Monopoly, anyone? How about Scrabble? Clue? Risk?
There's a new board game just waiting to be invented by someenterprising molecular biologist. Call it "Cell Cycle." Think of it as acircle cut into four unequal pie-shaped slices, called "G1," "S," "G2"and "M."
* The first segment, G1, cuts the pie in half, as if it were a clock face.This is when a cell starts to divide by uncoiling its DNA double helixand synthesizing RNA and protein. It lasts about 11 hours.
* Slice two cuts the remaining half in half again. During this seven-hour "S" phase, the parent cell synthesizes the DNA for thechromosomes in the nuclei of its two future daughter cells.
* The third phase, "G2," is a wedge averaging five hours that marksthe build-up between RNA and protein synthesis (which continues)and the climactic "M" stage of cell division, just ahead.
* "M" stands for "mitosis," an intense 1.5-hour labor during whichthe parent cell gives birth to its two daughters. Its now-duplicatedpair of chromosomes migrate to opposite poles, and the original cellpinches in the middle to form its offspring.
As in board games, this fanciful cellular progression from "Go" to"Home," (which may actually take from 10 to 24 hours) is fraughtwith all sorts of perils, particularly to DNA. Its fragile strands takehits from many genetic, chemical and environmental spoilers, andhave to be repaired on the run, typically by DNA polymerases.
For instance, the sun's ultraviolet rays break down the DNA in skincells, causing quick-onset sunburn, slower-developing skin cancerand late-in-life dermal aging. Healthy cells deploy battalions ofendonucleases to snip out the distressed nucleotide stretches on awounded strand, and patch over the gap with matching nucleic acidfrom the opposing DNA strand.
In some inherited ailments, this nucleotide excision repair process isfaulty. Perhaps the purest clinical example is the rare autosomalrecessive disease, xeroderma pigmentosum (XP). Dermatologists arequick to recognize XP in small children who break out in frecklesand suffer severe sunburn from even minimal solar exposure.
They are born without the functioning gene or genes that expressDNA-repair enzymes.
"Some xeroderma pigmentosum patients suffer neurodegeneration,"observed physician and molecular biologist Jay Robbins of theNational Cancer Institute's dermatology branch. "All normal healthypeople are always having their nerve cells damaged. One of the maincauses is the very high oxygen uptake that neurons require, so oxygenfree radicals often extract an electron from their DNA."
Robbins, who has studied neurodegeneration in XP for 30 years, wasstruck by its neuronal similarity to Alzheimer's disease (AD) andDown's syndrome (DS), which leads inexorably to AD. AD, bothfamilial and sporadic, as well as DS, share neurodegeneration anddeposition of amyloid plaques in the brain. So he wondered whetherthey might also share XP's defective DNA repair etiology.
The current Proceedings of the National Academy of Sciences(PNAS), dated May 14, 1996, reports the latest findings in Robbins'research to affirm this hypothesis. Its title: "Fluorescent light-inducedchromatid breaks distinguish Alzheimer's disease cells from normalcells in tissue culture."
If this preliminary, small-scale experiment can be replicated on alarger scale, Robbins told BioWorld Today, the DNA-repair assay hisco-authors developed might hold clinical implications fordifferentiating in geriatric patients between AD and treatable formsof senile dementia, plus predicting it in as-yet unaffected members ofAD-prone families.
Moreover, the oxygen-free-radical damage known to be inflicted byfluorescent radiation might lead to developing antioxidant therapiesacting directly on threatened neurons in the AD brain.
Robbins' tests exposed skin fibroblasts and blood cells from 27 ADpatients, 11 donors with other neurodegenerative diseases(Parkinson's and Huntington's) as well as 31 healthy donors to DNA-damaging ultraviolet and fluorescent irradiation, and blockage orprotection of DNA repair processes by various chemicals.
The assays correctly identified all AD cells, and distinguished themfrom the other neurodegeneration cells. In contrast, cells from 28 of31 normal donors came up negative.
"Nobody," Robbins observed, "has ever shown such a very bigdifference in vitro between Alzheimer's and normal cells. Weinterpret that," he added, "as indicating that the AD and DS cannotdo what normal cells are doing in this DNA-repair test." And he drewthe parallel with xeroderma pigmentosum, where the only differencebetween XP and normal is the one gene that prevents them fromcarrying out nucleotide excision repair."
Double Or Nothing: Diagnosis, Treatment
Robbins observed, "We didn't set out to develop a differentialdiagnosis test for AD, but rather to learn more about the disease." Hedid suggest a scenario for its possible clinical application some day:"Let's say someone comes in with a memory problem, and turns outnormal on our test. That would give you a probability that thecomplaint was not due to AD, so you would look harder for someother dementia."
As for therapy, his PNAS paper concludes: "If death of nerve cells inAD results from failure to repair free-radical-induced DNA damage,antioxidant therapy may prevent or delay neurodegeneration."
"If that's true," he commented, "I'm not afraid of being wrong in mytheory. Rather, I'm afraid of being right, because if I am, thesepatients can be treated. We don't want to find that out five or tenyears from now."
He continued: "I would like to have some biotechnology companyundertake to simplify and develop this very tedious test on a practicalscale. We've applied for a patent, assigned to the U.S. government. Itrust it will be granted. If so, I hope we can interest some company orcompanies, under license, to do a lot of the studies that still have tobe done before any such tests can be used clinically." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.