Part 5

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

(Page 5 of 5)

The Bishop-Varmus discovery set off a frenzy of research to find out exactly how oncogenes carry out their insidious cellular conversion. Before long, researchers identified just a handful of genes that appeared to cause a wide variety of cancers. Soon words like src, myb, ras, and erb permeated the lexicon of cancer researchers (by convention, cancer researchers usually give oncogenes three-letter names). One gene could somehow spark lung, colon, pancreatic, and dozens of other cancers. Amazingly, the particular genes whose mutations could lead to cancer in humans appeared throughout the animal kingdom. The same gene could be found in mice, people, ducks, even lowly yeast cells. These genes, which when altered could make normal cells multiply out of control, have persisted for hundreds of millions of years. Clearly, they survived intact because they performed some crucial function in the cells that evolution could not afford to discard. They also sowed the seeds of cancer and offered the tantalizing possibility of curing it.

At the time that Anne McNamara's cancer struck, Robert Weinberg, a thirty-one-year-old assistant professor at the Massachusetts Institute of Technology, led the pack of scientists chasing oncogenes. Loquacious and erudite, Weinberg is physically unprepossessing. Five foot six, he sports a bushy black mustache and combs his hair horizontally across the top of his balding head. He is that rare scientist able to communicate the significance of scientific achievements, his own or others', with great clarity, insight, and humor. Weinberg is always quick to point out that others in his lab did the actual work. "They feared my presence at the lab bench; I screwed everything up," he confesses.

Despite the professed deference Weinberg made huge contributions to basic research on cancer. He jumped into oncogene research as it was yielding its profound insights into the basic underpinnings of cancer. Among his earliest achievements was establishing that oncogenes themselves, not viruses, cause cancer. No one can say for certain what motivates the elders of the Karolinska Institute in Stockholm, but had Weinberg paid a bit more attention to a gene named neu, later Her-2/neu, he might have snared the great brass ring called the Nobel Prize.

The big challenge in 1979 for Weinberg and the tiny band of top scientists with whom he competed was to clone a pure sample of the DNA stretch that makes up an oncogene. By the late 1970s, the science of cloning was just giving birth to the biotechnology industry and allowing researchers to study genes in detail for the first time; though by today's standards, the early technology was primitive and the process very painstaking. That year, while Anne McNamara was recovering from her surgery, a postdoctoral fellow in Weinberg's lab discovered neu. Lakshmi Charon Padhy, a young researcher from Bombay, extracted DNA from neurological tumors in rats and injected it into normal mouse cells, which then turned cancerous. Padhy then discovered that sometimes these cancerous mouse cells trigger an immune response in the mice because of a particular rat protein now on the surface of the mouse cells, a product of one of the genes from the rat tumors. Weinberg dubbed the gene that produced the cancerous cells "neu" because it first appeared in tumors of the neurological system.

After naming neu, Weinberg more or less forgot about it. Over the years, he worked with it from time to time, but it never held a high priority. Other targets appeared more worthwhile. But as Weinberg would learn later, the neu protein was precisely the agent that the oncogene used to transform a normal cell into a cancer cell. If Weinberg had cloned neu, he would have had in hand the very protein the oncogene uses to make a cell cancerous. But Weinberg missed the opportunity and instead spent a frustrating two years trying to clone another oncogene called ras; it was produced in the neurological tumors Padhy and Weinberg were working with, but Weinberg went looking for it elsewhere.

"I can flagellate myself," Weinberg says now. "If I'd been more studious and more focused and not as monomaniacal about the ideas that I had at the time, I would have made that connection." Weinberg could have carried out the key experiment years ahead of his competitors. "It would have been an overnight experiment. We just didn't do it," he admits, adding, "That's life. I can't complain or be embittered. It's not as if I didn't have my share of good luck."

In the years to follow, achievements were such that, despite the missed opportunity of neu, Weinberg heard from friends that he would share a Nobel Prize with Bishop and Varmus. "Lots of people said to me, 'You're next, Bob.' " But when Bishop and Varmus got the award in 1989, there was no third winner. Weinberg, who won every significant honor in science save the big one, tries to remain philosophical. "How much do you need to make you happy?" he asks. "And in fifty years, who will care who won the Nobel Prize?"

No matter who got the credit, the discovery of oncogenes and the growing understanding of how they work revolutionized cancer research by providing the first understanding of the fundamental biology of the disease. A "magic bullet" therapy that would attack the disease at its root and halt its growth without inflicting any damage to healthy tissue had long been a dream in cancer treatment. But science needed a target. Now, finally, it had one. Researchers knew what they were looking for; they knew where to train their sights. In the late '70s and early '80s, scientists found dozens of oncogenes, along with a related class of genes called tumor suppressors that can also give rise to cancer. The neuoncogene, once bypassed by Weinberg, would play a key part in the struggle to bring the new genetic understanding of cancer out of the laboratory and to the patient's bedside.

© 1998 Robert Bazell.

About the Author

Robert Bazell is the chief science correspondent for NBC News. His reports, which appear on the NBC Nightly News, Today, and Dateline NBC, have won every major award in broadcasting. He has written for many publications, including The New Republic, The New York Times, and The New York Times Magazine. He lives in New York with his wife, Margot, and daughter, Stephanie.