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Normal cells don't live forever.

But some do continue dividing longer than other

s, seemingly controlled by a predetermined counting mechanism. Cells taken from
humans or horses outlast those from mice, for instance. Cells from younger donor
s will double more often than those from older ones, as if they know they had mo
re time allotted. The ability to divide slows as cells age.
One popular notion is that cellular aging is the cumulative result of small rand
om changes, a breakdown provoked by a torrent of unintended insults. Others argu
e that senescence in normal cells is probably controlled by specific genes. "If
you think that normal cells age because they are damaged, then immortal cells mu
st have something that lets them escape," says Olivia M. Pereira-Smith, a geneti
cist at Huffington Centre on Aging at the Baylor College of Medicine in Houston.
Pereira-Smith and her colleague Yi Ning began examining cells that divide indefi
nitely, searching for a gene to induce aging and to stop proliferation. Their re
sults, which will be published in the 'Proceeding' of the National Academy of Sc
iences, indicate that one such gene involved in aging may be located on chromoso
me 4 in humans.
The Texas researchers first fused normal cells with immortal ones that were canc
erous or vitally infected, to see whether the hybrid off spring would also divid
e indefinitely. Most did not. The tendency to be normal - and thus of limited li
fe span - is apparently the dominant inherited trait, whether cells originate in
skin, muscle, veins or blood. Therefore, the few cells that do manage to become
immortal must have a recessive gene for that trait, Pereira-Smith concluded.
Next, the team began fusing immortal cells with other immortal cells, assuming t
hat whatever recessive defect was responsible for each parent's longevity would
be passed on to the hybrid. If parents shared the same genetic defect, the hybri
d would also be immortal. But if parents were immortal and lacked the defect, th
eir capacity for division would not be passed on to the hybrid. These parent cel
l lines would be assigned to different groups for indefinite division, depending
on the other traits their hybrids inherited.
After fusing 30 cell lines from assorted tissues in all possible combinations, P
ereira-Smith and her collaborators found that any given immortal cell line would
fit into just one of four possible groups. This limited assignment indicates th
at a small number of highly specific genes are involved in senescence, she decla
res: "You need to turn on a certain set of genes to become senescent, so you hav
e to lose any one of the set to become immortal."
Having firmly established which cells could be expected to live forever, Pereira
-Smith decided to see whether they could be stopped from proliferating. "We deci
ded to look at the chromosomes that have been implicated in tumour suppression,"
she notes, explaining that senescence could be involved in tumor suppression be
cause it prevents cells from growing without control. Perhaps a gene sitting som
ewhere on one of those chromosomes would stop cells from dividing.
A procedure known as microcell fusion enabled the researchers to transfer a norm
al single human chromosome into an immortal cell line. The technique entails tre
ating cells so that the nuclei break up into little bags of nuclear membrane, ea
ch one of which contains only one or two chromosomes. The microsacs are blown ou
t of the cell cytoplasm and fused into the nucleus of another cell.
The first try was disappointing. When chromosome 11, which has been implicated i
n tumour suppression, was introduced to immortal cell lines "they proliferated j
ust fine," Pereira-Smith recalls. It may stop tumours but is apparently not invo
lved in cell aging, she observes. The team chose to repeat the microcell experim
ent with chromosome 4. "We got lucky," the laboratory chief says with obvious de
light. This chromosome was able to induce senescence in a line of cervical carci
noma cells but not in the other groups. Her laboratory continues examining other
cell lines within the group to see if the effect can be replicated.
The next step is to find where on the chromosome the gene is located and figure
out how it is regulated. Gene hunting is never an easy task., however. The class
ic example of the frustrating process is Huntington's disease. Researchers have
known for more than 10 years that the gene for the inherited disorder lies somew
here on chromosome 4, but no one has yet been able to pinpoint it. But technolog
y is getting better every day, the geneticist declares. Once the gene is in hand
, scientists will be able to study its involvement in the senescence of various
normal cells. Pereira-Smith muses that "may be then we will be able to intervene
not just in the laboratory but in aging people."