Nobel Telomeres

Nobel Prize in Physiology or Medicine — 2009
Peter Petrov, ElementsThis year, for the third time in a row, the Prize in Physiology and Medicine will be shared by three scientists again.

It was awarded "for the discovery of how telomeres and the enzyme telomerase protect chromosomes" ("for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase"). The discoverers of telomerase and the mechanism provided by these enzymes to protect chromosomes from shortening live and work in the USA. These are Elizabeth H. Blackburn from the University of California, San Francisco, Carol W. Greider from Johns Hopkins University School of Medicine and Jack W. Szostak from Harvard Medical School.

Elizabeth Blackburn was born in 1948 in Australia — in Hobart, the capital of Tasmania — in a family of doctors. When she was a schoolgirl, her family moved to Melbourne, where Blackburn studied at the University of Melbourne for college and a master's degree. She then went on to graduate school at Cambridge and received her PhD there. Subsequently, Blackburn worked for two years at Yale University, after which (in 1978) she moved to the University of California at Berkeley, where her most important discoveries related to telomerase were made. In 1990, she moved to another branch of the same huge university — the University of California in San Francisco, where she works to this day. In addition, she is an employee of the Salk Institute in San Diego, and from 2002 to 2004 she worked as a member of the Presidential Council on Bioethics. Her exclusion from this council is attributed to her position on the issue of embryonic stem cell research, which was objectionable to the administration of George W. Bush, who vetoed federal funding for these crucial studies. In April of this year, Blackburn was elected president of the American Association for Cancer Research (American Association for Cancer Research) and next year should lead this association.

Carol Greider was born in 1961 in San Diego (California). In 1983, she received a bachelor's degree from the University of California, Santa Barbara, after which she moved to the University of California, Berkeley, where Elizabeth Blackburn became her supervisor. Already in 1985, an article by Grader and Blackburn was published in the journal Cell, reporting the discovery of telomerase. After receiving her doctorate in 1987, Grader became an employee of the Cold Spring Harbor Laboratory, and in 1997 she moved to Johns Hopkins University, where she still works as a professor. The laboratory, headed by Carol Greider, continues to study telomeres and telomerase.

Jack Shostak was born in London in 1952. His parents soon moved to Montreal, where he attended college at McGill University and graduated with a bachelor's degree in 1972. He received his doctorate in 1977 at Cornell, where he remained for two more years, after which he moved to the Harvard School of Medicine, where he still works today as a professor in the Department of genetics. In addition to Harvard, Shostak is an employee of two other institutions — the Massachusetts General Hospital and the Howard Hughes Medical Institute. In addition to the discovery of telomerase, Shostak was the first to synthesize artificial yeast chromosomes. The creation of such artificial chromosomes has found wide application in mapping the genes of animals, including humans, and in the development of genetic engineering technologies. Currently, Shostak's Harvard laboratory deals primarily with issues related to the origin of life, and is working on the artificial synthesis of living cells.

At first, the functions of telomeres were unknown, as well as the sequence of nucleotides included in their composition was not known. In the late fifties, the enzyme DNA polymerase was discovered, which ensures the doubling of DNA molecules. To start working, this enzyme must join a primer synthesized by another enzyme — a short RNA fragment sitting on a DNA chain, which is subsequently removed. In this case, DNA polymerase can move along the DNA chain only in one direction - from the 5' end to the 3' end. As a result, DNA polymerase cannot completely copy the entire DNA molecule: an uncopied fragment must remain at one of the ends to which it is attached.

This was first noticed, independently of each other, by Alexey Matveevich Olovnikov (Olovnikov A.M. 1971. The principle of marginotomy in matrix synthesis of polynucleotides // Reports of the USSR Academy of Sciences. Vol. 201. pp. 1496-1499; Olovnikov A.M. 1973. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon // Journal of Theoretical Biology. V. 41. P. 181-190) and James Watson (Watson J.D. 1972. Origin of concatemeric T7 DNA // Nature New Biology. V. 239. P. 197–201). It turned out that the chromosomes should shorten with each cell division due to non-copied end sections. Watson suggested how this problem should be solved in bacteriophages, whose DNA is also not closed in a ring, and Olovnikov described how it can be solved in eukaryotes, and hypothesized the existence of an enzyme capable of adding repeating sequences to the end of the chromosome. He also suggested that the regulation of this enzyme may play a key role in the aging of the body (due to the gradual shortening of the end sections of chromosomes in cells that should divide only a limited number of times) and that malfunctions in the mechanism of such regulation may be the cause of uncontrolled cell division of malignant tumors.

Soon, repetitive sequences were actually discovered in the telomeres of some organisms. Experiments conducted in the laboratory of Jack Shostak at Harvard School of Medicine have shown that foreign DNA fragments embedded in yeast cells are capable of doubling, but, unlike yeast's own DNA, they do not exist in dividing cells for long. Elizabeth Blackburn, as a graduate student at Cambridge, mastered the DNA sequencing techniques developed at that time (reading the sequence of nucleotides) and subsequently at Yale established which sequence is repeated at the ends of chromosomes in the Tetrahymena thermophila infusoria (CCCAA). Meeting at a conference in 1980, Shostak and Blackburn conceived a joint experiment, the results of which indicated that it was telomeres that protect yeast's own chromosomes from degradation during repeated cell division. The researchers attached fragments with a repeating sequence of nucleotides found in the infusoria to small foreign DNA fragments and introduced the resulting molecules into yeast cells. Such molecules were successfully doubled in yeast cells, along with yeast's own chromosomes, and at their ends, as a result, there was a repeating sequence of nucleotides characteristic of yeast's own telomeres. The publication of these results in the journal Cell was the first work to experimentally demonstrate the protective role of telomeres.

The end section of the chromosome is the telomere.
Each chromosome contained in the nucleus of a cell,
before division , the cell is represented by two identical halves — chromatids,
each of which is based on one very long,
but a compactly folded DNA molecule,
at each end of which there are sections
from repeating sequences.
These end sections are telomeres.
In preparation for division, when chromatids double,
the ends of each chromosome would always shorten
(the DNA doubling mechanism does not allow them to be copied),
if the enzyme telomerase did not build up at the ends
new repeating sequences.

Shostak and Blackburn, following Olovnikov, suggested that the build-up of telomeres is provided by a certain enzyme. The search for this enzyme has begun. In 1984, Carol Greider, who was still a student at the time and worked under the guidance of Elizabeth Blackburn, was able to identify him for the first time. In an article also published in Cell, Grader and Blackburn first described the properties of the enzyme they discovered and called it telomerase. Studying this enzyme, they found an RNA fragment included in its composition, on the matrix of which repeated sequences of nucleotides are synthesized, added by telomerase to the end sections of chromosomes. This discovery was described in an article published in Nature.

The scheme of the telomerase enzyme (telomerase).
The enzyme increases the end sections of chromosomes,
by adding identical sequences of nucleotides to them.
This process involves two alternating stages:
(a) elongation, i.e. elongation, and (b) translocation, i.e. displacement.
During elongation, the end section of the DNA chain is bound to the RNA template,
part of the enzyme, and is lengthened by the nucleotides attached to it,
complementary to the free part of the matrix.
During translocation, the DNA molecule shifts by several nucleotides,
again freeing up a section of the RNA matrix, and the cycle repeats.
At the same time, only one DNA chain is built up, but a complex of other enzymes,
the basis of which is DNA polymerase, completes most of the second chain.
Only a small "tail" at the very end remains single-stranded.
If not for telomerase, such tails would shorten the length of double-stranded DNA
with each of its doubling, and any chromosome would be shortened
at each cell division.

Further studies conducted in the laboratories of Blackburn and Shostak showed that cells deprived of telomerase sooner or later stop dividing and die. Many types of cancer cells, on the contrary, have increased telomerase activity, which contributes to their uncontrolled division and the formation of malignant tumors. As suggested by Olovnikov, telomeres turned out to be an important tool for regulating both aging and the occurrence of cancer. Currently, drugs have already been developed and are being tested, which may make it possible to fight a number of forms of cancer by suppressing the activity of telomerase in cancer cells.

The development of congenital dyskeratosis (dyskeratosis congenita), a rare hereditary disease that causes premature aging of the skin, is also associated with the work of telomerase. The symptoms of this disease are associated with disorders in the regulation of telomere length. Congenital dyskeratosis is not yet able to be treated, but further research may allow us to find ways to stop its development.

Although the general principle of telomerase is already clear, many important details have yet to be clarified, in particular the regulatory mechanisms that prevent telomeres from growing indefinitely and determine their reduction in aging cells. As for the role of telomeres in aging, much remains unclear here, too, although a reduction in their length is indeed characteristic of aging eukaryotic cells.

According to the will of Alfred Nobel, no more than three scientists can share each prize. It is a pity that Olovnikov, who predicted the discovery noted by her, was not among those who received this award. At the same time, Blackburn, Grader and Shostak, who have devoted many years to successful experimental studies of telomeres and telomerase, undoubtedly deserve this award.

This year, one Nobel Prize was shared by two women for the first time in history. Among those who study telomeres today, there are an unusually large number of women. It is possible that this is no coincidence: the example of Elizabeth Blackburn and Carol Greider, who discovered telomerase and found out the structure of this enzyme, inspires other women to continue research in this area.

Main sources:
1) Alison Abbot. Chromosome protection scoops Nobel // Nature News. Published online 7 October 2009.
2) Gretchen Vogel. Three Americans win Physiology or Medicine Nobel // ScienceNOW Daily News. Published online 5 October 2009.
3) The Nobel Prize in Physiology or Medicine 2009 (message on the website of the Nobel Committee).

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12.10.2009