Telomerase, Cancer, and Aging So Many Promises to Keep by Jane Salodof MacNeil
Posted January 19, 2001 · Issue 94

Abstract

The research surrounding telomerase is tantalizing: this enzyme might be able to stop aging and cure cancer along with a host of other diseases. But it's a long leap from basic research to clinical applicability, and telomerase's high profile in so many cellular settings may make it more difficult to harness as a cure-all.

"I just found out about Telomerase today. I would like to try it. I'm in Nashville, TN. Where can I get it??"
                                                                        - from an online message board

Looking for a cure for cancer, Alzheimer's disease, muscular dystrophy, aging skin, cirrhosis of the liver, immune disorders such as AIDS, diabetes, macular degeneration, stroke . . . ? Try telomerase. A bit like the Woody Allen character Zelig, the enzyme seems to turn up these days wherever the human body has a disorder that scientists hope to prevent or cure.

Telomerase is often compared to the fountain of youth in news reports about its potential for averting the ills of old age by enabling cells to thrive beyond their scheduled time to die. The metaphor shifts, however, to gasoline in a car engine when scientists try to explain why telomerase is active in 85 to 90 percent of human cancers. Refreshing spring, lethal fuel - the images swing back and forth as teams of investigators explore ways to exploit telomerase that are often at cross-purposes.

For all the excitement, most telomerase work is still basic science in test tubes and mouse models. While components have been cloned, the entire telomerase complex has yet to be purified or crystallized. Likewise, while researchers can detect telomerase activity in human cells and are using it as a tumor marker, the U.S. Food and Drug Administration has approved assays only for research purposes. A FDA spokesman says they are in the early stages of evaluation for clinical use, a process that can take years.

What makes telomerase, a reverse transcriptase, so attractive is its power over telomeres, the repeated DNA sequences at the ends of chromosomes that shield vital genetic information from damage during cell division. Each time a normal cell splits, its telomeres become shorter until they become so short that the cell can't divide. This point, senescence, is usually followed by the death of the cell.

In 1998, Jerry W. Shay of the University of Texas Southwestern Medical Center in Dallas, Calvin B. Harley of Geron Corporation, and their colleagues used telomerase to extend telomeres, keeping cells alive past senescence. By making normal cells immortal, they supported a 30-year-old hypothesis that telomeres are a biological clock for counting down cell divisions to senescence and cell death. By stopping the clock, they raised the possibility of reversing the aging process in cells - a prospect that some have misinterpreted as eternal life for the organism.

Cancer researchers had already been studying telomerase, but they approached the enzyme from the position that immortality is not desirable: that the problem with cancer cells is that they will not die. Robert Weinberg of the Whitehead Institute for Biomedical Research has cloned the telomerase protein subunit TERT in human cells and established that telomerase activation is a critical step in tumor progression. He has used TERT to turn normal cells into cancer cells in a dramatic experiment that also provides science with a new tool for future investigations.

Weinberg cautions that telomerase is not the only step - it does not cause cancer by itself - and that scientists have a lot to learn about telomerase. Knowing that "myc upregulates telomerase and p53 downregulates it" is not enough, he says, to figure out a coherent scheme of the biological mechanisms behind telomerase.

Another mystery to be worked out is how some cancers are able to develop in the absence of telomerase. For example, Kathleen Collins of the University of California at Berkeley found that patients with a rare congenital disease, dyskeratosis congenita (DKC), have low telomerase levels. Yet they often die of skin and gastrointestinal cancers.

Testing cells for telomerase will likely be the first application to make it from the lab to clinical use. Numerous studies have shown that telomerase levels often correlate with the aggressiveness of tumors and the effectiveness of treatments. High levels suggest that a tumor will be harder to treat or that some cancer cells have survived treatment.

The United States has authorized telomerase testing in two clinical trials, one seeking better ways of diagnosing cervical cancer, the other evaluating a drug for myelogenous leukemia. In Japan, according to Shay, it is being used for children with 4S neuroblastoma. "These kids have metastatic disease, but their tumors are telomerase negative, and close to 80 percent of them go into spontaneous remission upon surgery for tumor burden reduction," he explains. "The issue is to identify the 20 percent that have telomerase, so they can be treated more aggressively."

Another hot area is development of a universal cancer vaccine, an old idea that has eluded immunologists for years. In principle, such a vaccine would not prevent cancer. It would cure it by training the patient's immune system to recognize and attack an antigen that is on the surface of tumor cells but not normal cells.

Teams led by Robert Vonderheide at the Dana Farber Cancer Institute and Maurizio Zanetti at the University of California at San Diego, have identified peptides on the surface of telomerase that could be that antigen. Although working separately, both scientists say telomerase could make an ideal vaccine target because it is active in most tumors but silent in normal cells. Another group led by Eli Gilboa at Duke University Medical Center is working on a vaccine that would make TERT the target. Cancer researchers have also made progress in identifying substances that can inhibit telomerase.

What would happen if cells had no telomerase? Ronald DePinho of Dana Farber knocked out telomerase genes in mice that he observed through six generations. Each successive generation had shorter telomeres. By the third generation, the mice had more symptoms of aging - for example, gray hair, baldness, and poor wound healing - that became progressively worse in succeeding generations. To the researcher's surprise, some mice also developed cancer.

In a later experiment, DePinho raised mice with telomeres so short that their cells were senescing. Atypically, these mice developed cancers that people get in old age - cancers that start in the high-turnover epithelial cells that line the breast and colon, for example.

DePinho speculates that the elderly may be more vulnerable to cancer and other conditions because cells with shortened telomeres cannot respond well to stress. He proposes that telomerase therapy could help patients with age-related disorders that occur when people have a limited reserve of proliferating cells and with diseases marked by chronic high turnover of cells, such as cirrhosis.

Similarly, Shay proposes that tissue engineering "could be important for kids with muscular dystrophy, patients with late-onset blindness, macular degeneration, wound healing for bedsores or for diabetic ulcers that do not heal, and rejuvenating pancreatic islet cells, just to name a few areas." He suggests that in the future physicians may be able to remove a patient's cells, rejuvenate them with telomerase so that they are not at the end of their life span, and return them to the patient in a cell-based therapy.

At the National Institute on Aging, laboratory of neurosciences chief Mark Mattson hopes to use telomerase expression to prevent the death of nerve cells in Alzheimer's and Parkinson's diseases, and in ALS and in stroke. He has shown that telomerase makes cultured nerve cells more resistant to amyloid peptides and oxidative attack. Now he is inducing telomerase expression in the brains of adult mice that he will be subjecting to toxins known to kill brain cells.

Nerve cells are postmitotic and cannot divide, so Mattson is not concerned about their becoming cancerous. Nonetheless, he says, one must be careful to stimulate telomerase production only in nerve cells and not in glial cells. Glial cells are mitotic, and keeping them alive could cause brain tumors.

Ultimately, the danger of a telomerase-based therapy being a prescription for cancer is a major concern. Yet not even skeptics rule out the possibility that telomerase might be used to rejuvenate cells whose aging and death cause disease.

Gregory Hannon of Cold Spring Harbor Laboratory published a paper in Nature in June 2000 that raised red flags about the enzyme's association with the c-myc oncogene. Hannon says he and his coauthors wrote it in response to excitement about making telomerase-engineered cells for use as therapeutic tools. "We're not saying you can't do this - we're saying we have to do a lot more [research]," he says.

Similarly, Weinberg says he would be "wary" about any therapy that puts cells immortalized by telomerase into a human body. Nonetheless, he can envision disease situations where saving a patient's life would in the short run outweigh the added risk for cancer developing in the long run. "It's the same as radiotherapy to reduce a tumor," Weinberg says. "Radiation is inherently carcinogenic, but you take the risk."

But first, Shay and the army of telomerase enthusiasts will have to prove that the enzyme really can make a difference in age-related diseases. "The role of telomere shortening in the aging process remains a matter of speculation and sadly nothing more than that," says Weinberg. "Would we really live longer if we had longer telomeres? As yet, there's no evidence of that."

Jane Salodof MacNeil is a freelance editor and writer. She frequently writes about health and medicine for Oncology News International, CBS HealthWatch, and other media.

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Endlinks

Shay/Wright Laboratory - the site's basic introduction to telomeres and related links includes a frequently asked questions page.

Don't Die, Stay Pretty - discusses the prospects for increasing human longevity. From the January 2000 issue of Wired.

TelDB - the GeneLink Multimedia Telomere Resource. Includes literature and protein databases (both are current only through 1999) and a forum for researchers.

Aging Research Center - a resource for aging-related research news, including meetings, publications, industry information, and more.

UCSD Team Demonstrates Potential for Widely Effective Cancer Vaccine - a press release describing Maurizio Zanetti's work with anti-telomerase cancer vaccines.

Related HMS Beagle Articles:

• Our Aging Genes - a review of the FASEB Summer Research Conference on Molecular Gerontology.
• Transforming Transplants - describes the merger between Geron and Roslin Bio-Med.

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