—Italo Calvino
Weinberg may briefly have forgotten about the therapeutic implication of neu, but oncogenes, by their very nature, could not easily be forgotten. In his book Invisible Cities, Italo Calvino describes a fictional metropolis in which every relationship between one household and the next is denoted by a piece of colored string stretched between the two houses. As the metropolis grows, the mesh of strings thickens and the individual houses blur away. In the end, Calvino’s city becomes no more than an interwoven network of colored strings.
If someone were to draw a similar map of relationships among genes in a normal human cell, then proto-oncogenes and tumor suppressors such as ras, myc, neu, and Rb would sit at the hub of this cellular city, radiating webs of colored strings in every direction. Proto-oncogenes and tumor suppressors are the molecular pivots of the cell. They are the gatekeepers of cell division, and the division of cells is so central to our physiology that genes and pathways that coordinate this process intersect with nearly every other aspect of our biology. In the laboratory, we call this the six-degrees-of-separation-from-cancer rule: you can ask any biological question, no matter how seemingly distant—what makes the heart fail, or why worms age, or even how birds learn songs—and you will end up, in fewer than six genetic steps, connecting with a proto-oncogene or tumor suppressor.
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.
Located on the southern edge of San Francisco, sandwiched among the powerhouse labs of Stanford, UCSF, and Berkeley and the burgeoning start-ups of Silicon Valley, Genentech—short for Genetic Engineering Technology—was born out of an idea imbued with deep alchemic symbolism. In the late 1970s, researchers at Stanford and UCSF had invented a technology termed “recombinant DNA.” This technology allowed genes to be manipulated—engineered—in a hitherto unimaginable manner. Genes could be shuttled from one organism to another: a cow gene could be transferred into bacteria, or a human protein synthesized in dog cells. Genes could also be spliced together to create new genes, creating proteins never found in nature. Genentech imagined leveraging this technology of genes to develop a pharmacopoeia of novel drugs. Founded in 1976, the company licensed recombinant DNA technology from UCSF, raised a paltry $200,000 in venture funds, and launched its hunt for these novel drugs.
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.
Before Genentech, protein drugs, although recognizably potent, had been notoriously difficult to produce. Insulin, for instance, was produced by grinding up cow and pig innards into a soup and then extracting the protein from the mix—one pound of insulin from every eight thousand pounds of pancreas. Growth hormone, used to treat a form of dwarfism, was extracted from pituitary glands dissected out of thousands of human cadavers. Clotting drugs to treat bleeding disorders came from liters of human blood.
Recombinant DNA technology allowed Genentech to synthesize human proteins de novo: rather than extracting proteins from animal and human organs, Genentech could “engineer” a human gene into a bacterium, say, and use the bacterial cell as a bioreactor to produce vast quantities of that protein. The technology was transformative. In 1982, Genentech unveiled the first “recombinant” human insulin; in 1984, it produced a clotting factor used to control bleeding in patients with hemophilia; in 1985, it created a recombinant version of human growth hormone—all created by engineering the production of human proteins in bacterial or animal cells.
By the late 1980s, though, after an astonishing growth spurt, Genentech ran out of existing drugs to mass-produce using recombinant technology. Its early victories, after all, had been the result of a process and not a product: the company had found a radical new way to produce old medicines. Now, as Genentech set out to invent new drugs from scratch, it was forced to change its winning strategy: it needed to find targets for drugs—proteins in cells that might play a critical role in the physiology of a disease that might, in turn, be turned on or off by other proteins produced using recombinant DNA.
It was under the aegis of this “target discovery” program that Axel Ullrich, a German scientist working at Genentech, rediscovered Weinberg’s gene—Her-2/neu, the oncogene tethered to the cell membrane.* But having discovered the gene, Genentech did not know what to do with it. The drugs that Genentech had successfully synthesized thus far were designed to treat human diseases in which a protein or a signal was absent or low—insulin for diabetics, clotting factors for hemophiliacs, growth hormone for dwarfs. An oncogene was the opposite—not a missing signal, but a signal in overabundance. Genentech could fabricate a missing protein in bacterial cells, but it had yet to learn how to inactivate a hyperactive protein in a human cell.
In the summer of 1986, while Genentech was still puzzling over a method to inactivate oncogenes, Ullrich presented a seminar at the University of California in Los Angeles. Flamboyant and exuberant, dressed in a dark, formal suit, Ullrich was a riveting speaker. He floored his audience with the incredible story of the isolation of Her-2, and the serendipitous convergence of that discovery with Weinberg’s prior work. But he left his listeners searching for a punch line. Genentech was a drug company. Where was the drug?
Dennis Slamon, a UCLA oncologist, attended Ullrich’s talk that afternoon in 1986. The son of an Appalachian coal miner, Slamon had come to UCLA as a fellow in oncology after medical school at the University of Chicago. He was a peculiar amalgam of smoothness and tenacity, a “velvet jackhammer,” as one reporter described him. Early in his academic life he had acquired what he called “a murderous resolve” to cure cancer, but thus far, it was all resolve and no result. In Chicago, Slamon had performed a series of exquisite studies on a human leukemia virus called HTLV-1, the lone retrovirus shown to cause a human cancer. But HTLV-1 was a fleetingly rare cause of cancer. Murdering viruses, Slamon knew, would not cure cancer. He needed a method to kill an oncogene.
Slamon, hearing Ullrich’s story of Her-2, made a quick, intuitive connection. Ullrich had an oncogene; Genentech wanted a drug—but an intermediate was missing. A drug without a disease is a useless tool; to make a worthwhile cancer drug, both needed a cancer in which the Her-2 gene was hyperactive. Slamon had a panel of cancers that he could test for Her-2 hyperactivity. A compulsive pack rat, like Thad Dryja in Boston, Slamon had been collecting and storing samples of cancer tissues from patients who had undergone surgery at UCLA, all saved in a vast freezer. Slamon proposed a simple collaboration. If Ullrich sent
him the DNA probes for Her-2 from Genentech, Slamon could test his collection of cancer cells for samples with hyperactive Her-2—thus bridging the gap between the oncogene and a human cancer.
Ullrich agreed. In 1986, he sent Slamon the Her-2 probe to test on cancer samples. In a few months, Slamon reported back to Ullrich that he had found a distinct pattern, although he did not fully understand it. Cancer cells that become habitually dependent on the activity of a gene for their growth can amplify that gene by making multiple copies of the gene in the chromosome. This phenomenon—like an addict feeding an addiction by ramping up the use of a drug—is called oncogene amplification. Her-2, Slamon found, was highly amplified in breast cancer samples, but not in all breast cancers. Based on the pattern of staining, breast cancers could neatly be divided into Her-2 amplified and Her-2 unamplified samples—Her-2 positive and Her-2 negative.
Puzzled by the “on-off” pattern, Slamon sent an assistant to determine whether Her-2 positive tumors behaved differently from Her-2 negative tumors. The search yielded yet another extraordinary pattern: breast tumors that amplified Ullrich’s gene tended to be more aggressive, more metastatic, and more likely to kill. Her-2 amplification marked the tumors with the worst prognosis.
Slamon’s data set off a chain reaction in Ullrich’s lab at Genentech. The association of Her-2 with a subtype of cancer—aggressive breast cancer—prompted an important experiment. What would happen, Ullrich wondered, if Her-2 activity could somehow be shut off? Was the cancer truly “addicted” to amplified Her-2? And if so, might squelching the addiction signal using an anti-Her-2 drug block the growth of the cancer cells? Ullrich was tiptoeing around the afternoon experiment that Weinberg and Padhy had forgotten to perform.
Ullrich knew where he might look for a drug to shut off Her-2 function. By the mid-1980s, Genentech had organized itself into an astonishing simulacrum of a university. The South San Francisco campus had departments, conferences, lectures, subgroups, even researchers in cutoff jeans playing Frisbee on the lawns. 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 mid-1970s, two immunologists at Cambridge University, Cesar Milstein and George Kohler, had devised a method to produce vast quantities of a single antibody using a hybrid immune cell that had been physically fused to a cancer cell. (The immune cell secreted the antibody while the cancer cell, a specialist in uncontrolled growth, turned it into a factory.) The discovery had instantly been hailed as a potential route to a cancer cure. But to exploit antibodies therapeutically, scientists needed to identify targets unique to cancer cells, and such cancer-specific targets had proved notoriously difficult to identify. Ullrich believed that he had found one such target. Her-2, amplified in some breast tumors but barely visible in normal cells, was perhaps Kohler’s missing bull’s-eye.
At UCLA, meanwhile, Slamon had performed another crucial experiment with Her-2 expressing cancers. He had implanted these cancers into mice, where they had exploded into friable, metastatic tumors, recapitulating the aggressive human disease. In 1988, Genentech’s immunologists successfully produced a mouse antibody that bound and inactivated Her-2. Ullrich sent Slamon the first vials of the antibody, and Slamon launched a series of pivotal experiments. When he treated Her-2 overexpressing breast cancer cells in a dish with the antibody, the cells stopped growing, then involuted and died. More impressively, when he injected his living, tumor-bearing mice with the Her-2 antibody, the tumors also disappeared. It was as perfect a result as he or Ullrich could have hoped for. Her-2 inhibition worked in an animal model.
Slamon and Ullrich now had all three essential ingredients for a targeted therapy for cancer: an oncogene, a form of cancer that specifically activated that oncogene, and a drug that specifically targeted it. Both expected Genentech to leap at the opportunity to produce a new protein drug to erase an oncogene’s hyperactive signal. But Ullrich, holed away in his lab with Her-2, had lost touch with the trajectory of the company outside the lab. Genentech, he now discovered, was abandoning its interest in cancer. Through the 1980s, as Ullrich and Slamon had been hunting for a target specific to cancer cells, several other pharmaceutical companies had tried to develop anticancer drugs using the limited knowledge of the mechanisms driving the growth of cancer cells. Predictably, the drugs that had emerged were largely indiscriminate—toxic to both cancer cells and normal cells—and predictably, all had failed miserably in clinical trials. Ullrich and Slamon’s approach—an oncogene and an oncogene-targeted antibody—was vastly more sophisticated and specific, but Genentech was worried that pouring money into the development of another drug that failed would cripple the company’s finances. Chastened by the experience of others—“allergic to cancer,” as one Genentech researcher described it—Genentech pulled funding away from most of its cancer projects.
The decision created a deep rift in the company. A small cadre of scientists ardently supported the cancer program, but Genentech’s executives wanted to focus on simpler and more profitable drugs. Her-2 was caught in the cross fire. Drained and dejected, Ullrich left Genentech. He would eventually join an academic laboratory in Germany, where he could work on cancer genetics without the fickle pressures of a pharmaceutical company constraining his science.
Slamon, now working alone at UCLA, tried furiously to keep the Her-2 effort alive at Genentech, even though he wasn’t on the company’s payroll. “Nobody gave a shit except him,” John Curd, Genentech’s medical director, recalled. Slamon became a pariah at Genentech, a pushy, obsessed gadfly who would often jet up from Los Angeles and lurk in the corridors seeking to interest anyone he could in his mouse antibody. Most scientists had lost interest. But Slamon retained the faith of a small group of Genentech scientists, scientists nostalgic for the pioneering, early days of Genentech when problems had been taken on precisely because they were intractable. An MIT-educated geneticist, David Botstein, and a molecular biologist, Art Levinson, both at Genentech, had been strong proponents of the Her-2 project. (Levinson had come to Genentech from Michael Bishop’s lab at UCSF, where he had worked on the phosphorylating function of src; oncogenes were stitched into his psyche.) Pulling strings, resources, and connections, Slamon and Levinson convinced a tiny entrepreneurial team to push ahead with the Her-2 project.
Marginally funded, the work edged along, almost invisible to Genentech’s executives. In 1989, Mike Shepard, an immunologist at Genentech, improved the production and purification of the Her-2 antibody. But the purified mouse antibody, Slamon knew, was far from a human drug. Mouse antibodies, being “foreign” proteins, provoke a potent immune response in humans and make terrible human drugs. To circumvent that response, Genentech’s antibody needed to be converted into a protein that more closely resembled a human antibody. This process, evocatively called “humanizing” an antibody, is a delicate art, somewhat akin to translating a novel; what matters is not just the content, but the ineffable essence of the antibody—its form. Genentech’s resident “humanizer” was Paul Carter, a quiet, twenty-nine-year-old Englishman who had learned the craft at Cambridge from Cesar Milstein, the scientist who had first produced these antibodies using fused immune and cancer cells. Under Slamon’s and Shepard’s guidance, Carter set about humanizing the mouse antibody. 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 t
he 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.
In the summer of 1990, Barbara Bradfield, a forty-eight-year-old woman from Burbank, California, discovered a mass in her breast and a lump under her arm. A biopsy confirmed what she already suspected: she had breast cancer that had spread to her lymph nodes. She was treated with a bilateral mastectomy followed by nearly seven months of chemotherapy. “When I was finished with all that,” she recalled, “I felt as if I had crossed a river of tragedy.”
But there was more river to ford: Bradfield’s life was hit by yet another incommensurate tragedy. In the winter of 1991, driving on a highway not far from their house, her daughter, twenty-three years old and pregnant, was killed in a fiery accident. A few months later, sitting numbly in a Bible-study class one morning, Bradfield let her fingers wander up to the edge of her neck. A new grape-size mass had appeared just above her collarbone. Her breast cancer had relapsed and metastasized—almost certainly a harbinger of death.
Bradfield’s oncologist in Burbank offered her more chemotherapy, but she declined it. She enrolled in an alternative herbal-therapy program and bought a vegetable juicer and planned a trip to Mexico. When her oncologist asked if he could send samples of her breast cancer to Slamon’s lab at UCLA for a second opinion, she agreed reluctantly. A faraway doctor performing unfamiliar tests on her tumor sample, she knew, could not possibly affect her.
One afternoon in the summer of 1991, Bradfield received a phone call from Slamon. He introduced himself as a researcher who had been analyzing her slides. Slamon told Bradfield about Her-2. “His tone changed,” she recalled. Her tumor, he said, had one of the highest levels of amplified Her-2 that he had ever seen. Slamon told her that he was launching a trial of an antibody that bound Her-2 and that she would be the ideal candidate for the new drug. Bradfield refused. “I was at the end of my road,” she said, “and I had accepted what seemed inevitable.” Slamon tried to reason with her for a while, but found her unbending. He thanked her for her consideration and rang off.