Chronicle of a death foretold

There are two main forms of cell death: the violent, unexpected, swift demise known as necrosis, in which the carpet is left stained with blood and gore; and the silent, premeditated swallow of a cyanide pill, apoptosis, in which all evidence of the deed is spirited away. This is the spooks' end, and it seems appropriate in the Stalinist state of the body. In contrast, death by necrosis incites an unruly inflammatory reaction, equivalent to an incendiary police investigation, in which more bodies turn up, and the ructions take a long time to fade.

Historically, there has been a curious reluctance among biologists to cede full significance to apoptosis. Biology, after all, is the study of life and there is a sense in which death, the absence of life, is beyond the remit of biology. Many of the early observations of programmed cell death were treated as curiosities without wider meaning. One of the earliest observations was in 1842, from the German revolutionary, savant, and materialist philosopher, Karl Vogt, whose politics had forced him to flee to Geneva, and whose dealings with Napoleon III later made him the target of Karl Marx's brilliant polemical pamphlet, Herr Vogt (1860). Perhaps it's more edifying to remember Vogt for his careful studies of the metamorphosis of the midwife toad, from the tadpole into the adult. In particular, Vogt used a microscope to follow the fate of the flexible, primitive backbone of the tadpole, the notochord: did the cells of the notochord transform into the spinal column of the adult toad, or did they disappear, making way for new cells which formed the spinal column? The answer turned out to be the latter: the cells of the notochord die off, by apoptosis as we now know, and are replaced by new cells.

Other ninteenth-century observations also concerned metamorphosis. The great German pioneer of evolutionary biology, August Weismann, noted in the 1860s that many cells die off quietly during the transformation of the caterpillar into the moth, but curiously he did not discuss his findings in relation to ageing and death, subjects that later made him famous. Most subsequent descriptions of orderly cell death also came from embryology—the changes that take place during development. Most strikingly, whole populations of neurons (nerve cells) were found to die off in fish and chick embryos. The same applies to us. Neurons disappear in successive waves during embryonic development. In some regions of the brain, more than 80 per cent of the neurons formed during the early phases of development disappear before birth! Cell death allows the brain to be 'wired' with great precision: functional connections are made between specific neurons, enabling the formation of neuronal networks. But the same general theme of sculpting pervades all of embryology. Just as the sculptor chips away at a block of marble to create a work of art, so too the sculpting of the body is achieved by subtraction rather than addition. Our fingers and toes, for example, are formed by orderly cell death between the digits, not by forming discrete extensions to a 'stump'. In web-footed animals such as ducks, some of the cells do not die, so the feet remain webbed.

Despite its importance in embryology, the role of apoptosis in adults was not appreciated until much later. The name itself was coined in 1972 by John Kerr, Andrew Wyllie, and Alastair Currie, all then at Aberdeen University, following the suggestion of James Cormack, professor of Greek at that university. It means 'falling off', and was introduced in the title of their paper in the British Journal of Cancer: 'Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics.' Being Greek, the second 'p' is silent, so the term should be pronounced 'ape-oh-toe-sis'. The word had been used by the ancient Greeks, originally Hippocrates, to mean 'the falling off of the bones', an opaque phrase that referred to the erosion of fractured bone beneath gangrenous bandages; while Galen later extended its meaning to 'the dropping off of scabs'.

In modern times, John Kerr noticed that in rats the size of the liver was not fixed, but changed dynamically with fluctuations in blood flow. If blood flow was impaired to certain lobes of the liver, the affected lobes compensated by becoming gradually smaller over a period of weeks, as cells were lost by apop-tosis. Conversely, if blood flow was restored, the corresponding lobes gained in weight, again over weeks, as cells proliferated in response. This balancing act is generally applicable. Every day in the human body, some 10 billion cells die and are replaced by new cells. The cells that die do not meet a violent unpremeditated end, but are removed silently and unnoticed by apoptosis, all evidence of their demise eaten by neighbouring cells. This means that apoptosis balances cell division in the body. It follows that apoptosis is just as important as cell division in normal physiology.

In their 1972 paper, Kerr, Wyllie, and Currie presented evidence that the form of cell death is basically similar in numerous disparate circumstances—in normal embryonic development as well as teratogenesis (malformation of the embryo); in healthy adult tissues, cancers, and tumour regression; and in the shrinkage of tissues with disuse and ageing. Apoptosis is also critical to immune function: immune cells that react against our own body tissues commit apoptosis during development, enabling the immune system to distinguish between 'self' and 'non-self'. Thereafter, immune cells exert many of their own effects by inducing damaged or infected cells to undergo apoptosis themselves. This kind of screening by immune cells eliminates incipient cancer cells before they get a chance to proliferate.

The sequence of events in apoptosis is precisely choreographed. The cell shrinks and begins to develop bubble-like blebs on its surface. The DNA and proteins in the nucleus (the chromatin) condense in the vicinity of the nuclear membrane. Finally, the cell breaks up into small membrane-wrapped structures called apoptotic bodies, which are taken up by immune cells. Effectively, the cell packages itself into bite-sized chunks, which are then cannibalized without fanfare. Consistent with such a choreography, apoptosis requires a source of energy in the form of ATP—if deprived of ATP, a cell cannot undergo apoptosis. So the process is very different from the swelling and rupture characteristic of necrosis, the violent unpremeditated form of cell death. Also unlike necrosis, there is no aftermath to apoptosis, in particular no inflammation: nothing to mark the passing of a cell but its absence. It is a death foretold, but unremembered.

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