The growth, development, and maintenance of multicellular organisms depend not only on the production of cells but also on mechanisms to destroy them. The maintenance of tissue size, for example, requires that cells die at the same rate as they are produced. During development, carefully orchestrated patterns of cell death help determine the size and shape of limbs and other tissues. Cells also die when they become damaged or infected, ensuring that they are removed before they threaten the health of the organism. In these and most other cases, cell death is not a random process but occurs by a programmed sequence of molecular events, in which the cell systematically destroys itself from within and is then eaten by other cells, leaving no trace. In most cases, this programmed cell death occurs by a process called apoptosis—from the Greek word meaning “falling off,” as leaves from a tree.
Cells dying by apoptosis undergo characteristic morphological changes. They shrink and condense, the cytoskeleton collapses, the nuclear envelope disassembles, and the nuclear chromatin condenses and breaks up into fragments (Figure 18–1A). The cell surface often bulges outward and, if the cell is large, it breaks up into membrane-enclosed fragments called apoptotic bodies. The surface of the cell or apoptotic bodies becomes chemically altered, so that a neighboring cell or a macrophage (a specialized phagocytic cell, discussed in Chapter 22) rapidly engulfs them, before they can spill their contents (Figure 18–1B). In this way, the cell dies neatly and is rapidly cleared away, without causing a damaging inflammatory response. Because the cells are eaten and digested so quickly, there are usually few dead cells to be seen, even when large numbers of cells have died by apoptosis. This is probably why biologists overlooked apoptosis for many years and still might underestimate its extent.
In contrast to apoptosis, animal cells that die in response to an acute insult, such as trauma or a lack of blood supply, usually do so by a process called cell necrosis. Necrotic cells swell and burst, spilling their contents over their neighbors and eliciting an inflammatory response (Figure 18–1C). In most cases, necrosis is likely to be caused by energy depletion, which leads to metabolic defects and loss of the ionic gradients that normally exist across the cell membrane. One form of necrosis, called necroptosis, is a form of programmed cell death that is triggered by a specific regulatory signal from other cells, although we are only just beginning to understand the underlying mechanisms.
Some form of programmed cell death occurs in many organisms, but apoptosis is found primarily in animals. This chapter focuses on the major functions of apoptosis, its mechanism and regulation, and how excessive or insufficient apoptosis can contribute to human disease.
The amount of apoptotic cell death that occurs in developing and adult animal tissues is astonishing. In the developing vertebrate nervous system, for example, more than half of many types of nerve cells normally die soon after they are formed. It seems remarkably wasteful for so many cells to die, especially as the vast majority are perfectly healthy at the time they kill themselves. What purposes does this massive cell death serve?
In some cases, the answer is clear. Cell death helps sculpt hands and feet during embryonic development: they start out as spade-like structures, and the individual digits separate only as the cells between them die, as illustrated for a mouse paw in Figure 18–2. In other cases, cells die when the structure they form is no longer needed. When a tadpole changes into a frog at metamorphosis, the cells in the tail die, and the tail, which is not needed in the frog, disappears. Apoptosis also functions as a quality-control process in development, eliminating cells that are abnormal, misplaced, nonfunctional, or potentially dangerous to the animal. Striking examples occur in the vertebrate adaptive immune system, where apoptosis eliminates developing T and B lymphocytes that either fail to produce potentially useful antigen-specific receptors or produce self-reactive receptors that make the cells potentially dangerous (discussed in Chapter 24); it also eliminates most of the lymphocytes activated by an infection, after they have helped destroy the responsible microbes.