Science: Suicide: Your Life Depends On It

The mysterious voluntary suicide of healthy cells has become the hottest research topic of the Nineties, with pharmaceuticals companies throwing millions at it in the hope that it will lead to cures for our deadliest diseases. Martin Raff reports

THE SUBJECT of suicide is frequently in the news. Are there circumstances where it should be made easier? Should doctors assist? While societies struggle for answers to these ethical questions, the cells in your body are just doing it - and in enormous numbers, too.

Every minute of every day, millions of your cells kill themselves, even though they are perfectly healthy. Not only do they self-destruct, but they sometimes help other cells to do the same.

You need not worry, however, about all this death going on inside you - it is good for you. Indeed, it is essential - without it you would die, and what's more, you'd never have been born. The reason you do not shrink away and disappear as a result of this large-scale cell destruction is that for every cell that dies, another is produced to take its place. But just how our tissues maintain this precise balance between cell death and cell production remains a mystery.

It is about 150 years since it was first recognised that all living things are made up of cells, the basic units of life. It was later discovered that cells can be produced only by dividing, whereby one cell splits to produce two "daughters". Thus, all living things, from single-celled bacteria to multicellular human beings, are products of repeated cell duplications, extending back to the very first cell division, thought to have taken place on primitive Earth over 3 billion years ago.

Ever since cells were discovered, biologists have been interested in how they divide, spurred on in part by the desire to understand and control cancer, which is largely a disease of unregulated cell division. Normally, a cell in your body will divide only if it is instructed by other cells to duplicate - an arrangement which ensures that cells propagate only when more are needed. Cancer cells, however, multiply even when they have not been told to, which is why they cause abnormal masses of tissue, or tumours.

The effort to understand cell division has paid off: a great deal is now known about how the process occurs, how it is normally regulated, and how this regulation goes wrong in cancer; although sadly this understanding has not yet led to a cure for most cancers, there is little doubt that some day it will.

Whereas the study of cell division has advanced rapidly since its first discovery, it took an inexplicably long time for biologists to take an interest in the process of cell death. Although it was known last century that some cells die during the development of certain animals (when a caterpillar turns into a moth, for example), the extent of normal cell death and its importance for our own development and survival were not appreciated until recently. Very few biologists considered cell death worth studying, and those who did had trouble funding their research.

Then, quite suddenly, this changed in the early 1990s. Cell death became all the rage and is now one of the most competitive areas of biological research. No one is quite sure why this happened, but most of the credit should probably go to a tiny worm, as I shall explain in a moment.

Among the small band of enlightened pioneers who recognised the significance of cell death early on were three pathologists, John Kerr, Andrew Wyllie and Alistair Currie, working in Australia and Scotland. In the early 1970s, they not only saw the importance of cell death, they interpreted it in a novel way. They made the startling proposal that many of the cell deaths that occur in animals are in fact suicides, with the cells actively participating in their own demise.

Examining normal and diseased tissues under the microscope, they noticed that cell deaths in healthy tissues look very different from those in acutely injured ones. When a cell is injured, it tends to swell and burst, spilling its contents all over its neighbours. In normal cell death, by contrast, the cell shrinks rapidly and condenses into a shrivelled corpse, which is immediately eaten by a neighbouring cell, well before the dead cell has leaked any of its contents. Kerr and his colleagues called this type of cell death "apoptosis", from the Greek ptosis which means falling (like the falling of withered leaves). They suggested that apoptosis is a special kind of death, in which the cell activates an internal suicide programme and kills itself in a tidy, controlled way. Their recognition was a brilliant insight, with important implications for understanding more about how cells work and about how animals develop and maintain themselves.

Yet for many years, this conceptual breakthrough had very little impact, and cell death was largely ignored. How could this crucially important process be neglected for so long?

One reason is that when cells undergo apoptosis they are eaten and digested so quickly by their neighbours that there are very few dead cells to be seen. Thus, until recently, most cell deaths went unrecognised, and even today it is likely that the amount of normal cell death is greatly underestimated. Another reason is that normal cell death seems so unnecessarily wasteful that some biologists were reluctant to believe that it occurs on a large scale, despite abundant evidence that wastefulness is a common feature of life: molecules, cells, and even organisms are often produced in enormous excess, with only a small fraction surviving.

It is also possible that associations with our own demise made cell death unattractive to study or even to contemplate. Woody Allen once said that, while he's not afraid of death, he doesn't want to be around when it happens. Our cells, apparently, have no such qualms.

It does seem inefficient for so many of our cells to self-destruct, especially as the majority of them are perfectly healthy. What useful purpose does this carnage serve? In some cases the answer is clear. Some parts of our body are sculpted by cell death: our hands start out as spade- like structures and the fingers emerge only as the cells between them die. In other cases, cells kill themselves when they are no longer needed: when a tadpole changes into a frog, the cells in the tail die so that this structure, which would be a hindrance to the frog, disappears.

Cell death also plays a crucial role in protecting us from infection. If cells become infected by a virus, they often commit suicide to prevent the virus from multiplying and spreading to neighbouring cells. Sometimes the infected cells have to be encouraged to kill themselves by signals from the uninfected white blood cells of the immune system - a clear example of assisted suicide. But in many cases, it is not clear what purpose a cell's death serves.

Our cells communicate with one another for many reasons apart from encouraging hara-kiri. Indeed, they usually exhort one another to survive, rather than to die. If a cell is isolated from its neighbours so that it cannot receive signals from them, it will activate its internal death programme and kill itself. It seems that the only thing our cells can do on their own is self-destruct, and that the only reason any cell in our bodies remains alive is that other cells are constantly telling them not to kill themselves.

At first glance, this might seem a strange and precarious way for an animal to function, but it is actually a clever strategy for ensuring that a cell survives only where and when it is needed. If, for example, a cell ends up in the wrong place, it will not receive the signals it needs to survive and will commit suicide as a result of its solitude.

As I mentioned, a similar mechanism governs cell division to ensure that a cell only divides when more are needed. The importance of such "social" controls on cell survival and cell division is underlined by the disaster that results when these controls fail, as occurs in cancer. Cancer cells not only divide intractably, but they also survive in places where they should not. Cancer cells that arise in one organ, for example, may be carried by the bloodstream to distant tissues, where they can thrive, forming metastases or secondary deposits. These grow inexorably, frequently causing pain and all too often killing the sufferer.

But what of the worms I mentioned earlier? How did they help to bring cell death from obscurity into the spotlight? Well, by playing a crucial part in the discovery of how cell suicide occurs, a discovery that propelled the field of cell death research from neglect to hysteria almost overnight. This breakthrough arose largely from the genetic experiments performed by Robert Horvitz and his colleagues at the Massachusetts Institute of Technology in Boston. They studied a tiny worm, the nematode, which is smaller than a grain of rice and composed of only about a thousand cells.

During the nematode's development, exactly 131 cells kill themselves by apoptosis. Horvitz identified a gene that was necessary for all these deaths to happen. If the gene was inactivated by a mutation (that is, a change in the gene's DNA), none of the cell deaths occurred. Once isolated, the gene was found to produce an enzyme that digests specific cellular proteins, thereby dispatching the cell in a controlled way. Remarkably, very similar enzymes were soon found to be responsible for cell suicide in human beings, emphasising how fundamental programmed cell death is to all life and how basically similar humans are, in molecular terms, to the simplest of animals.

Even the most sceptical biologists were convinced by these studies, which identified specific genes responsible for apoptosis. These experiments also caught the attention of pharmaceutical and biotechnology companies, as it seemed likely that this discovery would some day revolutionise the treatment of a number of diseases in which cell death is crucial.

There are many medical conditions in which cells die: heart muscle cells die in heart attacks, and nerve cells die in strokes, head injury, and neurodegenerative diseases such as Parkinson's and Alzheimer's. It is still not clear what proportion of the cell deaths in these conditions occur by apoptosis, but evidence is rapidly accumulating that it is substantial. This is not surprising, as injured cells, like normal ones, can undergo apoptosis, which is the altruistic way for an injured cell to die if it has the time; its end then is orderly, fast, and clean, as the dead cell is disposed of quickly, without waste or mess.

The challenge is to find drugs that can impede the death programme and thereby keep injured cells alive long enough for them to repair themselves. In conditions where damage is acute, as in heart attack, head injury or stroke, it may only be necessary to prevent cell death for a day or two for treatment to be effective. The first generation of drugs that block apoptosis are already being tested in mice and rats, and a number of these look promising.

In cancer, on the other hand, the goal is the opposite: to exploit the death programme in cancer cells so that they destroy themselves. In fact, it is now realised that most of the drugs that are used to treat cancer work in just this way, though they were originally thought to act only by blocking cell division. Unfortunately, many cancer cells have become resistant to these drugs, not because the death programme becomes de-activated, but rather because the cancer cells become reluctant to mobilise their death programme. As more is learnt about how this programme is regulated in normal cells and how the regulation goes awry in cancer cells, it may become possible to circumvent this type of drug resistance.

The cells in your body are often compared to people in a society, in that they depend on one another in complex ways for their survival. Generally, however, people are unwilling to kill themselves for the good of society (although some might argue that wartime is an exception). Be grateful, then, that your cells are more altruistic than people and, even in the best of times, are willing to sacrifice themselves in vast numbers to assure your survival.

Martin Raff is at UCL's Medical Research Council Laboratory for Molecular Cell Biology