The Nobel Prize in Physiology or Medicine 2009
for the discovery of how chromosomes are protected by telomeres and theenzyme telomerase"
Elizabeth H. Blackburn
Carol W. Greider
Jack W. Szostak
5 October 2009
The Nobel Assembly at Karolinska Institutet has today decided to award
The Nobel Prize in Physiology or Medicine 2009 jointly to
Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak
for the discovery of
"how chromosomes are protected by telomeres and the enzyme telomerase"
Summary
This year's Nobel Prize in Physiology or Medicine is awarded to three
scientists who have solved a major problem in biology: how the chromosomes
can be copied in a complete way during cell divisions and how they are
protected against degradation. The Nobel Laureates have shown that the
solution is to be found in the ends of the chromosomes – the telomeres –
and in an enzyme that forms them – telomerase.
The long, thread-like DNA molecules that carry our genes are packed into
chromosomes, the telomeres being the caps on their ends. Elizabeth Blackburn
and Jack Szostak discovered that a unique DNA sequence in the telomeres
protects the chromosomes from degradation. Carol Greider and Elizabeth
Blackburn identified telomerase, the enzyme that makes telomere DNA. These
discoveries explained how the ends of the chromosomes are protected by the
telomeres and that they are built by telomerase.
If the telomeres are shortened, cells age. Conversely, if telomerase
activity is high, telomere length is maintained, and cellular senescence is
delayed. This is the case in cancer cells, which can be considered to have
eternal life. Certain inherited diseases, in contrast, are characterized by
a defective telomerase, resulting in damaged cells. The award of the Nobel
Prize recognizes the discovery of a fundamental mechanism in the cell, a
discovery that has stimulated the development of new therapeutic strategies.
The mysterious telomere
The chromosomes contain our genome in their DNA molecules. As early as the
1930s, Hermann Muller (Nobel Prize 1946) and Barbara McClintock (Nobel Prize
1983) had observed that the structures at the ends of the chromosomes, the
so-called telomeres, seemed to prevent the chromosomes from attaching to
each other. They suspected that the telomeres could have a protective role,
but how they operate remained an enigma.
When scientists began to understand how genes are copied, in the 1950s,
another problem presented itself. When a cell is about to divide, the DNA
molecules, which contain the four bases that form the genetic code, are
copied, base by base, by DNA polymerase enzymes. However, for one of the two
DNA strands, a problem exists in that the very end of the strand cannot be
copied. Therefore, the chromosomes should be shortened every time a cell
divides – but in fact that is not usually the case (Fig 1).
Both these problems were solved when this year's Nobel Laureates discovered
how the telomere functions and found the enzyme that copies it.
Telomere DNA protects the chromosomes
In the early phase of her research career, Elizabeth Blackburn mapped DNA
sequences. When studying the chromosomes of Tetrahymena, a unicellular
ciliate organism, she identified a DNA sequence that was repeated several
times at the ends of the chromosomes. The function of this sequence, CCCCAA,
was unclear. At the same time, Jack Szostak had made the observation that a
linear DNA molecule, a type of minichromosome, is rapidly degraded when
introduced into yeast cells.
Blackburn presented her results at a conference in 1980. They caught Jack
Szostak's interest and he and Blackburn decided to perform an experiment
that would cross the boundaries between very distant species (Fig 2). From
the DNA of Tetrahymena, Blackburn isolated the CCCCAA sequence. Szostak
coupled it to the minichromosomes and put them back into yeast cells. The
results, which were published in 1982, were striking – the telomere DNA
sequence protected the minichromosomes from degradation. As telomere DNA
from one organism, Tetrahymena, protected chromosomes in an entirely
different one, yeast, this demonstrated the existence of a previously
unrecognized fundamental mechanism. Later on, it became evident that
telomere DNA with its characteristic sequence is present in most plants and
animals, from amoeba to man.
An enzyme that builds telomeres
Carol Greider, then a graduate student, and her supervisor Blackburn started
to investigate if the formation of telomere DNA could be due to an unknown
enzyme. On Christmas Day, 1984, Greider discovered signs of enzymatic
activity in a cell extract. Greider and Blackburn named the enzyme
telomerase, purified it, and showed that it consists of RNA as well as
protein (Fig 3). The RNA component turned out to contain the CCCCAA sequence
. It serves as the template when the telomere is built, while the protein
component is required for the construction work, i.e. the enzymatic activity
. Telomerase extends telomere DNA, providing a platform that enables DNA
polymerases to copy the entire length of the chromosome without missing the
very end portion.
Telomeres delay ageing of the cell
Scientists now began to investigate what roles the telomere might play in
the cell. Szostak's group identified yeast cells with mutations that led to
a gradual shortening of the telomeres. Such cells grew poorly and eventually
stopped dividing. Blackburn and her co-workers made mutations in the RNA of
the telomerase and observed similar effects in Tetrahymena. In both cases,
this led to premature cellular ageing – senescence. In contrast, functional
telomeres instead prevent chromosomal damage and delay cellular senescence.
Later on, Greider's group showed that the senescence of human cells is also
delayed by telomerase. Research in this area has been intense and it is now
known that the DNA sequence in the telomere attracts proteins that form a
protective cap around the fragile ends of the DNA strands.
An important piece in the puzzle – human ageing, cancer, and stem cells
These discoveries had a major impact within the scientific community. Many
scientists speculated that telomere shortening could be the reason for
ageing, not only in the individual cells but also in the organism as a whole
. But the ageing process has turned out to be complex and it is now thought
to depend on several different factors, the telomere being one of them.
Research in this area remains intense.
Most normal cells do not divide frequently, therefore their chromosomes are
not at risk of shortening and they do not require high telomerase activity.
In contrast, cancer cells have the ability to divide infinitely and yet
preserve their telomeres. How do they escape cellular senescence? One
explanation became apparent with the finding that cancer cells often have
increased telomerase activity. It was therefore proposed that cancer might
be treated by eradicating telomerase. Several studies are underway 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 congenital aplastic anemia, in which insufficient
cell divisions in the stem cells of the bone marrow lead to severe anemia.
Certain inherited diseases of the skin and the lungs are also caused by
telomerase defects.
In conclusion, the discoveries by Blackburn, Greider and Szostak have added
a new dimension to our understanding of the cell, shed light on disease
mechanisms, and stimulated the development of potential new therapies.
Elizabeth H. Blackburn has US and Australian citizenship. She was born in
1948 in Hobart, Tasmania, Australia. After undergraduate studies at the
University of Melbourne, she received her PhD in 1975 from the University of
Cambridge, England, and was a postdoctoral researcher at Yale University,
New Haven, USA. She was on the faculty at the University of California,
Berkeley, 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 born in 1961 in San Diego,
California, USA. She studied at the University of California in Santa
Barbara and in Berkeley, where she obtained her PhD in 1987 with Blackburn
as her supervisor. After postdoctoral research at Cold Spring Harbor
Laboratory, she 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. He was born in 1952 in London, UK and grew
up in Canada. He studied at McGill University in Montreal and at Cornell
University in Ithaca, New York, where he received his PhD in 1977. He has
been at Harvard Medical School since 1979 and is currently professor of
genetics at Massachusetts General Hospital in Boston. He is also affiliated
with the Howard Hughes Medical Institute.
References:
Szostak JW, Blackburn EH. Cloning yeast telomeres on linear plasmid vectors.
Cell 1982; 29:245-255.
Greider CW, Blackburn EH. Identification of a specific telomere terminal
transferase activity in Tetrahymena extracts. Cell 1985; 43:405-13.
Greider CW, Blackburn EH. A telomeric sequence in the RNA of Tetrahymena
telomerase required for telomere repeat synthesis. Nature 1989; 337:331-7. 又被美国垄断了。。。 楼主原来是博士？{:5_384:}
常来哦！！！ 其实，看看有可能获奖的成果，我们领域70%甚至80%以上都是美国人做的。所以拿奖也不奇怪了。 恩，这个领域确实牛人都在美国。不过去年倒是欧洲的天下，2个法国的加一个海德堡的，还指望今年也能看到一个欧洲面孔呢。
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