How Long are your Telomeres?

The telomere is a DNA/protein complex that caps the ends of chromosomes. Everyone has seen the X shaped chromosomes but few people think about why our DNA is split into chromosomes rather than one large circular plasmid or set of plasmids like with bacteria. Furthermore, few people think about why chromosomes form that X shape and what stops the lengthening of the p and q arms. We'll be looking at the latter in this post.

One can think of the telomere as the aglet on the end of a shoe lace, the cap on the end of a length of DNA to stop it getting any longer - it's what stops chromosome legs linking up end to end. The region of DNA on either end of a chromosome is actually a length of G-rich DNA with the pattern TTAGGG repeating over and over again for a length of 5-15kb, then finishing off with a long G tail of 50 - 300b. A protein complex, sheltrin, binds to this section of DNA and helps the legth of DNA form a T loop which is a bit like a knot at the end of a shoe lace.

It is generally well known in the scientific community that the length of the telomere is related to the life span of a cell or multicellular organisms - regulating how many times cells can replicate before they stop dividing, go into senescence and eventually die. Generally a human cell will go through 40-60 cycles or thereabouts (the Hayflick limit). The length of telomeres reduces with every-other revolution of the cell cycle and it gets to critical length before the cell stops dividing.

This year's (2009) nobel prize in phyisology/medicine was awarded to Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak for discovering how chromosomes are protected by telomeres and the enzyme telomerase. One of their key findings was that telomeres are not shortened with every cell cycle.

It is not known exactly to what level the length of telomeres or the rate of erosion affects people's life expectancy. The general rule is that if you start off with long telomeres and/or telomere shortening is slow, then your life expectancy will be longer. But life expectancy and longevity has multiple factors governing it.

Telomerase is the enzyme that keeps the telomere long. Some species even produce enough to lengthen their telomeres with every-other cycle so they live longer lives but they still die eventually. Telomerase and long telomeres may play a larger role in slowing the ageing process rather than extending life.

Because telomere erosion occurs consistantly during the cell cycle it can be used as a measurement of age of a species where it is difficult to predict the age of an animal. And intraspecies, the telomere lengths and rate of erosion is quite different. Compared to many animals the homo sapien has a really long life considering that human telomeres are only 8–12 kb in length or less at birth and reduce 2 - 4kb in a lifetime. The rate of change of telomere erosion plays a role but looking at the graph below it is not so clear cut if long telomere lengths extend life, especially when compared with our closest living relative, (Pan) the chimpanzee. And also, one wonders about trees - some trees are thousands of years old and still going! (see B.E. Falanary paper below)

Graph showing the relationship between rate of change in mean telomere length (TROC) (base pairs lost [negative numbers] or gained [positive numbers] per year) in various tissues and maximum life span for five birds shown in Table 1 (circles) and eight mammals (boxes) (see C.M. Vleck paper). Common names are: Mus spretus, western wild mouse; Ovis aries, domesticated sheep, Canis familiaris, dog; Macaca nemestrina, pigtailed macaque; Bos taurus, cattle; Macaca fascicularis, cynomolgus monkey; Pan troglodytes, chimpanzee; Homo sapiens, human. Taken from C.M. Vleck et al., The natural history of telomeres: tools for aging animals and exploring the aging process.

The role of telomeres is to maintain the chromosome package. In bacteria mutations are not a big deal but in higher organisms they can cause serious harm and even lead to cancer. The hayflick limit governed by telomere length is seen as a safety mechanism which limits the number of cycles a cell goes through in order to make sure the quality of the DNA does not deteriorate, because with age comes an increased risk of mutation and cancer development.

Recommended papers:
C.M. Vleck et al., 2003, The natural history of telomeres: tools for aging animals and exploring the aging process.
Y. Deng et al., 2008, Telomere dysfunction and tumour suppression: the senescence connection
P.M. Lansdorp, 2009, Telomeres and disease
B.E. Flanary, 2005, Analysis of telomere length and telomerase activity in tree species of various
life-spans, and with age in the bristlecone pine Pinus longaeva
T.J. Vulliami, 2009, Premature Aging
C. Auriche et al., 2007, Budding yeast with human telomeres: A puzzling structure

Nobel prize for chromosome find

This year's Nobel prize for medicine goes to three US-based researchers who discovered how the body protects the chromosomes housing vital genetic code.

Elizabeth Blackburn, Carol Greider and Jack Szostak jointly share the award.

Their work revealed how the chromosomes can be copied and has helped further our understanding on human ageing, cancer and stem cells.

The answer lies at the ends of the chromosomes - the telomeres - and in an enzyme that forms them - telomerase.

The 46 chromosomes contain our genome written in the code of life - DNA.

When a cell is about to divide, the DNA molecules, housed on two strands, are copied.

But scientists had been baffled by an anomaly.

For one of the two DNA strands, a problem exists in that the very end of the strand cannot be copied.

Protecting the code of life

Therefore, the chromosomes should be shortened every time a cell divides - but in fact that is not usually the case.

If the telomeres did repeatedly shorten, cells would rapidly age.

The discoveries ... have added a new dimension to our understanding of the cell, shed light on disease mechanisms, and stimulated the development of potential new therapies The Nobel Assembly

Conversely, if the telomere length is maintained, the cell would have eternal life, which could also be problematic. This happens in the case of cancer cells.

This year's prize winners solved the conundrum when they discovered how the telomere functions and found the enzyme that copies it.

Elizabeth Blackburn, of the University of California, San Francisco, and Jack Szostak, of Harvard Medical School, discovered that a unique DNA sequence in the telomeres protects the chromosomes from degradation.

Joined by Johns Hopkins University's Carol Greider, then a graduate student, Blackburn started to investigate how the teleomeres themselves were made and the pair went on to discover telomerase - the enzyme that enables DNA polymerases to copy the entire length of the chromosome without missing the very end portion.

Their research has led others to hunt for new ways to cure cancer.

It is hoped that cancer might be treated by eradicating telomerase. Several studies are under way in this area, including clinical trials evaluating vaccines directed against cells with elevated telomerase activity.

Some inherited diseases are now known to be caused by telomerase defects, including certain forms of anaemia in which there is insufficient cell divisions in the stem cells of the bone marrow.

The Nobel Assembly at Sweden's Karolinska Institute, which awarded the prize, said: "The discoveries... have added a new dimension to our understanding of the cell, shed light on disease mechanisms, and stimulated the development of potential new therapies."

Carol Greider, now 48, said she was phoned in the early hours with the news that she had won.

She said: "It's really very thrilling, it's something you can't expect."

Elizabeth Blackburn, now 60, shared her excitement, saying: "Prizes are always a nice thing. It doesn't change the research per se, of course, but it's lovely to have the recognition and share it with Carol Greider and Jack Szostak."

Professor Roger Reddel of the Children's Medical Research Institute in Sydney, Australia, said: "The telomerase story is an outstanding illustration of the value of basic research."

Sir Leszek Borysiewicz, chief executive of the Medical Research Council, said: "The Medical Research Council extends its congratulations to Blackburn, Greider and Szostak on winning the 2009 Nobel Prize.

"Their research on chromosomes helped lay the foundations of future work on cancer, stem cells and even human ageing, research areas that continue to be of huge importance to the scientists MRC funds and to the many people who will ultimately benefit from the discoveries they make."

http://news.bbc.co.uk/1/hi/health/8290094.stm