July 29, 1999

In Finding a Way to Create Cancer, Hope for New Test

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By GINA KOLATA

Using a precise molecular recipe, scientists have succeeded in turning normal human cells into cancer cells in the laboratory, a task that sounded simple but which eluded molecular biologists for more than 15 years.

In the end, what was required was just three genes. One pushed cells to grow unrelentingly, one inactivated signals for cells to stop growing and the third released a brake on the cells' life span.

A report on the work, by Dr. Robert A. Weinberg and his colleagues at the Whitehead Institute for Biomedical Research in Cambridge, Mass., appears Thursday in the journal Nature. It is accompanied by a commentary by Dr. Jonathan B. Weitzman and Dr. Moshe Yaniv of the Institut Pasteur in Paris, which calls it a "landmark paper."

While the researchers said the discovery will not lead immediately to a new treatment or cure for human cancer, they said they believe it may one day allow them to determine the blueprints for turning healthy cells into tumors.

"Right now the biology of a human cancer cell is a black box," Weinberg said.

Naturally occurring tumor cells are so deranged and vary so much from patient to patient that it is hard for scientists to understand which genetic changes are important.

When looking at the end product, a cancer cell, it is all but impossible to untangle the genetic steps that made it that way, Weinberg said.

But by working with cancer cells whose genetic changes are well defined, scientists can begin to ask questions about genes they find in tumors that they remove from patients, allowing them to add genes and take them away to learn what the genes do. "We can ask, 'What are the rules?"' Weinberg said.

The current discovery has its origins in another seminal paper, also published by Weinberg. In 1983, he reported that the addition of just two mutated genes which had been isolated from cancer cells can turn normal rat cells into cancer cells in the laboratory.

Dr. William C. Hahn, a postdoctoral student in Weinberg's lab, remembers the excitement. "It said that cancer was a molecular event," Hahn recalled. Everyone assumed that human cells would be next. But to scientists' surprise, when they did the same experiment with human cells it never worked.

Dr. Ronald DePinho, a professor at Harvard Medical School and the Dana Farber Cancer Institute, said that many molecular biologists took up the challenge.

"For many years many investigators have labored very intensively to get those cells to jump through the appropriate genetic hoops to form a tumor," he said. "They've thrown the book at these cells and have been horribly unsuccessful."

Scientists were troubled. They use rodents routinely to study cancer. They test hypotheses and treatments in rodents and apply them to human cancer. Why, then, were they able to make normal rodent cells become cancerous but unable to do the same with human cells?

The next advance came from a different direction -- the discovery of a gene for an enzyme, telomerase, that cells use to put caps on the ends of chromosomes. "They are like the caps on the end of shoelaces," Hahn explained. "They protect the ends of the chromosomes from damage."

In humans, telomerase is abundant during embryonic and fetal development, but there is significantly less of the enzyme when cells mature -- except in most human cancer cells, where it is once again plentiful.

Scientists discovered that if they added telomerase to adult human cells growing in the laboratory, the cells would divide for extended periods of time, living much longer than their normal life span, although they would not turn into cancer cells.

They also learned of a crucial difference between mice and humans: In mice, telomerase is present at high levels in adult cells as well as in fetal cells. Perhaps, Weinberg and his colleagues reasoned, if they added telomerase to normal human cells they could then add cancer genes and create human cancer cells in the laboratory.

The experiment worked. They gave the cells two cancer genes: ras, which pushes cells to grow unrelentingly, and a gene that codes for the "large-T oncoprotein," which prevents cells from responding to cellular signals to stop growing. Then they added telomerase.

All three elements were needed. When they were present, the cells grew and looked like cancer cells. More important, they formed tumors when they were transplanted onto mice -- a standard test to see if cells are cancerous.

Dr. John D. Minna, the director of the Hamon Center for Therapeutic Oncology Research at the University of Texas Southwestern Medical Center in Dallas, said he was struck by the fact that the cancer genes apparently could not act alone but needed telomerase to change a normal cell into a cancerous one.

That means, he said, that by looking for telomerase, it might be possible to decide when a benign mass of cells is about to turn cancerous, aiding in the early detection of cancer.

In the past, Minna said, he had considered using telomerase as an early marker for cancer, but had put the idea on hold. "This brings it to the front burner," he said.