| 2000 |
|
YEAR BOOK |
| Apoptosis: the art of cell death |
University College Cork
Why, you may ask, is apoptosis a sexy area of research at the moment? There are a number of good reasons. The main one is that apoptosis is a fundamental process that cuts across the boundaries of many scientific disciplines. It is of interest to the immunologist, because of its role in cell deletion in the immune system and the deregulation of the process seen in a number of autoimmune diseases and AIDS. To the cancer biologist, apoptosis not only appears to contribute to the development of some cancers, but also hinders their treatment when cells become resistant to apoptosis and are not killed following drug treatment. Developmental biologists also have a keen interest in the process because of the programmed loss of cells which occurs via apoptosis during tissue sculpting and is part and parcel of embryonic development.
Man is a multicellular organism, and cell division takes place by a process known as mitosis as it does in almost all higher life forms. During mitosis, the cell duplicates its DNA and divides to form two daughter cells, each exact replicas of their parent. Cell division by mitosis is a regular event in our bodies and is, for example, responsible for the replacement of the cells that line our gastrointestinal and respiratory tracts. This sort of cell replacement occurs every few days. So, even though there is a considerable amount of mitosis constantly going on in multicellular organisms like ourselves, there is no real change in the total number of cells in our bodies. This of course implies that, for every cell that is generated via mitosis, one must die to balance the 'cellular account book' of life. The question is, how do cells die (and die they must) if this balance is to be maintained. When it comes to cell death, we now know that a cell can die by a process known as apoptosis. Every year the average human looses half of his/her body weight in cells via apoptosis!
In 1972, Andrew Wyllie and colleagues published a paper that described the cell death process of apoptosis. The term apoptosis is of Greek origin, and is used to describe the falling of a petal from a flower or the loss of a leaf from a tree. In pronouncing the word correctly, the second 'p' is kept silent. What may appear as a rather obscure origin for the derivation of the term apoptosis does in fact have some relevance to the features of the death process itself. As cells die by apoptosis, they round-up and literary fall off the supporting tissue structures on which they are growing, just like leaves falling from a tree in autumn. The process of apoptosis was identified 1972, but before that there were many examples of the process reported in the literature, albeit using different termin-ology.
While apoptosis was discovered in 1972, it was almost a decade before it caught the imagination of scientists. In the mid to late 80's, immunologists and developmental biologists rediscovered the 1972 paper of Wyllie and began to explore the underlying biology of apoptosis in both immunological and development systems. This led to a slow increase in the number of publications in the area by the end of the 80's. The 90's have seen an explosion in the number of papers devoted to cell death. In addition, there are several dozen books and a number of journals specifically devoted to the study of apoptosis. The reason for this rapid surge of interest is that scientists have realised that cell death via apoptosis is a fundamental biological process, which we know very little about. In addition, the idea of a death process with 'suicide genes' has stirred a 'Faustian' interest in the subject. The quest to discover why and how a cell switches on its death programme is one of the most active areas of biology as we go into a new century, and for good reason, for if we can understand the process by which a cell kills itself, we may be to able to interfere and either prolong the life of the cell or speed up its death. This is a desirable objective in a number of human disease conditions.
Another example of the role played by apoptosis is in the development of the neural system. During development, the body makes a huge excess of neurons. These cells then compete in the newly forming nervous system to make connections with other cells. If they fail to make these connections, they die via apoptosis. In fact close to 90% of all neurons formed during our life die by apoptosis because they fail to make life-sustaining connections with their neighbours. This type of connect or die process is vitally important, because it ensures that our nervous system, which so crucially depends on proper cell connections being made, is carefully put together to form a fully functioning neural network.
A final example from the world of the development biologist, and one which will be familiar to most people, is the reabsorption of the tadpole tail during its transition into a frog. The cells of the tail are destroyed by apoptosis.
Biological features of apoptosis
One of the key biochemical hallmarks of apoptosis is the fragmentation of the cell's DNA into nucleosome fragments, which can be seen in an agarose electrophoresis gel as a DNA ladder. This occurs due to the activation of an endonuclease enzyme, which sits in an inactive state in the cell until the apoptosis programme is switched on. During apoptosis, there are a number of dramatic changes in the morphology of the dying cell, and one of these is the extrusion of water from the cell, leading to its shrinkage. Cells can shrink up to fifty percent during this process. Almost nothing is currently known about how or why the cell undergoes this shrinkage process. In addition to cell shrinkage, there is also a marked condensation of the cell's chromatin, giving rise to the formation of pycnotic (dense) nuclei. The apoptotic cells are then engulfed and destroyed by neighbouring phagocytic (engulfing) cells. During this whole process, there is no leakage of the cell's contents into the extra cellular milieu since the integrity of the plasma membrane is maintained.
Cell stress and apoptosis
In nature, there is a constant struggle for survival as organisms are subjected to a variety of natural stresses during the course of their life. This struggle even exists at the level of the cell in multicellular organisms, and strangely cell death, via apoptosis, may have an important role to play in the organism's survival response in the face of stress.
For example, when a cell is exposed to stress due to environmental or biological insult, it either survives or dies. This is a fact of cell life. If the cell experiences a low level of stress, then the synthesis of a group of stress or heat-shock proteins can afford a level of protection to the cell, providing the stressing agent is removed after a short period. These stress proteins are found in almost all cell types, from bacteria to humans, and may be a primitive self defence system. If, however, a cell experiences an insult which is not sufficient to kill it outright, and from which stress/heat shock proteins cannot protect it, then the programme for apoptosis is activated and the cell dies in a controlled fashion. This is of clear benefit to multicellular organisms because, when a cell dies via apoptosis, its contents are not released to the cell's exterior as is seen in necrosis. Such a release would cause injury or even death to its near neighbours and this can have serious detrimental effects for the survival of other cells and the organism itself. In other words, by dying via apoptosis a cell is performing an altruistic act to save its cellular neighbours! Finally, if the cell experiences a high insult such that there is no time to activate the apoptosis programme, then death occurs via necrosis with clear-cut damage and injury to neighbouring cells to due the release of cell contents from the dying cell. Research on how cell stress leads to the activation of apoptosis is a focus of research interest in my laboratory in University College Cork
Apoptosis and disease
Deregulation of apoptosis is associated with several diseases, and these include cancer, AIDS and neurodegenerative conditions. In the case of cancer, inhibition of the normal process of apoptosis can lead to the development of tumours, as cells that would normally have died live beyond the 'sell by date'. Usually what happens in cases like this is that there is a deregulated expression of particular genes that block apoptosis. The expression of such genes also hinders the treatment of tumours, since they protect cells from toxins used in the treatment of many cancers. This type of drug resistance is a significant problem in the treatment of cancer.
Currently my laboratory is not only exploring the underlying cell biology of this phenomenon but also strategies of circumventing it. In AIDS, the HIV virus infects a key cell in the immune system and destroys this cell by activating its apoptosis programme. This in turn leads to the collapse of the whole immune system with well-known consequences. Apoptosis in the central nervous system is also thought to play a key role in loss of cells, which is a key feature of diseases such as Alzheimer's and other related diseases.
Final comments
I am grateful to the many students, researchers and collaborators who have contributed to my work on apoptosis over the last ten years. I must also express my gratitude to organisations that have provided invaluable financial supports for research in this area. These include The Irish Cancer Society, The Children's Leukaemia Research Project, RP Ireland Fighting Blindness, The Health Research Board, Enterprise Ireland, the EU, and industries such as Schering Plough and Bausch and Lomb.
Contact: t.cotter@ucc.ie
* Professor Tom Cotter was the recipient of the 1999 Boyle Medal, awarded by the Royal Dublin Society and The Irish Times for scientific research of exceptional merit carried out in Ireland. The award carries a bursary of £30,000 to allow the recipient to employ a researcher for a period of three years in order to further advance the research.