What history tells us XXI. Apoptosis and programmed cell death: when biological categories are blurred 177 Series DOI 10.1007/s12038-010-0021-7 What history tells us XXI. Apoptosis and programmed cell death: when biological categories are blurred MICHEL MORANGE Centre Cavaillès, USR 3308, Ecole normale supérieure, 29 rue d’Ulm, 75230 Paris Cedex 05, France (Fax, 33-144-323941; Email, [email protected]) 1. Introduction 2. Apoptosis: a model process The description of programmed cell death (PCD) (Lockshin The visibility of the phenomena of apoptosis and PCD, and Williams 1964), the characterization of its most and the impact they had on the biological community have popular form, apoptosis (Kerr et al. 1972), and its rapid their origins in the rapidity with which these phenomena molecular description thanks to the model organism were characterized after their discovery. In fact, precise Caenorhabditis elegans (Ellis et al. 1991) might appear descriptions of PCD were given in the 19th century, but as a paradigmatic example of the success of what the the phenomenon as such was not recognized (Clarke and Norwegian philosopher of science Nils Roll-Hansen Clarke 1996). Similar observations were made during the has called “biological reductionism” (Roll-Hansen 1996): fi rst half of the 20th century, especially in studies of the biological phenomena are fi rst described in organisms development of the nervous system (Glücksmann 1951). and cells, in structural and functional terms; then, One had to wait until 1964 and the introduction of the term molecular mechanisms and components involved in “PCD” to distinguish this form of death, visible for instance their realization are described. Nils Roll-Hansen during metamorphosis, from the accidental form of death, opposed this form of reductionism, characteristic of necrosis (Lockshin and Williams 1964). In 1972, Kerr used present-day biology, with what he called physicalist the term apoptosis to describe a special form of programmed reductionism, in which the existence of biological cell death characterized by the morphology of the dying cell, phenomena is denied. and the absence of infl ammation resulting from it (Kerr et In the fi rst part of this article, I will argue that, for al. 1972). many reasons, PCD and apoptosis were models for the The genes involved in apoptosis were characterized whole of molecular and cell biology. But in the second part, in C. elegans, in which a complete pattern of cell fate, I will show that the picture has become fuzzy. The frontiers including cell division but also cell death, had been defi ned with other forms of death and other cellular processes have before (Ellis et al. 1991). The characterization of the genes been blurred. I will describe the notions which are used to involved in cell death was used to establish a list of molecular explain why the frontiers of these phenomena have been components necessary for this form of death. Among them, blurred, and why their molecular description has become caspases, proteases involved in the degradation of the cells, more and more complex. The diffi culties originate in the received most attention. They participate in the initiation complex evolutionary history of the systems under study. of cell death, as well as in its realization and last steps I will argue that these explanations are insuffi cient to face (Thornberry and Lazebnik 1998). One of these caspases the diffi culties. With the increasing role of evolutionary is indirectly responsible for the regular extra-nucleosomal questioning in functional biology, some of the categories cleavage of DNA, which is characteristic of apoptosis. used in the latter will have to be transformed, or will even Most of all, the functions of these forms of cellular death disappear. appeared clearly distinct from those of other forms of death Keywords. Apoptosis; categories; exaptation; programmed cell death; recruitment; tinkering http://www.ias.ac.in/jbiosci J. Biosci. 35(2), June 2010, 177–181, © Indian AcademyJ. Biosci. of 35 Sciences(2), June 2010 177 178 Michel Morange such as necrosis. Apoptosis and PCD are responsible for been questioned (Golstein and Kroemer 2006). As in the the sculpture of the organism, the elimination of useless case of apoptosis, there are molecular components which and misplaced cells, and the design of an effi cient and safe are characteristic of necrosis; necrosis can participate in immune system. physiological processes; and it can replace apoptosis when Evolutionary scenarios were rapidly proposed to explain the latter is blocked, for instance in the formation of fi ngers how this form of death might have been introduced in in mammals. eukaryotes from the mechanisms of prokaryotic cell More generally, new forms of cell death are progressively death involved, for instance, in quorum sensing, through being described (Bredesen et al. 2006; Golstein and the endosymbiosis of bacteria, and the formation of Kroemer 2007). The distinction between programmed mitochondria (Ameisen 1996, 2002, 2004). These scenarios and accidental cell death is becoming increasingly fuzzy, explained the central role played by mitochondria in and the efforts made to classify the different forms of cell apoptosis. The last reason for the overwhelming importance death look as desperate as those of Sisyphus (Kroemer of apoptosis was that its understanding could open up et al. 2009). therapeutic opportunities in diseases where cell death plays a major role, as in neurodegenerative diseases. 4. Saving appearances: the way to interpret these diffi culties 3. The picture becomes more and more fuzzy Different concepts and notions have been introduced by The fact that the picture was so clear in the 1980s-1990s biologists to account for this fuzziness. The fi rst, due enables us to see, better than in other fi elds, how subsequent to Darwin, found new life through its reintroduction discoveries made it more and more fuzzy. by François Jacob (1977). To evolve, organisms tinker Consider for instance caspases. It was quite rapidly shown with what they have to hand. They use pre-existing that some members of the caspase family are involved in pieces to generate new structures and new functions. other functions, such as the triggering of the infl ammatory Two other notions are frequently used: recruitment and response. The pruning of axons during the morphogenesis its corollary pleiotropy. They are also not newcomers of the central nervous system is due to caspases (Nikolaev in biology, at least in the case of the second, and they et al. 2009). A large number of additional vital functions tell the same story. They have the advantage of being of caspases have recently been described (Garrido and neutral, whereas the use of tinkering suggests that the result Kroemer 2004; Launay et al. 2005; Lamkanfi et al. 2007) might have been better if the work had been done by an and they concern members of the family involved in engineer. Another notion, used by evolutionary biologists, apoptosis. Caspases are also involved in the regulation of and only exceptionally by cell and molecular biologists, the pluripotent state of embryonic stem cells (Zwaka 2010). describes a similar process: exaptation. Nevertheless, More puzzling was the observation that a cellular exaptation consists more of the transformation of pre- rescue process was recently considered as the second form existing functions than of the addition of new functions, as of programmed cell death: autophagy. Autophagy was suggested by the notion of recruitment. The reason is that it described as a way for cells to maintain their supply of does not generally concern molecular functions, but more nutrients in situations of starvation, by digesting some of elaborate ones. their own components. Autophagy also participates in the When one considers a process like apoptosis, tinkering elimination of useless organelles and of protein aggregates and recruitment might have participated in its formation, by which form, in particular, in neurodegenerative diseases. using pre-existing molecular functions, or in its blurring by But autophagy is also a form of death. In addition, it attributing new functions to its components. crosstalks with apoptosis (Sandoval et al. 2008), and can A second, different explanation for the diffi culty of replace apoptosis when the latter has been experimentally delineating precise boundaries and of defi ning a process inactivated. The authors of many articles have argued that such as apoptosis originates in the recurrent action of the “true” function of autophagy is not cell death. It is only evolution to increase regulation and robustness. Such action an “impostor” of cell death (Cecconi and Levine 2008; limits the consequences of the impairment of one functional Levine and Kroemer 2009). Obviously, autophagy also system, and coordinates the different processes within cells has functions other than cell death. But how is it possible and organisms. It perfectly explains what is observed in to say that its “true” function is not cell death, when so the case of apoptosis: the molecular connections between many studies demonstrate that autophagy is involved in different forms of death, the capacity for one form of death physiological cell death? to replace another. The existence of a clear boundary between programmed These explanations propose that a process does exist, but cell death and accidental death, necrosis, has recently its frontiers and defi nitions have been blurred. It remains J. Biosci. 35(2), June 2010 What history tells us XXI. Apoptosis and programmed cell death: when biological categories are blurred 179 possible, by fi ltering out the noise that evolution has instead of considering a trade-off between costs and benefi ts, introduced into the system, to restore the “pure” process the different steps leading to the formation of an apoptotic of apoptosis. But is this the case? Before answering in process are seen as benefi cial whatever the environment. the negative, I will discuss the diffi culties encountered by And the scenarios are elaborated retrospectively, with the researchers in an apparently unrelated fi eld, the establishment obvious objective of explaining the present situation.