The Emperor of All Maladies: A Biography of Cancer

by Siddhartha Mukherjee

Since metastasis is what kills patients with breast cancer, it is, of course, generally true that the ability to detect and remove premetastatic tumors saves women’s lives. But it is also true that just because a tumor is small does not mean that it is premetastatic. Even relatively small tumors barely detectable by mammography can carry genetic programs that make them vastly more likely to metastasize early. Conversely, large tumors may inherently be genetically benign—unlikely to invade and metastasize. Size matters, in other words—but only to a point. The difference in the behavior of tumors is not just a consequence of quantitative growth, but of qualitative growth. A static picture cannot capture this qualitative growth. Seeing a “small” tumor and extracting it from the body does not guarantee our freedom from cancer—a fact that we still struggle to believe. In the end, a mammogram or a Pap smear is a portrait of cancer in its infancy. Like any portrait, it is drawn in the hopes that it might capture something essential about the subject—its psyche, its inner being, its future, its behavior. “All photographs are accurate,” the artist Richard Avedon liked to say, “[but] none of them is the truth.”

Ars longa, vita brevis. The art of medicine is long, Hippocrates tells us, “and life is short; opportunity fleeting; the experiment perilous; judgment flawed.”

On the morning of December 28, 1993, Mark Hiepler spent nearly two hours in the courtroom describing the devastating last year of his sister’s life. The balconies and benches overflowed with Fox’s friends and supporters and with patients, many of them weeping with anger and empathy. The jury took less than two hours to deliberate. That evening, it returned a verdict awarding Fox’s family $89 million in damages—the second-highest amount in the history of litigation in California and one of the highest ever awarded in a medical case in America.

By the mid-1990s, seven states required HMOs to pay for bone marrow transplantation, with similar legislation pending in seven additional states. Between 1988 and 2002, eighty-six cases were filed by patients against HMOs that had denied transplants. In forty-seven instances, the patient won the case.

Between 1970 and 1994, cancer mortality had, if anything, increased slightly, about 6 percent, from 189 deaths per 100,000 to 201 deaths. Admittedly, the death rate had plateaued somewhat in the last ten years, but even so, this could hardly be construed as a victory. Cancer, Bailar concluded, was still reigning “undefeated.” Charted as a graph, the nation’s progress on cancer was a flat line; the War on Cancer had, thus far, yielded a stalemate.

‘Cancer’ is, in truth, a variety of diseases. Viewing it as a single disease that will yield to a single approach is no more logical than viewing neuropsychiatric disease as a single entity that will respond to one strategy. It is unlikely that we will soon see a ‘magic bullet’ for the treatment of cancer. But it is just as unlikely that there will be a magic bullet of prevention or early detection that will knock out the full spectrum of cancers.… We are making progress. Although we also have a long way to go, it is facile to claim that the pace of favorable trends in mortality reflects poor policies or mistaken priorities.”

An era of oncology was coming to a close. Already, the field had turned away from its fiery adolescence, its entrancement with universal solutions and radical cures, and was grappling with fundamental questions about cancer. What were the underlying principles that governed the root behavior of a particular form of cancer? What was common to all cancers, and what made breast cancer different from lung or prostate cancer? Might those common pathways, or differences for that matter, establish new road maps to cure and prevent cancer? The quest to combat cancer thus turned inward, toward basic biology, toward fundamental mechanisms. To answer these questions, we must turn inward, too. We must, at last, return to the cancer cell.

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.”

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.

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.

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?

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?

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.*

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.

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.

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?

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.

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.

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.

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...

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.

Varmus and Bishop had demonstrated that precursors of oncogenes—protooncogenes—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.

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.

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.”

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.”

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.”

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.

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 ma...

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 ves...

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 immuno-logical 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.

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.

These were all deep, audacious, and meaningful victories borne on the backs of deep and meaningful labors. But, in truth, they were the victories of another generation—the results of discoveries made in the fifties and sixties. The core conceptual advances from which these treatment strategies arose predated nearly all the significant work on the cell biology of cancer. In a bewildering spurt over just two decades, scientists had unveiled a fantastical new world—of errant oncogenes and tumor suppressor genes that accelerated and decelerated growth to unleash cancer; of chromosomes that could be decapitated and translocated to create new genetic chimeras, of cellular pathways corrupted to subvert the death of cancer. But the therapeutic advances that had led to the slow attrition of cancer mortality made no use of this novel biology of cancer. There was new science on one hand and old medicine on the other. Mary Lasker had once searched for an epochal shift in cancer. But the shift that had occurred seemed to belong to another epoch.

For nearly a decade, practicing cancer medicine had become like living inside a pressurized can—pushed, on one hand, by the increasing force of biological clarity about cancer, but then pressed against the wall of medical stagnation that seemed to have produced no real medicines out of this biological clarity. In the winter of 1945, Vannevar Bush had written to President Roosevelt, “The striking advances in medicine during the war have been possible only because we had a large backlog of scientific data accumulated through basic research in many scientific fields in the years before the war.” For cancer, the “backlog of scientific data” had reached a critical point. The boil of science, as Bush liked to imagine it, inevitably produced a kind of steam—an urgent, rhapsodic pressure that could only find release in technology. Cancer science was begging to find release in a new kind of cancer medicine.

First, cancer cells are driven to grow because of the accumulation of mutations in their DNA. These mutations activate internal proto-oncogenes and inactivate tumor suppressor genes, thus unleashing the “accelerators” and “brakes” that operate during normal cell division. Targeting these hyperactive genes, while sparing their modulated normal precursors, might be a novel means to attack cancer cells more discriminately. Second, proto-oncogenes and tumor suppressor genes typically lie at the hubs of cellular signaling pathways. Cancer cells divide and grow because they are driven by hyperactive or inactive signals in these critical pathways. These pathways exist in normal cells but are tightly regulated. The potential dependence of a cancer cell on such permanently activated pathways is a second potential vulnerability of a cancer cell. Third, the relentless cycle of mutation, selection, and survival creates a cancer cell that has acquired several additional properties besides uncontrolled growth. These include the capacity to resist death signals, to metastasize throughout the body, and to incite the growth of blood vessels. These “hallmarks of cancer” are not invented by the cancer cell; they are typically derived from the corruption of similar processes that occur in the normal physiology of the body. The acquired dependence of a cancer cell on these processes is a third potential vulnerability of cancer.

The Ruijin discovery was remarkable: trans-retinoic acid represented the long-sought fantasy of molecular oncology—an oncogene-targeted cancer drug. But the discovery was a fantasy lived backward. Wang and Degos had first stumbled on trans-retinoic acid through inspired guesswork—and only later discovered that the molecule could directly target an oncogene. But was it possible to make the converse journey—starting from oncogene and going to drug? Indeed, Robert Weinberg’s lab in Boston had already begun that converse journey, although Weinberg himself was largely oblivious of it.

It should hardly come as a surprise, then, that neu was barely forgotten in Weinberg’s laboratory when it was resurrected in another. In the summer of 1984, a team of researchers, collaborating with Weinberg, discovered the human homolog of the neu gene. Noting its resemblance to another growth-modulating gene discovered previously—the Human EGF Receptor (HER)—the researchers called the gene Her-2. A gene by any other name may still be the same gene, but something crucial had shifted in the story of neu. Weinberg’s gene had been discovered in an academic laboratory. Much of Weinberg’s attention had been focused on dissecting the molecular mechanism of the neu oncogene. Her-2, in contrast, was discovered on the sprawling campus of the pharmaceutical company Genentech. The difference in venue, and the resulting difference in goals, would radically alter the fate of this gene. For Weinberg, neu had represented a route to understanding the fundamental biology of neuroblastoma. For Genentech, Her-2 represented a route to developing a new drug.

A “drug,” in bare conceptual terms, is any substance that can produce an effect on the physiology of an animal. Drugs can be simple molecules; water and salt, under appropriate circumstances, can function as potent pharmacological agents. Or drugs can be complex, multifaceted chemicals—molecules derived from nature, such as penicillin, or chemicals synthesized artificially, such as aminopterin. Among the most complex drugs in medicine are proteins, molecules synthesized by cells that can exert diverse effects on human physiology. Insulin, made by pancreas cells, is a protein that regulates blood sugar and can be used to control diabetes. Growth hormone, made by the pituitary cells, augments growth by increasing the metabolism of muscle and bone cells.

One afternoon, Ullrich walked to the Immunology Division at Genentech. The division specialized in the creation of immunological molecules. Ullrich wondered whether someone in immunology might be able to design a drug to bind Her-2 and possibly erase its signaling. Ullrich had a particular kind of protein in mind—an antibody. Antibodies are immunological proteins that bind their targets with exquisite affinity and specificity. The immune system synthesizes antibodies to bind and kill specific targets on bacteria and viruses; antibodies are nature’s magic bullets.

In the summer of 1990, Carter proudly produced a fully humanized Her-2 antibody ready to be used in clinical trials. The antibody, now a potential drug, would soon be renamed Herceptin, fusing the words Her-2, intercept, and inhibitor.* Such was the halting, traumatic birth of the new drug that it was easy to forget the enormity of what had been achieved. Slamon had identified Her-2 amplification in breast cancer tissue in 1987; Carter and Shepard had produced a humanized antibody against it by 1990. They had moved from cancer to target to drug in an astonishing three years, a pace unprecedented in the history of cancer.

The lump on Bradfield’s neck—the only tumor in the group that could be physically touched, measured, and watched—became the compass for the trial. On the morning of the first intravenous infusion of the Her-2 antibody, all the women came up to feel the lump, one by one, running their hands across Bradfield’s collarbone. It was a peculiarly intimate ritual that would be repeated every week. Two weeks after the first dose of the antibody, when the group filed past Bradfield, touching the node again, the change was incontrovertible. Bradfield’s tumor had softened and visibly shrunk. “We began to believe that something was happening here,” Bradfield recalled. “Suddenly, the weight of our good fortune hit us.” Not everyone was as fortunate as Bradfield. Exhausted and nauseous one evening, the young woman with relapsed metastatic cancer was unable to keep down the fluids needed to hydrate her body. She vomited through the night and then, too tired to keep drinking and too sick to understand the consequences, fell back into sleep. She died of kidney failure the next week.

Barbara Bradfield finished eighteen weeks of therapy in 1993. She survives today. A gray-haired woman with crystalline gray-blue eyes, she lives in the small town of Puyallup near Seattle, hikes in the nearby woods, and leads discussion groups for her church. She vividly remembers her days at the Los Angeles clinic—the half-lit room in the back where the nurses dosed the drugs, the strangely intimate touch of the other women feeling the node in her neck. And Slamon, of course. “Dennis is my hero,” she said. “I refused his first phone call, but I have never, ever, refused him anything since that time.” The animation and energy in her voice crackled across the phone line like an electrical current. She quizzed me about my research. I thanked her for her time, but she, in turn, apologized for the distraction. “Get back to work,” she said, laughing. “There are people waiting for discoveries.”

In 1995, a small delegation of Genentech scientists and executives thus flew to Washington to meet Frances Visco, the chair of the National Breast Cancer Coalition (NBCC), a powerful national coalition of cancer activists, hoping to use the NBCC as a neutral intermediary between the company and the local breast cancer activists in San Francisco. Pragmatic, charismatic, and savvy, Visco, a former attorney, had spent nearly a decade immersed in the turbulent politics of breast cancer. Visco had a proposal for Genentech, but her terms were inflexible: Genentech had to provide an expanded access program for Herceptin. This program would allow oncologists to treat patients outside clinical trials. In return, the National Breast Cancer Coalition would act as a go-between for Genentech and its embittered and alienated community of cancer patients. Visco offered to join the planning committee of the phase III trials of Herceptin, and to help recruit patients for the trial using the NBCC’s extensive network. For Genentech, this was a long-overdue education. Rather than running trials on breast cancer patients, the company learned to run trials with breast cancer patients. (Genentech would eventually outsource the compassionate-access program to a lottery system run by an independent agency. Women applied to the lottery and “won” the right to be treated, thus removing the company from any ethically difficult decision-making.)

Slamon paused for a theatrical moment before revealing the results of the trial. In the pivotal 648 study, 469 women had received standard cytotoxic chemotherapy (either Adriamycin and Cytoxan in combination, or Taxol) and were randomized to receive either Herceptin or a placebo. In every conceivable index of response, women treated with the addition of Herceptin had shown a clear and measurable benefit. Response rates to standard chemotherapy had moved up 150 percent. Tumors had shrunk in half the women treated with Herceptin compared to a third of women in the control arm. The progression of breast cancer had been delayed from four to seven and a half months. In patients with tumors heavily resistant to the standard Adriamycin and Cytoxan regimen, the benefit had been the most marked: the combination of Herceptin and Taxol had increased response rates to nearly 50 percent—a rate unheard of in recent clinical experience. The survival rate would also follow this trend. Women treated with Herceptin lived four or five months longer than women in the control group.

As with the study of any oncogene, the field now turned from structure to function: what did Bcr-abl do to cause leukemia? When Baltimore’s lab and Owen Witte’s lab investigated the function of the aberrant Bcr-abl oncogene, they found that, like src, it was yet another kinase—a protein that tagged other proteins with a phosphate group and thus unleashed a cascade of signals in a cell. In normal cells, the Bcr and abl genes existed separately; both were tightly regulated during cell division. In CML cells, the translocation created a new chimera—Bcr-abl, a hyperactive, overexuberant kinase that activated a pathway that forced cells to divide incessantly.