NEWS RELEASE, 12/01/99
Rare genetic disease linked to telomerase defect, revealing potential roles of enzyme in preventing tissue aging and cancer
By Robert Sanders, Public Affairs
BERKELEY-- In recent years, the enzyme telomerase has been touted as the key to cellular immortality, as a veritable "fountain of youth." Some have argued that it is a major reason cancers grow unchecked, as if they too are immortal.
Such speculation, however, has been based solely on studies in lower organisms, or experiments in cultured cells that show telomerase can make them live longer. The enzyme's role in normal humans has remained uncertain.
Now, researchers at the University of California, Berkeley, have found direct evidence for the enzyme's importance in humans - the first human disease caused by a defect in telomerase.
The finding confirms the role of telomerase in renewing human tissue, but also adds a bit of caution. Drugs that block telomerase activity, now being sought as a means of stopping the unlimited proliferation of cancer cells, might in turn promote cancer by making chromosomes unstable, the researchers say.
The discovery is reported in the Dec. 2 issue of the British journal Nature by Kathleen Collins, assistant professor of biochemistry and molecular biology at UC Berkeley, graduate student James R. Mitchell and former undergraduate Emily Wood. The researchers are part of UC Berkeley's Health Sciences Initiative, a research effort that draws scientists from both the physical and biological sciences into the search for solutions to today's major health problems.
Telomerase makes cells youthful by replacing short DNA tags that drop off the chromosome ends, called the telomeres, each time the chromosomes replicate and divide. Without the enzyme, the tags disappear one by one until the ends are so short they can start sticking together. This halts further division, and the tissue no longer regenerates, thereby contributing to aging.
While the telomerase gene is turned on in the fetus, it appears to be switched off shortly after birth, so that most cells in adults contain no telomerase activity. As a consequence, most human cells grow only for a fixed number of years.
"Turning off telomerase starts a natural clock that gives a cell only a certain number of divisions before it stops," Collins said. "For most humans, the telomeres we are born with will allow enough cell division for good health throughout a typical life span."
Only certain adult human cells, including skin cells and blood cells of the immune system, can activate telomerase and thus reset the clock limiting their replacement. If the enzyme is turned on full blast, however, cells can divide indefinitely. This is thought to underlie some cancers.
"Cancer and aging both involve alterations of proliferative renewal," Collins said. "With cancer there is inappropriately much cell proliferation. With aging, there is not enough."
The rare congenital disease dyskeratosis congenita (DKC) has not been linked with a telomerase defect until now, though it displays many symptoms one would expect in a disease that drastically limits the number of times a cell can divide. By about age five, people with the condition begin to exhibit problems with tissues that constantly are replaced, including skin and other epithelial tissues. Children with DKC develop atrophic, pigmented skin lesions, their nails and hair often fall out, and their mucous membranes develop abnormal plaques.
The bone marrow also is compromised, because of problems with the stem cells that constantly produce new red and white blood cells. Patients develop anemia, are prone to life-threatening infections, and most frequently die from bone marrow failure.
DKC patients who survive these travails often die in their twenties or thirties of cancer, mostly cancers of the skin (squamous cell carcinoma) and the gastrointestinal tract. Their chromosomes appear to tangle and fuse, Collins said.
"The only thing we can find wrong with these people is that they have much less telomerase than normal people and even their own relatives," she said. "And the problems they have turn out to be exactly what you would predict from the role telomerase plays in cells."
The fact that DKC patients, who have low levels of telomerase, also develop cancer suggests that giving telomerase blockers to people with cancer could stimulate other cancers.
"Turning off telomerase may inhibit established cancers, but over a longer term it also might promote cancer by promoting genomic instability," Collins said. "Taking a telomerase inhibitor to turn off telomerase in some tissues may promote cancer in other tissues."
The solution may be simple, however: just give telomerase inhibitors for a short period of time, and then stop.
As for using telomerase to stave off aging, Collins warns of the possibility of encouraging the growth of cancer cells as well as normal cells.
"If there were a telomerase pill, I'd take it," Collins said. "Not at the age of 10, but much later - maybe at 60."
Based on research reported last year, DKC, a disease caused by mutation of the X-chromosome and thus affecting predominantly male children, was thought to involve a defect in the molecules called ribosomes. Ribosomes are large complexes of protein and RNA that are the machines that assemble proteins from RNA.
Collins' lab, on the other hand, studies telomerase - a much smaller hybrid molecule composed of protein and RNA. She and her colleagues look at the enzyme primarily in the organism Tetrahymena thermophila, a ciliated protozoan long used in cell biology research, and the organism in which telomeres and telomerase were first isolated.
They stumbled upon the disease because it turns out that human telomerase - unlike Tetrahymena telomerase - contains a set of proteins that also functions in ribosome assembly. Mitchell and Collins reported this curious connection earlier this year. One protein of the set had been dubbed "dyskerin" because of its link with the disease.
Thanks to Mitchell's persistence in studying the more complex and less well understood human telomerase, he and Collins were able to show a link between telomerase, dyskerin and DKC. In fact, they found that the defect in dyskerin appears not to affect the functioning of ribosomes at all. As part of telomerase, however, the defective dyskerin leads to lower levels of telomerase in cells.
The researchers found, for example, that those with the disease have lower-than-normal levels of telomerase. As a result, the telomeres of white blood cells of seven-year-olds with DKC are shorter than those in normal 50-year-olds.
Defective dyskerin could lead to decreased levels of telomerase in several ways, Collins said. It could interfere with the assembly of proteins and RNA into a complete telomerase complex, or it could disrupt the final structure in a way that increases its turnover rate.
Telomeres were first discovered in Tetrahymena in the 1970s by Elizabeth Blackburn, formerly of UC Berkeley and now professor of microbiology and immunology at UC San Francisco. She and colleagues showed that they consist of repeating sequences of DNA that cap the ends of chromosomes and grow shorter each time a cell divides. Apparently, the telomeres protect the DNA strand from fraying, much like the plastic tip on the end of a shoelace.
In the 1980s, Blackburn's lab at UC Berkeley discovered telomerase. Scientists have since found that in multicellular organisms telomerase is not expressed in most cells, which means most cells have a predetermined ability to grow and divide - unless telomerase can be switched on.
In January of 1998, researchers at Texas Southwestern Medical Center and at Geron Corp. did just that: they turned on telomerase in a culture of human cells, which led to lengthened telomeres and an extension of the cells' lives. They referred to their discovery as a "cellular fountain of youth."
Despite such successful uses of telomerase, its role in normal human tissue remained murky. Do cancer cells really need telomerase? Is aging limited by telomerase?
"Speculation outpaced proof of principle," said Collins, who has worked for years to clarify telomerase's role and to determine how the right RNA and proteins combine into a functioning enzyme.
"We have been studying how telomerase RNA and proteins come together in ciliates for much longer, but in humans we found something that ultimately explained a whole series of puzzling observations at once," Collins said. "This work is another beautiful example of how exploring basic scientific questions in an academic setting can contribute to our understanding of human disease in a way that might otherwise never have happened."
The work was supported by grants from the National Science Foundation, the National Institutes of Health and UC Berkeley.
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