Nine months before we are born, we begin to die.
Unless precipitated by accident or disease, death "from naturalcauses" _ i.e., old age _ is determined from conception on forevery cell of every human body, except sperm and ova. Like aticking time bomb, each normal somatic cell division after birthbrings a body one tick closer to the built-in end of life, somewherearound 100 years of age.
Each tick shortens the long fuses leading to the bomb's detonator.Those fuses are, in fact, the twin tips of the 46 chromosomes in thenucleus of every non-reproductive human cell. Cytogeneticists callthese terminal-capping stretches of DNA "telomeres," meaning "farfrom the chromosome's centromere," or mid-section.
To switch metaphors, these telomeres can be pictured as the plasticor metal tips on the ends of shoelaces. At birth, these nucleoproteinstructures measure about one one-hundredth of 1 percent of achromosome's total genomic length. They consist mainly ofhundreds to thousands of six tandem-repeating DNA base pairs _TTAGGG.
A fertilized egg starts gestation with some 15,000 of the six-base-pair tandem repeats. By birth, a newborn's telomeres are down to10,000.
Every time a cell divides, and divvies up its chromosomes betweentwo daughter cells, it sheds 50 to 200 DNA base pairs off everytelomere's terminal cap. When this pruning repeats between 50 and100 times, that cell reaches the end of its string _ the Hayflicknumber _ and senesces. When enough senescent cells accumulateover a normal life span, the individual begins to die of diseasesassociated with old age.
Common Denominator For Cancer
Such, at any rate, is the scenario of senescence proposed bymolecular cell biologist Calvin Harley, vice-president of research atGeron Corp., in Menlo Park, Calif. The flip side of this hypothesis iskey to the anti-cancer action program he and his company arepursuing.
Cancer happens when a cell escapes its Hayflick limit and becomesimmortal. It and its malignant progeny multiply indefinitely, thanksto the enzyme that synthesized the telomere's terminal repeat DNAsequences at conception. This embryonic polymerase, aptly calledtelomerase, immortalizes tumor cells by constantly replenishing thefull length of their telomeres.
Telomerase is a germline enzyme, normally dedicated toimmortalizing reproductive cells that produce sperm and ova, thusensuring the perpetuation of the species, and the individual's DNAheritage. Its gene complex has not yet been completely cloned.Geron recently announced that it has cloned the RNA component ofthe telomerase gene network.
Geron's long-range goal is to find or fabricate compounds that willblock telomerase selectively in tumors, and return their immortalityreplicating cells to mortality. While screening for such inhibitors, thecompany, jointly with academic comprehensive cancer centers in theU.S. and Canada, is testing its hypothesis on human malignancies,and refining its assay for measuring the presumed effect oftelomerase on tumors.
Last Friday's Science, dated Dec. 23, carries the latest resultsreported by Harley and his collaborators at Geron and the Universityof Texas Southwestern Medical Center at Dallas, in achieving thesetwo goals. Its title: "Specific association of human telomeraseactivity with immortal cells and cancer."
These results, Harley told BioWorld Today, "confirm and extend ourearlier studies this year suggesting that telomerase might be aspecific and universal marker for cancer, with potential as a targetfor anti-tumor diagnostics and therapeutics." (See BioWorld Today,April 12, 1994, p. 1.)
He and his co-authors found telomerase to be active in 90 of 101fresh, malignant tumor samples from 12 human types of cancer,Science reports, and in 98 of 100 cultured tumor cell lines. They alsodiscovered the enzyme, as predicted, in germline tissue from non-cancerous ovaries and testes.
By the converse token, telomerase was duly absent in 100 percent of22 healthy somatic cell cultures, as well as in all 50 of 50 non-malignant biopsies from 18 different human tissue types.
"Telomerase appears to be stringently repressed in normal humansomatic tissues," Harley stated, "but is reactivated in cancer, givingmalignant cells an infinite capacity to replicate."
Candidate blocking compounds mentioned by Geron in a pendingpatent application include antisense molecules and ribozymes, aswell as prototype small-molecule inhibitors.
Because telomerase is active only in immortal cells (malignant orreproductive), Harley predicts that drugs that block its effects wouldhave minor side effects, if any, in healthy somatic cells.
Geron calls its new assay TRAP, for Telomeric Repeat AmplificationProtocol. As reported in Science, this polymerase chain reactionassay provides a 10,000-fold increase over Geron's previous methodin detecting telomerase activity. It can detect one immortal (i.e.,cancer) cell in 1,000.
Telomerase Blocker's Effect On Reproductive Cells
"Telomerase must be present in germline cells," Harley explained,"in order to maintain the integrity of the genome betweengenerations. So, in essence, a person's germline doesn't age. Ouroffspring are born with their full-length chromosomes. But our bodycells," he went on, "don't need to be passed on from generation togeneration, and they have to turn off telomerase as part of thegenetically determined cell-senescence mechanism."
He cited evidence that "for long-lived animals, such as humans,there's a very stringent repression of telomerase that reduces theprobability of cancer to a very low value. Most of us don't get cancerat all. Those of us who do usually don't get it till age 50 or 60 or 70."
To the question, how might telomerase-inhibiting therapy affectmale and female cancer patients, Harley noted that "in the femalereproductive tract, there is almost no cell division after birth. All theeggs, the ova, are already laid down, but their telomeres don't startgetting shorter until the fertilized egg divides."
It's a different story in males. "Because there is significant dailyturnover of spermatogonia," Harley said, "you would expect sometelomere shortening. These cells start with very long telomeres, andit's unlikely the telomerase inhibitor would cause the male germlinetissues to age."
Here, though, the Geron researcher sounds a note of caution:"Because of the potential that inhibition would shorten telomeres,that would cause problems with offspring of such sperm later." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.