Science: Death is our best friend for life: Knowledge of how cells constantly die may provide treatments for the most dangerous diseases. Ruth McKernan reports
Monday 17 May 1993
The predestined death of cells in the body is a normal process. It is vital in sculpting the body during foetal development. As a hand forms, two things happen: the fingers grow, but the web of skin between them dies. To shape a human body without programmed cell death would be like trying to make a chair without a saw and sandpaper.
The same principle applies during formation of many other tissues, including skin, brain and components of the immune system. Cells must die to allow new features to evolve. In other words, death becomes us.
In the developing brain, a complex network of connections form. To ensure that cells are correctly 'wired up', double the necessary number of cells are made.
Those which do not make proper contacts die automatically. Half of our brain cells are lost in this way. If we survived without programmed cell death, we could have brains twice the size, skin inches thick and webbed feet.
Scientists believe it is preferable for cells to die in a programmed way rather than necrotically, whereby a cell 'spills its guts' and activates a series of inflammatory clean-up systems. The quick and economical removal of cells is akin to dismantling a building carefully rather than demolishing it.
Programmed cell death is important not only in development but throughout life as well. Over four to five years, virtually all the molecules in our bodies are replaced, yet we remain pretty much the same, barring perhaps a few extra wrinkles and grey hairs.
According to Gerard Evan, a senior scientist from the Imperial Cancer Research Fund (ICRF) in London, programmed cell death is largely responsible for maintaining the status quo. 'Every normal cell when it starts to divide becomes a threat to the body.'
Just one cell in which the suicide pathway has gone awry is enough to cause cancer and death of the whole animal. As a failsafe mechanism, whenever a cell is instructed to grow it will also be given the potential order to die.
It is probably better to lose functional cells than to risk keeping overactive ones. For example, a party-goer can drink to excess, lose a few irreplaceable brain cells and, provided this is not a regular event, be little the worse for it. 'For a large organism, cells are cheap - it is the whole animal that is important,' Mr Evan says.
Individual tumour cells spring up all the time but are nipped in the bud by cell death. The ICRF has found that in several tumours, a gene (c-myc) which normally promotes cell growth, is active when it should not be and seems to push the cell one step closer to being cancerous.
Other failsafe mechanisms can still trigger cell death, and it is only when there are multiple mutations that the cell will escape with its life and develop into a tumour. With greater understanding of the suicide pathway, scientists may be able to activate it in tumour cells and persuade them to self-destruct.
Martin Raff, professor of biology at University College London, believes programmed cell death does not just prevent cancer; it exists in all our cells all the time. 'Left to themselves, our cells will actively kill themselves unless continuously instructed by other cells not to do so,' he says.
The command to stay alive comes in the form of constant stimulation by growth factors and other recently discovered signalling molecules.
Several factors that can rescue nerve cells from death under laboratory conditions are undergoing clinical trials for treatment of the neuro-degeneration that underlies motor neuron disease.
As with all bodily processes, cell death is controlled by genes - so far, only a few have been identified - and rendering them inactive has serious repercussions.
One might imagine that removing a gene for cell death would make an animal live longer. Not so. Flies fail to develop at all, and the microscopic worm C. elegans lives only as long as its normal relatives, but with an extra 131 cells. Scientists know little about the genes controlling cell death in humans, but they have found one, similar to the worm gene, which means that the process is fundamentally important and conserved throughout evolution.
Two British scientists, Tom Curran and James Morgan, associate director and head of neurobiology respectively at the Roche Institute for Molecular Biology in the United States, are investigating what happens once the lethal process is switched on.
They report in Nature that they have found a gene (c-fos) which is activated in cells destined to die, the earliest event identified so far. They do not yet know whether this gene directs or merely monitors cell death, but it is active for prolonged periods whenever cell death takes place, during development of the hand or brain and, like a harbinger of death, under other circumstances too.
'It happens in all situations we've looked at: naturally, in response to an environmental toxin and after anti- cancer agents,' Dr Morgan says. While turning on cell death may be useful in controlling cancer, however, it may have dire consequences in more specialised brain or nerve cells that do not divide and cannot be replaced.
Some scientists believe that disorders in which brain cells are lost could result from problems with the suicide system. Two environmental toxins, domoic acid and kainic acid, present in algae and concentrated throughout the food chain, are neurotoxic to humans and other species. When administered to laboratory animals, Drs Curran and Morgan found that both chemicals turn on the 'grim reaper' gene and nerve cells subsequently die.
In an animal model of Parkinson's disease, where mice lost brain cells of the same type and location as in human sufferers, the Roche group found that the gene was activated only in the relevant cells.
'If we could find agents that prevent our gene switching on, these would be candidates for the treatment of Parkinson's disease,' Dr Curran says.
In principle, factors that prevent cell death or rescue dying cells may be useful in treating many degenerative diseases, including Alzheimer's. And now that there is a 'window on the process of cell death', the Roche group says that scientists can begin to seek such therapeutics.
Programmed cell death has brought scientists from different fields together. Italian scientists suspect that the agent which causes bovine spongiform encephalopathy - better known as mad cow disease and the related human Creutzfeldt-Jakob condition - can also activate the cell death programme.
Although programmed cell death has not been proved responsible for any disease, so many links have been found that there is excitement among medical researchers.
The fatal system may well turn out to be as fundamental as life itself. Contrary to Woody Allen's pessimistic dictum, it may now be possible to experience one's own death objectively, and still carry a tune.
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