem. In viruses, genes are sometimes carried in their intermediary RNA form. Certain viruses have dispensed with the original DNA copy of genes and keep their genome in the RNA form, which is directly translated into viral proteins once the virus infects a cell.

Temin knew from work performed by other researchers that Rous sarcoma virus is one such RNA virus. But if the virus genes started as RNA, then how could a copy of its genes convert into DNA? The central dogma of molecular biology forbade such a transition. Biological information, the dogma proposed, only travels down a one-way street from DNA to RNA to proteins. How on earth, Temin wondered, could RNA turn around acrobatically and make a DNA copy of itself, driving the wrong way down the one-way street of biological information?

Temin made a leap of faith; if the data did not fit the dogma, then the dogma—not the data—needed to be changed. He postulated that Rous sarcoma virus carried a special property, a property unprecedented in any other living organism: it could convert RNA back into DNA. In normal cells, the conversion of DNA into RNA is called transcription. The virus (or the infected cell) therefore had to possess the reverse capacity: reverse transcription. “Temin had an inkling, but his proof was so circumstantial—so frail—that he could barely convince anyone,” the virologist Michael Bishop recalled twenty-five years later. “The hypothesis had earned him little but ridicule and grief.”


At first, Temin could barely even convince himself. He had made a bold proposition, but he needed proof. In 1960, determined to find experimental proof, Temin moved his lab to the McArdle laboratory in Wisconsin. Madison, unlike Caltech, was a frozen, faraway place, isolated both physically and intellectually, but this suited Temin. Standing unknowingly at the edge of a molecular revolution, he wanted silence. On his daily walk along Lakeshore path, often blanketed in dense snow, Temin planned experiments to find evidence for this reverse flow of information.

RNA into DNA. Even the thought made him shiver: a molecule that could write history backward, turn back the relentless forward flow of biological information. To prove that such a process existed, Temin would need to isolate in a test tube the viral enzyme that could reverse transcription and prove that it could make a DNA copy out of RNA. In the early 1960s, pursuing the enzyme, he hired a Japanese postdoctoral student named Satoshi Mizutani. Mizutani’s task was to purify this reverse transcription enzyme from virus-infected cells.

Mizutani was a catastrophe. Never a cell biologist at heart, as a colleague recalled, he contaminated the cells, infected the cultures, and grew out balls of fungi in the petri dishes. Frustrated, Temin moved Mizutani to a project involving no cells. If Mizutani couldn’t manipulate cells, he could try to purify the enzyme out of chemical extracts made from virus-infected cells. The move played to Mizutani’s natural skills: he was an incredibly gifted chemist. Overnight, he picked up a weak, flickering enzymatic activity in the cellular extracts of the Rous virus that was capable of converting RNA into DNA. When he added RNA to this cellular extract, he could “see” it creating a DNA copy—reversing transcription. Temin had his proof. Rous sarcoma virus was no ordinary virus. It could write genetic information backward: it was a retrovirus.*

At MIT, in Boston, another young virologist, David Baltimore, had also picked up the hint of an RNA → DNA conversion activity, although in a different retrovirus. Brilliant, brash, and single-minded, Baltimore had met and befriended Howard Temin in the 1940s at science summer camp in Maine, where Temin had been a teaching assistant and Baltimore a student. They had parted ways for nearly a decade, yet their intellectual paths had kept crisscrossing. As Temin was exploring reverse transcription in Rous sarcoma virus in Madison, Baltimore had begun to amass evidence that his retrovirus also possessed an enzyme that could convert RNA into DNA. He, too, was steps away from isolating the enzyme.

On the afternoon of May 27, 1970, a few weeks after he had found initial evidence for the RNA → DNA converting enzyme in his lab, Temin caught a flight to Houston to present his work at the Tenth International Cancer Congress. The next morning, he walked to the cavernous auditorium at the Houston Civic Center. Temin’s talk was entitled “The Role of DNA in the Replication of RNA Viruses,” a title left intentionally bland. It was a short, fifteen-minute session. The room was filled mainly with tumor virus specialists, many already dozing off to sleep.

But as Temin began to unfold his findings, the importance of his talk dawned on the audience. On the surface, as one researcher recalled, “It was all very dry biochemistry. . . . Temin spoke in his usual nasal, high-pitched monotone, giving no indication of excitement.” But the significance of the work crystallized out of the dry biochemical monotone. Temin was not just talking about viruses. He was systematically dismantling one of the fundamental principles of biology. His listeners became restive, unnerved. By the time Temin reached the middle of the talk, there was an awestruck silence. Scientists in the audience were feverishly taking notes, filling page after page with harrowed scribbles. Once outside the conference room, Temin recalled, “You could see people on the telephone. . . . People called people in their laboratories.” Temin’s announcement that he had identified the long-sought-after enzyme activity in the virus-infected cells left little doubt about the theory. RNA could generate DNA. A cancer-causing virus’s genome could become a physical part of a cell’s genes.

Temin returned to Madison the next morning to find his laboratory inundated with phone messages. The most urgent of these was from David Baltimore, who had heard an inkling of Temin’s news from the meeting. Temin called him back.

“You know there is [an enzyme] in the virus particles,” Baltimore said.

“I know,” said Temin.

Baltimore, who had kept his own work very, very quiet, was stunned. “How do you know?”

“We found it.”

Baltimore had also found it. He, too, had identified the RNA → DNA enzymatic activity from the virus particles. Each laboratory, working apart, had converged on the same result. Temin and Baltimore both rushed their observations to publication. Their twin reports appeared back-to-back in Nature magazine in the summer of 1970.

In their respective papers, Temin and Baltimore proposed a radical new theory about the life cycle of retroviruses. The genes of retroviruses, they postulated, exist as RNA outside cells. When these RNA viruses infect cells, they make a DNA copy of their genes and attach this copy to the cell’s genes. This DNA copy, called a provirus, makes RNA copies, and the virus is regenerated, phoenixlike, to form new viruses. The virus is thus constantly shuttling states, rising from the cellular genome and falling in again—RNA to DNA to RNA; RNA to DNA to RNA—ad infinitum.


It is surely a sign of the prevailing schizophrenia of the time that Temin’s work was instantly embraced as a possible mechanistic explanation for cancer by cancer scientists, but largely ignored by clinical oncologists. Temin’s presentation in Houston was part of a mammoth meeting on cancer. Both Farber and Frei had flown in from Boston to attend. Yet, the conference epitomized the virtually insurmountable segregation between cancer therapy and cancer science. Chemotherapy and surgery were discussed in one room. Viral carcinogenesis was discussed in another. It was as if a sealed divider had been constructed through the middle of the world of cancer, with “cause” on one side and “cure” on the other. Few scientists or clinical oncologists crossed between the two isolated worlds. Frei and Farber returned to Boston with no significant change in the trajectories of their thoughts about curing cancer.

Yet for some scientists attending the conference, Temin’s work, pushed to its logical extreme, suggested a powerful mechanistic explanation for cancer, and thus a well-defined path toward a cure. Sol Spiegelman, a Columbia University virologist known for his incendiary enthusiasm and relentless energy, heard Temin’s talk and instantly built a monumental theory out of it—a theory so fiercely logical that Spiegelman could almost conjure it into reality. Temin had suggested that an RNA virus could enter a cell, make a DNA copy of its genes, and attach itself to a cell’s genome. Spiegelman was convinced that this process, through a yet unknown mechanism, could activate a viral gene. That activated viral gene must induce the infected cell to proliferate—unleashing pathological mitosis, cancer.

It was a tantalizingly attractive explanation. Rous’s viral theory of the origin of cancer would fuse with Boveri’s internal genetic theory. The virus, Temin had shown, could become an endogenous element attached to a cell’s genes, and thus both an internal aberration and an exogenous infection would be responsible for cancer. “Spiegelman’s conversion to the new religion [of cancer viruses] took only minutes,” Robert Weinberg, the MIT cancer biologist recalled. “The next day [after Temin’s conference] he was back in his lab at Columbia University in New York City, setting up a repeat of the work.”

Spiegelman raced off to prove that retroviruses caused human cancers. “It became his single-minded preoccupation,” Weinberg recalled. The obsession bore fruit quickly. For Spiegelman’s schema to work, he would need to prove that human cancers had retrovirus genes hidden inside them. Working fast and hard, Spiegelman found traces of retroviruses in human leukemia, in breast cancer, lymphomas, sarcomas, brain tumors, melanomas—in nearly every human cancer that he examined. The Special Virus Cancer Program, launched in the 1950s to hunt for human cancer viruses, and moribund for two decades, was swiftly resuscitated: here, at long last, were the thousands of cancer viruses that it had so long waited to discover. Money poured into Spiegelman’s lab from the SVCP’s coffers. It was a perfect folie à deux—endless funds fueling limitless enthusiasm and vice versa. The more Spiegelman looked for retroviruses in cancer cells, the more he found, and the more funds were sent his way.

In the end, though, Spiegelman’s effort turned out to be systematically flawed. In his frenzied hunt for human cancer retroviruses, Spiegelman had pushed the virus-detection test so hard that he saw viruses or traces of viruses that did not exist. When other labs around the nation tried to replicate the work in the mid-1970s, Spiegelman’s viruses were nowhere to be found. Only one human cancer, it turned out, was caused by a human retrovirus—a rare leukemia endemic in some parts of the Caribbean. “The hoped-for human virus slipped quietly away into the night,” Weinberg wrote. “The hundreds of millions of dollars spent by the SVCP . . . could not make it happen. The rocket never left its launching pad.”

Spiegelman’s conjecture about human retroviruses was half-right and half-wrong: he was looking for the right kind of virus but in the wrong kind of cell. Retroviruses would turn out to be the cause of a different disease—not cancer. Spiegelman died in 1983 of pancreatic cancer, having heard of a strange illness erupting among gay men and blood-transfusion recipients in New York and San Francisco. One year after Sol Spiegelman’s death in New York, the cause of that disease was finally identified. It was a human retrovirus called HIV.

* Other cancer-causing viruses, such as SV40 and human papillomavirus (HPV), would eventually be discovered in 1960 and 1983, respectively.

* Temin’s statement was speculative, but it bore his unerring biological instinct. Formal proof of the structural attachment of RSV genes into the cellular genome would only come years later.

* The term retrovirus was coined later by virologists.

“The hunting of the sarc”

For the Snark was a Boojum, you see.

—Lewis Carroll

Sol Spiegelman had got hopelessly lost hunting for cancer-causing retroviruses in humans. His predicament was symptomatic: cancer biology, the NCI, and the targeted Special Virus Cancer Program had all banked so ardently on the existence of human cancer retroviruses in the early 1970s that when the viruses failed to materialize, it was as if some essential part of their identity or imagination had been amputated. If human cancer retroviruses did not exist, then human cancers must be caused by some other mysterious mechanism. The pendulum, having swung sharply toward an infectious viral cause of cancer, swung just as sharply away.

Temin, too, had dismissed retroviruses as the causal agents for human cancer by the mid-1970s. His discovery of reverse transcription had certainly overturned the dogma of cellular biology, but it had not pushed the understanding of human carcinogenesis far. Viral genes could attach themselves to cellular genes, Temin knew, but this could not explain how viruses caused cancer.

Faced with yet another discrepancy between theory and data, Temin proposed another bold conjecture—again, standing on the thinnest foundation of evidence. Spiegelman and the retrovirus hunters, Temin argued, had conflated analogy with fact, confused messenger with message. Rous sarcoma virus could cause cancer by inserting a viral gene into cells. This proved that genetic alterations could cause cancer. But the genetic alteration, Temin proposed, need not originate in a virus. The virus had merely brought a message into a cell. To understand the genesis of cancer, it was that culprit message—not the messenger—that needed to be identified. Cancer virus hunters needed to return to their lamplit virus again, but this time with new questions: What was the viral gene that had unleashed pathological mitosis in cells? And how was that gene related to an internal mutation in the cell?

In the 1970s, several laboratories began to home in on that gene. Fortuitously, RSV possesses only four genes in its genome. In California, by then the hotbed of cancer virus research, the virologists Steve Martin, Peter Vogt, and Peter Duesberg made mutants of the Rous virus that replicated normally, but could no longer create tumors—suggesting that the tumor-causing gene had been disrupted. By analyzing the genes altered in these mutant viruses, these groups finally pinpointed RSV’s cancer-causing ability to a single gene in the virus. The gene was called src (pronounced “sarc”), a diminutive of sarcoma.

Src, then, was the answer to Temin’s puzzle, the cancer-causing “message” borne by Rous sarcoma virus. Vogt and Duesberg removed or inactivated src from the virus and demonstrated that the src-less virus could neither induce cell proliferation nor cause transformation. Src, they speculated, was some sort of malformed gene acquired by RSV during its evolution and introduced into normal cells. It was termed an oncogene,* a gene capable of causing cancer.

A chance discovery in Ray Erikson’s laboratory at the University of Colorado further elucidated src’s function. Erikson had been a graduate student in Madison in the early 1960s when Temin had found retroviruses. Erikson had followed the discovery of the srcgene in California and had been haunted by the function of src ever since. In 1977, working with Mark Collett and Joan Brugge, Erikson set out to decipher the function of src. 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. Indeed, scientists had found a number of similar proteins in normal cells—enzymes that attached phosphate groups to other proteins. These enzymes were called the “kinases,” and they were soon found to behave as molecular master switches within a cell. The attachment of the phosphate group to a protein acted like an “on” switch—activating the protein’s function. Often, a kinase turned “on” another kinase, which turned “on” another kinase, and so forth. The signal was amplified at each step of the chain reaction, until many such molecular switches were thrown into their “on” positions. The confluence of many such activated switches produced a powerful internal signal to a cell to change its “state”—moving, for instance, from a nondividing to a dividing state.

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 phosphorylated anything and everything around it, including many crucial proteins in the cell. Src worked by unleashing an indiscriminate 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 nondividing to dividing, ultimately inducing accelerated mitosis, the hallmark of cancer.

By the late 1970s, the combined efforts of biochemists and tumor virologists had produced a relatively simple view of src’s ability to transform cells. Rous sarcoma virus caused cancer in chickens by introducing into cells a gene, src, that encoded a hyperactive overexuberant kinase. This kinase turned “on” a cascade of cellular signals to divide relentlessly. All of this represented beautiful, careful, meticulously crafted work. But with no human cancer retroviruses in the study, none of this research seemed relevant immediately to human cancers.


Yet the indefatigable Temin still felt that viral src would solve the mystery of human cancers. In Temin’s mind, there was one riddle yet to be solved: the evolutionary origin of the src gene. How might a virus have “acquired” a gene with such potent, disturbing qualities? Was src a viral kinase gone berserk? Or was it a kinase that the virus had constructed out of bits of other genes like a cobbled-together bomb? Evolution, Temin knew, could build new genes out of old genes. But where had Rous sarcoma virus found the necessary components of a gene to make a chicken cell cancerous?

At the University of California in San Francisco (UCSF), in a building perched high on one of the city’s hills, a virologist named J. Michael Bishop became preoccupied with the evolutionary origin of viral src. Born in rural Pennsylvania, where his father had been a Lutheran minister, Bishop had studied history at Gettysburg College, then drastically altered his trajectory to attend Harvard Medical School. After a residency at Massachusetts General Hospital, he had trained as a virologist. In the 1960s, Bishop had moved to UCSF to set up a lab to explore viruses.

UCSF was then a little-known, backwater medical school. Bishop’s shared office occupied a sliver of space at the edge of the building, a room so cramped and narrow that his office-mate had to stand up to let him through to his desk. In the summer of 1969, when a lanky, self-assured researcher from the NIH, Harold Varmus, then on a hiking trip in California, knocked on Bishop’s office door to ask if he might join the lab to study retroviruses, there was hardly any standing room at all.

Varmus had come to California seeking adventure. A former graduate student in literature, he had become enthralled by medicine, obtained his M.D. at Columbia University in New York, then learned virology at the NIH. Like Bishop, he was also an academic itinerant—wandering from medieval literature to medicine to virology. Lewis Carroll’s Hunting of the Snark tells the story of a motley crew of hunters that launch an agonizing journey to trap a deranged, invisible creature called the Snark. That hunt goes awfully wrong. Unpromisingly, as Varmus and Bishop set off to understand the origins of the src gene in the early 1970s, other scientists nicknamed the project “the hunting of the sarc.”


Varmus and Bishop launched their hunt using a simple technique—a method invented, in part, by Sol Spiegelman in the 1960s. Their goal was to find cellular genes that were distantly similar to the viral src gene—and thus find src’s evolutionary precursors. DNA molecules typically exist as paired, complementary strands, like yin and yang, that are “stuck” together by powerful molecular forces. Each strand, if separated, can thus stick to another strand that is complementary in structure. If one molecule of DNA is tagged with radioactivity, it will seek out its complementary molecule in a mixture and stick to it, thereby imparting radioactivity to the second molecule. The sticking ability can be measured by the amount of radioactivity.

In the mid-1970s, Bishop and Varmus began to use the viral src gene to hunt for its homologues, using this “sticking” reaction. Src was a viral gene, and they expected to find only fragments or pieces of src in normal cells—ancestors and distant relatives of the cancer-causing src gene. But the hunt soon took a mystifying turn. When Varmus and Bishop looked in normal cells, they did not find a genetic third or fifth cousin of src. They found a nearly identical version of viral src lodged firmly in the normal cell’s genome.

Varmus and Bishop, working with Deborah Spector and Dominique Stehelin, probed more cells, and again the src gene appeared in them: in duck cells, quail cells, and geese cells. Closely related homologues of the src gene were strewn all over the bird kingdom; each time Varmus’s team looked up or down an evolutionary branch, they found some variant of src staring back. Soon, the UCSF group was racing through multiple species to look for homologues of src. They found src in the cells of pheasants, turkeys, mice, rabbits, and fish. Cells from a newborn emu at the Sacramento zoo had src. So did sheep and cows. Most important, so did human cells. “Src,Varmus wrote in a letter in 1976, “. . . is everywhere.”

But the src gene that existed in normal cells was not identical to the viral src. When Hidesaburo Hanafusa, a Japanese virologist at Rockefeller University in New York, compared the viral src gene to the normal cellular src gene, he found a crucial difference in the genetic code between the two forms of src. Viral src carried mutations that dramatically affected its function. Viral src protein, as Erikson had found in Colorado, was a disturbed, hyperactive kinase that relentlessly tagged proteins with phosphate groups and thus provided a perpetually blaring “on” signal for cell division. Cellular src protein possessed the same kinase activity, but it was far less hyperactive; in contrast to viral src, it was tightly regulated—turned “on” and turned “off”—during cell division. The viral src protein, in contrast, was a permanently activated switch—“an automaton,” as Erikson described it—that had turned the cell into a dividing machine. Viral src—the cancer-causing gene—was cellular src on overdrive.

A theory began to convulse out of these results, a theory so magnificent and powerful that it would explain decades of disparate observations in a single swoop: perhaps src, the precursor to the cancer-causing gene, was endogenous to the cell. Perhaps viral src had evolved out of cellular src. Retrovirologists had long believed that the virus had introduced an activated src into normal cells to transform them into malignant cells. But the src gene had not originated in the virus. It had originated from a precursor gene that existed in a cell—in all cells. Cancer biology’s decades-long hunt had started with a chicken and ended, metaphorically, in the egg—in a progenitor gene present in all human cells.

Rous’s sarcoma virus, then, was the product of an incredible evolutionary accident. Retroviruses, Temin had shown, shuttle constantly out of the cell’s genome: RNA to DNA to RNA. During this cycling, they can pick up pieces of the cell’s genes and carry them, like barnacles, from one cell to another. Rous’s sarcoma virus had likely picked up an activated src gene from a cancer cell and carried it in the viral genome, creating more cancer. The virus, in effect, was no more than an accidental courier for a gene that had originated in a cancer cell—a parasite parasitized by cancer. Rous had been wrong—but spectacularly wrong. Viruses did cause cancer, but they did so, typically, by tampering with genes that originate in cells.


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.

Varmus and Bishop’s experiments had precisely such a crystallizing, zippering effect on cancer genetics. The crucial implication of the Varmus and Bishop experiment was that a precursor of a cancer-causing gene—the “proto-oncogene,” as Bishop and Varmus called it—was a normal cellular gene. Mutations induced by chemicals or X-rays caused cancer not by “inserting” foreign genes into cells, but by activating such endogenous proto-oncogenes.

Nature,” Rous wrote in 1966, “sometimes seems possessed of a sardonic humor.” And the final lesson of Rous sarcoma virus had been its most sardonic by far. For nearly six decades, the Rous virus had seduced biologists—Spiegelman most sadly among them—down a false path. Yet the false path had ultimately circled back to the right destination—from viral src toward cellular src and to the notion of internal proto-oncogenes sitting omnipresently in the normal cell’s genome.

In Lewis Carroll’s poem, when the hunters finally capture the deceptive Snark, it reveals itself not to be a foreign beast, but one of the human hunters sent to trap it. And so it had turned out with cancer. Cancer genes came from within the human genome. Indeed the Greeks had been peculiarly prescient yet again in their use of the term oncos. Cancer was intrinsically “loaded” in our genome, awaiting activation. We were destined to carry this fatal burden in our genes—our own genetic “oncos.”

Varmus and Bishop were awarded the Nobel Prize for their discovery of the cellular origin of retroviral oncogenes in 1989. At the banquet in Stockholm, Varmus, recalling his former life as a student of literature, read lines from the epic poem Beowulf, recapitulating the slaying of the dragon in that story: “We have not slain our enemy, the cancer cell, or figuratively torn the limbs from his body,” Varmus said. “In our adventures, we have only seen our monster more clearly and described his scales and fangs in new ways—ways that reveal a cancer cell to be, like Grendel, a distorted version of our normal selves.”

* The term oncogene had been coined earlier by two NCI scientists, Robert Huebner and George Todaro, in 1969, although on scant evidence.

Art Levinson, in Mike Bishop’s lab at UCSF, also discovered this phosphorylating activity; we will return to Levinson’s discovery in later pages.

The Wind in the Trees

The fine, fine wind that takes its course through the chaos of the world

Like a fine, an exquisite chisel, a wedge-blade inserted . . .

—D. H. Lawrence

The developments of the summer of 1976 drastically reorganized the universe of cancer biology, returning genes, again, to its center. Harold Varmus and Michael Bishop’s proto-oncogene theory provided the first cogent and comprehensive theory of carcinogenesis. The theory explained how radiation, soot, and cigarette smoke, diverse and seemingly unrelated insults, could all initiate cancer—by mutating and thus activating precursor oncogenes within the cell. The theory made sense of Bruce Ames’s peculiar correlation between carcinogens and mutagens: chemicals that cause mutations in DNA produce cancers because they alter cellular proto-oncogenes. The theory clarified why the same kind of cancer might arise in smokers and nonsmokers, albeit at different rates: both smokers and nonsmokers have the same proto-oncogenes in their cells, but smokers develop cancer at a higher rate because carcinogens in tobacco increase the mutation rate of these genes.

But what did human cancer genes look like? Tumor virologists had found src in viruses and then in cells, but surely other endogenous proto-oncogenes were strewn about in the human cellular genome.

Genetics has two distinct ways to “see” genes. The first is structural: genes can be envisioned as physical structures—pieces of DNA lined up along chromosomes, just as Morgan and Flemming had first envisioned them. The second is functional: genes can be imagined, à la Mendel, as the inheritance of traits that move from one generation to the next. In the decade between 1970 and 1980, cancer genetics would begin to “see” cancer-causing genes in these two lights. Each distinct vision would enhance the mechanistic understanding of carcinogenesis, bringing the field closer and closer to an understanding of the core molecular aberration in human cancers.

Structure—anatomy—came first. In 1973, as Varmus and Bishop were launching their initial studies on src, a hematologist in Chicago, Janet Rowley, saw a human cancer gene in a physical form. Rowley’s specialty was studying the staining patterns of chromosomes in cells in order to locate chromosomal abnormalities in cancer cells. Chromosome staining, the technique she had perfected, is as much an art as a science. It is also an oddly anachronistic art, like painting with tempera in an age of digital prints. At a time when cancer genetics was zooming off to explore the world of RNA, tumor viruses, and oncogenes, Rowley was intent on dragging the discipline back to its roots—to Boveri’s and Flemming’s chromosomes dyed in blue. Piling anachronism upon anachronism, the cancer she had chosen to study was chronic myelogenous leukemia (CML)—Bennett’s infamous “suppuration of blood.”

Rowley’s study was built on prior work by a duo of pathologists from Philadelphia who had also studied CML. In the late 1950s, Peter Nowell and David Hungerford had found an unusual chromosomal pattern in this form of leukemia: the cancer cells bore one consistently shortened chromosome. Human cells have forty-six chromosomes—twenty-three matched pairs—one inherited from each parent. In CML cells, Nowell found that one copy of the twenty-second chromosome had its head lopped off. Nowell called the abnormality the Philadelphia chromosome after the place of its discovery. But Nowell and Hungerford could not understand where the decapitated chromosome had come from, or where its missing “head” had gone.

Rowley, following this study, began to trace the headless chromosome in her CML cells. By laying out exquisitely stained photographs of CML chromosomes enlarged thousands of times—she typically spread them on her dining table and then leaned into the pictures, hunting for the missing pieces of the infamous Philadelphia chromosome—Rowley found a pattern. The missing head of chromosome twenty-two had attached itself elsewhere—to the tip of chromosome nine. And a piece of chromosome nine had conversely attached itself to chromosome twenty-two. This genetic event was termed a translocation—the flip-flop transposition of two pieces of chromosomes.

Rowley examined case after case of CML patients. In every single case, she found this same translocation in the cells. Chromosomal abnormalities in cancer cells had been known since the days of von Hansemann and Boveri. But Rowley’s results argued a much more profound point. Cancer was not disorganized chromosomal chaos. It was organized chromosomal chaos: specific and identical mutations existed in particular forms of cancer.

Chromosomal translocations can create new genes called chimeras by fusing two genes formerly located on two different chromosomes—the “head” of chromosome nine, say, fused with the “tail” of a gene in chromosome thirteen. The CML translocation, Rowley postulated, had created such a chimera. Rowley did not know the identity or function of this new chimeric monster. But she had demonstrated that a novel, unique genetic alteration—later found to be an oncogene—could exist in a human cancer cell, revealing itself purely by virtue of an aberrant chromosome structure.


In Houston, Alfred Knudson, a Caltech-trained geneticist, also “saw” a human cancer-causing gene in the early 1970s, although in yet another distinct sense.

Rowley had visualized cancer-causing genes by studying the physical structure of the cancer cell’s chromosomes. Knudson concentrated monastically on the function of a gene. Genes are units of inheritance: they shuttle properties—traits—from one generation to the next. If genes cause cancer, Knudson reasoned, then he might capture a pattern in the inheritance of cancer, much as Mendel had captured the idea of a gene by studying the inheritance of flower color or plant height in peas.

In 1969, Knudson moved to the MD Anderson Cancer Center in Texas, where Freireich had set up a booming clinical center for childhood cancers. Knudson needed a “model” cancer, a hereditary malignancy whose underlying pattern of inheritance would reveal how cancer-causing genes worked. The natural choice was retinoblastoma, the odd, rare variant of eye cancer that de Gouvêa had identified in Brazil with its striking tendency to erupt in the same family across generations.

Retinoblastoma is a particularly tragic form of cancer, not just because it assaults children but because it assaults the quintessential organ of childhood: the tumor grows in the eye. Afflicted children are sometimes diagnosed when the world around them begins to blur and fade. But occasionally the cancer is incidentally found in a child’s photograph when the eye, lit by a camera flash, glows eerily like a cat’s eyes in lamplight, revealing the tumor buried behind the lens. Left untreated, the tumor will crawl backward from the eye socket into the optic nerve, and then climb into the brain. The primary methods of treatment are to sear the tumor with high doses of gamma radiation or to enucleate the eye surgically, leaving behind an empty socket.

Retinoblastoma has two distinct variants, an inherited “familial” form and a sporadic form. De Gouvêa had identified the familial form. Children who suffer from this familial or inherited form may carry strong family histories of the disease—fathers, mothers, cousins, siblings, and kindred affected—and they typically develop tumors in both eyes, as in de Gouvêa’s case from Rio. But the tumor also arises in children with no family history of the disease. Children with this sporadic form never carry a history in the family and always have a tumor in only one eye.

This pattern of inheritance intrigued Knudson. He wondered whether he could discern a subtle difference in the development of cancer between the sporadic and the inherited versions using mathematical analyses. He performed the simplest of experiments: he grouped children with the sporadic form into one cohort and children with the familial form in a second. And sifting through old hospital records, Knudson tabulated the ages in which the disease struck the two groups, then plotted them as two curves. Intriguingly, he found that the two cohorts developed the cancers at different “velocities.” In inherited retinoblastoma, cancer onset was rapid, with diagnosis typically two to six months after birth. Sporadic retinoblastoma typically appeared two to four years after birth.

But why did the same disease move with different velocities in different children? Knudson used the numbers and simple equations borrowed from physics and probability theory to model the development of the cancer in the two cohorts. He found that the data fit a simple model. In children with the inherited form of retinoblastoma, only one genetic change was required to develop the cancer. Children with the sporadic form required two genetic changes.

This raised another puzzling question: why was only one genetic change needed to unleash cancer in the familial case, while two changes were needed in the sporadic form? Knudson perceived a simple, beautiful explanation. “The number two,” he recalled, “is the geneticist’s favorite number.” Every normal human cell has two copies of each chromosome and thus two copies of every gene. Every normal cell must have two normal copies of the retinoblastoma gene—Rb. To develop sporadic retinoblastoma, Knudson postulated, both copies of the gene needed to be inactivated through a mutation in each copy of the Rb gene. Hence, sporadic retinoblastoma develops at later ages because two independent mutations have to accumulate in the same cell.

Children with the inherited form of retinoblastoma, in contrast, are born with a defective copy of Rb. In their cells, one gene copy is already defective, and only a single additional genetic mutation is needed before the cell senses the change and begins to divide. These children are thus predisposed to the cancer, and they develop cancer faster, producing the “rapid velocity” tumors that Knudson saw in his statistical charts. Knudson called this the two-hit hypothesis of cancer. For certain cancer-causing genes, two mutational “hits” were needed to provoke cell division and thus produce cancer.

Knudson’s two-hit theory was a powerful explanation for the inheritance pattern of retinoblastoma, but at first glance it seemed at odds with the initial molecular understanding of cancer. The src gene, recall, requires a single activated copy to provoke uncontrolled cell division. Knudson’s gene required two. Why was a single mutation in src sufficient to provoke cell division, while two were required for Rb?

The answer lies in the function of the two genes. Src activates a function in cell division. The mutation in src, as Ray Erikson and Hidesaburo Hanafusa had discovered, creates a cellular protein that is unable to extinguish its function—an insatiable, hyperactive kinase on overdrive that provokes perpetual cell division. Knudson’s gene, Rb, performs the opposite function. It suppresses cell proliferation, and it is the inactivation of such a gene (by virtue of two hits) that unleashes cell division. Rb, then, is a cancer suppressor gene—the functional opposite of src—an “anti-oncogene,” as Knudson called it.

Two classes of genes are apparently critical in the origin of the cancers of children,” he wrote. “One class, that of oncogenes, acts by virtue of abnormal or elevated activity. . . . The other class, that of anti-oncogenes [or tumor suppressors], is recessive in oncogenesis; cancer results when both normal copies have been mutated or deleted. Some persons carry one such mutation in the germline and are highly susceptible to tumor because only one somatic event is necessary. Some children, even though carrying no such mutation in the germline, can acquire tumor as a result of two somatic events.”

It was an exquisitely astute hypothesis spun, remarkably, out of statistical reasoning alone. Knudson did not know the molecular identity of his phantasmic anti-oncogenes. He had never looked at a cancer cell to “see” these genes; he had never performed a biological experiment to pin down Rb. Like Mendel, Knudson knew his genes only in a statistical sense. He had inferred them, as he put it, “as one might infer the wind from the movement of the trees.”


By the late 1970s, Varmus, Bishop, and Knudson could begin to describe the core molecular aberration of the cancer cell, stitching together the coordinated actions of oncogenes and anti-oncogenes. Cancer genes, Knudson proposed, came in two flavors. “Positive” genes, such as src, are mutant activated versions of normal cellular genes. In normal cells, these genes accelerate cell division, but only when the cell receives an appropriate growth signal. In their mutant form, these genes are driven into perpetual hyperactivity, unleashing cell division beyond control. An activated proto-oncogene, to use Bishop’s analogy, is “a jammed accelerator” in a car. A cell with such a jammed accelerator careens down the path of cell division, unable to cease mitosis, dividing and dividing again relentlessly.

“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. In cells with missing brakes, to use Bishop’s analogy again, the “stop” signals for mitosis can no longer be registered. Again, the cell divides and keeps dividing, defying all signals to stop.

Both abnormalities, activated proto-oncogenes and inactivated tumor suppressors (“jammed accelerators” and “missing brakes”), represent the core molecular defects in the cancer cell. Bishop, Knudson, and Varmus did not know how many such defects were ultimately needed to cause human cancers. But a confluence of them, they postulated, causes cancer.

A Risky Prediction

They see only their own shadows or the shadows of one another, which the fire throws on the opposite wall of the cave.


The philosopher of science Karl Popper coined the term risky prediction to describe the process by which scientists verify untested theories. Good theories, Popper proposed, generate risky predictions. They presage an unanticipated fact or event that runs a real risk of not occurring or being proven incorrect. When this unanticipated fact proves true or the event does occur, the theory gains credibility and robustness. Newton’s understanding of gravitation was most spectacularly validated when it accurately presaged the return of Halley’s comet in 1758. Einstein’s theory of relativity was vindicated in 1919 by the demonstration that light from distant stars is “bent” by the mass of the sun, just as predicted by the theory’s equations.

By the late 1970s, the theory of carcinogenesis proposed by Varmus and Bishop had also generated at least one such risky prediction. Varmus and Bishop had demonstrated that precursors of oncogenes—proto-oncogenes—existed in all normal cells. They had found activated versions of the src proto-oncogene in Rous sarcoma virus. They had suggested that mutations in such internal genes caused cancer—but a crucial piece of evidence was still missing. If Varmus and Bishop were right, then mutated versions of such proto-oncogenes must exist inside cancer cells. But thus far, although other scientists had isolated an assortment of oncogenes from retroviruses, no one had isolated an activated, mutated oncogene out of a cancer cell.

Isolating such a gene,” as the cancer biologist Robert Weinberg put it, “would be like walking out of a cave of shadows. . . . Where scientists had previously only seen oncogenes indirectly, they might see these genes, in flesh and blood, living inside the cancer cell.”

Robert Weinberg was particularly concerned with getting out of shadows. Trained as a virologist in an era of great virologists, he had worked in Dulbecco’s lab at the Salk Institute in the sixties isolating DNA from monkey viruses to study their genes. In 1970, when Temin and Baltimore had discovered reverse transcriptase, Weinberg was still at the bench, laboriously purifying genes out of monkey viruses. Six years later, when Varmus and Bishop had announced the discovery of cellular src, Weinberg was still purifying DNA from viruses. Weinberg felt as if he was stuck in a perpetual penumbra, surrounded by fame but never famous himself. The retrovirus revolution, with all its mysteries and rewards, had quietly passed him by.

In 1972, Weinberg moved to MIT, to a small laboratory a few doors down from Baltimore’s lab to study cancer-causing viruses. “The chair of the department,” he said, “considered me quite a fool. A good fool. A hardworking fool, but still a fool.” Weinberg’s lab occupied a sterile, uninspiring space at MIT, in a sixties-style brutalist building served by a single creaking elevator. The Charles River was just far enough to be invisible from the windows, but just near enough to send freezing puffs of wind through the quadrangle in the winter. The building’s basement connected to a warren of tunnels with airless rooms where keys were cut and machines repaired for other labs.

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. By the mid-1970s, Weinberg had acquired a reputation among his colleagues as a careful, technically competent scientist, but one who lacked direction. Weinberg felt his work was stagnating. What he needed was a simple, clear question.

Clarity came to him one morning in the midst of one of Boston’s infamously blinding blizzards. On a February day in 1978, walking to work, Weinberg was caught in an epic snowstorm. Public transportation had ground to a halt, and Weinberg, in a rubber hat and galoshes, had chosen to plod across the blustering Longfellow Bridge from his home to his lab, slowly planting his feet through the slush. The snow blotted out the landscape and absorbed all sounds, creating a silent, hypnotic interior. And as Weinberg crossed the frozen river, he thought about retroviruses, cancer, and human cancer genes.


Src had been so easy to isolate and identify as a cancer-causing gene, Weinberg knew, because Rous sarcoma virus possesses a measly four genes. One could scarcely turn around in the retroviral genome without bumping into an oncogene. A cancer cell, in contrast, has about twenty thousand genes. Searching for a cancer-causing gene in that blizzard of genes was virtually hopeless.

But an oncogene, by definition, has a special property: it provokes unbridled cellular proliferation in a normal cell. Temin had used this property in his cancer-in-a-dish experiment to induce cells to form “foci.” And as Weinberg thought about oncogenes, he kept returning to this essential property.

Of the twenty thousand genes in a cancer cell, Weinberg reasoned the vast majority were likely normal and only a small minority were mutated proto-oncogenes. Now imagine, for a moment, being able to take all twenty thousand genes in the cancer cell, the good, the bad, the ugly, and transferring them into twenty thousand normal cells, such that each cell receives one of the genes. The normal, unmutated genes will have little effect on the cells. But an occasional cell will receive an oncogene, and, goaded by that signal, it will begin to grow and reproduce insatiably. Reproduced ten times, these cells will form a little clump on a petri dish; at twelve cell divisions, that clump will form a visible “focus”—cancer distilled into its primordial, elemental form.

The snowstorm was Weinberg’s catharsis; he had rid himself of retroviruses. If activated oncogenes existed within cancer cells, then transferring these genes into normal cells should induce these normal cells to divide and proliferate. For decades, cancer biologists had relied on Rous sarcoma virus to introduce activated src into cells and thereby incite cell division. But Weinberg would bypass Rous’s virus; he would determine if cancer-causing genes could be transferred directly from cancer cells to normal cells. At the end of the bridge, with snow still swirling around him, he found himself at an empty intersection with lights still flashing. He crossed it, heading to the cancer center.


Weinberg’s immediate challenge was technical: how might he transfer DNA from a cancer cell to a population of normal cells? Fortunately, this was one of the technical skills that he had so laboriously perfected in the laboratory during his stagnant decade. His chosen method of DNA transfer began with the purification of DNA from cancer cells, grams of it precipitated out of cell extracts in a dense, flocculent suspension, like curdled milk. This DNA was then sheared into thousands of pieces, each piece carrying one or two genes. To transfer this DNA into cells, he next needed a carrier, a molecule that would slip DNA into the interior of a cell. Here, Weinberg used a trick. DNA binds to the chemical calcium phosphate to form minuscule white particles. These particles are ingested by cells, and as the cells ingest these particles, they also ingest the DNA pieces bound to the calcium phosphate. Sprinkled on top of a layer of normal cells growing in a petri dish, these particles of DNA and calcium phosphate resemble a snowglobe of swirling white flakes, the blizzard of genes that Weinberg had so vividly imagined in his walk in Boston.

Once that DNA blizzard had been sprinkled on the cells and internalized by them, Weinberg envisioned a simple experiment. The cell that had received the oncogene would embark on unbridled growth, forming the proliferating focus of cells. Weinberg would isolate such foci and then purify the DNA fragment that had induced the proliferation. He would thus capture a real human oncogene.

In the summer of 1979, Chiaho Shih, a graduate student in Weinberg’s lab, began to barrel his way through fifteen different mouse cancer cells, trying to find a fragment of DNA that would produce foci out of normal cells. Shih was laconic and secretive, with a slippery, quicksilver temper, often paranoid about his experiments. He was also stubborn: when he disagreed with Weinberg, colleagues recalled him thickening his accent and pretending not to understand English, a language he spoke with ease and fluency under normal circumstances. But for all his quirks, Shih was also a born perfectionist. He had learned the DNA transfection technique from his predecessors in the lab, but even more important, he had an instinctive feel for his cells, almost a gardener’s instinct to discriminate normal versus abnormal growth.

Shih grew enormous numbers of normal cells in petri dishes and sprinkled them weekly with genes derived from his panel of cancer cells. Plate after plate of transfected cells piled up in the laboratory. As Weinberg had imagined in his walk across the river, Shih soon stumbled upon a crucial early result. He found that transferring DNA from mouse cancer cells invariably produced foci in normal cells, proof that oncogenes could be discovered through such a method.*

Excited and mystified, Weinberg and Shih performed a bolder variant of the experiment. Thus far they had been using mouse cancer cell lines to obtain their DNA. Changing tactics and species, they moved on to human cancer cells. “If we were going to trap a real oncogene so laboriously,” Weinberg recalled, “we thought that we might as well find it in real human cancers.” Shih walked over to the Dana-Farber Cancer Institute and carried back a cancer cell line derived from a patient, Earl Jensen, a long-term smoker who had died of bladder cancer. DNA from these cells was sheared into fragments and transfected into the normal human cell line. Shih returned to his microscope, scouring plate after plate for foci.

The experiment worked yet again. As with the mouse cancer cell lines, prominent, disinhibited foci appeared in the dishes. Weinberg pushed Shih to find the precise gene that could convert a normal cell to a cancer cell. Weinberg’s laboratory was now racing to isolate and identify the first native human oncogene.

He soon realized the race had other contenders. At the Farber, across town, Geoff Cooper, a former student of Temin’s, had also shown that DNA from cancer cells could induce transformation in cells. So had Michael Wigler at the Cold Spring Harbor Lab in New York. And Weinberg, Cooper, and Wigler had yet other competitors. At the NCI, a little-known Spanish researcher named Mariano Barbacid had also found a fragment of DNA from yet another cancer cell line that would transform normal cells. In the late winter of 1981, all four laboratories rushed to the finish line. By the early spring, each lab had found its sought-after gene.

In 1982, Weinberg, Barbacid, and Wigler independently published their discoveries and compared their results. It was a powerful, unexpected convergence: all three labs had isolated the same fragment of DNA, containing a gene called ras, from their respective cancer cells. Like src, ras was also a gene present in all cells. But like src again, the ras gene in normal cells was functionally different from the ras present in cancer cells. In normal cells, the ras gene encoded a tightly regulated protein that turned “on” and “off” like a carefully modulated switch. In cancer cells, the gene was mutated, just as Varmus and Bishop had predicted. Mutated ras encoded a berserk, perpetually hyperactive protein permanently locked “on.” This mutant protein produced an unquenchable signal for a cell to divide—and to keep dividing. It was the long-sought “native” human oncogene, captured in flesh and blood out of a cancer cell. “Once we had cloned a cancer gene,” Weinberg wrote, “the world would be at our feet.” New insights into carcinogenesis, and new therapeutic inroads would instantly follow. “It was,” as Weinberg would later write, all “a wonderful pipe dream.”


In 1983, a few months after Weinberg had purified mutant ras out of cancer cells, Ray Erikson traveled to Washington to receive the prestigious General Motors prize for his research on src activity and function. The other awardee that evening was Tom Frei, being honored for his advancement of the cure for leukemia.

It was a resplendent evening. There was an elegant candlelit dinner in a Washington banquet hall, followed by congratulatory speeches and toasts. Scientists, physicians, and policymakers, including many of the former Laskerites,* gathered around linen-covered tables. Talk turned frequently to the discovery of oncogenes and the invention of curative chemotherapy. But the two conversations seemed to be occurring in sealed and separate universes, much as they had at Temin’s conference in Houston more than a decade earlier. Frei’s award, for curing leukemia, and Erikson’s award, for identifying the function of a critical oncogene, might almost have been given to two unconnected pursuits. “I don’t remember any enthusiasm among the clinicians to reach out to the cancer biologists to synthesize the two poles of knowledge about cancer,” Erikson recalled. The two halves of cancer, cause and cure, having feasted and been feted together, sped off in separate taxis into the night.


The discovery of ras brought one challenge to a close for cancer geneticists: they had purified a mutated oncogene from a cancer cell. But it threw open another challenge. Knudson’s two-hit hypothesis had also generated a risky prediction: that retinoblastoma cancer cells contained two inactivated copies of the Rb gene. Weinberg, Wigler, and Barbacid had proved Varmus and Bishop right. Now someone had to prove Knudson’s prediction by isolating his fabled tumor suppressor gene and demonstrating that both its copies were inactivated in retinoblastoma.

This challenge, though, came with an odd conceptual twist. Tumor suppressor genes, by their very nature, are asserted in their absence. An oncogene, when mutated, provides an “on” signal for the cells to grow. A tumor suppressor gene when mutated, in contrast, removes an “off” signal for growth. Weinberg and Chiaho Shih’s transfection assay had worked because oncogenes can cause the normal cells to divide uncontrollably, thus forming a focus of cells. But an anti-oncogene, transfected into a cell, cannot be expected to create an “anti-focus.” “How can one capture genes that behave like ghosts,” Weinberg wrote, “influencing cells from behind some dark curtain?”

In the mid-1980s, cancer geneticists had begun to glimpse shadowy outlines behind retinoblastoma’s “dark curtain.” By analyzing chromosomes from retinoblastoma cancer cells using the technique pioneered by Janet Rowley, geneticists had demonstrated that the Rb gene “lived” on chromosome thirteen. But a chromosome contains thousands of genes. Isolating a single gene from that vast set—particularly one whose functional presence was revealed only when inactive—seemed like an impossible task. Large laboratories professionally equipped to hunt for cancer genes—Webster Cavenee’s lab in Cincinnati, Brenda Gallie’s in Toronto, and Weinberg’s in Boston—were frantically hunting for a strategy to isolate Rb. But these efforts had reached a standstill. “We knew where Rb lived,” Weinberg recalled, “but we had no idea what Rb was.”

Across the Charles River from Weinberg’s lab, Thad Dryja, an ophthalmologist-turned-geneticist, had also joined the hunt for Rb. Dryja’s laboratory was perched on the sixth floor of the Massachusetts Eye and Ear Infirmary—the Eyeball, as it was known colloquially among the medical residents. The ophthalmological infirmary was well-known for its clinical research on eye diseases, but was barely recognized for laboratory-based research. Weinberg’s Whitehead Institute boasted the power of the latest technologies, an army of machines that could sequence thousands of DNA samples and powerful fluorescent microscopes that could look down into the very heart of the cell. In contrast, the Eyeball, with its proud display of nineteenth-century eyeglasses and lenses in lacquered wooden vitrines, was almost self-indulgently anachronistic.

Dryja, too, was an unlikely cancer geneticist. In the mid-1980s, having completed his clinical fellowship in ophthalmology at the infirmary in Boston, he had crossed town to the science laboratories at Children’s Hospital to study the genetics of eye diseases. As an ophthalmologist interested in cancer, Dryja had an obvious target: retinoblastoma. But even Dryja, an inveterate optimist, was hesitant about taking on the search for Rb. “Brenda [Gallie] and Web [Cavenee] had both stalled in their attempts [to clone Rb]. It was a slow, frustrating time.”

Dryja began his hunt for Rb with a few key assumptions. Normal human cells, he knew, have two copies of every chromosome (except the sex chromosomes), one from each parent, twenty-three pairs of chromosomes in all, a total of forty-six. Every normal cell thus has two copies of the Rb gene, one in each copy of chromosome thirteen.

Assuming Knudson was right in his two-hit hypothesis, every eye tumor should possess two independent inactivating mutations in the Rb gene, one in each chromosome. Mutations, Dryja knew, come in many forms. They can be small changes in DNA that can activate a gene. Or they can be large structural deletions in a gene, stretching over a large piece of the chromosome. Since the Rb gene had to be inactivated to unleash retinoblastoma, Dryja reasoned that the mutation responsible was likely a deletion of the gene. Deleting a sizable piece of a gene, after all, is perhaps the quickest, crudest way to paralyze and inactivate it.

In most retinoblastoma tumors, Dryja suspected, the two deletions in the two copies of the Rb gene would lie in different parts of the gene. Since mutations occur randomly, the chance of both mutations lying in precisely the same region of the gene is a little akin to rolling double sixes in dice that have one hundred faces. Typically, one of the deletions would “hit” the front end of the gene, while the other deletion might hit the back end (in both cases, the functional consequences would be the same—inactivating Rb). The two “hits” in most tumors would thus be asymmetric—affecting two different parts of the gene on the two chromosomes.

But even hundred-headed dice, rolled many times, can yield double sixes. Rarely, Dryja knew, one might encounter a tumor in which both hits had deleted exactly the same part of the gene on the two sister chromosomes. In that case, that piece of chromosome would be completely missing from the cell. And if Dryja could find a method to identify a completely missing piece of chromosome thirteen in a retinoblastoma tumor cell, he would instantly land on the Rb gene. It was the simplest of strategies: to hunt the gene with absent function, Dryja would look for absence in structure.

To identify such a missing piece, Dryja needed structural mileposts along chromosome thirteen—small pieces of DNA called probes, which were aligned along the length of the chromosome. He could use these DNA probes in a variant of the same “sticking” reaction that Varmus and Bishop had used in the 1970s: if the piece of DNA existed in the tumor cell, it would stick; if the piece did not exist, the probe would not stick, identifying the missing piece in the cell. Dryja had assembled a series of such probes. But more than probes, he needed a resource that he uniquely possessed: an enormous bank of frozen tumors. The chances of finding a shared deletion in the Rb gene in both chromosomes were slim, so he would need to test a vast sample set to find one.

This, then, was his crucial advantage over the vast professional labs in Toronto and Houston. Laboratory scientists rarely venture outside the lab to find human samples. Dryja, a clinician, had a freezer full of them. “I stored the tumors obsessively,” he said with the childlike delight of a collector. “I put news out among patients and doctors that I was looking for retinoblastoma cases. Every time someone saw a case, they would say, ‘Get that guy Dryja.’ I would then drive or fly or even walk to pick up the samples and bring them here. I even got to know the patients by name. Since the disease ran in families, I would call them at home to see if there was a brother or sister or cousin with retinoblastoma. Sometimes, I would know [about a tumor] even before doctors knew.”

Week after week, Dryja extracted the chromosomes from tumors and ran his probe set against the chromosomes. If the probes bound, they usually made a signal on a gel; if a probe was fully missing, the signal was blank. One morning, having run another dozen tumors, Dryja came to the lab and held up the blot against the window and ran his eyes left to right, lane after lane automatically, like a pianist reading a score. In one tumor, he saw a blank space. One of his probes—H3-8, he had called it—was deleted in both chromosomes in that tumor. He felt the brief hot rush of ecstasy, which then tipped into queasiness. “It was at that moment that I had the feeling that we had a gene in our hands. I had landed on retinoblastoma.”


Dryja had found a piece of DNA missing in tumor cells. Now he needed to find the corresponding piece present in normal cells, thus isolating the Rb gene. Perilously close to the end, Dryja was like an acrobat at the final stretch of his rope. His one-room lab was taut with tension, stretched to its limit. He had inadequate skills in isolating genes and limited resources. To isolate the gene, he would need help, so he took another lunge. He had heard that researchers in the Weinberg lab were also hunting for the retinoblastoma gene. Dryja’s choices were stark: he could either team up with Weinberg, or he could try to isolate the gene alone and lose the race altogether.

The scientist in Weinberg’s lab trying to isolate Rb was Steve Friend. A jovial, medically trained molecular geneticist with a quick wit and an easy manner, Friend had casually mentioned his interest in Rb to Dryja at a meeting. Unlike Dryja, working with his growing stash of tumor samples, Friend had been building a collection of normal cells—cells in which the Rb gene was completely intact. Friend’s approach had been to find genes that were present in normal retinal cells, then to try to identify ones that were abnormal in retinoblastoma tumors—working backward toward Dryja.

For Dryja, the complementarity of the two approaches was obvious. He had identified a missing piece of DNA in tumors. Could Friend and Weinberg now pull the intact, full-length gene out of normal cells? They outlined a potential collaboration between the two labs. One morning in 1985, Dryja took his probe, H3-8, and virtually ran across the Longfellow Bridge (by now, the central highway of oncogenesis), carrying it by hand to Friend’s bench at the Whitehead.

It took Friend a quick experiment to test Dryja’s probe. Using the DNA “sticking” reaction again, Friend trapped and isolated the normal cellular gene that stuck to the H3-8 probe. The isolated gene “lived” on chromosome thirteen, as predicted. When Dryja further tested the candidate gene through his bank of tumor samples, he found precisely what Knudson had hypothesized more than a decade earlier: all retinoblastoma cells contained inactivations in both copies of the gene—two hits—while normal cells contained two normal copies of the gene. The candidate gene that Friend had isolated was indisputably Rb.

In October 1986, Friend, Weinberg, and Dryja published their findings in Nature. The article marked the perfect complement to Weinberg’s ras paper, the yin to its yang—the isolation of an activated proto-oncogene (ras) and the identification of the anti-oncogene (Rb). “Fifteen years ago,” Weinberg wrote, “Knudson provided a theoretical basis for retinoblastoma tumorigenesis by suggesting that minimally two genetic events are required to trigger tumor development.” Weinberg noted, “We have isolated [a human gene] apparently representing one of this class of genes”—a tumor suppressor.

What Rb does in normal cells is still an unfolding puzzle. Its name, as it turns out, is quite a misnomer. Rb, retinoblastoma, is not just mutated in rare eye tumors in children. When scientists tested the gene isolated by Dryja, Friend, and Weinberg in other cancers in the early nineties, they found it widely mutated in lung, bone, esophageal, breast, and bladder cancers in adults. Like ras, it is expressed in nearly every dividing cell. And it is inactivated in a whole host of malignancies. Calling it retinoblastoma thus vastly underestimates the influence, depth, and prowess of this gene.

The retinoblastoma gene encodes a protein, also named Rb, with a deep molecular “pocket.” Its chief function is to bind to several other proteins and keep them tightly sealed in that pocket, preventing them from activating cell division. When the cell decides to divide, it tags Rb with a phosphate group, a molecular signal that inactivates the gene and thus forces the protein to release its partners. Rb thus acts as a gatekeeper for cell division, opening a series of key molecular floodgates each time cell division is activated and closing them sharply when the cell division is completed. Mutations in Rb inactivate this function. The cancer cell perceives its gates as perpetually open and is unable to stop dividing.


The cloning of ras and retinoblastoma—oncogene and anti-oncogene—was a transformative moment in cancer genetics. In the decade between 1983 and 1993, a horde of other oncogenes and anti-oncogenes (tumor suppressor genes) were swiftly identified in human cancers: myc, neu, fos, ret, akt (all oncogenes), and p53, VHL, APC (all tumor suppressors). Retroviruses, the accidental carriers of oncogenes, faded far into the distance. Varmus and Bishop’s theory—that oncogenes were activated cellular genes—was recognized to be widely true for many forms of cancer. And the two-hit hypothesis—that tumor suppressors were genes that needed to be inactivated in both chromosomes—was also found to be widely applicable in cancer. A rather general conceptual framework for carcinogenesis was slowly becoming apparent. The cancer cell was a broken, deranged machine. Oncogenes were its jammed accelerators and inactivated tumor suppressors its missing brakes.*

In the late 1980s, yet another line of research, resurrected from the past, yielded a further bounty of cancer-linked genes. Ever since de Gouvêa’s report of the Brazilian family with eye tumors in 1872, geneticists had uncovered several other families that appeared to carry cancer in their genes. The stories of these families bore a familiar, tragic trope: cancer haunted them generation upon generation, appearing and reappearing in parents, children, and grandchildren. Two features stood out in these family histories. First, geneticists recognized that the spectrum of cancers in every family was limited and often stereotypical: colon and ovarian cancer threading through one family; breast and ovarian through another; sarcomas, leukemias, and gliomas through a third. And second, similar patterns often reappeared in different families, thereby suggesting a common genetic syndrome. In Lynch syndrome (first described by an astute oncologist, Henry Lynch, in a Nebraskan family), colon, ovarian, stomach, and biliary cancer recurred generation upon generation. In Li-Fraumeni syndrome, there were recurrent bone and visceral sarcomas, leukemias, and brain tumors.

Using powerful molecular genetic techniques, cancer geneticists in the 1980s and 1990s could clone and identify some of these cancer-linked genes. Many of these familial cancer genes, like Rb, were tumor suppressors (although occasional oncogenes were also found). Most such syndromes were fleetingly rare. But occasionally geneticists identified cancer-predisposing gene alterations that were quite frequently represented in the population. Perhaps the most striking among these, first suggested by the geneticist Mary Claire-King and then definitively cloned by Mark Skolnick’s team at the pharma company Myriad Genetics, was BRCA-1, a gene that strongly predisposes humans to breast and ovarian cancer. BRCA-1 (to which we will return in later pages) can be found in up to 1 percent of women in selected populations, making it one of the most common cancer-linked genes found in humans.

By the early 1990s, the discoveries of cancer biology had thus traversed the gap between the chicken tumors of Peyton Rous and real human cancers. But purists still complained. The crusty specter of Robert Koch still haunted the genetic theory of cancer. Koch had postulated that for an agent to be identified as the “cause” of a disease, it must (1) be present in the diseased organism, (2) be capable of being isolated from the diseased organism, and (3) re-create the disease in a secondary host when transferred from the diseased organism. Oncogenes had met the first two criteria. They had been found to be present in cancer cells and they had been isolated from cancer cells. But no one had shown that a cancer gene, in and of itself, could create a bona fide tumor in an animal.

In the mid-1980s, a series of remarkable experiments allowed cancer geneticists to meet Koch’s final criteria. In 1984, biologists working on stem cells had invented a new technology that allowed them to introduce exogenous genes into early mouse embryos, then create a living mouse out of those modified embryos. This allowed them to produce “transgenic mice,” mice in which one or more genes were artificially and permanently modified. Cancer geneticists seized this opportunity. Among the first such genes to be engineered into a mouse was c-myc, an oncogene discovered in lymphoma cells.

Using transgenic mouse technology, Philip Leder’s team at Harvard altered the c-myc gene in mice, but with a twist: cleverly, they ensured that only breast tissue in the mouse would overexpress the gene. (Myc could not be activated in all cells. If myc was permanently activated in the embryo, the embryo turned into a ball of overproliferating cells, then involuted and died through unknown mechanisms. The only way to activate myc in a living mouse was to restrict the activation to only a subset of cells. Since Leder’s lab was studying breast cancer, he chose breast cells.) Colloquially, Leder called his mouse the OncoMouse. In 1988, he successfully applied for a patent on the OncoMouse, making it the first animal patented in history.

Leder expected his transgenic mice to explode with cancer, but to his surprise, the oncomice sprouted rather mousy cancers. Even though an aggressive oncogene had been stitched into their chromosomes, the mice developed small, unilateral breast cancers, and not until late in life. Even more surprisingly, Leder’s mice typically developed cancers only after pregnancy, suggesting that environmental influences, such as hormones, were strictly required to achieve full transformation of breast cells. “The active myc gene does not appear to be sufficient for the development of these tumors,” Leder wrote. “If that were the case, we would have expected the uniform development of tumor masses involving the entire bilateral [breast] glands of all five tumor-bearing animals. Rather, our results suggest at least two additional requirements. One of these is likely to be a further transforming event. . . . The other seems to be a hormonal environment related to pregnancy that is only suggested by these initial studies.”

To test the roles of other oncogenes and environmental stimuli, Leder created a second OncoMouse, in which two activated proto-oncogenes, ras and myc, were engineered into the chromosome and expressed in breast cells. Multiple tumors sprouted up in the breast glands of these mice in months. The requirement for the hormonal milieu of pregnancy was partially ameliorated. Still, only a few distinct clones of cancer sprouted out of the ras-myc mice. Millions of breast cells in each mouse possessed activated ras and myc. Yet, of those millions of cells, each endowed with the most potent oncogenes, only a few dozen turned into real, living tumors.

Even so, this was a landmark experiment: cancer had artificially been created in an animal. “Cancer genetics,” as the geneticist Cliff Tabin recalls, “had crossed a new frontier. It was not dealing with just genes and pathways and artificial lumps in the lab, but a real growing tumor in an animal.” Peyton Rous’s long squabble with the discipline—that cancer had never been produced in a living organism by altering a defined set of cellular genes—was finally laid to its long-overdue rest.

* In fact, the “normal” cells that Weinberg had used were not exactly normal. They were already growth-adapted, such that a single activated oncogene could tip them into transformed growth. Truly “normal” cells, Weinberg would later discover, require several genes to become transformed.

In fact, ras, like src, had also been discovered earlier in a cancer-causing virus—again underscoring the striking capacity of these viruses to reveal the mechanisms of endogenous oncogenes.

* The Laskerites had largely been disbanded in the aftermath of the 1971 National Cancer Act. Mary Lasker was still involved in science policy, although with nowhere near the force and visceral energy that she had summoned in the sixties.

* Although cancer is not universally caused by viruses, certain viruses cause particular cancers, such as the human papilloma virus (HPV), which causes cervical cancer. When the mechanism driving this cancer was deciphered in the 1990s, HPV turned out to inactivate Rb’s and p53’s signal—underscoring the importance of endogenous genes in even virally induced cancers.

The Hallmarks of Cancer

I do not wish to achieve immortality through my works. I wish to achieve immortality by not dying.

—Woody Allen

Scurrying about in its cage in the vivarium atop Harvard Medical School, Philip Leder’s OncoMouse bore large implications on small haunches. The mouse embodied the maturity of cancer genetics: scientists had created real, living tumors (not just abstract, etiolated foci in petri dishes) by artificially manipulating two genes, ras and myc, in an animal. Yet Leder’s experiment raised further questions about the genesis of cancer. Cancer is not merely a lump in the body; it is a disease that migrates, evolves, invades organs, destroys tissues, and resists drugs. Activating even two potent proto-oncogenes had not recapitulated the full syndrome of cancer in every cell of the mouse. Cancer genetics had illuminated much about the genesis of cancer, but much, evidently, remained to be understood.

If two oncogenes were insufficient to create cancers, then how many activated proto-oncogenes and inactivated tumor suppressors were required? What were the genetic steps needed to convert a normal cell into a cancer cell? For human cancers, these questions could not be answered experimentally. One could not, after all, proactively “create” a human cancer and follow the activation and inactivation of genes. But the questions could be answered retrospectively. In 1988, using human specimens, a physician-scientist named Bert Vogelstein at Johns Hopkins Medical School in Baltimore set out to describe the number of genetic changes required to initiate cancer. The query, in various incarnations, would preoccupy Vogelstein for nearly two decades.

Vogelstein was inspired by the observations made by George Papanicolaou and Oscar Auerbach in the 1950s. Both Papanicolaou and Auerbach, working on different cancers, had noted that cancer did not arise directly out of a normal cell. Instead, cancer often slouched toward its birth, undergoing discrete, transitional stages between the fully normal and the frankly malignant cell. Decades before cervical cancer evolved into its fiercely invasive incarnation, whorls of noninvasive premalignant cells could be observed in the tissue, beginning their first steps in the grisly march toward cancer. (Identifying and eradicating this premalignant stage before the cancer spreads is the basis for the Pap smear.) Similarly, Auerbach had noted, premalignant cells were seen in smokers’ lungs long before lung cancer appeared. Colon cancer in humans also underwent graded and discrete changes in its progression, from a noninvasive premalignant lesion called an adenoma to the highly invasive terminal stage called an invasive carcinoma.

Vogelstein chose to study this progression in colon cancer. He collected samples from patients representing each of the stages of colon cancer. He then assembled a series of four human cancer genes—oncogenes and tumor suppressors—and assessed each stage of cancer in his samples for activations and inactivations of these four genes.*

Knowing the heterogeneity of every cancer, one might naively have presumed that every patient’s cancer possessed its own sequence of gene mutations and its unique set of mutated genes. But Vogelstein found a strikingly consistent pattern in his colon cancer samples: across many samples and many patients, the transitions in the stages of cancer were paralleled by the same transitions in genetic changes. Cancer cells did not activate or inactivate genes at random. Instead, the shift from a premalignant state to an invasive cancer could precisely be correlated with the activation and inactivation of genes in a strict and stereotypical sequence.

In 1988, in the New England Journal of Medicine, Vogelstein wrote: “The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors.” He proposed, “Early in the neoplastic process one colonic cell appears to outgrow its companions to form a small, benign neoplasm. During the growth of [these] cells, a mutation in the ras gene . . . often occurs. Finally, a loss of tumor suppressor genes . . . may be associated with the progression of adenoma to frank carcinoma.”

Since Vogelstein had preselected his list of four genes, he could not enumerate the total number of genes required for the march of cancer. (The technology available in 1988 would not permit such an analysis; he would need to wait two decades before that technology would become available.) But he had proved an important point, that such a discrete genetic march existed. Papanicolaou and Auerbach had described the pathological transition of cancer as a multistep process, starting with premalignancy and marching inexorably toward invasive cancer. Vogelstein showed that the genetic progression of cancer was also a multistep process.

This was a relief. In the decade between 1980 and 1990, proto-oncogenes and tumor suppressor genes had been discovered in such astonishing numbers in the human genome—at last count, about one hundred such genes—that their abundance raised a disturbing question: if the genome was so densely littered with such intemperate genes—genes waiting to push a cell toward cancer as if at the flick of a switch—then why was the human body not exploding with cancer every minute?

Cancer geneticists already knew two answers to this question. First, proto-oncogenes need to be activated through mutations, and mutations are rare events. Second, tumor suppressor genes need to be inactivated, but typically two copies exist of each tumor suppressor gene, and thus two independent mutations are needed to inactivate a tumor suppressor, an even rarer event. Vogelstein provided the third answer. Activating or inactivating any single gene, he postulated, produced only the first steps toward carcinogenesis. Cancer’s march was long and slow and proceeded though many mutations in many genes over many iterations. 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.


While Bert Vogelstein was describing the slow march of cancer from one gene mutation to the next, cancer biologists were investigating the functions of these mutations. Cancer gene mutations, they knew, could succinctly be described in two categories: either activations of proto-oncogenes or inactivations of tumor suppressor genes. But although dysregulated cell division is the pathological hallmark of cancer, cancer cells do not merely divide; they migrate through the body, destroy other tissues, invade organs, and colonize distant sites. To understand the full syndrome of cancer, biologists would need to link gene mutations in cancer cells to the complex and multifaceted abnormal behavior of these cells.

Genes encode proteins, and proteins often work like minuscule molecular switches, activating yet other proteins and inactivating others, turning molecular switches “on” and “off” inside a cell. Thus, a conceptual diagram can be drawn for any such protein: protein A turns B on, which turns C on and D off, which turns E on, and so forth. This molecular cascade is termed the signaling pathway for a protein. Such pathways are constantly active in cells, bringing signals in and signals out, thereby allowing a cell to function in its environment.

Proto-oncogenes and tumor suppressor genes, cancer biologists discovered, sit at the hubs of such signaling pathways. 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.

But the activated ras pathway (Ras→ Mek → Erk) does not merely cause accelerated cell division; the pathway also intersects with other pathways to enable several other “behaviors” of cancer cells. At Children’s Hospital in Boston in the 1990s, the surgeon-scientist Judah Folkman demonstrated that certain activated signaling pathways within cancer cells, ras among them, could also induce neighboring blood vessels to grow. A tumor could thus “acquire” its own blood supply by insidiously inciting a network of blood vessels around itself and then growing, in grapelike clusters, around those vessels, a phenomenon that Folkman called tumor angiogenesis.

Folkman’s Harvard colleague Stan Korsmeyer found other activated pathways in cancer cells, originating in mutated genes, that also blocked cell death, thus imbuing cancer cells with the capacity to resist death signals. Other pathways allowed cancer cells to acquire motility, the capacity to move from one tissue to another—initiating metastasis. Yet other gene cascades increased cell survival in hostile environments, such that cancer cells traveling through the bloodstream could invade other organs and not be rejected or destroyed in environments not designed for their survival.

Cancer, in short, was not merely genetic in its origin; it was genetic in its entirety. Abnormal genes governed all aspects of cancer’s behavior. Cascades of aberrant signals, originating in mutant genes, fanned out within the cancer cell, promoting survival, accelerating growth, enabling mobility, recruiting blood vessels, enhancing nourishment, drawing oxygen—sustaining cancer’s life.

These gene cascades, notably, were perversions of signaling pathways used by the body under normal circumstances. The “motility genes” activated by cancer cells, for instance, are the very genes that normal cells use when they require movement through the body, such as when immunological cells need to move toward sites of infection. Tumor angiogenesis exploits the same pathways that are used when blood vessels are created to heal wounds. Nothing is invented; nothing is extraneous. Cancer’s life is a recapitulation of the body’s life, its existence a pathological mirror of our own. Susan Sontag warned against overburdening an illness with metaphors. But this is not a metaphor. Down to their innate molecular core, cancer cells are hyperactive, survival-endowed, scrappy, fecund, inventive copies of ourselves.


By the early 1990s, cancer biologists could begin to model the genesis of cancer in terms of molecular changes in genes. To understand that model, let us begin with a normal cell, say a lung cell that resides in the left lung of a forty-year-old fire-safety-equipment installer. One morning in 1968, a minute sliver of asbestos from his equipment wafts through the air and lodges in the vicinity of that cell. His body reacts to the sliver with an inflammation. The cells around the sliver begin to divide furiously, like a minuscule wound trying to heal, and a small clump of cells derived from the original cell arises at the site.

In one cell in that clump an accidental mutation occurs in the ras gene. The mutation creates an activated version of ras. The cell containing the mutant gene is driven to grow more swiftly than its neighbors and creates a clump within the original clump of cells. It is not yet a cancer cell, but a cell in which uncontrolled cell division has partly been unleashed—cancer’s primordial ancestor.

A decade passes. The small collection of ras-mutant cells continues to proliferate, unnoticed, in the far periphery of the lung. The man smokes cigarettes, and a carcinogenic chemical in tar reaches the periphery of the lung and collides with the clump of ras-mutated cells. A cell in this clump acquires a second mutation in its genes, activating a second oncogene.

Another decade passes. Yet another cell in that secondary mass of cells is caught in the path of an errant X-ray and acquires yet another mutation, this time inactivating a tumor suppressor gene. This mutation has little effect since the cell possesses a second copy of that gene. But in the next year, another mutation inactivates the second copy of the tumor suppressor gene, creating a cell that possesses two activated oncogenes and an inactive tumor suppressor gene.

Now a fatal march is on; an unraveling begins. The cells, now with four mutations, begin to outgrow their brethren. As the cells grow, they acquire additional mutations and they activate pathways, resulting in cells even further adapted for growth and survival. One mutation in the tumor allows it to incite blood vessels to grow; another mutation within this blood-nourished tumor allows the tumor to survive even in areas of the body with low oxygen.

Mutant cells beget cells beget cells. A gene that increases the mobility of the cells is activated in a cell. This cell, having acquired motility, can migrate through the lung tissue and enter the bloodstream. A descendant of this mobile cancer cell acquires the capacity to survive in the bone. This cell, having migrated through the blood, reaches the outer edge of the pelvis, where it begins yet another cycle of survival, selection, and colonization. It represents the first metastasis of a tumor that originated in the lung.

The man is occasionally short of breath. He feels a tingle of pain in the periphery of his lung. Occasionally, he senses something moving under his rib cage when he walks. Another year passes, and the sensations accelerate. The man visits a physician and a CT scan is performed, revealing a rindlike mass wrapped around a bronchus in the lung. A biopsy reveals lung cancer. A surgeon examines the man and the CT scan of the chest and deems the cancer inoperable. Three weeks after that visit, the man returns to the medical clinic complaining of pain in his ribs and his hips. A bone scan reveals metastasis to the pelvis and the ribs.

Intravenous chemotherapy is initiated. The cells in the lung tumor respond. The man soldiers through a punishing regimen of multiple cell-killing drugs. But during the treatment, one cell in the tumor acquires yet another mutation that makes it resistant to the drug used to treat the cancer. Seven months after his initial diagnosis, the tumor relapses all over the body—in the lungs, the bones, the liver. On the morning of October, 17, 2004, deeply narcotized on opiates in a hospital bed in Boston and surrounded by his wife and his children, the man dies of metastatic lung cancer, a sliver of asbestos still lodged in the periphery of his lung. He is seventy-six years old.

I began this as a hypothetical story of cancer. The genes, carcinogens, and the sequence of mutations in this story are all certainly hypothetical. But the body at its center is real. This man was the first patient to die in my care during my fellowship in cancer medicine at Massachusetts General Hospital.

Medicine, I said, begins with storytelling. Patients tell stories to describe illness; doctors tell stories to understand it. Science tells its own story to explain diseases. This story of one cancer’s genesis—of carcinogens causing mutations in internal genes, unleashing cascading pathways in cells that then cycle through mutation, selection, and survival—represents the most cogent outline we have of cancer’s birth.


In the fall of 1999, Robert Weinberg attended a conference on cancer biology in Hawaii. Late one afternoon, he and Douglas Hanahan, another cancer biologist, trekked through the lava beds of the low, black mountains until they found themselves at the mouth of a volcano, staring in. Their conversation was tinged with frustration. For too long, it seemed, cancer had been talked about as if it were a bewildering hodgepodge of chaos. The biological characteristics of tumors were described as so multifarious as to defy any credible organization. There seemed to be no organizing rules.

Yet, Weinberg and Hanahan knew, the discoveries of the prior two decades had suggested deep rules and principles. Biologists looking directly into cancer’s maw now recognized that roiling beneath the incredible heterogeneity of cancer were behaviors, genes, and pathways. In January 2000, a few months after their walk to the volcano’s mouth, Weinberg and Hanahan published an article titled “The Hallmarks of Cancer” to summarize these rules. It was an ambitious and iconic work that marked a return, after nearly a century’s detour, to Boveri’s original notion of a “unitary cause of carcinoma”:

We discuss . . . rules that govern the transformation of normal human cells into malignant cancers. We suggest that research over the past decades has revealed a small number of molecular, biochemical, and cellular traits—acquired capabilities—shared by most and perhaps all types of human cancer.”

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.

Notably, Weinberg and Hanahan wrote, these six rules were not abstract descriptions of cancer’s behavior. Many of the genes and pathways that enabled each of these six behaviors had concretely been identified—ras, myc, Rb, to name just a few. The task now was to connect this causal understanding of cancer’s deep biology to the quest for its cure:

“Some would argue that the search for the origin and treatment of this disease will continue over the next quarter century in much the same manner as it has in the recent past, by adding further layers of complexity to a scientific literature that is already complex almost beyond measure. But we anticipate otherwise: those researching the cancer problem will be practicing a dramatically different type of science than we have experienced over the past 25 years.”

The mechanistic maturity of cancer science would create a new kind of cancer medicine, Weinberg and Hanahan posited: “With holistic clarity of mechanism, cancer prognosis and treatment will become a rational science, unrecognizable by current practitioners.” Having wandered in the darkness for decades, scientists had finally reached a clearing in their understanding of cancer. Medicine’s task was to continue that journey toward a new therapeutic attack.

* In 1988, the precise identity of only one gene—ras—was known. The other three were suspected human anti-oncogenes, although their identity would only become known later.

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