Apoptosis: A general comment

Special

Feature

Apoptosis:

a general

comment

A. ALLES, K. ALLEY, J. C. BARRETT, R. BUTTYAN, A. COLUMBANO, F. 0. COPE, E. A. COPELAN, R. C. DUKE, P. B. FAREL, L. E. GERSHENSON, D. GOLDGABER, D. R. GREEN, K. V. HONN, J. HULLY, J. T ISAACS, J. F. R. KERR, P. H. KRAMMER, R. A. LOCKSHIN, D. P. MARTIN, D. J. MCCONKEY, J. MICHAELSON, R. SCHULTE-HERMANN, A. C. SERVER, B. SZENDE, L. D. 1OMEI,’ T R. TRIT1DN,

S. R. UMANSKY,

K. VALERIE,

AND H. R. WARNER

DEATH IN NORMAL TISSUES is a universal biological phenomenon in developing vertebrate and invertebrate animals. Gl#{252}cksmann (1) first classified developmental cell death on the basis of its usefulness for the developing organism. Saunders (2) proposed that the pattern of cell death is programmed as a normal morphogenetic event in the development of multicellular organisms. The use of the term programmed has often been interpreted as meaning that death was a consequence of a yet undefined intrinsic cellular process. Thus the general concept emerged that cell death may be the outcome of complex coordinated events in the developing organism and may require an empirical definition. Kerr had drawn attention to the importance of growing evidence that cell death occurred by distinct and different mechanisms (3). Shortly thereafter, efforts to develop a comprehensive scientific hypothesis of cell death were significantly advanced in 1972 by Kerr, Wyllie, and Currie (4). Based on morphological characteristics of cell disintegration in a variety of tissues, they developed the concept of apoptosis to describe naturally occurring cell death that plays a complementary but opposite role to mitosis in regulation of animal cell populations. They also proposed that living cells have a metabolic cascade, which when activated can lead to their removal. These authors were the first to recommend that cell death that results from severe environmental perturbations and not from processes intrinsic to the cell should be considered distinctly different, and only this latter type of process should be referred to as necrosis. It is now evident that a wide variety of modes of cell injury can lead to either apoptotic or necrotic cell death, with distinct and profound implications associated with each alternative mechanism. The deceptively small but critical distinction introduced by Kerr, Wylie, and Currie has provided the basis for a new scientific perspective on cell death; under specific circumstances, death of cells may be considered a direct consequence of gene expression. A corollary of this is that apoptotic cell death is modulated and can be of diagnostic importance and accessible to therapeutic intervention. The broad implications of this simple concept have slowly become evident to biologists, as demonstrated by the recent surge of new publications from a wide variety of biomedical research areas. However, as scientists begin to recognize the importance of apoptosis in the study of cell biology and pathology, a problem arises regarding the terminology with which experimental observations and hypothetical mechanisms are communicated to one another in the literature. Apoptosis is an emergent scientific hypothesis with few welldefined morphological and molecular characteristics to distinguish it from necrotic cell death at a time when molecular biology dominates most biomedical research. The only commonly associated molecular characteristic of apoptosis is the internucleosomal DNA cleavage pattern, a phenomenon that CELL

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May 1991

has been clearly correlated with apoptosis (5) but has not been universally associated with ultrastructural changes (6). Consequently, the scientist is faced with the need to express empirical concepts while avoiding any implication of mechanism. For instance, programmed cell death is a widely used term that describes cell death and implies a general mechanism. Specifically, the term programmed clearly implies specific gene activity that ultimately leads to cell death in normal development. However, this term is imprecise as a genetic program may not be directly associated with the death of individual cells. It is possible that this implication has contributed to the slow recognition that cells may often initiate a process of gene-directed death in response to a variety of physiological and environmental factors. Recently, scientists have begun to recognize the importance of apoptosis in the study of cell physiology and disease. However, they have been faced with a fundamental problem regarding the description of cell death in the literature. This dilemma was addressed by a group of international scientists from different fields in biology and experimental medicine who recently met at the Banbury Center, Cold Spring Harbor Laboratories, Cold Spring Harbor, N.Y. The group realized that the concept of apoptosis needed to be further refined. We wish to take the initiative and propose to the scientific community that the literature that deals with cellular death be concerned with the development of a clear terminology. This requires that scientists and journal editors appreciate the fact that the concept of apoptosis and the new research that is emerging internationally on this subject carry with it the need to continuously clarify nomenclature. We propose that the initial steps involve 1) the introduction of specific terms that distinguish different modes of cell death, and 2) the elimination of terms that may be misleading through their unintended implication of mechanism. We suggest the following guidelines regarding terminology. Cell death should be used as the general, non-specific term, whereas necrosis and apoptosis should represent specific terms. Cell deletion may be useful occasionally where spatially or temporally significant cell death is to be considered; however, this term should not carry any inferences regarding mechanism. The terms mitotic death and interphase death, frequently used by radiologists, should not be equated with a particular mode or mechanism of death and would be included among the terms to be avoided in such contexts. Another term that should be avoided is controlled cell death, as death with the ultrastructure and DNA fragmentation pattern of apoptosis can be produced by mild cell injury. Shrinkage necrosis, necrobiosis, and zeiosis are among the terms used in early literature that should be ‘To whom correspondence should be addressed, G. James Cancer Hospital and Research Institute, University, Columbus, OH 43210, USA

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abandoned for reasons already discussed by Wyllie et al. (7). However, apoptotic bodies remains a useful term that designates cell fragments that appear in latter stages of apoptosis. References to single cell death or single cell necrosis are not appropriate; single cells undergo necrosis in situ, but it is a rare event. Moreover, in liver diseases single cell necrosis has often been applied to apoptosis. Cytolysis is a confusing term because it has been used to describe cell-mediated immune killing, which is now known to involve induction of apoptosis; the suffix -lysis conjures up the image of cell membrane rupture and should be avoided in the absence of such an observation. Cell suicide should be confined to the imagery of unscientific accounts of cell death. As mentioned previously, apoptosis should never be considered synonymous with programmed cell death, a term that has become quite popular in the literature but nevertheless should be avoided. We strongly encourage continued research into the mechanisms of gene-directed cell death and the development of specific molecular markers of apoptosis.

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REFERENCES 1. Gl#{252}cksmann,A. (1951) Cell deaths in normal vertebrate ontogeny. Biol. Rev. 26, 59-86 2. Saunders, J. W. (1966) Death in embryonic systems. Science 154, 604-612 3. Kerr,J. F. R. (1971) Shrinkage necrosis: a distinct mode of cellular death. j Pathol. 105, 13-20 4. Kerr, J. F. R., Wyllie, A. H., and Currie, A. R. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implication in tissue kinetics. Br. j Cancer 26, 239-257 5. Wyllie, A. H. (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature (London) 284, 555-556 6. Gromkowski, S. H., Brown, T. C., Masson, D., and Tschopp, J. (1988) Lack of DNA degradation in target cells lysed by granules derived from cytolytic T lymphocytes. j Immunol. 141, 774-7

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7. Wyllie, A. H., Kerr, death: the significance

J. F. R., and Currie, of apoptosis.

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