A New Way of Doing Science - Her-2, The Making of Herceptin

Excerpted from
Her-2, The Making of Herceptin: a Revolutionary Treatment for Breast Cancer
By Robert Bazell

As often happens in science, the research that led to an important innovation in cancer treatment began not with hundreds of scientists working toward a stated goal but with a lone researcher who happened onto the trail by accident. In the case of the first gene-based cancer treatment, that person worked not for the government, academia, or a giant pharmaceutical company, the three traditional loci of medical research, but for that infant phenomenon of the late 1970s and early '80s: the biotechnology industry.

Axel Ullrich did not set out to break one of cancer's secret codes. He was universally recognized as a master cloner, a wizard at isolating the specific stretches of DNA that comprise genes. He likes to boast of his scientific exploits, great insights that he says were ahead of their time. "That was sort of the story of my life," he says without a trace of irony. "That I had all these ideas that people were not quite ready for, and yet then I leave, and then they reinvent the idea." Ullrich possesses the rugged good looks and swagger of an American cowboy. When he talks, he sounds like Henry Kissinger.

Educated through the doctorate level in his native Germany, he won a postdoctoral fellowship in the Biochemistry Department of the University of California at San Francisco. There could be no more exciting place for a young biologist to be. There he witnessed the birth of biotechnology and made his own contributions to it. When Ullrich arrived at UCSF in 1975, Bishop and Varmus were down the hall working on their chicken oncogene, and their colleague Herb Boyer was helping develop the technology of gene splicing, the critical tool of genetic engineering. Boyer would soon cofound Genentech, one of the first companies to exploit the new techniques of genetic engineering.

One of Ullrich's achievements at UCSF was to isolate the gene that produces insulin in rats and transfer it into bacteria, thereby transforming them into microscopic insulin factories. This was the first time anyone had induced bacteria to produce a mammalian protein, the premier demonstration of the very technique that would form the backbone of the biotechnology industry. But that triumph turned sour at a press conference called to announce this discovery. Ullrich's supervisor, who had been on sabbatical when most of the work was done and had discouraged him from pursuing his hypothesis, swooped in to stand before the cameras and take all the credit. Ullrich was left looking like a bit player. He determined never to let himself be burned like that again.

Along with several of his colleagues at UCSF, Ullrich eventually moved to South San Francisco to work at the newly founded Genentech, although he resisted at first. In 1977, Robert Swanson, the twenty-seven-year-old venture capitalist who had cofounded the company with Boyer, nearly succeeded in luring Ullrich away from the university. At the last minute Ullrich told him that he feared he might never be allowed to return to academic research if he joined what was then a suspect enterprise. Swanson tore up his contract. Six months later, Ullrich finally made the jump. He acknowledges that the six-month delay cost him $10 million in Genentech stock and laughs at the thought, displaying a gambler's nonchalance about fortunes lost and won on the frontier of biotechnology. He can afford to laugh: over the years, he has made back that loss and much more.

But more alluring than the money, according to Ullrich, was Swanson's willingness to allow the top scientists to carry out their own research virtually unfettered by the traditional standards of the drug industry and other profit-making corporations that sponsor research. The new Genentech scientists would have almost the same freedom as those in universities to pursue whatever ideas they chose. Corporate scientists, often working in secret, carried out applied science-directed toward the goal of creating a product. Says Ullrich, "We just convinced Bob Swanson that he had to allow us to publish and publish fast and be in contact with the academic scientific community. And that became the basis of this completely new way of doing science," an approach that would prove productive both for basic science and for drug discovery.

Genentech was not the first biotechnology company-Cetus, across the bay in Berkeley, had opened its doors in 1971. Nor was it the most successful-Amgen in southern California earned greater profits. But on October 14, 1980, Genentech's initial public stock offering soared from thirty-five dollars per share to eighty-nine dollars in the first twenty minutes of trading and closed that day at just about seventy dollars. This unprecedented performance instantly made Genentech the avatar of a fledgling industry synonymous with great risk and great reward. Wall Street had clearly discovered biotechnology.

The very essence of biotechnology was the arrangement Ullrich and the other young scientists won from Swanson. The early biotechnologists believed they would carry out research of the highest quality and then turn the results into new drugs with a swiftness that the staid pharmaceutical industry could not match. In the years before the industry emerged, the pharmaceutical giants ("big pharma," in the lexicon of biotechnology) rarely carried out experiments without having a clear goal. For the most part, they left pure research to the scientists at university and government labs. Drug-company scientists concentrated on the often boring and repetitious steps necessary either to find a drug at random or to convert someone else's basic research discovery into a useful medicine. Genentech's bravado was rooted in the then novel idea that the same scientists could carry out top-notch basic research, be instantly aware of its potential for dmg development, and help bring it to market. In time, researchers would realize some limitations to this approach. But in the early days, they saw none.

Ullrich's first foray into cancer research involved a critically important chemical called epidermal growth factor. As the name implies, EGF helps control the growth of the epidermis, or skin. Like estrogen, EGF belongs to a class of chemicals, called growth factors, that carry orders that regulate not just growth but every body function, from food digestion and blood pressure to sleeping and breathing. (A chemical that carries such signals through the entire body is called a hormone. But not all growth factors travel through the body; EGF, for example, only goes from one cell to the next.) Because of their important role in so many processes, these chemicals were of great interest to scientists at Genentech and elsewhere who believed they held the key to understanding many fundamentals of physiology. With that understanding, these scientists could develop drugs to combat many kinds of ailments.

While the chemical orders move through the body, they do not deliver their messages to every cell. Like the handful of children in a classroom who raise their hands in response to an assignment, only a few cells are inclined to get the message. In fact, the only cells that understand the chemical's message are those that carry a receptor, a specific antenna-like protein on the cell's surface. EGF's orders are always the same-to grow and divide-and to deliver them, it attaches to the EGF receptor on a cell's surface.

Just before Christmas in 1983, Ullrich got a phone call from Mike Waterfield, a top protein chemist in London. Waterfield believed he might have the first evidence of what an oncogene actually does to cause cancer. Many scientists had postulated but not yet proved that oncogenes are related to chemicals like EGF, which control growth. But Waterfield had the proof. He told Ullrich he had purified the protein that acts as the EGF receptor. Based on the structure of the protein, Waterfield had an inkling that the EGF receptor was not just related to the protein product of an oncogene called erb-b, which causes a blood cancer in chickens, but was identical to it. Waterfield needed Ullrich to join him in London to clone the gene for the human EGF receptor by working backward from the structure of the protein.

With the gene in hand, Waterfield, Ullrich, and an Israeli protein expert named Joseph Schlessinger were able to offer the first experimental proof of the extraordinarily important theory that growth factors are related to cancer. They showed that the oncogene called erb-b is indeed a mutated form of the gene that programs the receptor for EGF. In early 1984, the three men published their landmark findings in the prestigious journal Nature.

Their conclusion was a milestone in cancer research because it drew a critical connection between what had been two separate areas of biology-the study of cell-growth signals and the study of cancer-and for the first time explained how an oncogene works. When functioning normally, the gene regulates the delicate ballet of cell growth and division. When mutated, it brings on unrestrained growth-cancer. Almost all oncogenes turn out to be mutated forms of the genes that regulate cell growth and division. In just a decade and a half, that discovery became so widely accepted that it was soon taught in high-school biology classes.