The search for immortality brings immediate benefits

Reading the latest blog in Carey's Commentary entitled 'Telomerase – Elixir of youth or something more Nobel?' about the recent award of the Nobel Prize for Physiology and Medicine to three scientists, set me thinking about one of the applications of their discovery that the charity I used to work for (FRAME – Fund for the Replacement of Animals in Medical Experiments) has been utilising in its development of non-animal models of disease and toxicity testing.

The three Nobel Laureates showed that the ends of chromosomes (that contain DNA in plant and animal cells) are protected by structures called telomeres. Cells age by a process of progressive shortening of these telomere regions which occurs at every cell division. However, they also discovered an enzyme called telomerase that can reverse this process. These findings have obvious implications for research on ageing, but they have been applied in other ways, one of which I explain below.

The individual cells that make up the tissues and organs from animals, including humans, can be maintained and grown outside the body in a process called tissue culturing. Such cells can be used for biomedical research, and in the development of new products, such as drugs and cosmetics by testing for efficacy and safety. Scientists then extrapolate from the responses and properties of cells observed when outside the body to predict how they might function and react inside the body, and, by implication, how the whole animal might react and function. These are known as in vitro models, as opposed to the in vivo situation of using whole animals. It is even possible to get the cells to grow into three dimensional representations of some organs and tissues, which more closely model the in vivo situation.

One major advantage of using tissue culture over studying whole animals is that human cells can be used, thereby simplifying the problem of interpreting the meaning of the data obtained, since animals and their cells may well not react and behave in the same way as humans and their cells. However, there are problems with obtaining human cells for tissue culture, particularly primary cells. These are cells that have been taken directly from a tissue, whether it be the liver, the kidney, the lung, the skin, the brain and so on, and then cultured in vitro. Primary cells of each tissue are the most useful type of cell to study in vitro as they exhibit characteristics that differentiate them from those cells in each of the other types of tissue. Therefore, primary cells allow the study of some aspects of tissue function, without the ethical implications of either using animals or humans directly.

There are, however, two serious problems with studying primary cells, once they have been removed from the body. These limitations, which are particularly acute when using human cells, are firstly due to the fact that primary cells have a finite life span and senesce in tissue culture, and secondly they tend to de-differentiate (lose their defining characteristics). These changes seriously compromise their usefulness, and mean that primary cells have to be isolated repeatedly from fresh tissue, which is not always available when it is most needed. This is time-consuming, logistically difficult and raises ethical problems, particularly in the case of primary human cells, which are in short supply in any case.

The problem of senescence can be overcome by using cell lines, which have often been obtained originally from tumours, or from primary cell cultures that have been treated in certain ways. Such cells can continue to proliferate in culture and can be maintained free of the body indefinitely, as long as they are kept under the right conditions. There are many human and animal cell lines that are routinely used in research and testing. Such cell lines long outlive their original donors, be they human patients or animals. However, most cell lines, especially those obtained from tumours, still suffer from the problem of de-differentiation and they have undergone changes that are associated with cancer and therefore might not be useful for research.

One way to solve this limitation is to use cells that have been immortalised, as these combine the properties of both primary cells and cell lines. In other words, they retain their differentiated status and do not senesce in tissue culture. Several techniques have been tried for producing immortalised cell lines from primary cells, with varying degrees of success. The discovery of the telomerase enzyme and its role in reversing the loss of the telomere regions at the ends of chromosomes (structures that carry the genetic information in cells), has led to the development of one of these immortalisation techniques. Each time a cell divides to form two cells, telomere regions are progressively lost from the chromosomes and the cell ages. This phenomenon is called 'telomere-controlled senescence'. When a cell has undergone a certain number of divisions it differentiates into a nerve cell, or a liver cell, for example. If the loss of telomeres from the chromosomes in a primary cell could be reversed, the cell could continue to divide, even though it has differentiated. A technique that can cause these changes in primary cells could, therefore, be a way of immortalising them.

Telomerase is a way of immortalising cells, since it blocks the erosion of telomeres from the ends of chromosomes at cell division thereby inhibiting 'telomere-controlled senescence'. The enzyme does this by restoring the DNA sequences in the telomere chromosome ends that were lost at each division. However, the gene for this enzyme (known as hTERT) is only normally expressed in cells undergoing early development in the embryo. The technique of telomerase immortalisation involves the artificial introduction into primary cells of this telomerase gene, which is then expressed to produce the enzyme which restores the telomeres, forming differentiated cells that can continue to divide in culture, and which do not become cancer cells.

The above method has been much the most successful of the techniques for immortalising primary human cells that have so far been tried, and has greatly facilitated the availability of human cells that are useful for undertaking biomedical research and testing, without having to rely on repeated supplies of primary cells from biopsies and other sources, or having to use animal models of disease and toxicity.

It is no exaggeration to say that the discovery of telomeres and their function in cellular senescence, as well as the elucidation of the role of telomerase in reversing this process, have revolutionised the science of tissue culturing with all of its varied applications.

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