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Life Extension Magazine

LE Magazine January 1997

Geron Corporation Update

By John Hammell, Political Coordinator, Life Extension Foundation

As part of our PROJECT 2020 program to achieve total control over human aging by the year 2020, The Life Extension Foundation has contributed $136,000.00 to the Geron Corporation. Geron was the first company devoted substantially to age-related genetic research.

We've published several articles about Geron's research in Life Extension Magazine based upon our interpretation of the scientific literature and discussions with one of Geron's scientists. The following report, however, is based upon the company's own description of its research and proprietary technologies.

The Company

Geron is a biopharmaceutical company exclusively focused on discovering and developing therapeutic and diagnostic products based upon common biological mechanisms underlying cancer and other age-related diseases. As the pioneer in researching these mechanisms, the Company focuses on telomeres, which are structures at the ends of chromosomes that the Company has shown act as a molecular "clock" of cellular aging, and telomerase, an enzyme which appears to stop the "clock" and lead to cellular immortality.

Cellular Aging and Cellular Immortalization

Cells are the building blocks for all tissues in the human body. Cell division plays an important role in the normal growth, maintenance and repair of human tissue. However, cell division is a limited process in that cells generally divide only 60 to 100 times in the course of their normal lifespans. Once cells reach the end of their replicative capacity, they senesce. Cellular aging or senescence, although influenced by environmental factors, is a genetically determined process.

Geron and its collaborators have demonstrated that telomeres, the repeated sequence of DNA at the ends of each chromosome, are key genetic elements in this process. Telomeres are necessary to protect chromosomes from degradation and fusion. Each time a normal cell divides, however, telomeres shorten because cells are unable to replicate fully these repeated DNA sequences. Thus, Geron believes that telomeres serve as a molecular "clock" governing normal cell replication and lifespan. Geron has demonstrated that once telomeres reach a certain short length, cell division is halted, which is known as cell senescence. Although senescent cells have stopped dividing, these cells are still metabolically active and demonstrate an altered pattern of gene expression. Specifically, in senescent cells, some genes expressed by young and healthy cells are turned off and other genes are turned on, creating an imbalance of proteins and other cell products that has a direct and potentially destructive effect on the surrounding tissue. Geron believes that this cellular dysfunction, which occurs in numerous tissues throughout the body, causes or contributes to age-related diseases and conditions. The converse of cell senescence occurs in cancer cells. Normal cells have the potential to become cancerous if random mutations activate various oncogenes and deactivate tumor suppressor genes. With each mutation, pre-cancerous cells become increasingly aberrant and uncontrolled, and may begin to generate a tumor mass. The Company believes, however, that most cells which undergo such changes are eliminated when telomere shortening leads to either cell senescence or chromosomal instability and cell death. Geron and its collaborators' research indicates that for most cancerous tumors to attain life threatening size, or for cancer to metastasize throughout the body, cancer cells must become immortal, through activation of telomerase.

What Is Telomerase?

Telmerase
Figure 1


Telomerase is a complex germ line enzyme, composed of RNA and protein components, that maintains telomere length by replacing the DNA that is lost each time a cell divides. The result is that telomeres do not shorten and cell death is averted. (Fig. 1) Geron's research has shown that telomerase is abnormally reactivated in all of the major cancer types and that, conversely, it is not present in most normal cell types. Telomerase enables cancer cells to maintain telomere length, providing them with indefinite replicative capacity or cellular immortality.

Geron's Research Programs

Geron is applying its proprietary scientific platform to discover and develop novel therapeutics and diagnostics for cancer and other age-related diseases and conditions. In support of its programs, the Company employs advanced drug discovery technologies including proprietary assays, high-throughput screening, combinatorial chemistry, proprietary differential gene expression techniques, protein purification and gene sequencing.

Telomerase Inhibition and Detection

Geron seeks to develop a small molecule telomerase inhibitor, which, by blocking the activity of telomerase, will allow cancer cell telomeres to resume shortening, ultimately leading to cancer cell death. In addition, the Company seeks to develop telomerase as a marker for cancer diagnosis, prognosis, monitoring and screening.

Telomerase is not present in most normal cells and as a result these cells age through telomere shortening. In contrast, telomerase is abnormally active in cancer cells causing telomere length to be maintained, which in turn appears to confer immortality to cancer cells in malignant tumors.

Breast Tissue Research has shown that telomerase is present in all of the over 20 different cancer types that Geron and its collaborators have studied, including the ten most prevalent cancers of prostate, breast, lung, colon, bladder, uterus and ovary, along with lymphomas, melanomas and oral cancers. In all of these cancers, the majority of tumor samples contain telomerase. Because telomerase is present in all cancer types evaluated and is not biologically active in most normal cells, telomerase appears to be a universal and highly specific marker of cancer. These characteristics combine to make telomerase an attractive target for inhibition to treat cancer, and for detection to diagnose cancer.