Apoptosis

Apoptosis (from Ancient Greek: ἀπόπτωσις, romanized: apóptōsis, lit. 'falling off') is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.

In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular injury, apoptosis is a highly regulated and controlled process that confers advantages during an organism's life cycle. For example, the separation of fingers and toes in a developing human embryo occurs because cells between the digits undergo a form of apoptosis that is genetically determined. Unlike necrosis, apoptosis produces cell fragments called apoptotic bodies that phagocytes are able to engulf and remove before the contents of the cell can spill out onto surrounding cells and cause damage to them.

Because apoptosis cannot stop once it has begun, it is a highly regulated process. Apoptosis can be initiated through one of two pathways. In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. Weak external signals may also activate the intrinsic pathway of apoptosis. Both pathways induce cell death by activating caspases, which are proteases, or enzymes that degrade proteins. The two pathways both activate initiator caspases, which then activate executioner caspases, which then kill the cell by degrading proteins indiscriminately.

In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in a wide variety of diseases. Excessive apoptosis causes atrophy, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer. Some factors like Fas receptors and caspases promote apoptosis, while some members of the Bcl-2 family of proteins inhibit apoptosis.

German scientist Carl Vogt was first to describe the principle of apoptosis in 1842. In 1885, anatomist Walther Flemming delivered a more precise description of the process of programmed cell death. However, it was not until 1965 that the topic was resurrected. While studying tissues using electron microscopy, John Kerr at the University of Queensland was able to distinguish apoptosis from traumatic cell death. Following the publication of a paper describing the phenomenon, Kerr was invited to join Alastair Currie, as well as Andrew Wyllie, who was Currie's graduate student, at the University of Aberdeen. In 1972, the trio published a seminal article in the British Journal of Cancer. Kerr had initially used the term programmed cell necrosis, but in the article, the process of natural cell death was called apoptosis. Kerr, Wyllie and Currie credited James Cormack, a professor of Greek language at University of Aberdeen, with suggesting the term apoptosis. Kerr received the Paul Ehrlich and Ludwig Darmstaedter Prize on March 14, 2000, for his description of apoptosis. He shared the prize with Boston biologist H. Robert Horvitz.

For many years, neither "apoptosis" nor "programmed cell death" was a highly cited term. Two discoveries brought cell death from obscurity to a major field of research: identification of the first component of the cell death control and effector mechanisms, and linkage of abnormalities in cell death to human disease, in particular cancer. This occurred in 1988 when it was shown that BCL2, the gene responsible for follicular lymphoma, encoded a protein that inhibited cell death.

The 2002 Nobel Prize in Medicine was awarded to Sydney Brenner, H. Robert Horvitz and John Sulston for their work identifying genes that control apoptosis. The genes were identified by studies in the nematode C. elegans and homologues of these genes function in humans to regulate apoptosis.

In Greek, apoptosis translates to the "falling off" of leaves from a tree. Cormack, professor of Greek language, reintroduced the term for medical use as it had a medical meaning for the Greeks over two thousand years before. Hippocrates used the term to mean "the falling off of the bones". Galen extended its meaning to "the dropping of the scabs". Cormack was no doubt aware of this usage when he suggested the name. Debate continues over the correct pronunciation, with opinion divided between a pronunciation with the second p silent (/æpəˈtoʊsɪs/ ap-ə-TOH-sis) and the second p pronounced (/eɪpəpˈtoʊsɪs/ ^ⓘ). In English, the p of the Greek -pt- consonant cluster is typically silent at the beginning of a word (e.g. pterodactyl, Ptolemy), but articulated when used in combining forms preceded by a vowel, as in helicopter or the orders of insects: diptera, lepidoptera, etc.