NY Times on telomeres (no CYGS mention)........Graham
Cell Rejuvenation May Yield Medical Advances
By NICHOLAS WADE c.1998 N.Y. Times News Service
The report last week that human cells can be rejuvenated, at least in test tubes, suggests new remedies for many
major diseases of aging.
The inventors of the technique believe that treatments could in principle be devised for the wrinkling of the skin,
some kinds of eye degeneration, hardening of the arteries, and even cancer. Other experts, while conceding the
promise of the discovery, point to various limitations and obstacles that lie ahead.
Hovering over the discussion is the dream of lengthening the maximum human life span, an age-old fantasy that for
the first time could have acquired some glint of a scientific basis.
The cell rejuvenation technique depends on lengthening the structures known as telomeres that cap the ends of the
chromosomes, the long strands of DNA that hold the cell's genetic instructions. The telomeres get shorter each
time a cell divides, as if marking off the number of times a cell can divide before lapsing into senescence.
Last week, a team of biologists, led by Dr. Calvin Harley at the Geron Corp., in Menlo Park, Calif., and by Dr.
Jerry Shay and Dr. Woodring Wright at the University of Texas Southwestern Medical Center, at Dallas, showed
they could take two types of human cells far past the usual senescence point by restoring the cell's telomeres to
youthful length.
Treated skin cells, Shay said, had doubled 40 times more after untreated cells had become senescent, and, as of last
week, were still growing strongly.
The method is to insert into cells a vital component of the enzyme known as telomerase, which is used in egg and
sperm cells to maintain the telomeres at a constant, youthful length. Although all cells possess a gene that makes
this component, known as human telomerase reverse transcriptase, or hTRT, in almost all normal cells the gene is
switched off. An important exception is cancer cells, which have learned to switch the gene on so as to grow
indefinitely.
Last week's result dramatically resolves the confusion that had surrounded telomerase. Until now, the finding of
shorter telomeres in older cells has been a correlation, not a proof of cause and effect. Also, for various reasons to do
with the complex behavior of telomerase in different tissues and different species, critics had begun to doubt its
relevance to either senescence or cancer.
With the new experiment, however, ''The doubt has now come to an end,'' Dr. Titia de Lange, a telomerase expert
at Rockefeller University, in New York, wrote last week in the journal Science.
''I think the finding is spectacular,'' said Dr. Vincent Cristofalo, a gerontologist at the Medical College of
Pennsylvania, ''and validates for the first time the concept of telomere length as a cell division clock.'' He added,
though, that he would like to see the cells undergo more doublings to prove that their life span had been made
indefinite, as well as further tests to make sure they were not cancerous.
The question now is what use can be made of the potentially awesome power to rejuvenate human cells.
Geron and scientists associated with the company believe that many diseases of aging can be treated by removing
cells from a patient's body, restoring their telomeres and replacing the cells. As examples, they cite aging of the
skin, macular degeneration - or retinal decay, a leading and incurable cause of blindness - and atherosclerosis, or
hardening of the arteries. An advance in any one of these areas would be a notable success.
The technique, the scientists say, could also be used to grow new skin for burn victims from their own cells.
Further ahead, lies the possibility of developing drugs to shut telomerase down in the many kinds of cancer cells
that activate the gene.
As to the possibility of a drug that turned on telomerase so as to rejuvenate the body's tissues wholesale, Harley
said: ''It could be that is the ultimate upside, but we must move slowly on that.''
Whether any of these hopes can be brought to fulfillment is an issue now overshadowed by several major doubts.
Experts in aging and the biology of telomeres, while praising the new result, stress four outstanding limitations.
First, the body has many types of cells, including nerve and muscle cells, that never divide after the infant's
development is complete and therefore never come up against the Hayflick limit - the finding that cells in test tubes
divide about 50 times and then die, named after its discoverer, Leonard Hayflick.
No one knows what causes these cells to age, but it is clear that telomerase is not going to reverse the process or
have any effect on major diseases of senescence like Alzheimer's.
Second, if the telomere shortening system evolved in humans as a last-ditch defense against cancer, as seems
probable, any intervention that paralyzes the system will postpone cell senescence at the high price of encouraging
cancer.
Third, the aging of cells in the test tube is not necessarily the same as the aging of tissues in the body. Do people
in fact die because their cells run out of telomeres?
''If it is true that our life span is dictated by telomere shortening, then you would imagine that some humans die
because their critical cells run out of telomeres, and there is no evidence for that at all,'' said Dr. Robert Weinberg,
of the Whitehead Institute, in Boston. ''It is plausible that the telomeres are long enough to allow all of us to live
to 200.''
Fourth, it is not clear that telomere shortening is the fundamental cause of cellular aging. Some other process of
aging may emerge beyond the Hayflick limit. ''I don't think this is the basic mechanism of aging,'' said Cristofalo,
the gerontologist. ''It is the mechanism that defines cellular replicative aging.''
Geron scientists acknowledge the risk of cancer but believe experts can work around it. What is dangerous, they
say, is to make telomerase permanently active, as it is in cancer cells. But a transient activation, just long enough
to rebuild the telomeres, should present no problem.
This brief activation could be achieved either with limited doses of a drug, yet to be developed, that switched on
the cell's own hTRT gene - the gene that makes telomerase - or by introducing the active gene into cells on the
back of a harmless infective virus. The virus and its active hTRT gene would soon be eliminated by natural
mechanisms, said Dr. Malcolm A.S. Moore, a hematologist at the Memorial Sloan Kettering Cancer Center, in
New York, who is collaborating with Geron.
As to Weinberg's point that no one is known to have died from shortened telomeres, other experts agreed that this
had never been formally proved but said there were several situations in which cells' limited ability to divide
impeded the treatment of disease. Ordinary skin cells do not grow enough to make new skin for burn patients.
Biologists trying to juice up immune system cells to fight tumors have run up against the same barrier;
lymphocytes that recognize prostate tumor cells can be removed from a patient's blood and grown in the test tube,
but not in sufficient numbers to make a difference, a failure that might be reversed by the telomerase insertion
technique, Moore said.
It remains to be seen whether the return of rejuvenated cells to the body could restore health. Geron scientists say
they hope to treat macular degeneration, and one of the two types of human cells they have rejuvenated is the retinal
epithelial cells of the eye. Weinberg, however, said there was no reason to think this would work. ''Biological
degradation of the retinal environment is the heart of the problem,'' he said, ''so even if you put in new cells with
long telomeres, as far as I know, the cells would die.''
As to whether or not the telomere-telomerase system is a basic mechanism of aging, scientists are struck with the
vigor of the treated cells. It is not just that they undergo more divisions; they also divide at a speed typical of
young cells.
''I looked at the cells and was very impressed. They look like young cells,'' said Cristofalo, who is on Geron's
board of scientific advisers.
Moore said that ''maybe long telomeres confer additional biological properties, ones that increase the rate of
proliferation, not just the number of divisions.''
Unless some unexpected flaw appears, the new technique promises to have a major impact in medicine because it
opens up so wide a range of possible applications. An immediate use is in tissue culture, the growing of cells in the
test tube. The only human cells that grow indefinitely in culture now, are ones that have taken the first steps toward
becoming cancerous. The ability to grow normal cells indefinitely would be a boon to biologists and vaccine
makers.
''Will this make us live longer?'' Cristofalo said. ''Aging is so complex, with so many things failing, that it is
unlikely we can modulate any one system and expect it significantly to extend life span. But this is a quantum leap
in our understanding of how cell replication is controlled, and the downstream effects of this understanding, for
diseases like cancer and atherosclerosis, are of enormous importance.''
23:25 EST JANUARY 19, 1998 |
