The deaths of a cell: How language and metaphor influence the science of cell death

Studies in History and Philosophy of Biological and Biomedical Sciences 48 (2014) 175e184

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The deaths of a cell: How language and metaphor influence the science of cell death Andrew S. Reynolds* Cape Breton University, 1250 Grand Lake Road, Sydney, Nova Scotia B1P 6L2, Canada

a r t i c l e i n f o

a b s t r a c t

Article history: Available online 30 July 2014

Multicellular development and tissue maintenance involve the regular elimination of damaged and healthy cells. The science of this genetically regulated cell death is particularly rich in metaphors: ‘programmed cell death’ or ‘cell suicide’ is considered an ‘altruistic’ act on the part of a cell for the benefit of the organism as a whole. It is also considered a form of ‘social control’ exerted by the body/organism over its component cells. This paper analyzes the various functions of these metaphors and critical discussion about them within the scientific community. Bodies such as the Nomenclature Committee on Cell Death (NCCD) have been charged with bringing order to the language of cell death to facilitate scientific progress. While the NCCD recommends adopting more objective biochemical terminology to describe the mechanisms of cell death, the metaphors in question retain an important function by highlighting the broader context within which cell death occurs. Scientific metaphors act as conceptual ‘tools’ which fulfill various roles, from highlighting a phenomenon as of particular interest, situating it in a particular context, or suggesting explanatory causal mechanisms. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Cell suicide Programmed cell death Apoptosis Metaphor Nomadic concepts

When citing this paper, please use the full journal title Studies in History and Philosophy of Biological and Biomedical Sciences

1. Introduction A cell is, by definition, the fundamental unit of life, so it is understandable that biologists were slow to recognize that sometimes its greatest accomplishment is achieved through its death. It was a counterintuitive idea (called by Ameisen (2003) “un mystère au coeur du vivant”), because the growth and development of a multicellular organism would seem to require continuous addition and differentiation of cells, not their purposeful elimination, and the death of tissue is so strongly associated with pathological conditions of disease and injury. So despite having been observed throughout the 19th century, it was not until the mid-20th century that cell death was recognized to be a normal and important * Tel.: +1 (902) 563 1301. E-mail address: [email protected]. 1 Active cell death is also a relatively quick process, taking as little as 34 min to complete (Majno & Joris, 1995, p. 8). Moreover the remains of the dead cell are typically consumed by neighboring cells, thereby removing evidence of the event. This paper concentrates on studies of cell death in animals. For descriptions of cell death in the nineteenth century see Clarke & Clarke (2012). http://dx.doi.org/10.1016/j.shpsc.2014.06.003 1369-8486/Ó 2014 Elsevier Ltd. All rights reserved.

element in the development and maintenance of multicellular plants and animals.1 Eventually it came to seem reasonable that for homeostasis of adult animal tissues and organs each mitotic event must be balanced by a cell elimination. In the 1970s a distinction was drawn between pathological or unnatural cell death (necrosis) and the regulated and constructive form of cell death known as ‘apoptosis’ (Kerr, Wyllie, & Currie, 1972). Apoptosis was initially used to denote the morphological features of dying cells, characterized by shrinkage of the cell cytoplasm, disassembly of the nuclear DNA into regular-sized chunks, and ultimate consumption by neighboring phagocytic cells. Whereas cell necrosis is an accidental and passive type of death due to external factors such as injury or trauma, in apoptosis the cell plays an active role in its own demise. By the mid-1980s molecular genetic investigations began to reveal the specific mechanisms of this ‘programmed cell death’ and the subject became an important field of research in its own right (Jiang, 2012). Programmed cell death (PCD), of which apoptosis is but one form, is now understood to be a complex biochemical process with multiple pathways triggered by both external and internal factors, frequently, but not always, involving the release of

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protein-degrading enzymes (caspases) from the cell’s mitochondria (Green, 2011). Scientific investigation and understanding of cell deathdlike many other subjects in sciencedhas been significantly influenced by scientists’ choice of metaphors in their discussions of the topic. Thanks largely to the work of Lakoff and Johnson (2003) it is now widely recognized that metaphors influence more than just the way we talk about things, they also shape or inform the way we think about and experience things. Cells themselves have historically been conceptualized in accordance with two fundamental categories of metaphor, or what the German philosopher Hans Blumenberg called ‘background’ (Hintergrund) metaphors (Blumenberg, 2010). These are very general categories of metaphor that typically get filled in with more specific instances of metaphors from within that category. The first category is of human artifacts: cells have been conceived as rooms enclosed behind a solid wall (the original cell concept), as building stones or blocks (Bausteine), and as various types of machine (computers being the current favorite). Because humans create artifacts they are familiar to us and we consequently understand well how they work. The more specific background metaphor CELLS ARE MACHINES has helped scientists to tease apart their inner workings and causal mechanisms. But cells have also been thought of as elementary organisms (Elementarorganismen) which lead rich ‘social’ lives in the human body (itself a ‘society of cells’), wherein they make ‘decisions’ about which developmental ‘fates’ to pursue and so on. This form of talking and thinking about cells rests upon the background metaphor that CELLS ARE (SOCIAL) ORGANISMS OR AGENTS. Thinking of cells in human terms also helps make them seem familiar, but of course both metaphorical approaches have the potential to mislead and distort our understanding of those aspects of cells that do not fit the set of properties associated with the metaphor’s source domain, i.e. machines or humans. In this paper I discuss the concept of ‘programmed cell death’ as an instance of the machine metaphor and the concept of ‘cell suicide’ as an instance of the social agent metaphor. Cell suicide is also commonly construed, in further accordance with the background social metaphor, in two seemingly incompatible ways: i) as an act of altruism on the part of the cell dying, and ii) as a form of ‘social control’ exerted by the collective organism over its individual cellconstituents. In light of the complex interactions between cells which precede a particular cell’s ‘decision’ to die, scientists working within the conceptual space created by this social metaphor have been led to wonder whether such a death is best described as a ‘suicide’ or an ‘execution’. Hence, the import of concepts from the domain of human social experience by means of metaphor has the potential to create tensions in the scientist’s understanding of a natural phenomenon, but it can be a creative frissure that helps to uncover further complexities previously unanticipated.2 In their description of what they call ‘metaphor analysis’ Sabine Maasen and Peter Weingart state that “The single most important feature of a term or phrase being a metaphor is that they are ‘nomadic’, that is, taken up by and interacting with various discourses over time, thereby showing their malleability both actively and passively” (Massen & Weingart, 2000, p. 3). Concepts like computer programs, suicide, execution, altruism and social control are in this sense nomadic when they cross the borderlands between human experience and scientific discourse, where there are often greater expectations for precision, clarity, and objectivity of language. I argue that these metaphors have served useful functions for research into cell death, and that recommendations to dispense with figurative

2 ‘Frissure’ is a portmanteau term combining frisson (emotional thrill) with fissure (a chasm or gap).

language, made by professional bodies such as the Nomenclature Committee on Cell Death (NCCD) (to be discussed below), whose mission is to clear up confusions and ambiguities in scientific terminology, serve different intellectual and more specifically, biomedical interests. My emphasis will be on the introduction, function and accommodation of these metaphors or nomadic concepts within specific biological sub-disciplines: pathology, developmental biology, molecular genetics, and evolutionary biology. In addition to playing a communicative role these metaphors also function as conceptual ‘tools’ of analysis and explanation. Like other scientific instruments a metaphor may be well-suited for one purpose but not another, so that even when some scientists are critical of it for being ill-suited for some specific purpose, it may continue to be useful for others. And like other instruments scientific metaphors sometimes require refinement or calibration for greater precision. As with any tool or technique, however, metaphors are most effective when used with critical awareness of their implicit assumptions and how these may limit or misdirect the focus of investigation. The history of apoptosis as a scientific concept has enjoyed a good deal of attentiondmostly from scientists themselves (Curtin & Cotter, 2003; Duque-Parra, 2005; Lockshin, 1997; Lockshin, 2008; Lockshin & Zakeri, 2001; Maghsoudi, Zakeri, & Lockshin, 2012)dbut the closely related concepts of ‘programmed cell death’ and ‘cell suicide’ are as yet under-explored. This is in part because apoptosis, although a relatively recent creation, has assumed a prominent position as a general term encapsulating all phenomena of regulated cell death. But as Ameisen (2002) warns, while ‘programmed cell death’, ‘cell suicide’, and ‘apoptosis’ have been frequently used interchangeably, they are not synonyms and each carries its own metaphors and philosophical assumptions (Ameisen, 2002, p. 368). Section two provides highlights in the history of cell death research, with special attention to the language used to characterize and understand the phenomenon. Section three discusses the recommendations of the NCCD and its own specific objectives. Section four provides a critical discussion of the metaphors: how they have both helped and hindered different sorts of question, but ultimately, I argue, have assisted progress in the scientific understanding of this aspect of cell and organismal biology. 2. A brief history of modern accounts of cell death 2.1. Cellular degeneration Although cell death had been observed in the nineteenth century (see Clark & Clark, 2012) its establishment as a normal event in animal development can be traced to Alfred Glücksmann’s (1951) review of existing literature. Glücksmann made the case for the wide-spread occurrence of cell death as an important process in normal vertebrate ontogeny. The development of many of the early structures in embryogenesis (e.g. the primitive node, mid-ventral region) and organogenesis (e.g. central nervous system, sensory organs, and formation of lumina in solid glands) requires the degeneration of preliminary cell and tissue structures. Cell death Glücksmann noted is prevalent wherever cell migration is required for the change in shape of tissues and organs. One of the most cited examples of cell death’s constructive role in ontogeny, the dying off of interdigital cells in the formation of fingers and/or toes, was explained for the case of birds by Saunders and Fallon (1967) just shortly after. Glücksmann used the terms ‘cell death’, ‘cellular disintegration’, ‘necrobiosis’ and ‘cell degeneration’, to describe “the process of slow cell death in contradistinction to the instantaneous cell death produced by histological fixatives” (Glücksmann, 1951, p. 60). The terms ‘degeneration’ and ‘necrobiosis’ go back to

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Virchow’s Cellular Pathology of 1859 (Clarke & Clarke, 2012; Majno & Joris, 1995). Cellular degeneration was further distinguished by Glücksmann by consideration of developmental function into ‘morphogenetic’, ‘histiogenetic’ and ‘phylogenetic’ varieties. Morphogenetic degeneration describes cell deaths that allow for otherwise restricted cell movements necessary for the rearrangement and migration of cells involved in changes in form of organs or tissues (Glücksmann, 1951, p. 75). Histiogenetic degenerations are involved in tissue and organ differentiation (Glücksmann, 1951, p. 78), whereas phylogenetic degeneration describes cell deaths relating to the regression of larval or vestigial organs such as the tadpole or human tail (Glücksmann, 1951, p. 79). Glücksmann’s review proved to be very influential in drawing attention to cell death, helping to pave the way for one of the most influential metaphors in the field, programmed cell death. 2.2. Programmed cell death The term ‘programmed cell death’ was introduced in 1964 in a paper by Richard Lockshin, then a Harvard doctoral student working on insect physiology and development, and his supervisor Carroll Williams. Lockshin studied the carefully timed and experimentally manipulable breakdown of the intersegmental muscles of silkworm moth pupae during a specific developmental stage. The predictable timing of these cell deaths suggested some mechanism for their control. Lockshin’s thesis resulted in a series of coauthored papers, beginning (somewhat out of sequence) with the Lockshin and Williams (1964) paper “Programmed cell death e II. Endocrine potentiation of the breakdown of intersegmental muscles of silkmoths.” In addition to the introduction of the term ‘programmed cell death’ in the title this paper also talks of ‘autonomous cell death’ and ‘mechanisms for programming the autonomous death of intersegmental muscles’. The idea that such ontogenetic cell deaths are under the control of a ‘programme’ led rather inevitably to the suggestion that there was a genetic basis to be discovered within the cell itself. Lockshin has noted that his supervisor Williams was known for his creative use of language, a trait which his students attempted to emulate (Lockshin & Zakeri, 2001, p. 546). More recently Lockshin has said of the coining of the term: Because computers were just beginning to be talked about at the time, programmed cell death seemed to be a particularly modern and colorful way of describing what we saw. It was a metaphor stating what I thought was pretty obviousdif a biological process occurs at a defined location and time, then it must in some fashion be programmed or written into the genetics of the organismdbut, as in poetry, metaphors help people see things that they otherwise would not have noticed. Thus a relatively straightforward observation gained some currency. (Maghsoudi et al., 2012, p. 146) From the 1950s on there was considerable import into theoretical biology of ideas from computer science via cybernetic theory and the developing perspective of molecular biology. The notion of a genetic program can be traced to Jacob and Monod’s landmark 1961 paper on the operon model of protein synthesis (Keller, 2002, p. 135). So the idea of programs was, as they say, ‘in the air’ and all the more natural that it should catch on. 2.3. Cell suicide The idea of programmed cell death was picked up and discussed quite quickly by John W. Saunders Jr., then at Marquette University and investigating the development of the limb bud in the chick embryo. Saunders and his colleague Mary Gasseling discovered the

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zone of polarizing activity (ZPA) and the posterior necrotic zone (PNZ), areas of tissue folding and differentiation exhibiting significant cell death (Saunders, 1966). Saunders (1966, n.61) thanked Williams and Lockshin for showing him their “recent manuscripts” (presumably the 1964 paper) before publication. In his own paper Saunders used the earlier terms ‘morphogenetic cell death’ and ‘necrosis’, but also described cell death as ‘programmed’. Evidence from transplantation experiments of cells from the PNZ suggested that once the death program had been initiated by reception of a relevant hormone, the ‘death clock’ had been set ticking (Saunders, 1966, p. 606) and the cell (a region of cells actually) had been handed a ‘death sentence’ that could only be repealed prior to a specific stage of development by its transplantation to a different region of the embryo. One hypothesis was that the death program involved the release of toxic chemicals from the cell’s own lysosomes, the organelles discovered in the early 1950s by Christian de Duve, and described by him as ‘suicide bags’ (de Duve, 1959, p. 154), or ‘biological booby traps’ (another term attributed to Carroll Williams).3 If cells are capable of initiating their own self-destruct program it made some sense to describe the event as a ‘suicide’. But given that cell death in an embryological context was never an isolated affair but one taking place in the presence of other cells, it was also a possibility that the degenerating cell was marked for death by others. Saunders devoted a section of his paper to the question whether normal embryonic cell death was really a case of “suicide or assassination?” (Saunders, 1966, pp. 608e609).4 It was his opinion that, for the PNZ at least, evidence suggested that the cells died not as a result of having their lysosomal hydrolases released on command of other cells, but from other morbid changes which trigger their phagocytic engulfment by macrophages. Release of the lysosome’s contents he believed, were an effect, not the cause of, the cell’s death. Saunders did not pronounce a definite conclusion on the suicide or assassination question, but he did describe planned cell death as serving ‘utilitarian goals’ (Saunders, 1966, p. 611) in light of its significance for the construction of the embryo. The description of cell death as an act of altruism will be considered further below. 2.4. Apoptosis A key moment in the study of cell death occurred in 1972 when three pathologists working at the University of Aberdeen introduced the term ‘apoptosis’ to describe an ‘active, inherently programmed’ form of ‘controlled cell deletion’ of wide-spread occurrence and significance for development and cell turnover in normal tissue maintenance (Kerr et al., 1972). The authors introduced the term ‘apoptosis’ (from the Greek for ‘falling away’, as of leaves from a tree or plant) to denote a specific set of morphologies characteristic of cells undergoing what had till then been variously described as ‘necrobiosis,’ ‘controlled cell deletion,’ or ‘physiological cell death.’ The characteristic morphologies of a cell undergoing apoptosis included shrinkage of the cell cytoplasm, fragmentation of the nuclear chromatin into regular-sized chunks, formation of bulges in the cell membrane (‘blebbing’) giving the appearance of boiling, dissolution of the cell into smaller membrane-bound bits (‘apoptotic bodies’), and eventual consumption or phagocytosis by

3 de Duve (1959) wrote that the evidence then available did not allow one to decide whether lysosomes may be considered as potential killers or ‘suicide bags’. de Duve shared the Nobel Prize in Physiology or Medicine with Albert Claude and George Palade for this work in 1974. It is now understood that many forms of PCD are largely reliant upon proteases stored in the cell’s mitochondria. See Turk & Turk (2009). 4 See Martin (1993) for a later review of this question.

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neighboring cells, followed by the recycling of the dead cell’s components. Kerr et al. did not use the term ‘suicide’ but did describe the phenomenon as being ‘programmed’, and from this time on apoptosis and programmed cell death would be used interchangeably by many researchers. The next step was to investigate the causal mechanism responsible for this programmed cell death. 2.5. Genetic studies of programmed cell death (PCD) Throughout the 1980s Robert Horvitz and his collaborators at MIT successfully uncovered the molecular details of the cell death program. Horvitz was a developmental geneticist who had worked on the nematode Caenorhabiditis elegans in the lab of Sydney Brenner and John Sulston in Cambridge England. By tracing the cell lineages and fates of the 1090 cells that make up the tiny worm, it was found that 131 undergo a predictable and tightly scheduled death. Brenner, Horvitz, and Sulston received the Nobel Prize for Physiology or Medicine in 2002 for their work revealing that programmed cell death requires the cell to actively synthesize key proteins involved in its own demise. As Horvitz explained in his Nobel Lecture: “Thus we could think of programmed cell death as a cell fate, much like other cell fates.if so, we reasoned, there should be genes that control both the decision to express that fate and the execution (so to speak) of the fate itself” (Horvitz, 2003, p. 702, emphases added to highlight key metaphors). Horvitz and his team identified several key genes involved in the cell death programme and were able to begin sketching out a ‘genetic pathway’ for programmed cell death (Ellis & Horvitz, 1986). Two of these genes (ced3 and ced-4) Horvitz called ‘killer genes’, while another, ced-9, acts as a ‘protector’ gene preventing programmed cell death. Mutations in a mammalian homolog (Bcl-2) of the latter have been implicated in the development of cancer in humans and other mammals. When a gene like Bcl-2 which prevents cell death is ‘switched on’ when it ought to be ‘off’, cells that should be eliminated are permitted to live and perhaps then to divide (Hengartner & Horvitz, 1994). Horvitz and his team were able to identify a wild-type genotype for programmed cell death that was ‘cell autonomous’, i.e. occurred regardless of the behavior or influence of neighboring cells, and mutant-types that occurred only in the presence or under the influence of other cells. They called the cell autonomous variety cases of genuine ‘suicide’ (Ellis & Horvitz, 1986, p. 826), while the latter they referred to as cases of cell ‘murder’ (Ellis & Horvitz, 1986, pp. 818, 826). In this way they carried on Saunders’ (1966) question whether programmed cell death was best considered ‘suicide or assassination.’ What their findings suggested was that the ‘social’ context (made up of other cells) in which cell death occurred mattered. This was an aspect of cell death further developed in the 1990s by the developmental neurobiologist Martin Raff at University College London. 2.6. A form of social control The lessons learned from the molecular genetic details of the death program in the tiny worm C. elegans spurred a rapid growth of publications on PCD in other animal systems throughout the 1990s. Raff, working chiefly with oligodendrocytes of the central nervous system (where nearly 50 per cent of developing neurons undergo programmed cell death (Raff et al., 1993)), was an important contributor to the field’s growing popularity. Using evocative metaphors Raff captured the imagination of scientists and lay people alike in a series of high profile scientific papers and essays written for a more general audience. Raff popularized the idea that PCD or apoptosis, as the two were becoming synonymous

at this time, is a form of altruistic cell suicide. He was of course not the first to talk of ‘cell suicide’ or to describe it in utilitarian terms (this may have been Saunders5), and others were doing so in the 1970s and 80s, (e.g. Couly, 1982; Duke & Cohen, 1986; Kondo, 1988), but Raff did much to draw attention to the topic by emphasizing the parallels between the life and deaths of cells and humans. His most original contribution to the study of cell death, however, was the idea that PCD functions as a means for the developing embryo or adult organism to exert control over its component cells. Raff’s 1992 Nature paper “Social controls on cell survival and cell death” (Raff, 1992) has been widely cited and influential. Speaking in the new language of ‘cell signaling’ which was becoming increasingly important to modern biology, Raff proposed that the potential for self-destruction was a trait shared by all cells in higher animals: “an extreme view is that, in higher animals at least, just as a cell seems to need signals from other cells in order to proliferate, so it needs signals from other cells in order to survive; in their absence, the cell kills itself by activating an intrinsic suicide programme” (Raff, 1992, p. 397). Such social controls would ensure that cells survive only where and when they are needed. Richard Lockshin and Zahera Zakeri have reflected that “Martin Raff succinctly summarized an idea that was not rare among embryologists in an aphorism, ‘the social control of apoptosis’” (Lockshin & Zakeri, 2001, p. 549). In fact social analogies by means of metaphor have a long history in cell theory, going back to the idea popularized by Virchow and Haeckel in the 19th century that the body is a ‘cell state.’ Not only does the organism use PCD as a means of ‘sculpting’ the body from a mass of embryonic cells, but it can use the intrinsic cell death program carried in each cell as a means of destroying ‘renegade’ cells which may lead to cancer. Virchow himself described cancer cells as ‘free-loaders’ or ‘parasites’ within the society of cells (Johach, 2008) and today cancerous cells are frequently described as ‘selfish’ or “antisocial cellsdcells that are not dying when they are supposed to” (Lockshin, 2008, p. 1093). Raff’s work on PCD emphasized this social dimension of cell suicide. His 1996 popular essay “Death Wish” discussed the biological problem of cell suicide in the language of French existentialist philosophy. “On a microscopic scale [biologists] are finding cell suicide raises some of the questions that haunted Camus and Sartre. To what extent is cell suicide an individual decision, and to what degree a social one?” (Raff, 1996, p. 36). Viewed as a form of ‘social control’ whereby the organism or collection of cells as a whole marks specific cells for death cast ‘cell suicide’ in a differentdand more sinisterdlight. “Cellular neighborhoods,” Raff wrote, “seem to be more conformist than any middle-class suburb. As long as cells reproduce and behave according to local norms, they are allowed to go on living” (Raff, 1996, p. 39). Putting things in these terms also highlighted the logical tension between conceptualizing cell suicide as an act of altruism and as a form of social control. If the portrayal of PCD as a form of ‘social control’ evokes images of a totalitarian ‘big brother’ scenario, well established evidence that individual mammalian cells fail to survive in culture conditions outside the body except when in the company of a sufficient number of other cells puts a different spin on things (Fischer, 1923; Ishizaki, Cheng, Mudge, & Raff, 1995; Raff et al., 1993, 1994). Raff suggested that if the reception of a ‘death signal’ could lead a cell to

5 There is an earlier discussion of ‘cell suicide’ in Strauss (1958) with respect to the bread mold Neurospora crassa, the system with which Beadle and Tatum developed their Nobel prize winning ‘one gene, one enzyme’ hypothesis. Saunders (1966) does not, however, mention this paper, so it is unclear whether it had any influence on his thinking about cell death in animal development.

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self-destruct, the constant reception of ‘survival signals’ from a cell’s companions might also be necessary to keep it from doing itself in. “Apparently,” Raff wrote in his 1998 Nature review “Cell suicide for beginners”, “the only thing our cells can do on their own is kill themselves, and the only reason they normally remain alive is that other cells are constantly stimulating them to live” (Raff, 1998, p. 121). This suggested what essentially social creatures our cells are. In fact a new form of PCD was identified in 1994 which affects epithelial cells dislodged from their normal interaction with the extracellular matrix, the network of proteins and polysaccharides which maintain tissue organization and intercellular communication (Frisch & Francis, 1994). This form of PCD was dubbed ‘anoikis’ after the Greek word for ‘homelessness’, and introduces another social metaphor emphasizing the strong social ties affecting the lives and deaths of cells.6 3. Responses to metaphorical descriptions of cell death: the Nomenclature Committee on Cell Death As interest in PCD increased throughout the 1980s, 90s and on, scientists working in various sub-disciplines documented a multitude of different modes of cell death, some peculiar to specific types of cells or circumstances. This led to a confusing bloom of terminology, including: apoptosis, extrinsic apoptosis, caspasedependent apoptosis, caspase-independent apoptosis, anoikis, autophagy, cornification, entosis, excitotoxicity, mitotic catastrophe, individual or single cell necrosis, necroptosis, netosis, paratopsis, parthanatos, pyronecrosis, pyrotopsis, regulated necrosis, and Wallerian degeneration. Scientists were no longer talking about programmed cell death in the singular but of multiple deaths of the cell. Much of this effusion of terminology was due to increased knowledge of the molecular components, the genetic sequences and protein products involved in the initiation, regulation, and execution of programmed cell death, but many of the new terms for sub-routines of cell death were based on observed morphological characteristics that were difficult to associate uniquely with underlying mechanisms. Further confusion resulted from routine use of ‘programmed cell death’ and ‘apoptosis’ as synonymous terms. This was problematic as it became clear that (i) not all instances of programmed cell death (i.e. cell elimination under genetic regulation) take the morphological form of apoptosis (i.e. characteristic cell shrinkage, chromatin condensation and fragmentation, membrane blebbing, and engulfment by phagocytes); and (ii) apoptosis can result from environmental stress and injury, thereby also blurring the distinction between necrosis and apoptosis. This tangled and confused state of cell death language has elicited frequent comment by the scientific community. One of the first was the effort of an international group of biologists and researchers in experimental medicine which met at the Cold Spring Harbor Laboratories in 1991 (Alles et al., 1991). This group made several recommendations aimed at creating clearer terminology, including the “elimination of terms that may be misleading through their unintended implication of mechanism” (Alles et al., 1991, p. 2127). Among the recommendations made by the team of authors, which included Richard Lockshin and John Kerr, were that “Cell suicide should be confined to the imagery of unscientific accounts of cell death”, and that apoptosis not be considered synonymous with “programmed cell death, a term that has become

6 Evidence suggests that metastatic cancer cells have a mutation that suppresses initiation of the cell death program allowing them to survive their ‘homeless’ state and to relocate (Liotta & Kohn, 2004). Liotta and Kohn refer to these wandering cancer cells as displaying ‘nomadic’ [!] behavior.

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quite popular in the literature but nevertheless should be avoided” (Alles et al., 1991, p. 2128). In 1995 the pathologists Guido Majno and Isabelle Loris wrote in the American Journal of Pathology that “The rapidly developing tale of apoptosis warns us that generalizations are dangerous because, first, cell suicide does not always take the form of apoptosis; second, cell murder by cytotoxic lymphocytes leads to apoptosis; third, there seem to be several varieties of apoptosis and fourth, different cell types may follow different rules” (Majno & Joris, 1995, p. 8). In 1999 the Society of Toxicologic Pathologists struck an ad hoc committee on the Nomenclature of Cell Death to make recommendations for the use of the terms apoptosis and necrosis in toxicological studies. As the authors of the report explained, toxicologists have a special interest in the effective and clear communication of their observations of dead tissues and cells because their studies are routinely submitted to regulatory agencies for safety assessment of drugs and chemicals for human use and exposure (Levin et al., 1999). Effective communication between pathologists and those reading their reports therefore requires terminology that “accurately and adequately indicate what the pathologist has seen” (Levin et al., 1999, p. 484), and avoidance of terms with potentially misleading implications about the mechanisms by which the cell death has occurred are to be preferred. This report recommended using the term ‘necrosis’ to describe any dead cell in living tissue regardless of phenotype or pathway leading to its death, effectively dissolving the purported dichotomy between apoptosis and necrosis. This was followed by the creation in 2005 of the Nomenclature Committee on Cell Death (NCCD) by the editors of the journal Cell Death and Differentiation, a journal first established in 1994 to provide “a unified forum for scientists and clinical researchers”.7 The NCCD’s mission is to propose “unified criteria for the definition of cell death and of different cell death morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research” (Kroemer et al., 2005, p. 1463). Three reports have been released to date (Galluzzi et al., 2012; Kroemer et al., 2005, 2009). As explained in the second report the NCCD “provides a forum in which names describing distinct modalities of cell death are critically evaluated and recommendations on their definition and use are formulated, hoping that a non-rigid, yet uniform, nomenclature will facilitate the communication among scientists and ultimately accelerate the pace of discovery” (Kroemer et al., 2009, p. 3). Those investigating cell death seek to advance analytically through a dense thicket of molecular details,8 and so accuracy of language is important; yet the practical demands of communication also require a currency that can be conveniently circulated within and between specialized sub-disciplines of the biological and biomedical sciences. This places conflicting demands on those who would create a suitable terminology. In its first report the NCCD attempted to articulate this difficulty in philosophical terms when it wrote: “It is obvious that clear definitions of objects that are only shadows in Plato’s cage [sic] are difficult to be achieved. Cell death and the different subroutines leading to cell death do not escape this rule. Even worse, the notion of death is strongly influenced by religious and cultural beliefs, which may

7 From the journal website. http://www.nature.com/cdd/about.html. (Accessed June 7, 2013). 8 In fact the dynamic and complex nature of what were initially called signaling ‘pathways’ is slowly being replaced by the metaphor of signaling ‘networks.’ This shift in language has been driven by recognition of the ubiquity of ‘cross talk’ that takes place between pathways.

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subliminally influence the scientific view of death” (Kroemer et al., 2005, p. 1463). The innovative allusion to Plato’s ‘cage’ may be a typographical error or perhaps a sly reference to Nietzsche’s notion of the ‘prison house of language’. For the research community the authors say is divided between those who consider nomenclature to be an “intellectual cage” and “forever ‘premature’” on the one hand, and those suspicious of subjective judgments of the “I know it when I see it” variety on the other (Kroemer et al., 2005). The goal then is to strike a balance that will facilitate progress in the understanding of cell death and its implications for positive medical intervention in particular. The second NCCD report makes clear that the desideratum for an adequate scientific language regarding cell death is instrumental in nature by stating that “a cell death nomenclature will be considered useful only if it predicts the possibilities to pharmacologically/genetically modulate (induce or inhibit) cell death and/or if it predicts the consequences of cell death in vivo, with regard to inflammation and recognition by the immune system” (Kroemer et al., 2009, p. 10). It is for this reason that the NCCD has most recently recommended relinquishing descriptive characterizations based on morphological features, which can be misleading as to the causal mechanism responsible for the type of cell death in question and its function, for the adoption of definitions based on precise, measurable biochemical and molecular genetic criteria (Galluzzi et al., 2012). Descriptive terms based on what they call ‘functional’ considerations are to be preferred, by which they mean biochemical and genetic targets of therapeutic intervention (e.g. RNA interruption, gene knock-down or knockout). But it is worth noting that this is all premised on a rather narrower conception of what counts as utility or successful terminology than other researchers who are not so focused on applied objectives. The point of the language sought by the NCCD is not it seems first and foremost to be an objective description of a reality, which is after all, only a shadow in Plato’s ‘cage’ or cave. The language is intended chiefly to serve an analyticaleexperimental purpose of helping scientists to intervene and to manipulate the system for therapeutic and biomedical objectives. An earlier recommendation by the neuropharmocologist Robert S. Sloviter to simplify the language used to discuss cell death reinforces this by emphasizing that the identification of apoptosis (a morphological concept) with programmed cell death (a molecular process) promotes the mistaken idea that apoptosis is an identifiable target for therapeutic intervention (Sloviter, 2002). Inducing cell death is a therapeutic goal for instance in the treatment of cancer (most chemotherapies work by doing so) or auto-immune diseases, and preventing it is a potential treatment for neurodegenerative illnesses like Parkinson’s and Alzheimer’s; but the morphological features that cells assume during their death should not be relevant to attempts at positive medical intervention. Sloviter proposed doing away with both ‘apoptosis’ and ‘programmed cell death’ as poorly defined and perhaps undefinable, and replacing them with the term ‘active cell death’ which would be defined more clearly as “any lethal process requiring active intracellular processes”. Necrosis likewise would be replaced with ‘passive cell death’ defined as “instantaneous cell death in which the cell plays no role in its own demise” (Sloviter, 2002, p. 23). Sloviter’s recommendations are he claims founded on philosophical considerations of the difference between describing a real entity and defining a mental concept, guided by discussions of the philosophies of Plato, Aristotle and William of Ockham. Definitions, he says, call for precise statements of the necessary and sufficient conditions for their application; whereas dying cells can at best be described with greater or less clarity and utility. What Sloviter may be missing though is the

theory-constitutive capacity of scientific metaphor (Boyd, 1993), i.e. its ability to help fix the reference of a theoretical term in the absence of criteria for a rigid definition. An earlier attempt to categorize the modes of cell death by more general terms has also been popular. The anatomists Schweichel and Merker (1973) identified three distinct types of cell death: Type 1, 2, and 3. Type 1 corresponds to apoptosis, Type 2 to what is known as autophagy, and Type 3 to necrosis. Autophagy or autophagocytosis (from the Greek for ‘self-eating’) refers to the internal lysis of dysfunctional or unnecessary proteins, organelles, or other sub-cellular components. It is distinct from apoptosis in appearance and may or may not lead to cell death, in some instances it actually saves the cell from death by isolating and degrading dysfunctional cytoplasmic components, and in conditions of starvation allows the cell to recycle components in short supply. The NCCD has however expressed concern that “the term ‘autophagic cell death’ is a linguistic invitation to believe that cell death is occurring through autophagy” rather than occurring with autophagy (Kroemer et al., 2005, p. 1465), and the second and third NCCD reports recommend the abandonment of this language based on morphological characteristics in favor of biochemical definitions as described above (Galluzzi et al., 2012; Kroemer et al., 2009).

4. Analysis of the metaphors: strengths and weaknesses It is time to ask ‘What work do these various metaphors do?’ and ‘Have they been beneficial to the science or have they hindered it?’ These questions will be considered with respect to the chief metaphors discussed in this paper in the following sub-sections.

4.1. Programmed cell death Reflecting on the creation of the programmed cell death metaphor Richard Lockshin wrote, “When an observation reaches the threshold of relevance, a particular concatenation of words or a specific phrase renders what has been subliminal, now obvious” (Lockshin, 1997, p. 347). The death programme metaphor helped to situate cell death as a worthy topic of interest in the context of the new molecular biology with its background of cybernetic theory, computer metaphors of genetic codes, and the general perspective that the cell can be considered similar in important respects to a computer. But it also suggested a possible explanation for the spatial and temporal regularity of cell death in development, that within the cell there is a causal mechanism (a ‘programme’) of coordinated molecular elements involving a signal (internal or external) that triggers a sequence of events leading to the cell’s orderly demise. This was something lacking in more descriptive terms such as ‘cellular degeneration’ or even ‘apoptosis’, which although also a metaphor makes no suggestions as to a possible causal mechanism. Dying cells do share a similarity with falling leaves, but because falling leaves are themselves the result of the programmed death of cells in the leaf stem (Gadjev, Stone, & Gechev, 2008), the metaphor of apoptosis provides no helpful suggestions about how the process occurs. CELLS ARE MACHINES/ COMPUTERS metaphors are frequently invoked for the purpose of formulating causal explanations precisely because we understand how the artifacts we create function, and so drawing analogies between cells and computers provides at least a hypothetical model with which to work, even if, as is widely recognized, cellular complexity far exceeds anything created by humans. When we describe the cell as a machine we immediately think of taking it apart to find its essential parts and how they work together to produce its behavior.

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4.2. Cell suicide But understanding the mechanics of the cell death program on its own is only part of the story. In addition to understanding how it works scientists also want to know why it occurs, and this is where the CELLS ARE SOCIAL AGENTS metaphors have been of greatest appeal. Because the cell takes an active role in its own demise (utilizing its own energy sources and genetic material to construct the caspase proteins involved in its death), scientists were inclined to think of this as a ‘suicide.’ One benefit of the cell suicide metaphor was that it helped draw attention to the phenomenon of ‘physiological cell death’ as of particular interest, for why would an apparently healthy and otherwise normal cell choose to ‘kill’ itself? Here is a real mystery any curious human would consider worth solving. But as Richard Lockshin noted, merely describing these events as a form of suicide fails to shed light on why it occurs: “The explanation of a suicide is not that the victim died of a skull fracture when he hit the pavement, but what went on in his life and his mind that led him to jump” (Lockshin, 2008, p. 1094). Indeed suicide may be death by one’s own hand, but that does not necessarily make it entirely voluntary or autonomous, as the rash of recent teen suicides attributed to cyber-bullying makes clear.9 The social context consisting of the other cells with which a cell undergoing PCD communicates and interacts is surely relevant for understanding the bigger picture. And as it turns out, the biochemical pathways involved in PCD are so complex, involve so many components, and are regulated by so many different signals and conditions that scientists continue to ask whether it is best described as ‘suicide, execution or murder’ (Martin, 1993). There are at least three scenarios of PCD to be noted: one in which protein synthesis is required for the cell to die; one in which protein synthesis is not required; and lastly one in which it is the interruption of protein synthesis that triggers cell death. While scenarios in which the cell must actively synthesize its own proteins in order to die are suggestive of suicide, those in which it is already primed to die and merely awaiting an external signal or trigger are like executions, and those in which it is prevented from synthesizing a protein that would prevent its death are said to resemble murder. Thus, as one researcher explains, “when a cell dies by apoptosis it may not necessarily be committing suicide” (Martin, 1993, p. 143). 4.3. PCD as altruism Because PCD is a normal and essential component of animal development it was early on regarded as occurring for the benefit of the embryo or organism as a whole. Because of its constructive role in the sculpting of the embryo Saunders referred to it as serving ‘utilitarian goals’ (Saunders, 1966, pp. 604, 611; Kondo, 1988). Apoptosis in particular represents a ‘socially responsible’ means for a cell to kill itself: when watched in time-lapsed microcinematography it resembles the carefully engineered implosion of a building, resulting in minimal damage to its neighbors, whereas death by necrosis, which involves inflammation and potential rupture of the cell membrane and exposure of nearby cells to the toxic contents, might be compared to a building exploding due to a gas leak or other catastrophic accident.10 As Martin Raff wrote, “These cellecell interactions are part of the

9 Ameisen (2002, pp. 68e69) discusses the ritualistic aspect of suicide in different cultures and how its social functions can outweigh considerations of individual choice, for example Socrates being forced to drink hemlock in ancient Greece. 10 The documentary film “Death by Design” (1995) by Peter Friedman and JeanFrancois Burnet contains striking footage of cell death juxtaposed with suggestive footage of controlled demolition of buildings for comparison.

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complex ‘social’ controls that ensure that individual cells behave for the good of the animal as a whole.” (Raff, 1998, p. 121, emphasis added). Describing PCD in this way emphasized its multicellular social context and its positive effects for the organism or ‘society of cells.’ But because PCD was construed in these strongly social terms and because it plays such an important role in the ontogeny of multicellular organisms, it was rather naturally assumed that its origins must have been coincident with the origin of multicellularity itself, from colonies of ancient single-celled microbes. However, the immunologist Jean-Claude Ameisen has been critical of this assumption (Ameisen, 2002, 2003), referring to it as a ‘dogma’, whose first published statement he ascribes to Umansky (1982). If PCD is indeed a form of ‘altruistic suicide’ then one would hardly expect to find it among unicellular organisms, for these were long considered to be immortal and largely asocial; and yet PCD or ‘PCDlike death’ is found in single-celled bacteria and eukaryotic microbes.11 Recognition that many unicellular bacteria engage in social (i.e. multicellular) behavior (e.g. living in biofilm communities, communicating via chemical signals, ‘quorum sensing’) removes reason for surprise that they also exhibit versions of programmed cell death. But there is also good reason to separate the mechanistic details of how cell death occurs from its functional and social contexts, i.e. why it occurs (Ratel, Boisseau, Nasser, Berger, & Wion, 2001). Ratel et al. (2001) make a distinction between a ‘cell death programme’dwhich refers solely to the molecular-mechanical details of how a cell kills itselfdand ‘programmed cell death’dwhich refers to the adaptive function of a cell’s death within a social multicellular context. This opens the possibility of recognizing that not all cell ‘suicides’ need be ‘altruistic’ acts conferring an adaptive benefit to other cells of either a multicellular organism or community of semi-autonomous microbe cells (Nedelcu, Driscoll, Durand, Herron, & Rashidi, 2011). The cell death programme may have its evolutionary origins in the invasion of a prokaryote cell by a plasmid-encoded ‘addiction module’ whose ability to encode a mixture of both a toxin and its antidote destroys any cells that manage to discharge it (Engelberg-Kulka & Glaser, 1999); a secondary acquisition of the ancestor of the current eukaryote mitochondrion that either brought with it or developed its own addiction module may have given eukaryotes their cell death programme (Ameisen, 2002, 2003). This originally maladaptive ‘cell death programme’ may then have later been repurposed or exapted as ‘programmed cell death’ in an evolutionary transition to a multicellular individual (Ameisen, 2002, 2003; Koonin & Aravind, 2002). Therefore, while these social metaphors likely did help to draw interest to the issue of cell death (Ameisen, 2002, p. 362) and highlighted its social context and utility, assuming that all instances of programmed cell death are altruistic suicides made it difficult to recognize its occurrence in single-celled microbes and to understand how such a self-destructive, and therefore fitness-lowering, act might have originated in the first place. As some evolutionary microbiologists have argued “unreservedly importing the paradigm of altruistic cell death from multicellular organisms to explain selfdestruction in unicellular lineages can limit the types of questions we ask and bias our understanding of the nature, origin, and maintenance of this trait” (Nedelcu et al., 2011, pp. 5e6). In reevaluating these earlier assumptions, Martin Raff has also concluded that, “In retrospect, using the term altruistic was not very helpful, although it did seem to catch the interest of journalists

11 See Fröhlich & Frank (2000), Engelberg-Kulka, Amitai, Kolodkin-Gal, & Hazan (2006), and Ramsdale (2012).

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and documentary makers, which was not my intention” (Raff, personal communication, 2012).12 This speaks to the potential danger of metaphors and other ‘nomadic concepts.’ The “subliminal translation of concepts into science” can be problematic, especially a concept like death with its “ethical, theological and social resonance[s]” (Melino, Knight, & Nicotera, 2005, p. 1458). The potential for nomadic movement of ideas from science back into broader cultural discussions is also of great interest; for instance Martin Raff is an advocate for the legalization of physician-assisted suicide, though he denies a connection between his scientific research on cell suicide and his position on this social-legal issue (Raff, personal communication).13 Despite the NCCD’s recommendations articles employing the term ‘cell suicide’ continue to appear, though more rarely, in the journal Cell Death and Differentiation, (e.g. Lu & Finn, 2008; Ishikawa, Watanabe, Nagano, Kawai-Yamada, & Lam, 2011; Vaux, 2013). Nor have attempts to explicate the different mechanisms of cell death avoided further use of metaphors. Douglas Green, an immunologist and a co-author of the latest NCCD report, recently asked “Why are there so many forms of cell death?” Perhaps, he says, because there are so many ways by which the cell ‘machinery’ can be ‘sabotaged’ leading it to run itself to the ground (Green & Victor, 2012). Many forms of active cell death he argues may not be instances of suicidal ‘sacrifices’ so much as happenstance ‘system crashes’, such as the newly described non-apoptotic form of cell death known as ‘ferrotopsis’ which results from an irondependent accumulation of reactive oxygen species (Green & Victor, 2012, pp. 555e556). Only if these instances of ‘sabotage’ are eventually co-opted for the selective advantage they might confer to other living cells of the organism would it make sense, he says, to describe them as suicides (Green & Victor, 2012, p. 556). Here then we see an appeal to machine metaphors to explain how and why cell death occurs without any teleological assumptions about agency and utility. 5. Conclusion In conclusion I’d like to consider the question, What would have happened had scientists continued to talk only of cell degeneration and never introduced any of the metaphors discussed here? How productive would their investigations have been? Would knowledge and understanding of this aspect of cell biology look quite different? Would it even have become the area of intense investigation it did? Of course one can only speculate, but it is clear that Lockshin’s death programme metaphor was more than just a façon de parler for communicating with an audience of non-scientists. It was constitutive of an entire research program and theory about cell behavior that has contributed immensely to scientific understanding of development and disease, and to the discovery of new drugs and therapeutic interventions to alleviate human suffering. It helped situate this research into the general approach of a molecular biology strongly influenced by cybernetics and computer metaphors, and in this sense it probably worked as an effective ‘promotional metaphor’ encouraging others to turn their attention to the question of cell death.14 Likewise the significance of ‘cell degeneration’ as a question worthy of serious investigation relied to a significant

12 Raff and other scientists working on PCD are interviewed in the documentary film “Death by Design” (1995). 13 Raff’s story of how his parents arranged their own suicides in the face of opposition from police and state government officials can be found on the ‘Web of Stories’ site (http://www.webofstories.com/play/martin.raff/23). (Accessed 14 March 2014). 14 For promotional metaphors see Nelkin (1994), cited in Larson (2009).

degree I believe on its metaphorical characterization as a form of ‘altruistic’ cell ‘suicide’, and these metaphors continue to be important, not only for drawing attention to the phenomenon of active cell death, but also for theoretical and experimental attempts to understand its function, causes and mechanisms. As a general conclusion it bares stating that science would be impossible without language and that metaphors are important conceptual ‘tools’ in the scientific tool-kit. It is because scientific terms are not just communicative devices used as convenient currency or bridges between different disciplines, including the non-professional public, but that they also act as conceptual tools of analysis and experimental manipulation that bodies like the NCCD insist on their being precisely defined and free of misleading connotations, which may act like imperfect instruments that introduce artifacts and distortions into the scientist’s view of the system in question. On the other hand, the less figurative language preferred by the NCCD (‘precise, measurable biochemical and molecular genetic criteria’) may invite less ambiguity and facilitate biomedical interventions, but it fails to provide the insights which are the strengths of the metaphors in question. We often use different descriptions of a thing, for instance a person can be described as ‘homeless’, ‘displaced’, ‘vagrant’, or ‘nomadic’, and which we choose depends on our attitude toward and our plans for them. There will be as many appropriate descriptions of a thing as there are questions and projects we find ourselves interested in pursuing with respect to that thing. This is just to say that language and description serve instrumental ends; science is not just the discovery of one uniquely true description of the world, although it is often portrayed that way. But to do so ignores the human element in science, and that science is ultimately meant to be useful to us, and that it can be so in many different ways. A metaphor may be valuable if it suggests helpful experimental approaches and/or explanations and if it assists understanding of the phenomenon in question. These functions are different from the widely recognized rhetorical or communicative roles played by metaphor, they are cognitive or theoretical functions of relevance to the construction of scientific explanations (Bradie, 1999). The notion of ‘programmed cell death’ or a ‘cell death programme’ (an example of the machine/computer metaphor) did this by encouraging pursuit of the mechanisms of cell death in terms of the molecular signals, receptors, and effectors etc. by which the process is initiated and executed, in the hopes that scientists could find ways to ‘turn it on’ (in cancerous tumors) or ‘off’ (in the case of neurodegenerative and auto-immune diseases). In this regard the metaphor served as a label for what Evelyn Fox Keller has called ‘causal handles for experimental intervention’ used by scientists to manipulate a biological system (Keller, 2000, p. 141). On the other hand, we have also seen how metaphors can be misleading. The practice of thinking of active cell death as suicide proved to be misleading in some respects as to the functional details of cell death and its evolutionary origins. Additionally, some scientists (e.g. Sloviter) find the metaphor of a cell death programme vague, and yet this does not mean it lacks power. A vague scientific concept like programmed cell death can be valuable precisely because its ambiguity allows it to “circulate between different domains of research” (Morange, 2010, p. 180). That the power of some scientific terms derives from their imprecision or ambi-valence is a point made by Evelyn Fox Keller (2000, especially pp. 139e148) with respect to the language of the gene. Morange however echoes the NCCD in cautioning that too much imprecision can amount to confusion and misdirection, orienting researchers “towards questions that have no answers and to efforts that have no sense” (Morange, 2010, p. 180). There is also a tension inherent in the scientific enterprise between two conflicting tendencies: one restrictive and conservative;

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the other more expansive and liberal. They differ on the question whether it is a proper goal of science to assist in the creation of a unified picture of human experience, a philosophy or Weltanschauung (think of Raff’s philosophically-tinged accounts of cell death); or should each sub-field of science remain a technical discipline alone? The first seeks to keep a discipline narrow and professional; it seeks precise and clear language free of distracting anthropomorphism, so as to keep the science ‘pure’ and insulated from contamination of external values from the rest of human culture; the second considers it a legitimate goal of science to assist in the creation of a unified account of human experience in the universe, and regards metaphor as a natural and effective means of making science relevant to broader human concerns and for creating a more ‘philosophical’ science. The practice of scientists themselves suggests that these may both be legitimate projects undertaken at separate times and in different environments. For instance some metaphorical language deemed inappropriate for an original journal article reporting novel results may be apt for a review article intended to synthesize a diversity of facts scattered throughout the literature in specialized sub-disciplinary journals. Moreover, as already noted, interesting hypotheses and models often emerge from the fortuitous use of metaphor, and the articulation of scientific explanations in terms of causal ‘mechanisms’ is feeble without it, as is illustrated by the reliance of so much of successful modern biology on the metaphors of cell ‘signaling’, genetic ‘programs’ and ‘circuits’, and gene ‘regulatory networks.’15 Here too though care must be taken not to mistake the usefulness of a metaphor for understanding a part of a living system as indicating its adequacy for understanding the living organism as a whole.16 When concepts go ‘nomadic’ they not only bring fresh perspectives, they may also create tension with existing concepts and ways of seeing things, but this too can be productive if only by pointing to the limitations or inadequacies in our ways of thinking about something. In summary, the different metaphors surveyed here highlight different aspects of cell death and facilitate different questions and approaches to its study and possible intervention. And because there are not only so many different ways for a cell to die, but many different perspectives from which to consider its death (its morphology, its current physiological function, its evolutionary origins, its genetic and molecular mechanisms), it is possible for us to speak in the plural of the ‘deaths of a cell.’17

Acknowledgments I am grateful to Peter Haslinger, Katalin Stráner, and Jan Surman for the invitation to present at the workshop “Nomadic Concepts: conceptual reciprocities in biological and non-biological knowledge” held at the Herder Institute for Historical Research on East Central Europe, in Marburg 18e19 October 2012. I also wish to thank Martin Raff for graciously and promptly responding to email questions about his research into programmed cell death, and to Scott Gilbert for drawing my attention to anoikis. Comments from two anonymous reviewers pressed me to make my thesis and arguments clearer, and I am grateful for their helpful encouragement and prompting to improve the paper.

15 See the introduction by Davidson & Levine (2005) to the special issue of PNAS devoted to gene regulatory networks for the strong causal and explanatory claims couched in these metaphorical terms. 16 See Nicholson (2013). 17 I hope that Lewis Thomas would approve of my playful twist on the title of his excellent collection of essays The Lives of a Cell: Notes of a Biology Watcher (New York: Viking, 1974).

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