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A 25-YEAR TREK TOWARD A CURE

THE BALTIMORE SUN

Discoveries by Nobel laureate Carol W. Greider and her colleagues have led to advances toward potential cures or treatments for certain types of cancer, and for a growing list of diseases rooted in malfunctions of the DNA-protecting enzyme, called telomerase, that she discovered.

In cancer, the overproduction of telomerase enables tumor cells to maintain unchecked reproduction, and researchers are trying to inhibit the telomerase as a way to shut down the tumor and allow it to die. One experiment involves a potential vaccine to battle runaway cell division in metastatic breast cancer.

Other disorders appear to be caused by underproduction of telomerase. For example, Greider and colleagues at the Johns Hopkins University have developed a mouse model for a rare and fatal inherited disorder called dyskeratosis congenita. Victims cannot maintain production of stem cells in bone marrow because of a shortage of telomerase.

"There are various strategies related to telomerase in clinical trials now," said Jeremy Berg, director of the National Institute of General Medicine, part of the National Institutes of Health. "It's a novel approach, and in principle it should have beneficial effects. But until you do studies in humans, you never know how it's going to turn out."

None of these hopeful implications for human health could have been predicted 25 years ago when Greider discovered telomerase while working as a graduate student in the lab of Elizabeth Blackburn, then at the University of California, Berkeley. She was studying chromosomes, which carry the strands of DNA that hold the instructions for human cell development.

"We were just curious to know how it is that the chromosomes can be maintained, when we knew [they] should shorten over time. We didn't know at the time there were any particular disease implications," Greider, 48, said Monday.

She spoke at Johns Hopkins Hospital, where she is director of molecular biology and genetics at the Institute for Basic Biomedical Sciences. She shares her Nobel Prize with Blackburn, now of the University of California, San Francisco, and Jack Szostak of Harvard Medical School.

By 1984, Blackburn and Szostak had already demonstrated that simple, repeated DNA sequences - which they dubbed telomeres - made up the ends of the chromosomes, stabilizing them from damage during cell division.

They had also predicted that some sort of enzyme must be working to replenish the DNA sequences at the ends of those telomeres to prevent damage to the genetic coding further up the DNA strands. This protective role of telomeres has often been likened to the plastic tips on shoelaces that keep them from unraveling.

Greider was assigned by Blackburn to track down, purify and describe the enzyme. On Christmas Day 1984, she found it, in the cells of a pond-dwelling microorganism called Tetrahymena. The enzyme was named telomerase (ta-LAW-mer-ace).

That was an important advance in fundamental biology. But it wasn't until around 1990 that scientists made a connection between telomerase and cancer, Berg said.

Cancer cells reproduce more frequently than normal cells, leading to uncontrolled growth of tumors and other abnormal tissue. To maintain high rates of cell division, tumors need to manufacture high levels of telomerase to prevent the degeneration and cell death that befalls slower-growing normal cells as they age and divide.

"The realization that cancer cells are dependent on telomerase to grow as rapidly as they do suggested a strategy targeting telomerase in cancer cells as a cancer treatment," Berg said. If telomerase production could be inhibited in tumor cells, perhaps they would age and die.

The challenge, Greider said Monday, is to inhibit the telomerase in a way that kills cancer cells without harming normal cells.

Happily, Greider said, mouse models of a form of lymphoma do indeed show that the cancer cells starved of telomerase wear out their telomeres and die before healthy cells - with much longer telomeres - are damaged.

At the University of Pennsylvania, Dr. Robert H. Vonderheide has reported some preliminary success with a "telomerase vaccine."

The experimental vaccine is designed to prompt the body's own immune system to attack telomerase in patients with metastatic breast cancer. The vaccine led to "widespread" cell death in the tumors, Vonderheide has reported.

With other diseases, scientists need to find ways to encourage telomerase production to maintain the replenishment of healthy cells.

At Hopkins, researcher Mary Armanios, an assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center, and her colleagues had already identified the genetic cause of an inherited disease that causes fatal scarring of the lungs, killing about 20,000 people each year. Lung transplants are the only cure for the disease, called idiopathic pulmonary fibrosis.

But some patients became sick despite having no family history of the illness. Investigating the telomeres in the blood and lung tissue of those patients, Armanios and her team discovered last year that almost all of them had shortened telomeres compared with healthy people.

Armanios has said the findings are a major advance in understanding a disease once thought to be an immune system disorder. "We may now begin to think about using drugs that prevent telomere shortening and stop cells from dying."

And this may just be the beginning, said Chi Van Dang, vice dean of research at the Hopkins School of Medicine.

Biotech companies are eager to develop and market drugs to control telomerase production. Future research, he said, is turning to revealing how healthy cells regulate telomerase production, preventing overproduction that allows cancer cells to survive and grow; or underproduction that stops the body from renewing healthy cells, accelerating the aging process.

Slowing down, or at least improving, the aging process has always been an intriguing possibility in the field.

For Greider, the future of this field looks bright.

"I think [the disease processes illuminated so far] may be the tip of the iceberg," she said. "Maybe there are other degenerative diseases associated with aging in which telomerase may play a role. This is a very, very hot area of research right now."

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