Cell Agent May Help To Treat Liver Illness

A possible new approach to treating cirrhosis of the liver, the seventh leading cause of death in the world, has emerged from studies of telomerase, a recently discovered agent that indefinitely prolongs the life of human cells grown in the laboratory.

So far the treatment has worked only in mice that have artificially been given cirrhosis. If it works in people, too, it would offer a new way of tackling a major, intractable disease, as well as of averting liver cancer, the leading cause of cancer cases worldwide, 80 percent of which originate from liver cirrhosis.

The research is the work of Dr. Ronald DePinho, a mouse geneticist at the Dana-Farber Cancer Institute, and colleagues, and is reported in Friday's issue of Science.

Cirrhosis is the scarring of the liver that results when toxins like alcohol or hepatitis viruses B and C kill liver cells and exhaust the organ's usual capacity to regenerate itself. The scarring blocks blood flow and the liver's ability to function properly, leading to symptoms that can be postponed but not reversed.

The mechanism by which the various liver toxins cause cirrhosis is unknown, but Japanese scientists recently noticed that liver cells from cirrhosis patients had an anomaly in their chromosomes, the giant DNA molecules in which the cell's programming instructions are encoded. The end sections of the chromosomes, known as the telomeres, were unusually short. Each time a cell divides, its telomeres get shorter, as if counting off some permissible number of divisions, until at a certain minimum telomere length the cell is thrown into crisis and dies.

Telomeres are kept long in egg and sperm cells by the enzyme telomerase. But the telomerase gene is suppressed in most normal cells, and as people age, their telomeres decrease.

Scientists supported by Geron Corp. of Menlo Park, California, discovered recently that human cells grown in glassware could be made to divide indefinitely - becoming in principle immortal - if given an active copy of the telomerase gene that builds their telomeres back to youthful length.

Telomeres in general do not seem to place a limit on the human life span. Their purpose seems to be as a last-ditch defense against tumors, zapping malignant cells after they have reached their quotas of divisions.

But some biologists believe short telomeres may be a drawback in diseases where a cell type is forced to divide unusually often. When DePinho heard of the Japanese finding of short telomeres in cirrhosis, he decided to test the idea in mice by seeing if insertion of the telomerase gene into liver cells could stop the development of cirrhosis.

Mice have very long telomeres, so to obtain animals with telomeres as short as those of elderly people, he took a strain that lacked the telomerase gene and bred the mice through several generations.

Cirrhosis was induced in the short-telomere mice by injecting them with a liver-poisoning chemical. In addition, one group of mice was injected with a virus carrying a copy of the mouse telomerase gene. In these mice, development of cirrhosis was blocked, presumably because the telomerase rescued certain short-telomere cells from crisis, enabling them to regenerate the liver.

DePinho and colleagues conclude, "It is reasonable to anticipate that activation of telomerase could inhibit the development of liver cirrhosis or terminal liver failure in humans."

If the telomere-shortening system protects against cancer, an artificial lengthening of the telomeres might raise a cancer risk. In their article, the authors suggest the telomerase treatment could be tested in patients awaiting a liver transplant, since the liver was due for removal anyway.