Nobel prize goes to scientists who discovered why chromosomes don't degrade on copying


Nobel prize goes to scientists who discovered why chromosomes don't degrade on copying

The 2009 Nobel Prize in Physiology or Medicine goes to three American scientists Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak, who solved a major puzzle in biology; they discovered that chromosomes don't degrade when they replicate because it's all to do with how telomerase makes telomeres to protect the ends of the chromosomes. Their discoveries led to a new understanding of how cells work and opened new avenues for researching and treating many diseases.

The Nobel Assembly at Karolinska Institutet in Stockholm, Sweden, announced on Monday that the three Nobel Laureates won their award for the discovery of "how chromosomes are protected by telomeres and the enzyme telomerase".

The genes that make up our genome are the blueprint of our biology. They are made of two intertwined strands of DNA written in an alphabet comprising just four base codes, packed into chromosomes with telomere "caps" on their ends. The three Nobel Laureates discovered that telomeres contain a unique sequence of DNA code that stops the chromosomes from degrading as they reproduce. This has opened the door to developing new treatments for diseases.

Cells age as telomeres get shorter, and conversely, they don't age when telomerase activity is high and protects telomere length. This property is reflected in various diseases. For example, cancer cells are considered to have eternal life because their telomere length is preserved when they replicate, while certain other diseases are characterized by defective telomerase, resulting in damaged cells.

In the 1930s, two other Nobel Laureates (Hermann Muller, who won the Nobel Prize in 1946, and Barbara McClintock, who won it in 1983), noticed that telomeres seemed to stop chromosomes from attaching to each other and postulated that they protected the chromosomes somehow, but exactly how was somewhat of a mystery.

Then in the 1950s another problem came to light: when a cell is about to split, DNA polymerase enzymes copy the exact code sequence of a DNA molecule base by base. This is like someone painstakingly copying a very large book, word for word onto blank sheets. But it appeared that for one of the two DNA strands, the very end of the strand (the last few pages of the "book"), couldn't be copied. However, now it appears that this is not always the case.

This year's three Laureates, Blackburn, Greider and Szostak solved both these problems.

In her work mapping DNA sequences in the 1970s, Blackburn studied the chromosomes of the single-celled ciliate protozoa Tetrahymena and discovered that a particular DNA sequence kept repeating several times at the end. The "spelling" of this sequence in the DNA alphabet code was CCCCAA, but its function was a mystery.

At around the same time, Szostak noticed that when he introduced a type of "minichromosome" made of a linear DNA molecule into yeast cells, they degraded quite rapidly.

Szostak got interested in Blackburn's discovery after she presented her results at a conference in 1980, and the two scientists agreed to do a joint experiment where Blackburn isolated the CCCCAA sequence from Tetrahymena and Szostak coupled it to the minichromosomes before inserting them into yeast cells. The results, which they published in 1982, were astounding: the CCCCAA sequence appeared to stop the minichromosomes from degrading.

This was a big discovery not only because the telomere sequence appeared to stop minichromosomes from degrading, but also because the telomeres and minichromosomes came from two completely unrelated species, showing that this phenomenon was a previously unrecognized fundamental mechanism of biology.

Later it became clear that most plants and animals, from amoeba to man have telomere DNA.

At around the time that Blackburn and Szostak got together, Blackburn was supervising a graduate student, Greider, who started looking into how telomere DNA was made and which enzyme was involved. On Christmas Day 1984, Greider found enzyme activity in a cell extract. She and Blackburn named the enzyme telomerase. They purified it and found it was made of protein plus RNA. The RNA contained the CCCCAA sequence which acted as a "template" for building telomeres, while the protein supplied the material for the enzymatic activity.

After this the scientists starting investigating the role of telomeres. Szostak and his team found some mutations of yeast cells whose telomeres were gradually getting shorter and shorter as they replicated. These cells grew poorly and then stopped dividing altogether. Blackburn and her team made mutant forms of the telomerase RNA and found similar effects in Tetrahymena.

In both cases, with the mutant yeast cells and the mutant telomerase RNA, the cells were ageing prematurely, their "senescence" was speeded up.

The scientists also showed that on the other hand, functional telomeres prevent chromosomal damage and delay cellular senescence, and later on Greider and her team showed that telomerase can delay senescence in human cells.

These discoveries led to intense activity in the field of ageing and the role played by telomeres in cellular senescence, which many scientists suggested was the key to the ageing of the organism as a whole. However, we now know that ageing of the overall organism is more complex than this and depends on several factors, only one of which is the part played by telomeres.

For instance, most normal cells do not divide frequently, so their chromosome integrity is not at risk and they don't need high telomerase activity.

One area that is attracting a lot of activity as a result of these discoveries is cancer research. Cancer cells have the ability to keep on dividing without suffering chromosome damage because they preserve their telomeres. This is a puzzle, because strictly speaking their telomeres should get shorter and shorter with each cell division until one day there isn't enough left to preserve chromosome integrity and thus they start ageing. But cancer cells appear to remain forever young: how do they escape cellular senescence?

One explanation appears to be that cancer cells often have increased telomerase activity, so one proposal is that cancer might be treated by eradicating their telomerase. This idea has already sparked off several studies, including clinical trials of vaccines that target cells with high telomerase activity.

Other areas of new research sparked by these discoveries has found that some inherited diseases are caused by telomerase defects, including some types of congenital aplastic anemia, where stem cells in the bone marrow don't divide enough. Other inherited diseases that affect the skin and the lungs appear also to be caused by telomerase defects.

Elizabeth H. Blackburn has US and Australian citizenship and since 1990 has been professor of biology and physiology at the University of California, San Francisco.

Carol W. Greider is a US citizen and was appointed professor in the department of molecular biology and genetics at Johns Hopkins University School of Medicine in Baltimore in 1997.

Jack W. Szostak is a US citizen and has been at Harvard Medical School since 1979, He is currently professor of genetics at Massachusetts General Hospital in Boston and is also affiliated with the Howard Hughes Medical Institute.

Source: Nobel Foundation.

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