When SIR Isaac Newton's famous apple impacted unceremoniously on his wise head not only did he unlock the secrets of gravity, he also fell victim to an explosive phenomenon of current biological research termed "apoptosis".
In the various fields of biomedical science, the discovery of apoptosis is one of the most exciting developments of the past 20 years. It is slowly being recognised there are few areas in modern medicine that will not benefit from this surge of research.
So what is apoptosis? Apoptosis is a genetically controlled mechanism of cell death in which the cell activates a specific set of instructions which lead to the deconstruction of the cell from within. Such cell death contrasts markedly with the more familiar mechanism known as necrosis. Necrosis occurs when a cell is injured or receives some shock whereby it is unable to continue carrying out the activities of life. Though the end result of both apoptosis and necrosis are the same, that is, the death of the cell, the mechanisms leading to such death are crucially different. Necrosis is characterised by swelling, rupture, leakage and inflammation. Apoptosis appears as a more deliberate and choreographed affair. Cells dying by apoptosis replace swelling with shrinkage and rupture with an elegant packaging of cellular contents into a convenient size for disposal. There is no leakage of cellular material and no inflammation. The remaining fragments of an apoptosed cell are neatly and quietly disposed of by either neighbouring healthy cells or by the body's household staff - the macrophages.
Apoptosis is a silent mode of death often referred to as "cell suicide" or "programmed cell death" because the cell plays an active role in its own demise. Intriguingly, this code of death emanates from the renowned code of life -DNA - whose mystery was unravelled by Watson and Crick in 1953. It transpires that locked into each and every one of our cells is the capability for self destruction. So why should evolution retain a set of instructions for death through thousands of generations of human life?
To understand the existence of a suicide program written into our genes we need to look at death in a different light. Without cellular death there would simply be no development. The proper development of multi-cellular organisms depends very much on the orchestrated elimination of selected cells. Research has now shown this elimination to be mediated through apoptosis. Much of the classical research into apoptosis has been carried out on a simple roundworm known as Caenorhabditis elegans, an organism consisting of exactly 1,090 cells. As this worm matures to its adult form it loses precisely 131 of these 1,090 cells, all of which die apoptotically. In a similar fashion, as a tadpole develops into a mature adult frog it must delete its tail cells in preparation for an amphibian existence. A classical example of developmental apoptosis may be observed in the growing limb buds of a human foetus within the womb. For a developed hand to form from the immature limb bud, the tissue joining the individual digits together must be removed - it is now known that this task is achieved through apoptosis.
The antiquity and ubiquity of apoptosis as a biological process is underscored by the fact that many of the genes known to control apoptosis in the simple roundworm are found to have very similar counterparts in humans. Thus, apoptosis in dinosaurs and daisies and in mice and men, at a fundamental level, is essentially the same.
So why all the interest? Apoptosis is appropriate under many circumstances (such as the limb bud above) and it is currently accepted to be a normal physiological process continuously occurring from day to day in the human body. However, if apoptosis does not occur as it should, or if it occurs to excess then the resultant imbalance in a cell population can lead to serious consequences.
It has been well documented that apoptosis is a genetically controlled mechanism of cell death - if we could manipulate this genetic programme to our own ends then we may greatly advance our ability to treate a wide variety of human diseases. Diseases associated with too little apoptosis include many cancers, autoimmune diseases and many forms of viral infection which interfere with the apoptotic machinery. Diseases associated with too much apoptosis include neurodegenerative disorders such as Retinitis pigmentosa, Parkinson's disease and Alzheimer's disease, stroke, heart attack, and AIDS.
Cancer has for decades been perceived to be the result of uncontrollable cell division. However, if we look at cancer in another light (the light of apoptosis) we may simultaneously perceive it to be the result of inefficient cell death. Just as too much cell division leads to cancer, too little cell death may also create the same net effect - that is, an accumulation of unneeded cells.
Of the many types of cancer in existence the vast majority involve a mutation in a gene known as p53. Cells grown in the laboratory containing a mutated version of the p53 gene readily undergo transformation into tumour cells giving rise to rapid malignant growth. It is no coincidence then that research into the mechanism of apoptosis has revealed an intimate connection with this mysterious p53 gene. Several different experiments in many independent laboratories have demonstrated that the restoration of p53's function results in active apoptosis and the reversal of malignancy. Suddenly, the vast majority of human cancers make perfect sense - if p53 is one of the mediators of apoptosis and, for whatever reason becomes dysfunctional, then the cell loses its ability to activate its cell suicide machinery. It is this lack of ability that leads to the development of many forms of cancer.
Studies in several cancers have thrown up a handful of regular players, like p53, that continually appear to be involved in some way with malignant growth. Many of these old players in cancer are also turning up to be new players in the mechanism of programmed cell death. Cancer and apoptosis seem to be different sides of the same coin, both being mediated by common cellular proteins. Two questions of paramount importance now arise: how does a living cell decide to commit either to cancer or apoptosis? If science could understand this, could we then persuade cells to make more ["]appropriate["] decisions? As we have seen, cancer is a prime example of a cell's inability to die at a convenient time for the benefit of the organism as a whole, but what happens when cells readily activate their death machinery and begin to die when it would be more useful for them to stick around?
Retinitis pigmentosa (RP), is the collective term for a group of debilitating degenerative disorders that affect the light-capturing cells at the back of the eye known as photoreceptors. These genetically inherited diseases affect over one and a half million people worldwide. Some sufferers may become blind as young as 30 years of age while the majority are legally blind by the age of 60. For over 10 years, research funded by the Wellcome Trust, RP Ireland, the HRB, the Medical Supply Company and many others, have permitted the Ocular Genetics Unit at Trinity College Dublin to focus on degenerative retinal diseases. Many of these photoreceptor ailments can arise from a broad array of genetic mutations in different genes. However, it is very probable that despite the initial diversity of cause, many of these disorders progress in a comparable fashion with a gradual apoptotic loss of photoreceptors. Similarly, many viral diseases such as AIDS, and many neurological afflictions such as Parkinson's and Alzheimer's progress through their ability to manipulate the apoptotic machinery. Despite the fact that biology has classified humans as complex and sophisticated, it is the viruses, such as HIV, classified as simple and primitive, that have perfected the technology in subverting the apoptotic programme to their own ends. Whether the disease is characterized by insufficient cell death, as in cancer, or by an excess of cell death, as in degenerative illnesses, there is an underlying mechanism to connect the two. Many of these diseases may be amenable to therapy by developing technology allowing us to turn on or turn off the apoptotic machinery as circumstances require. So where are we to look for appropriate opportunities to interfere with the programmed cell death apparatus?
Cells in a living system are in continuous communication with each other, with themselves and with distant tissues and organs. They achieve this through an intricate and sophisticated system of chemical signalling pathways many times more complex than any man made machine. When a cell has evaluated the variety of incoming information a decision is made on whether to commit to apoptosis. Once the cell has committed itself to the suicide programme the machinery of death is unleashed.
The process of programmed cell death may be divided into 4 distinct stages: a) the decision to commit to apoptosis, b) the operation of the cell death machinery, c) the phagocytosis of the apoptosed cell and finally, d) the engulfment of the remnants of the cell corpse. It is obvious that the first two stages provide the greatest opportunity for therapeutic intervention. At present, the more attractive appears to be the actual protein tools of the apoptotic programme - the "caspases". Recent research has uncovered this new family of proteins as the mediators of the cell death program. This family of proteins represents the executioners responsible for the internal deconstruction of the cell, and the deciphering of their exact biochemistry is the subject of an energetic research programme by Dr Seamus Martin and colleagues of the National University of Ireland at Maynooth. The caspases are a group of proteins that act as a selective set of molecular scissors capable of cutting a variety of structural and physiological proteins in the cell. Though there are many types of caspases, they all possess a similar shaped blade which provides researchers with the opportunity of a common therapeutic target. Designing a sheath to house these blades is one route to preventing the deconstruction of the cell progressing. Such a strategy is currently underway at the Ocular Genetics Research Unit at TCD under the direction of Professor Pete Humphries, Dr Jane Farrar and Dr Paul Kenna. Preventing these scissors from doing their work or, inhibiting the cellular signals from unleashing these mediators of apoptosis, are areas of very active research in many molecular biology laboratories.
What initially appears to be a code of death may be more accurately described as an inbuilt code for the progression of life itself. The movement of the seasons, the cycle of nature and the development of our own bodies and brains from the womb to death are all dependent on the successful operation of this most fascinating of genetic secrets.
Finally, it is the ancient Greeks who may claim credit for the labelling of this biological process. The word "apoptosis" originates with the Greek description for the shedding of leaves as autumn progresses. The drifting flight of a leaf from the tree to the earth occurs as cells between the leaf stem and branch gradually die off by a process of programmed cell death.