Part 4

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

(Page 4 of 5)

With James Watson and Francis Crick's landmark discovery of the structure of DNA in 1953, alterations in genes, the units of heredity spelled out in the DNA molecule, became obvious candidates for cancer's cause. Watson and Crick's double helix offered nothing less that the master blueprint for all of life. It followed that the double helix also held the secret of cancer.

For centuries, biologists had theorized about the nature and function of genes, which are passed on from generation to generation and determine myriad characteristics, from physical traits to psychological dispositions. But until the Watson and Crick discovery, no one knew exactly what a gene was made of.

Suddenly, it was clear. The DNA molecule is made up of a string of millions of pairs of units, called nucleotides, that contain one of only four bases - adenine, cytosine, thymine, and guanine - that spell the genetic code. A single gene is a string of the ACTG alphabet that carries the instructions for the cell to make a particular protein. The proteins in turn usually provide one of two essential components: the cell's structural scaffolding or the enzymes that guide biochemical reactions - the central engine for the entire organism. So the genes contained in every cell encode information that determines not only how the individual cells look and behave but also how the entire organism looks and behaves. By establishing what proteins a cell produces, the genes on the DNA helix direct the formation of all life, from blades of grass to the human brain. Wouldn't abnormal changes to this master blueprint be responsible for cancer? This sounded plausible, especially since X rays and many of the chemicals that cause cancer also bring mutations to DNA. According to Robert Weinberg, many scientists believed that with the discovery of the DNA structure, "answers to the cancer problem would be all there, waiting to be discovered." But no one could prove a connection between genes and cancer until the mid-1970s, when new technologies for manipulating and understanding genes led to a revolution in the understanding of the disease.

Two researchers at the University of California, San Francisco, carried out the critical experiment that showed definitively that the roots of cancer lay in the genes of cells. Michael Bishop, a virologist, and his postdoctoral fellow, Harold Varmus, who went on to head the National Institutes of Health, were studying a chicken virus first discovered in 1911.

Viruses are the smallest bits of life - often called tiny packets of trouble. They never divide as cellular organisms, including bacteria, do. While bacteria and cells in higher creatures carry tens of thousands of genes, viruses make do with much less - often fewer than a dozen genes. Viruses survive from generation to generation because the viral genes carry the program for a commando raid. Usually when a virus infects a cell, its genes take over the control of a cell's machinery and transform "the cell into a virus-making factory that eventually explodes, spewing out thousands of new viruses. But occasionally a virus employs a different strategy. It does not kill the cell but transforms it into a cancer cell. Other scientists had determined that only one gene in the cancer-causing chicken virus was responsible for the malignant transformation. What was this gene? What was this single unit of information that could cause cancer?

Initially, Bishop and Varmus - along with everyone else - thought that it was a viral gene. But certain viruses have a curious ability to act as gene kidnappers. Viruses occasionally capture a gene from a cell of the organism they invade and carry that gene as a passenger alongside its own set of genes. Bishop and Varmus found that the crucial cancer-causing gene was one of these accidental passengers carried by the virus. The Bishop and Varmus lab then determined that the gene dwells peacefully in chicken cells, where it performs some normal, harmless function. But in the virus, the same gene exists in a slightly mutated form.

The only conclusion - and it was a monumental one - was that within the normal chicken cell is a gene that, at least under some conditions, has the potential to cause cancer. In this case, a virus triggers the gene's potential to cause cancer. But soon experiments would show that other factors could coax the gene to cause cancer. It turns out that the switch that transforms a cell from normal to cancerous is a class of genes given the name oncogenes. The potentially cancer-causing genes, called proto-oncogenes in their normal state, perform functions critical to normal cellular behavior. But when these normal genes mutate to become oncogenes, they cause the cell to grow out of control into a potentially life-threatening mass.

This discovery of oncogenes brought mind-boggling implications: cancer might be triggered by some outside agent, such as radiation or chemicals, that might damage the gene, but the critical change actually takes place within the cell. Occasionally a human or other animal inherits an oncogene in the mutated form that gives rise to cancer. But far more often the gene mutates in the cell of the adult. Thus all cancer is genetic even if it is not usually inherited. In fact, all the cells of the body carry their own potential to become cancerous. With this first discovery came the rudiments of an accurate, detailed description of cancer. Only by understanding the foe could scientists even hope to devise significantly better ways of attacking it.

© 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.