By a Thousand Cuts

By Lori Oliwenstein|Monday, February 01, 1993
RELATED TAGS: GENES & HEALTH
Each time a cell divides, its chromosome tips are cut off, until finally it dies.

But some cells--including some cancerous ones--are immortal.

Each time a cell in your body divides, a clock ticks: there’s a limit to the number of times the average body cell can replicate before it dies. Stick an infant’s skin cells in a petri dish and they’ll divide a hundred times or so before the culture peters out. A 60-year-old’s skin cells won’t divide more than 20 times. Biologists call this cellular senescence.

But what mechanism drives the clock? How can a cell count its own divisions and know when to stop splitting in two? Biologists think they may have found the clock at the end of a cell’s chromosomes. And now they think they know what happens when human cells are able to ignore or even stop the clock: it seems the cells turn cancerous.

Like aglets, those tiny bits of plastic that keep the ends of your shoelaces from fraying, specialized structures called telomeres protect the ends of chromosomes so they don’t break and get tangled up with one another. If you break a chromosome, the end will fuse with another chromosome in the cell, explains cell biologist Carol Greider of the Cold Spring Harbor Laboratory in New York. But normal chromosomes don’t do that. There’s something special about the ends of the chromosomes that protects them from degradation and fusion. That something is the telomere.

Like the rest of a chromosome, telomeres are simply strings of nucleotides--the letters of the genetic code--coiled into a DNA double helix. In a telomere, though, the same sequence of nucleotides is repeated over and over, a thousand times or more. Thymine-thymine-adenine-guanine- guanine-guanine is the sequence of a human telomere--TTAGGG. The sequence doesn’t code for a protein the way a gene does. But each time a normal body cell divides, says Greider, its telomeres get a little bit shorter, losing between 50 and 100 Ts, As, and Gs. That’s the ticking of the clock-- although nobody really knows how the telomere clock might control cell division. There may be something that senses how long the telomere is, says Greider, and when it gets to a certain length, it sends a signal saying ‘Stop dividing.’

Some cells, however, have found a way to beat the clock. Back in 1985, Greider and Elizabeth Blackburn (who was then Greider’s adviser) discovered an unusual enzyme in the single-celled protozoan Tetrahymena thermophila. The enzyme, which the researchers dubbed telomerase, adds nucleotides to the telomeres each time the organism divides, replacing the nucleotides that are lost. As a result, the telomeres never get shorter, and the signal to stop dividing never gets sent. Each Tetrahymena cell is immortal, in the sense that it doesn’t die unless something kills it.

The cells in our body, as we know all too well, are generally mortal, and those that Greider and other telomere researchers have looked at so far don’t produce telomerase. Why? The answer, it seems, lies in the difference between us and single-celled organisms. In the latter, cellular immortality equals survival. But if there were no brakes on cell division in multicelled animals like us, many more of us would die of cancer. So evolution may have chosen telomere shortening as the lesser of these two evils--as a way of programming cell death so that uncontrolled cell growth doesn’t kill an organism before it has a chance to reproduce.

If the shortening of telomeres leads to cell death, Greider and other scientists began to wonder, might cancer cells somehow circumvent that mechanism? Recently she and a group of researchers from McMaster University in Ontario, led by Calvin Harley and Silvia Bacchetti, examined that possibility.

The researchers took millions of cells and put a cancer gene into each of them. Then they watched the cells divide. They observed that the cancerous cells extended their lives in two ways. Most of the cells did die eventually, but not before they had gone through between 20 and 40 more divisions than a normal cell of the same type. When the researchers analyzed these cells they found no sign of telomerase; they also noted that nucleotides still got knocked off the ends of the telomeres at each division. Somehow, though, these cancer cells were blocking the stop signal and were continuing to divide with much shorter telomeres than are found in normal cells--until finally they too succumbed to frayed chromosome ends.

A few of the cancer cells, however, did a more thorough job of avoiding cell death: they became immortal. For a cancer cell to become immortal, says Greider, takes a second event, some unknown mutation. About one in 10 million cells will become immortal, just by chance. The existence of immortal cancer cells has been known for some time. The most treacherous cells, those that wander away from a growing tumor to start a new one, are often immortal cells. What Greider and her colleagues think they’ve discovered now is a clue to the mechanism underlying cellular immortality. When the team examined the immortal cells in their experiment, they found telomeres that could maintain their length through an unlimited number of divisions--and they found telomerase.

Apparently human beings still have the ability to make telomerase; indeed it may be essential in egg and sperm cells, which need to be able to divide repeatedly and yet still deliver intact telomeres to the next generation. And Greider says it’s possible that some telomerase may one day be found in tissue that has to regenerate constantly, such as the stomach lining. But her team’s findings suggest that the same enzyme that may play an essential role in some healthy cells may play a nefarious one in cancer cells. Furthermore, the results point toward a practical goal for telomere research: a drug that could disable telomerase in immortal cancer cells and thus perhaps tame their metastatic tendencies.

As is so often the case with biomedical research, however, the practical applications are still far down the road. Greider and her colleagues have yet to do the experiments that would prove, once and for all, that telomerase is necessary for immortality. We need to take immortal cells, make it so the telomerase is not functioning, see the telomeres get shorter, and see if the life of the cell is shortened, she says. Then we’d have a direct answer to our question.
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