Originally created 05/14/98

Scientists study genes linked to aging, cancer



Telomeres, the small bits of genetic material that anchor the ends of chromosomes, are a hot topic in biomedical research, because they seem to be key players in two important processes, aging and cancer.

Now, scientists in New York City and Maryland are using gene-splicing techniques in laboratory mice to eliminate an enzyme that keeps those anchors intact in cancer. In doing so, they hope to gain insight into how telomeres work and what can go haywire.

The aging process that affects human cells is akin to erosion, experts say: Every time a cell divides, a tiny DNA fragment is lopped off each telomere, making it shorter and shorter. Once the telomeres get too short, the chromosomes -- which carry our genes -- become unstable, eventually committing suicide.

In cancer, though, the opposite occurs. Scientists say the telomeres in 90 percent of cancer cells do not shorten. By genetic trickery, the cancer cell activates a gene that makes the enzyme telomerase, which replaces the tiny bits of DNA normally lopped off during cell division. This subverts the cell's suicide system, allowing uncontrolled cell growth -- cancer -- to occur.

But telomerase has a positive role, as well, experts say. It helps keep a small number of special cells alive, the so-called germ cells that produce the sperm and eggs that give rise to the next generation. The telomeres in germ cells must remain long so each new infant begins life with full-length telomeres.

To study the process, scientists are shutting down the enzyme system in mice to determine the effects on both cancer cells and germ cells. Does loss of the enzyme, telomerase, do any harm, either in the present generation or in generations to come?

Using the gene-splicing technique, biologists Ron DePinho and Carol Greider created laboratory mice that are unable to make telomerase, even in stem cells, which are immature disease-fighting cells of the immune system.

DePinho, at the Albert Einstein College of Medicine in the Bronx, and Greider, at Johns Hopkins University in Baltimore, recently reported in the science journal Nature that the first through fifth generations of mice seemed normal, even though their telomeres were shorter.

But problems occurred in the sixth generation: Males became infertile and their blood-forming systems began showing signs of failure.

Additionally, all of the sixth-generation mice exhibited chaotic disruption of their chromosomes, with some of their cells committing suicide. This was especially true for cells that need to divide a lot, such as the blood-forming cells in bone marrow.

Although the results took some time to show up, DePinho said the research "substantiates that genetic chaos ensues in successive generations of telomerase-deficient mice. "

Even so, he added, enough blood-forming cells were left functioning for the mice to survive over a normal life span. The telomere-deficient cells were "very well compensated for, in that the animals are not anemic, and they can fight infection," DePinho said.

In the reproductive cells, however, the damage from lack of telomerase becomes severe enough to make it unlikely a seventh generation will exist.

"We see a more marked impact in males than in females," DePinho said. "There is an absence of sperm. In the females we see decreased oocyte (egg) numbers, and decreased function of the reproductive tracts," meaning that endometrial tissue lining the uterus shows signs of failing.

So by the sixth generation, "we've reached the point where the germ cells are so depleted that they cannot produce offspring," DePinho said.

Although the research doesn't yet explain the role of telomeres and telomerase in cancer, and suggests a very complex process is involved in aging, it does show that telomeres are vital for normal life.

Distributed by the Los Angeles Times-Washington Post News Service