apoptosis, inbiology, a mechanism that allowscells to self-destruct whenstimulated by the appropriate trigger. Apoptosis can be triggered by mild cellular injury and by various factors internal or external to the cell; the damaged cells are then disposed of in an orderly fashion. As a morphologically distinct form of programmed celldeath, apoptosis is different from the other major process of cell death known asnecrosis. Apoptosis involves condensation of thenucleus andcytoplasm, followed by cellular partitioning into well-defined fragments for disposal. In multicellular organisms, cell number normally results from the rate of cell production minus the rate of apoptosis.

Discovery of programmed cell death

In the early 1840s, a biological use for the mechanism of planned apoptosis became apparent when scientists realized that the development from fertilized egg to adult is not a linear process. In many instances, initial structures, such as the tadpole’s tail, aresuperseded by entirely distinct adult systems, such as the frog’s legs. In the 20th century the medical significance of cell death was recognized by Australian researcher John Foxton R. Kerr and Scottish scientists Andrew H. Wyllie and Alastair Currie. In a paper published in 1972, they used the termapoptosis (from the Greek word meaning “falling off,” as leaves do in autumn) to describe the occurrence of apoptotic cells in human tissues.

The discovery of the developmental lineage and death of each cell in thenematodeCaenorhabditis elegans confirmed the role of programmed cell death in development. South African-born biologistSydney Brenner, American biologistH. Robert Horvitz, and British biologistJohn E. Sulston shared theNobel Prize in Physiology or Medicine in 2002 for this work.

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cancer: Apoptosis and cancer development

In adult animals apoptosis is used to remove cells that have become a threat to survival. Such cells can includecancer cells or cells that are infected withbacteria or avirus. Apoptosis also removes cells that are normal but no longer needed, such as cells that produceantibodies after the need for the antibody has passed. Apoptosis can also be triggered in otherwise normal cells by external stimuli, including nutrient removal,toxins,hormones, heat, andradiation. It is estimated that a mass of cells equal to body weight is removed by apoptosis each year. Given this range of critical situations in which apoptosis occurs or is required, the possibility for therapeutic intervention is extraordinary. This realization has generated a massive research effort focused on apoptosis.

Regulation of apoptosis

Apoptosis occurs on a cell-by-cell basis. For each affected cell, two primary phases are observed: one of initiation and a second of execution. The resulting cell remnants are processed for reuse. Both phases are complex and requireexquisite organization of multiple cellular systems, including interactions betweenproteins and cellular membranes. The initiation phase, or “death decision,” became of significant interest following the description of a group of proteins in mammals known as theBCL-2protein family. This protein family, which provides the framework for controlling apoptosis, takes its name from a type of cancer called B-celllymphoma. BCL-2, the first family member, forms the molecular basis for sustaining the lymphoma cancer cells. The BCL-2 family of proteins has at least 25 members. Most of these are known asBH-3-only proteins. BH-3-only proteins function as activators or sensitizers of apoptosis and monitor important cell processes fordysfunction. They also control the function of two death-initiating, or pro-apoptotic, proteins (Bax and Bak) and a large number of death-preventing, or anti-apoptotic, proteins, which include BCL-XL and BCL-2. In mammals this control occurs primarily on the membranes ofmitochondria, where the mortality decision for each cell is constantly reviewed under the supervision of the three contesting factions of the BCL-2 protein family.

A second family of proteins, thecaspase proteolyticenzymes, contributes to both regulation by the BCL-2 family and execution of apoptosis after the death decision is confirmed. Caspases function in large part by the activation of other enzymes thatdismantle the cellularcytoskeleton and cellularorganelles and that degrade the nuclearDNA (deoxyribonucleic acid), from which there is no possibility of recovery. The cellular destruction occurs in place (in situ), and the cellular membrane system is reorganized to package the degraded components, including the digested genetic material, in membrane compartments. This packaging system prevents the materials from being released generally within tissues. Macrophages and other scavenger cells then engulf the membrane packets and process them for reuse as the most basic cellular components. In some instances, neighbouring cells may also engulf the degraded components.

Employing theintrinsic pathway, cancer cells, cells that are infected with bacteria or virus particles, and mutant cells can be assigned to apoptosis. Theextrinsic pathway is commonly associated with cellular death receptors.

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Apoptosis in medicine

Manipulating apoptosis is one avenue through which scientists can address a number of vexing medical problems.Cancer requires the suppression of apoptosis to allow survival of the abnormal tumour cells. Restoring effective surveillance of abnormal cells can contribute dramatically to cancer eradication. Likewise,enhanced targeting of infected cells for apoptotic destruction mimics the physiological role of apoptosis in resolving infection by disposing of the infected cells.

Inhibition of apoptosis has the potential to dramatically limit the damage resulting from episodes ofischemia in cardiac and neural tissue (ischemia is a reduction in blood flow to affected tissues). In addition, the selective control of apoptosis in theimmune system can dramatically improve therapy for diseases fromdiabetes mellitus to HIV/AIDS. These opportunities and a basiccuriosity about how cells regulate their own mortality sustain an extensive research effort centring around the mechanisms controlling and executing apoptosis.