In a finding that suggests the thread of life can be extended, at least for human cells, biologists have managed for the first time to coax cells grown in the test tube to live far beyond the limit at which they usually fail.
The finding may help answer the question of why human cells age, and may also offer a practical means of treating certain diseases by rejuvenating aging cells.
Despite some scientists' euphoric talk about the discovery of a cellular "fountain of youth," however, others cautioned that the cell senescence mechanism is also a principal defense against cancer, and that bypassing it could be dangerous.
The finding makes use of a newly discovered human gene which resets an inherent limit imposed by nature on the number of times a human cell can divide. Human cells grown in the test tube will usually divide about 50 times and then stop. But cells treated with the new method have bypassed this limit and as of today have divided 90 times with no sign of abnormality.
The result has broad scientific and medical interest because it describes a mechanism in living cells that is central both to aging and to cancer. Although the mechanism, known as telomere shortening, had long been suspected to work this way, proof has been delayed until now.
The Geron Corp. of Menlo Park, Calif., which owns or has applied for several patents on the gene, known as the telomerase gene, says its technology will rejuvenate cells involved in age-related diseases and help to diagnose and treat cancer.
"These cells have an indefinite life span as far as you can tell," said Dr. Calvin Harley, an author of the new finding and vice president of Geron.
"It will now allow us to take a person's own cells, manipulate and rejuvenate them and give them back to the same patient," said another author of the study, Dr. Jerry Shay of the University of Texas Southwestern Medical Center. The rejuvenated cells could help grow new skin for burn victims and in diseases caused by the failure of aging cells to divide, such as macular degeneration, Shay said.
The new research was conducted by two teams of scientists led by Harley at Geron and by Shay and Dr. Woodring Wright of the University of Texas Southwestern Medical Center. Their work is reported in this week's issue of Science.
Disclosure of the findings on Tuesday sent Geron's stock up 44 percent, on the Nasdaq stock exchange, where it closed at $14.375 a share.
Experts cautioned, however, that important as the new results are, there is a Catch-22 in the way evolution has designed the telomerase system. The mechanism almost certainly evolved, at least in humans, as a way to limit cancer. Hence any medical use of rejuvenated cells in which the division limit has been subverted may weaken one of the body's salient defenses against tumors.
"Geron would have us believe that telomerase is the key to immortal life, and I have no idea if there is any wisp of truth in that," said Dr. Robert Weinberg, a leading expert on cancer genetics at the Massachusetts Institute of Technology. Any such claim should be taken with a grain of salt, he said.
The mechanism at the heart of the new work is a system developed by certain living cells for managing their chromosomes, the rod-shaped structures in which the cell packages its genetic programming tapes. The device that copies the long double helix of DNA when the cell divides has a peculiar defect: it cannot copy the last few units of DNA at the chromosome's tip. Hence each time a cell divides, its chromosomes get a little bit shorter.
The end section of the chromosomes, known to biologists as the telomere, thus resembles some thread of life that is used as the tally for counting off cell divisions and which, when it runs out, means the cell's ability to divide is over.
This tempting analogy became much strengthened when biologists found that all human cells possess a gene whose product, named telomerase, can lengthen the telomeres. In normal cells, the gene is firmly silenced. But in human germ line cells, the egg and sperm, telomerase is active and maintains the telomeres at a constant length - some 15,000 chemical letters of DNA. It is also active in cancer cells, which have learned to switch on telomerase and bypass a mechanism that would otherwise shut them down.
Skeptics of this theory began to question whether the telomerase shortening, evocative as it might appear, was really as important as advertised. Last year Dr. Carol Greider of Johns Hopkins University engineered a breed of mice that completely lacked a telomerase gene. The mice are alive and well after several generations, and their cells show no particular cancerous tendencies.
"The theory came under tremendous skepticism,"said Harley, who was one of the theory's earliest proponents. "People said it was gibberish or based on theology."
Harley has been able at last to put the theory to rigorous test because of the recent discovery of the human telomerase gene. Inserting this gene into human cells, along with a signal that forced the gene to become active, he and his colleagues found that the cells quickly built their shrinking telomeres back up to youthful length, and continued to divide way past the usual limit.
"Our results indicate that telomere loss in the absence of telomerase is the intrinsic timing mechanism that controls the number of cell divisions prior to senescence," the biologists write in their report in Science.
"Their work makes a strong statement that the telomeres have something to do with the life of the cell," said Greider, who noted that mice regulate their telomerase gene very differently from humans.
Dr. Leonard Guarente, an expert on cellular aging at MIT, described the research as "a beautiful piece of work" but said its relation to human aging remained to be defined.
Weinberg, a cancer expert who has recently entered the telomere field, said the experiment "directly proves a point believed by many but never actually demonstrated." The finding is relevant to the senescence of human cells, he said, but not necessarily to that of the human body. "If it were true that our life span is dictated by telomere shortening, then you would imagine that some humans die because there critical cells run out of telomeres, but there is no evidence for that at all. The Geron people are pushing this hard but to my mind there is not much evidence for it."
Weinberg suggested that everyone might have enough telomeres to live to be 200. What limits human life span is diseases, especially cancer, and the telomere shortening system is a way of insuring that the growth of incipient cancer cells is quickly halted.
"If you put telomerase into all our cells maybe they could live longer," Weinberg said, "but on balance it would be a very bad thing because it would no longer prevent those cells from growing without limits, and in the end malignancy is the greatest threat to human longevity."
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