Cancer Made to Order

By MICHAEL D. LEMONICK

Scientists have known for more than two decades that cancer is a disease of the genes. Something scrambles the Dna inside a nucleus, and suddenly, instead of dividing in a measured fashion, a cell begins to copy itself furiously. Unlike an ordinary cell, it never stops. But describing the process isn't the same as figuring it out. Cancer cells are so radically different from normal ones that it's almost impossible to untangle the sequence of events that made them that way. So for years researchers have been attacking the problem by taking normal cells and trying to determine what changes will turn them cancerous--always without success.

Until now. According to a report in the current issue of Nature, a team of scientists based at M.I.T.'s Whitehead Institute for Biomedical Research has finally managed to make human cells malignant--a feat they accomplished with two different cell types by inserting just three altered genes into their DNA. While these manipulations were done only in lab dishes and won't lead to any immediate treatment, they appear to be a crucial step in understanding the disease. This is a "landmark paper," wrote Jonathan Weitzman and Moshe Yaniv of the Pasteur Institute in Paris, in an accompanying commentary.

The dramatic new result traces back to a breakthrough in 1983, when the Whitehead's Robert Weinberg and colleagues showed that mouse cells would become cancerous when spiked with two altered genes. But when they tried such alterations on human cells, they didn't work. Since then, scientists have learned that mouse cells differ from human cells in an important respect: they have higher levels of an enzyme called telomerase. That enzyme keeps caplike structures called telomeres on the ends of chromosomes from getting shorter with each round of cell division. Such shortening is part of a cell's aging process, and since cancer cells keep dividing forever, the Whitehead group reasoned that making human cells more mouselike might also make them cancerous.

The strategy worked. The scientists took connective-tissue and kidney cells and introduced three mutated genes--one that makes cells divide rapidly; another that disables two substances meant to rein in excessive division; and a third that promotes the production of telomerase, which made the cells essentially immortal. They'd created a tumor in a test tube. "Some people believed that telomerase wasn't that important," says the Whitehead's William Hahn, the study's lead author. "This allows us to say with some certainty that it is."

Understanding cancer cells in the lab isn't the same as understanding how it behaves in a living body, of course. But by teasing out the key differences between normal and malignant cells, doctors may someday be able to design tests to pick up cancer in its earliest stages. The finding could also lead to drugs tailored to attack specific types of cancer, thereby lessening our dependence on tissue-destroying chemotherapy and radiation. Beyond that, the Whitehead research suggests that this stubbornly complex disease may have a simple origin, and the identification of that origin may turn out to be the most important step of all.

--Reported by Richard Diaz/New York

With reporting by Richard Diaz/New York