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Cell Suicide in Health and Disease
Cells can—and often do—kill themselves, in a process known as apoptosis. This capacity is essential to the proper functioning of the body; flawed regulation may lie behind many diseases
by Richard C. Duke, David M. Ojcius and John Ding-E Young

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s you read this article, millions of your cells are dying. Relax. Most are sacrificing themselves to ensure yoursurvival. Burgeoning research indicates that the health of all multicellular organisms, including humans, depends not only on the body’s ability to produce new cells but on the ability of individual cells to self-destruct when they become superfluous or disordered. This critical process, today called apoptosis, or programmed cell death, was overlooked for decades. But biologists have recently maderapid strides in understanding how cellular suicide is enacted and controlled. Many investigators are motivated both by scientific curiosity and by a desire to combat some of the world’s most frightening diseases. It turns out that aberrant regulation of apoptosis—leading to too much or too little cell suicide—probably contributes to such varied disorders as cancer, AIDS, Alzheimer’s disease andrheumatoid arthritis. Researchers who studied embryonic development in the first half of the 20th century were the earliest to realize that cell death is not, as had long been assumed, invariably bad for the body; in fact, it is necessary. By the 1950s, they had shown that multicellular creatures obtain their final form by predictably eliminating selected cells. The tadpole deletes its tail duringtransformation into a frog; mammals erase countless neurons as the nervous system takes shape. Microscopists had also identified major signposts distinguishing this physiological cell death from accidental destruction, or necrosis. Necrotic death occurs when a cell is severely injured, by a physical blow or by oxygen deprivation, for example.
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Swelling is a defining feature. Internalorganelles—most obviously the mitochondria (the cell’s power plants)—and the entire cell balloon and rupture. These effects occur because injury prevents the cell from controlling its fluid and ion balance; water and charged particles (especially sodium and calcium ions) that are normally pumped out now stream in. Another hallmark is inflammation: circulating macrophages and other white blood cells of the immunesystem converge on the necrotic cells and ingest them. Inflammation helps to limit infection and clear away debris, but the activities and secretions of the white cells can also damage normal tissue in the vicinity, sometimes extensively. Scientists viewing the cell undergoing apoptosis see very different changes. They find no swelling. Instead the dying cell shrinks and pulls away from itsneighbors. Soon it appears to boil: blebs form on the surface and disappear, immediately replaced by others. Internal organelles retain their structure, but the nucleus, which is altered little during necrosis, invariably changes dramatically during apoptosis. Most prominently, its usually dispersed chromatin (chromosomal DNA with its associated proteins) condenses into one or more distinct blobs nearthe nuclear envelope. At this point, apoptotic cells are often ingested by neighboring cells—including by scavenger cells that reside in all tissues—without inciting an inflammatory response. Dying cells that are not consumed may undergo further changes: typically the nucleus comes apart, and the cells divide into a number of “apoptotic bodies” that can contain a piece or two of the nucleus. Asbefore, these bodies are removed quietly. (Bio-

chemical studies contributed another signature of apoptosis in the late 1970s— the chromatin frequently breaks into fragments that produce a ladderlike pattern when the pieces are sorted by size on laboratory gels.) Interestingly, certain cells that undergo programmed death are not gobbled up; today we know they persist for a long time or even...