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Telomeres, Senescence, History
Posted on: May 27, 2003

Telomeres now are well known units of molecular cell system. They play great role in cell life cycle regulation, sometimes they are called molecular clock of the cell. Lets remember the history of telomeres, how everything started?

The cells

In 1908, A.Carrel, a Nobel prize-winning surgeon, became interested in the growth of cells in culture, in 1912; he established a culture of chick heart fibroblast cells, which he then grew in the laboratory for 34 years. This work led to the general acceptance of the notion that vertebrate cells can divide indefinitely in culture. As individual cells were immortal, Carrel reasoned that aging is "an attribute of the multicellular body as a whole". In 1961, this concept of cell immortality was challenged by experiments published by Hayflick and Moorehead. They found that fibroblast cultures derived from human skin would divide 40 to 50 times, and then stop and "undergo senescence". Further work showed chat cells from older people underwent fewer divisions than cells from younger people, suggesting that it was the total number or divisions since birth, not total divisions in culture that was important. When subsequent work showed that Carrel's immortal chicken cell cultures were not reproducible, Hayflick's senescence model eventually became accepted. Two important questions emerged from the nascent field of cellular senescence. First, what is the role of cellular senescence in humans? Does the limited capacity of cells to divide relate to human aging, or it is a mechanism to prevent tumor formation? Second, what tells cells to stop dividing?

The telomere

In 1978, Blackburn, working in Gall's laboratory at Yale, was interested in determining the DNA sequence that allowed the Tetrahymena rDNA molecule to be maintained as a linear chromosome. Her work led to the finding that chromosome ends, or telomeres, are made of simple repeat DNA sequences. It soon became apparent that this motif was conserved throughout evolution and that a common mechanism might exist in eukaryotes for the maintenance of telomeres. In 1984, working in Blackburn's laboratory, Carol W. Greider identified an enzyme, telomerase that added telomere repeats onto chromosome ends. He suggested that telomerase would compensate for the incomplete replication of chromosome ends. This would explain the telomere length maintenance seen in organisms such as Tetrachymena and yeast. Telomerase is an unusual polymerase; it contains an integral RNA component that provides the template for synthesis of telomere repeats.

The connection

Insight into the molecular structure of the ends of human chromosomes came from using a probe representing a sequence on the Y chromosome that was near enough to the telomere to follow the terminal chromosome fragment. Using this probe, Cooke found that telomeres in germ line tissue (sperm) were longer than telomeres in somatic tissue (blood cells), He speculated that telomere length is tissue-specific and that telomere length shortens between germ line and somatic tissues. Subsequently, the identification of the simple-sequence telomere repeat from human, cells allowed a simple analysis of telomere length and cell senescence. Harley, Furcher, and Greider then found that telomeres indeed shorten as normal human fibroblasts grow in culture. Telomeres were also shorter in skin samples from older people than from younger people, suggesting that the shortening was not a tissue culture phenomenon. At about the same time, Hastie and de Lange found that tumor samples had shorter telomeres than adjacent normal tissue, providing the first suggestion of a connection between telomeres and cancer.

The synthesis

In the early 1990s, a model emerged which had two parts: one that replaced telomeres to cell senescence, and the other that 1inked telomeres, telomerase and cancer. The model stated that telomeres shorten during growth of primary fibroblasts, because of the end replication problem and the absence of telomerase. Germ line cells, in contrast, have telomerase and thus maintain telomere length. Telomere shortening signals cells, to senescence. Senescence however can be bypassed by expression of viral oncogenes. During this extended life span, telomeres continue to shorten until the cell culture reaches a crisis. At crisis many cells die. The few cells that survive, can divide indefinitely. These cells have activated telomerase and maintain or even elongate telomeres. With the demonstration that tumor cells, like immortal cells in culture, express the enzyme, telomerase was proposed as a potential target for anti-cancer therapy. The reports by Bodner, Vaziri and Benchimol provided strong evidence for the first part of this hypothesis that telomere shortening is a mechanism that limits cell division capacity.

Later what they found was hTERT gene. The initial surprise was that simply expressing hTERT in primary cells led to telomerase activity. Although telomerase is composed of both protein and RNA, the RNA component is often present even in cells that do not normally have activity. Apparently, this level of RNA was sufficient for telomerase activity when hTERT was present. The next surprise was that the presence of telomerase activity in primary cells was sufficient for telomere elongation. Although it was the result that many had hoped for, as evidence suggested that the availability of telomere-binding proteins might limit telomere growth. At last the experiment was made: the frequency of senescent primary cell clones was compared between cell that had telomerase activity and those that did not. Cells with longer telomeres did not undergone senescence, whereas those with short telomeres did. So it was concluded and showed that telomere length was one criterion that determinate entry into cell senescence.

So telomeres and telomerase became the object of gerontology, oncology, cell biology etc.

Such a simple answer to a hard question! It's another example of nature's simple solution due to complicated questions. Nature does it in the simplest way.

Source: Carol W. Greider; Telomeres and senescence: The history, the experiment, the future; Current biology 1998, 8: R178-R181.
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