By David N. Leff

Many cells in the bodies of many people are caught between the rock of cancer and the hard place of old age.

A 10-year journey has yielded the riches of discovery that will add to researchers' armamentariums in fighting the disease of aging and cancer: a long-sought gene for cell aging has been cloned.

One ubiquitous but seldom-seen enzyme, telomerase, is responsible for both the immortal proliferation of tumor cells and the senescence of cells in the elderly. In malignancy, telomerase acts by its unintended reappearance and reactivation; in senescence by its unwelcome absence.

Both extremes have in the last decade made telomerase the target of drug discovery — seeking a new take on cancer chemotherapy and new vistas for treating the degenerative diseases of superannuation. (See BioWorld Today, Sept. 1, 1995, p. 1.)

Telomerase stage-manages the reproduction of every cell in the fast-growing fetus. It does so by capping both ends of all the chromosomes in the cells' nuclei with layers of short DNA repeat sequences. These tips protect the chromosomes from damage and unintended fusion. But they do so at a price.

Once born, the neonatal infant is on its own. Telomerase retires from the scene, leaving the capped chromosomes to fend for themselves. As the months and years of life go by, each time a cell divides, one more protective layer drops off, shortening the chromosome's tip-ends — and the lifespan of the cell. By the time old age advances, the chromosome is virtually stripped bare of its telomeric caps; the cell stops dividing and changes its character for the worse.

The main exception to this rule is the continued activity of telomerase in the cells of the male reproductive system. Thus, the enzyme enables spermatozoa to arise and multiply, by maintaining their chromosomal ends, the telomeres, at full length. This immortalization of those germline cells allows the human species to perpetuate itself.

Ova are exempt from this telomerase attention because the enzyme has completed capping the chromosomal complement of eggs prior to the birth of the fetus.

Today's Science, dated Aug. 15, 1997, marks a giant step forward, in announcing cloning of the gene for the human telomerase catalytic protein, and how it may be deployed against cancer and diseases of aging.

The journal carries a paper by Nobelist Thomas Cech, of the University of Colorado, Boulder, and his colleagues titled: "Telomerase catalytic subunit homologs from fission yeast and humans."

"For 10 years," Cech told BioWorld Today, "everyone has been looking for the human component of the telomerase gene. In terms of pharmaceutical development, or diagnosis, the molecular nature of its catalytic subunit was completely unknown until now."

He continued: "This discovery is an important step toward critically testing the idea that telomerase inhibition will have an effect on tumor cells."

That idea is particularly critical to Geron Corp., of Menlo Park, Calif., which focuses on cancer and diseases of aging. Its scientists are among the Science paper's co-authors. Cech, a close scientific collaborator of the company, did the basic genomic work that led to pinpointing the human gene for the telomerase catalytic subunit to the short arm of chromosome 5.

Shaking Eukaryotic Family Tree Yields Human Gene

Cech's homology approach to gene-finding began with a minute, fraction-of-a-millimeter-long, ciliated protozoan called Euplotes aediculatus, a favorite eukaryotic model for telomere researchers.

"The rationale for using that organism," he continued, "is that it has about 80 million telomeres per nucleus, which is roughly 1 million-fold more than in a human nucleus. So that gave us a huge increase in all of the components that deal with telomeres. The reason is that it has incredibly small chromosomes; each one contains a single gene.

"It was our work on the Euplotes enzyme," Cech recalled, "that led directly to the human enzyme.

"It took Joachim Lingner, then my postdoc, three years to purify, sequence and clone the gene for the Euplotes enzyme," he continued. "And then it took a few minutes to leapfrog from that to yeast cells and on to the human, using the computer and the Human Genome Project."

Geron's president and CEO, Ron Eastman, picked up the story: "With Cech's discoveries, we could then leap to the human sequence of the enzyme.

"Through the homology approach," he told BioWorld Today, "we identified in a database an expressed sequence tag [EST] that matched pretty closely the sequences that Cech had identified in the lesser organisms. In fact, it turned out to be the basis for the full sequence of the human catalytic protein component of telomerase, which we accomplished earlier this year."

Armed with this new knowledge, Geron is confronting the yin-and-yang questions: How to turn off the wild-card telomerase gene in immortalized tumor cells? How to reactivate the gene from its lifelong dormancy in order to postpone the onset of senescence in cells that are losing all their telomere DNA caps?

"It's now very clear," Eastman observed, "that telomerase, using antibodies to the enzyme, is almost an ideal marker for cancer diagnostics — which includes prognosis, monitoring and screening. And now," he added, "we have for the first time an opportunity to use this protein component for doing rational anticancer drug design." Telomerase shows up in at least 85 percent of all human tumors studied to date.

The company already has two diagnostic kits in pre-commercial use, licensed to researchers only. One measures the level of telomerase activity in cells; the other, telomere length. Once these kits have been automated and optimized, Eastman said, the company will apply to the FDA for clinical trials.

Depriving Tumor Cells Of Life Everlasting

The next antitumor step will be development of telomerase-inhibiting drugs. On this score, Eastman made several points: "We were the first to identify and patent the human RNA component, the first to patent screens for drug discovery, the first to identify and patent this human catalytic protein. So we would expect to be first on the market with an anti-cancer telomerase inhibitor."

The second sizable market would be resurrecting the telomerase gene to restore capping DNA layers to aging chromosomes. Here, the company sees as one logical target "the area of organ transplantation, where you extract and reintroduce cells. The transient reactivation of telomerase ex vivo," Eastman pointed out, "has the potential to increase the replicative life span of these donor cells, thereby increasing the efficacy of the transplant."

In geriatric medicine, he went on, "there's very strong evidence that cellular senescence, the aging of cells in the absence of telomerase, is playing a causative role. Besides skin atrophy, macular degeneration, osteoporosis and atherosclerosis," the Geron executive pointed to neurodegenerative diseases. "While it's not widely known," he observed, "senescence does appear to occur in cells, in tissues, implicated in these diseases — like astrocytes in Alzheimer's disease and neurons in Parkinson's. These, in fact, are therapeutic areas that Geron is targeting." *