Fountain of Youth?
By Dawn Stover // Popular Science February 1999
Normal human cells are mortal. After they divide 50 to 100 times, they get old. Or as scientists put it, they senescence. Senescent cells are bigger than young cells, excrete proteins at a different rate, and no longer divide.
About a year ago, a team of biomedical researchers announced that they had discovered a way to prevent cells from aging. Jerry Shay and Woodring Wright, professors of cell biology and neuroscience at the University of Texas Southwestern Medical Center in Dallas; took cells from foreskins (byproducts of circumcisions) and added a gene that causes cells to produce an enzyme called telomerase. Normally, foreskin cells divide about 60 times faster before becoming senescent. But in this case, the cells divided more than 300 times and show no sign of stopping at all. Nor do they show any signs of abnormality. ÒWith telomerase, cells are like the Energizer bunny,Ó says Shay. ÒThey just keep going and going and going.Ó Meanwhile, at the Geron Corporation in Menlo Park, California, researchers collaborating with Shay and Wright have done similar experiments with human retinas. These cells also appear to have become immortal.
Researchers, though hopeful, donÕt yet know whether this method for putting cellular aging on hold will eventually be useful in slowing the aging of the human body, so nobody is suggesting that we start adding telomerase to our Corn Flakes. In fact, telomerase has a darker side: It is found in 85 percent of all cancers, and it may be the reason cancer cells proliferate out of control. But if researchers can gain a better understanding of how telomerase works, they may be able to develop methods for thwarting both aging and cancer.
In 1961, a cancer researcher named Leonard Hayflick discovered that normal human cells are mortal. He also noticed that the oldest cell cultures in his lab usually died first. Hayflick suspected that cells contain some sort of clock that tells them when it is time to stop dividing. Later he discovered that cells have what he calls an Òevent counter,Ó which measures the number of cell division rather than the passing of time. If a cell culture is frozen for decades and then thawed, it will resume its doubling at exactly the point where it left off.
Scientists now think they know where the counter is- on the ends of chromosomes. The chromosome tips are called telomeres, and they consist of thousands of identical sections of DNA strung together like beads on a necklace. Each time a cell goes through mitosis some of the beads are lost. And finally, when telomeres reach a certain length, the cell stops dividing.
In the early 1970Õs, a Russian immunologist named Alexy Olovnikov proposed a theory for why cell division ceases. He was waiting for the subway in a Moscow station when he had a revelation: Imagining that the train track was DNA, he observed that the engine would never make a complete pass over the beginning and end sections of the track. For the track to be replicated in its entirety, it would need a buffer at each end. Olovnikov theorized that telomeres perform this buffering action.
Evidence that the length of our telomeres has something to do with how quickly we ago comes from studies of people with progeria, a mysterious syndrome that causes premature aging. The average life span of progeria patients is 12.7 years. These Òchildren without childhoods,Ó who look like wizened old men and women, are born with short telomeres.
In the laboratory, the enzyme telomerase appears to stabilize telomore length and keep cells youthful. But in the human body, it may not be that simple. A lot of changes occur in cells as they age, and most scientists doubt that one enzyme can reverse all those changes. But the fact that telomerase can make some cells immortal in the lab has stirred up a lot.
It has also stirred up some fears. When he first heard the news, Robert Weinberg of MITÕs Whitehead Institute of Biomedical Research reportedly had this to say:Great! Nice way of making cancer!Ó Weinberg fears that telomerase could breathe new life into pre-malignant cells that would otherwise be too old to cause trouble. ÒI think it could unleash a whole torrent of malignant changes,Ó he warns.
And that is the paradox of telomerase: While it may have the power to rejuvenate old or damaged cells, it may also promote the uncontrolled growth of cancer cells. Indeed, telomerase is found in most, though not all, cancer tumors. But therein may lie a potential weapon against cancer: By neutralizing the activity of telomerase, researchers hope to Òre-mortalizeÓ cancer cells and make them easier to kill.
Geron is already working to devlop drugs that would inhibit telomerase. Nobody has yet tried a telomerase inhibitor in human patients, however. ÒIt would clearly be unrealistic to expect that a telomerase inhibitor will be a magic bullet,Ó says Geron chief scientist Calvin Harley.
As Harley and his collaborators see it, telomerase itself probably doesnÕt cause cancer. High levels are found in reproductive tissue such as testicles, but testicular cancer rates arenÕt unusually high. More likely, telomerase makes it possible for cells that are already cancerous to continue dividing.
Even if a telomerase inhibitor canÕt cure cancer, monitoring the substance may make early detection easier. High levels of telomerase found in urine, blood, or Pap smears could be an indicator of cancer. It might be possible to detect bladder cancer, for example, using a urine test instead of an invasive probe. Telomerase monitoring might also help detect recurrences of cancer after treatment.
In any case, telomerase is teaching scientists much about the relationship between cancer and aging. Many experts in the field now believe that cell senescence may have evolved to keep us tumor-free during our reproductive years. Limiting the number of times a cell can divide also limits the number of mutations that can occur. But the average American now lives well past reproductive age, and this defense doesnÕt protect us in later years.
In fact, different strategies may be appropriate for different stages of life. One approach might be to take telomerase activators while we are young, and then switch to telomerase inhibitors to prevent cancer later in life. But it will be many years before such choices are available.
ÒThe telomerase era is now less than a year old in terms of real applications,Ó explained Weinberg at a recent telomerase conference. ÒThis is just the beginning.Ó