The Emperor of All Maladies: A Biography of Cancer (78 page)

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
Gen
etic
En
gineering
Tech
nology—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.