Barely visible to a sharp naked eye, the pond-dwellingprotozoan, Tetrahymena, has 20,000 chromosomes in itsgenome _ about 500 times more than H. sapiens. Giventhat each and every chromosome in both these forms ofeukaryotic life have two ends or tips, Tetrahymena's genecomplement contains 40,000 of these chromosomalextremities, called telomeres.
That is why, observes Calvin Harley, vice president ofresearch at the Geron Corp., of Menlo Park, Calif."Tetrahymena was the first organism in which telomerasewas discovered, about a decade ago."
Telomerase is the enzyme that adds repeat DNAsequences to the ends of growing fetal chromosomes, tocap and protect them from genetic damage during the celldivisions of prenatal development. Once born,mammalian telomerase shuts down, its job done, andchromosomes steadily shed the tip-ends of theirtelomeres, a few nucleotides at a time, for life. (SeeBioWorld Today, April 12, 1994 and Dec. 28, 1994, p.1.)
Only the reproductive tissues, testes and ovaries still needthe services of this rare enzyme, as their germlinechromosomes continue to replicate for producing spermand ova.
One other exception has made telomerase a hot researchand development property of academia and industry inrecent years: When somehow, a certain cell in the bodymutates to switch on the long-dormant DNA polymerasegene in its genome, that enzyme picks up where it left offafter being repressed since gestation, and starts those cellsto multiplying again, this time as immortal, malignant,tumors.
All major types of cancer cells studied by Geron andothers, Harley told BioWorld Today, notably breast,colon, prostate, lung and ovarian, have revealedtelomerase at work. "The evidence that we have now," hesaid, "is that telomerase is a critical component in thesequence of events leading to full cellular transformationand immortalization."
This still-conjectural scenario has opened up the newfield of anti-telomerase cancer therapy. "Most of the othermutational events characterized these past 25 years in themolecular genetics of cancer," Harley observed, "havebeen in the field of growth control and signaltransduction, which are common to mortal cells as well.
"That's the problem with drug discovery directed at thosetargets," he pointed out. "The cytokines, the growthfactors, the oncogenes that we currently know about arealso utilized in normal cells. But the telomeraseactivation, as far as we can tell, is a unique event causallyinvolved in immortalization."
In the quest for a telomerase-based therapeutic, Harleyregards Geron as a lonely long-distance front-runner. "Iam sure there are other companies trying to discoverinhibitors," he commented, "but none of the industrial oracademic labs has a direct drug-discovery program thatwe're aware of."
Telomerase works by clinging to the telomere andsynthesizing six-base repetitive sequences, TTAGGG,over and over again. These are the DNA units thatgradually fall away as a cell, and a body, age.
In today's Science, he and his associates report jumping amajor hurdle in this obstacle course to telomeraseinhibition. Their research paper describes how theycloned the RNA component of the human telomerasegene.
"This cloning," he said, "is a milestone that has allowedus to achieve proof of principle. In terms of the biologicalapplication," he continued, "the key experiment describedin the paper is the antisense expression of taking thetelomerase gene and reversing it. In vitro, we were able toinhibit enzyme activity, induce telomere loss andultimately, tumor death."
This does not mean that Geron intends to pursue anantisense approach to cancer treatment. "There are stillsignificant technical and human hurdles for that type oftherapy," Harley explained. "Therefore, our focus as acompany is to discover a small-molecule inhibitorthrough the efforts of screening and medicinal chemistry.
"We are making good progress," he added, "but it's verydifficult to predict how long it's going to be before we arein clinical trials, or have a compound for preclinicalstudies."
A partner in this endeavor is Japan's leading oncologycompany, Kyowa Hakko Kogyo Ltd., based in Tokyo.(See BioWorld Today, May 16, 1995, p. 1.) "With KyowaHakko," Harley said, "we have a drug discovery anddevelopment partnership. They are actively working withus on this project; not merely providing financialsupport."
Mice Weigh In As Potential Knockouts
Geron's closest academic ally is biochemist CarolGreider at the Cold Spring Harbor Laboratory in ColdSpring Harbor, N.Y. That institution's president is JamesWatson, a member of the company's scientific advisoryboard.
Greider, a co-discoverer of telomerase, is senior author ofa second paper in today's Science, titled: "Functionalcharacterization and developmental regulation of mousetelomerase RNA." It reports cloning the mouse DNAcomponent of the enzyme's RNA gene.
"That paper is an important research milestone," Harleysaid. "Mice have a very high frequency of cancer, sogenerating knockout mice without an RNA-componentgene will be very informative in later control of cancerdevelopment."
Nobel laureate Thomas Cech is a leading telomeraseresearcher at the University of Colorado's HowardHughes Medical Institute. Regarding Geron's latestresult, he told BioWorld Today:
"If your goal is to develop pharmaceuticals directedagainst a particular molecular species, you absolutelywant to have that molecule in your hands to study itsinteraction with drug candidates. Now one is in a positionwhere one of the telomerase gene subunits, the RNAsubunit, has been identified. This provides us anidentification of one of the components that can now beused as a fish-hook to try to pull out the protein subunits,and try to understand how, why, when and where thething works." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.