2002 Nobel prize winners reveal a message of death in the code of life

RESEARCH by this year's Nobel Prize-winning biologists will have significant implications for a broad range of disease including ocular disorders such as inherited retinopathies, age related macular degeneration (AMD) and glaucoma.

The biologists, Robert Horovitz, Sydney Brenner and John Sulston, won the 2002 Nobel Prize for Physiology or Medicine for "their discoveries concerning genetic regulation of organ development and programmed cell death", as cited by the Nobel committee.

The discoveries of the three scientists has opened an entirely new field of biological research termed "apoptosis", although the phenomenon itself has existed for aeons.
Apoptosis genetically controlled
So what is apoptosis? It is a genetically controlled mechanism of cell death in which the cell activates a specific set of instructions that 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 mechanically or receives some shock whereby it is unable to continue carrying out the activities of life.

Although the end result of both apoptosis and necrosis are the same - i.e. the death of the cell - the mechanisms leading to such death are crucially different. Whereas necrosis is characterised by swelling, rupture, leakage and inflammation, apoptosis appears as a more deliberate and choreographed affair.

Although apoptosis may initially appear to be a code of death, it may be more accurately described as an in-built 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.

Apoptosis in AMD
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.
It is this form of death that often characterises the death of photoreceptors in the retina in cases of AMD and inherited retinopathy.

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?

Cell death means 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.
The researchers just recognised by the Nobel committee showed this elimination is 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 way, as a tadpole develops into a mature adult frog it must delete its tail cells in preparation for an amphibian existence.
So why all the interest? Apoptosis is appropriate under many circumstances - such as the limb bud development - 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 treat a wide variety of human diseases.

Too little apoptosis bad
Diseases associated with too little apoptosis include many cancers such as follicular lymphomas, some carcinomas, breast, prostate and ovarian 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, ischaemic injuries such as stroke, heart attack, and reperfusion injury and finally, AIDS.
It is this growing impact of the phenomenon of apoptosis on an expanding list of diseases that fuels the current surge in biological research. Because apoptosis appears to be a common link among such a variety of modern ailments, there is great potential for developing therapeutic interventions to treat several diverse disorders.

Cancer and apoptosis
One such disorder, 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 - 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.

Role of 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, which continually appear to be involved in some way with malignant growth.
It is now coming to light that 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, the mechanisms of both being mediated by common cellular proteins.

Apoptosis decision-making
Two questions of paramount importance now arise: what criteria does a living cell evaluate in making the decision whether to commit either to cancer or to apoptosis? If science could define these criteria could we then persuade cells to make more "appropriate" decisions? Such questions are currently the topic of vibrant research all over the world.
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 rather more useful for them to stick around?

Retinitis pigmentosa affected
Retinitis pigmentosa 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 while the majority are legally blind by the age of 60.

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.

AIDS and apoptosis
Similarly, many viral diseases such as AIDS and many neurological afflictions like 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.
From a broad perspective, a picture is beginning to emerge to illustrate that, whether the disease is characterised 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 that allows us to turn on or off the apoptotic machinery as circumstances require. So where are we to look for appropriate opportunities to interfere with the programmed cell death apparatus?

Apoptosis signals
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 or not 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 four distinct stages: the decision to commit to apoptosis; the operation of the cell death machinery; the phagocytosis of the apoptosed cell; and the engulfment of the remnants of the cell corpse.
It is obvious that the first two stages provide the greatest opportunity for therapeutic intervention. There has been much basic research performed on the signalling processes that leads the cell to an apoptotic commitment.

However, the sheer volume of components involved in the biochemical cascades of signalling favour the identification of a viable target for therapy sooner rather than later.
In the various fields of biomedical science, the discovery of apoptosis is one of the most exciting developments of the past twenty years; it is slowly being recognised that most areas in modern medicine - including many in ophthalmology - will benefit from this surge of research.

Apoptosis responsible for foetal hand development

A classic example of developmental apoptosis may be observed in the growing limb buds of a human foetus in the womb. For a developed hand to form from the immature limb bud, the tissue joining the individual digits together must be removed; that removal process occurs 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, is fundamentally the same.

Newton's 'gravity apple' an apoptosis event

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 "apoptosis" event.

The word originates in the Greek description for the shedding of leaves as autumn progresses. The drifting flight of a leaf from the tree - or fall of an apple - occurs as cells between the leaf stem or fruit stem and branch gradually die off by the process of programmed cell death.

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