Death is an inevitable fact of life for organisms. Increasingly, biologists have come to realize that death is also, in many cases, an important and predestined fate of individual cells of organisms. Apoptosis is a process by which cells in a multicellular organism commit suicide. While cells can die as a result of necrosis, apoptosis is a form of death that the cell itself initiates, regulates, and executes using an elaborate arsenal of cellular and molecular machinery. For this reason, the term apoptosis is often used interchangeably with the term "programmed cell death," or PCD (although technically, apoptosis is but one particular form of programmed cell death). There is some disagreement on the origins of the word. The word apoptosis has ancient Greek origins, referring to the falling of leaves, or possibly "dropping of scabs" or "falling off of bones." There is even less agreement on its proper pronunciation, and even specialists in the field seem to use every possible way to say the word. "A-pop-TOE-sis" and "AP-oh-TOE-sis" are both common.
Magnification (6000×) of apoptosis, or cell death. Programmed cell death in the human body allows, among other things, for young children's brains to develop and for a female's monthly menstruation to occur.
Why Cells Commit Suicide
Why do cells commit apoptosis? There seem to be two major reasons. First, apoptosis is one means by which a developing organism shapes its tissues and organs. For instance, a human fetus has webbed hands and feet early on its development. Later, apoptosis removes skin cells, revealing individual fingers and toes. A fetus's eyelids form an opening by the process of apoptosis. During metamorphosis, tadpoles lose their tails through apoptosis. In young children, apoptosis is involved in the processes that literally shape the connections between brain cells, and in mature females, apoptosis of cells in the uterus causes the uterine lining to slough off at each menstrual cycle.
Cells may also commit suicide in times of distress, for the good of the organism as a whole. For example, in the case of a viral infection, certain cells of the immune system, called cytotoxic T lymphocytes, bind to infected cells and trigger them to undergo apoptosis. Also, cells that have suffered damage to their DNA, which can make them prone to becoming cancerous, are induced to commit apoptosis.
The Regulatory Mechanism
The cellular mechanisms that regulate and cause apoptosis were first elucidated by genetic studies of the roundworm, Caenorhabditis elegans. Normally, in the development of a C. elegans worm, one out of every eight body cells produced is eliminated by programmed cell death. By studying mutants in which either too many or too few cells died, worm geneticists identified many of the proteins that control apoptosis. Subsequently, the critical medicalrelevance of apoptosis became clear when biologists discovered that mammals contain many of the same genes that control apoptosis in worms. More strikingly, they found that many of these genes were mutated in tumors from cancer patients. Other genes often found to be mutated in cancers are those which regulate the cell cycle, which is the complex set of processes controlling how and when cells divide. These two findings led cancer researchers to recognize that cancer, a disease of uncontrolled cell proliferation, can result either from too much cell division or not enough apoptosis. Because of this important finding, apoptosis has become the subject of intense medical research, and molecules that regulate apoptosis are being studied as potential targets for anti-cancer drug therapies.
A cell can be triggered to undergo apoptosis either by external signaling molecules, such as so-called "death activator" proteins, or through molecules that reside within the cell and monitor events that might commit the cell to suicide, such as damage to DNA. There are several biochemical pathways that lead to apoptosis. One of the major pathways involves inducing mitochondria to leak one of their proteins, cytochrome c, into the cystosol. This in turn activates a set of related proteases (enzymes that degrade proteins) called caspases. Ultimately, the caspases degrade proteins in the cell and activate enzymes that degrade other cell constituents, such as the DNA. Cells undergoing apoptosis exhibit characteristic morphological and biochemical traits, which can be recognized by microscopic examination or biochemical assays. Apoptosis can occur in as little as twenty minutes, after which the cell "corpse" typically becomes engulfed and completely degraded by neighboring phagocytic cells that are present in the tissue and attracted to the apoptotic cell.
Apoptosis Genes in C. Elegans
Much of our understanding of what causes apoptosis comes from genetic studies in Caenorhabditis elegans. Several cell death proteins (CED) proteins were identified in C. elegans by studying apoptosis-defective mutants. The main executioner is CED-3, a caspase, which becomes activated by CED-4, another caspase. The central guardian protecting cells against apoptosis is CED-9, which inhibits the actions of CED-4 and CED-3. CED-9 has a mammalian homolog, called BCL-2, which serves a similar role in mammals.
Caspase inhibitors are being investigated as a possible means to slow the progress of Huntington's disease, a degenerative brain disease.
