An Adaptationist View of Apoptosis

In multicellular organisms, cells are frequently programmed to die. This makes good sense: cells that fail to, or are no longer playing important roles are eliminated. From the cell's perspective, this also makes sense, since somatic cells in multicel-lular organisms require the cooperation of clonal relatives. In unicellular organisms, however, programmed cell death (PCD) poses a difficult and unresolved evolutionary problem. The empirical evidence for PCD in diverse microbial taxa has spurred debates about what precisely PCD means in the case of unicellular organisms (how it should be defined). In this article, we survey the concepts of PCD in the literature and the selective pressures associated with its evolution. We show that definitions of PCD have been almost entirely mechanistic and fail to separate questions concerning what PCD fundamentally is from questions about the kinds of mechanisms that realize PCD. We conclude that an evolutionary definition is best able to distinguish PCD from closely related phenomena. Specifically, we define " true " PCD as an adaptation for death triggered by abiotic or biotic environmental stresses. True PCD is thus not only an evolutionary product but must also have been a target of selection. Apparent PCD resulting from pleiotropy, genetic drift, or trade-offs is not true PCD. We call this " ersatz PCD. " Keywords Adaptation · Aging · Apoptosis · Price equation · Programmed cell death · Selection · Unicellular organisms

Cell Death & Differentiation, 2002

Biotecnología …, 2004

Programmed Cell Death (PCD) is an emerging topic contributing actively to basic biology, and in the near future, we could expect practical applications improving human health and the productivity of our crops. Current results relate this complex and paradoxical process with the physiological development, stress response and diseases of plants and animals. With the aim of improving the exchange as a starting point to future cooperation in the field of PCD, the International Cell Death Society (ICDS) and the European Cell Death Organization (ECDO) organized in Havana on February 24th the International Seminar Programmed Cell Death in Plants: a challenge to the new millennium, sponsored by the Tobacco Research Institute of Havana. To this historical meeting, the first co-organized by the two most important organizations on PCD, were invited recognized scientists from Italy, USA, France, Belgium, Switzerland, Czech Republic and Cuba. Although the seminar was organized to deal with the basic aspects of cell death in plants, speeches referred frequently to animal models. Session chairs, Mauro Piacentini and Zahra Zakeri, presidents of ECDO and ICDS, respectively, guided thirty minute speeches of ten speakers. The opening words of Vladimir Andino, head of the Tobacco Research Institute of Havana, and Mauro Piacentini, were followed by the speech of Richard A Lockshin from the Department of Biological Science of St. John's University, USA. He dealt with the historical origins of PCD research [1]. According with his speech, cell death as a normal, physiological process was recognized in the 19 th Century. One hundred years later, many of these deaths (in animals) were described as programmed, deriving from the recognition that, in embryonic development and metamorphosis, cells died at predictable times and places. Thus the assumption was that cell death was genetic in origin, and not a random loss of control. Later, Kerr, Wyllie, and Currie [2] called attention to a common morphology of many cell deaths and coined the term "apoptosis" in order to assert its importance in homeostasis as opposite and equal to mitosis (Figure 1). Shortly thereafter, a group of researchers ultimately led by Horvitz [3] proved the existence of genes that controlled all cell deaths in the embryo of the nematode Caenorhabditis elegans. Their research led rapidly to the identification of these genes. These included genes that could turn on or off the activation of death, genes that produced products that could kill cells, inhibitors of those products-activation of death often consisted of release from inhibition of death-and genes involved in the scavenging of the remnants of the dead cells. Two profound arguments developed from these discoveries: First, that all cells carried within them

Yale Journal of Biology and Medicine, 2023

Theoretical frameworks concerning cell fate typically center on proximate causes to explain how cells know what type they are meant to become. While major advances in cell fate theory have been achieved by these mechanism-focused frameworks, there are some aspects of cell decision-making that require an evolutionary interpretation. While mechanistic biologists sometimes turn to evolutionary theory to gain insights about cell fate (cancer is a good example), it is not entirely clear in cell fate theory what insights evolutionary theory can add, and why in some cases it is required for understanding cell fate. In this perspective we draw on our work on cellular mortality to illustrate how evolutionary theory provides an explanation for death being selected as one of the potential cell fates. Using our hypothesis for why some microbes in a community choose death as their fate, we suggest that some insights in cell fate theory are inaccessible to a theoretical framework that focuses solely on proximate causes.

Trends in Biochemical Sciences, 1999

A poptosis is a morphologically distinct form of cell death that is designed to rapidly remove unwanted and potentially dangerous cells 1,2. During the development of most metazoan animals, many more cells are produced than are eventually needed, and apoptosis plays a key role in removing surplus cells and sculpting the developing embryo 3 (Fig. 1). In addition, the inappropriate regulation of apoptosis is associated with a variety of diseases, including cancer, AIDS, neurodegenerative diseases and ischaemic stroke 4. Because apoptosis represents an active, gene-directed mechanism, it should eventually be possible to control this process for therapeutic purposes. During the past few years, rapid progress has been made in identifying some of the molecules that are responsible for the regulation and execution of apoptosis. The existence of a cell-suicide programme was originally proposed on the basis of the stereotyped, morphological changes associated with natural cell death, but definitive evidence for the existence of a designated death programme came from genetic studies of cell death in Caenorhabditis Millennium issue Zhiwei Song

Nature Reviews Molecular Cell Biology, 2001

PERSPECTIVES research into caspases and the role of mitochondria in apoptosis -are mentioned only briefly.

Cell, 1997

condense, and the organelles and plasma membrane retain their integrity in a process Kerr and his colleagues and Martin C. Raff Developmental Neurobiology Programme named apoptosis. The dead cells or their fragments are rapidly phagocytosed by neighboring cells or macro-MRC Laboratory for Molecular Cell Biology University College London phages before there is any leakage of the contents of the cells, and thus they do not induce an inflammatory London, WC1E 6BT United Kingdom response. Apoptotic cells in developing tissues are almost always inside other cells (Figures 1A-1C), suggesting that dying cells are usually phagocytosed before they display the morphological changes of apoptosis. Programmed cell death (PCD) occurs during the devel-Because apoptotic cell deaths usually look so similar opment of all animals that have been studied, but only from tissue to tissue and animal to animal (Figures 1Arecently has its molecular basis been discovered. In this 1C), Kerr and his colleagues proposed that these deaths review, we briefly consider some of the main events reflect the operation of an active, intracellular death proin the history of PCD in animal development. We then gram that can be activated or inhibited by a variety of summarize what has been learned about the molecular physiological or pathological environmental stimuli. mechanism of PCD and some of the intracellular pro-It took almost another 20 years, however, before the teins that control it. We next discuss the functions of idea that animal cells have a built-in death, or suicide, PCD in development and how PCD is regulated during program became generally accepted, largely through development by signals from other cells. Finally, we genetic studies in the nematode Caenorhabditis elegans consider what the evolutionary origins of PCD may have that identified genes that seem dedicated to the death been. program and its control (Horvitz et al., 1982; Ellis and Horvitz, 1986), and then through the finding that some Some History of these genes were homologous to mammalian genes Soon after it was recognized in the middle of the last

Advances in Experimental Medicine and Biology, 2008

Cell death was observed and understood since the 19th century, but there was no experimental examination until the mid-20th century. Beginning in the 1960s, several laboratories demonstrated that cell death was biologically controlled (programmed) and that the morphology was common and not readily explained (apoptosis). By 1990, the genetic basis of programmed cell death had been established, and the first components of the cell death machinery (caspase 3, bcl-2, and Fas) had been identified, sequenced, and recognized as highly conserved in evolution. The rapid development of the field has given us substantial understanding of how cell death is achieved. However, this knowledge has made it possible for us to understand that there are multiple pathways to death and that the commitment to die is not the same as execution. A cell that has passed the commitment stage but is blocked from undergoing apoptosis will die by another route. We still must learn much more about how a cell commits to death and what makes it choose a path to die.

Cell, 2011

Current Opinion in Neurobiology, 1998

Natural selection acts primarily on organisms, and the existence of evolved, active, internal mechanisms that cause organismal death would seem paradoxical. However, there is substantial evidence that internal death promoting mechanisms exist and are taxonomically widespread. Where these are argued to be ‘programmed organismal death’ (POD), they require evolutionary explanations. Any such explanation must draw on our understanding of fitness trade-offs and multiple levels of selection in evolution. This review includes two main categories of putative POD: senescence in multicellular-organisms, and programmed cell death in unicellular organisms. The evidence for POD as a genetically controlled phenotype is strong for semelparous and significant but more controversial for iteroparous plants and animals. In multicellular organisms the program frequently (although not always) appears to be the result of fitness trade-offs. Here the death phenotype itself is not adaptive but the fitness related program most likely is. However, in some cases of behavioral suicide, particularly in insects, there are distinct advantages to kin and group level benefits may play a role. In unicells, programmed death is ubiquitous and POD often provides benefits to others. While benefits do not equate with adaptations, they are consistent with it. Here, death may be adaptive at a level other than the individual cell. In other instances of POD in unicells the phenotype (eg autophagy) can be explained as pleiotropy. The overall picture of POD as a natural phenomenon is still emerging, and continued work on diverse lines of evidence is necessary to complete our evolutionary understanding of this apparent paradox. While some questions remain, we conclude that POD is most likely, in some circumstances at least, adaptive.

Current Opinion in Neurobiology, 2009

Studies of developmental cell death in the nervous system have revealed two different modes of programmed cell death (PCD). One results from competition for target-derived trophic factors and leads to the stochastic removal of neurons and/or glia. A second, hard-wired form of PCD involves the lineage-specific, stereotypical death of identifiable neurons, glia or undifferentiated cells. Although traditionally associated with invertebrates, this 'programmed PCD' can also occur in vertebrates. Recent studies have shed light on its genetic control and have revealed that activation of the apoptotic machinery can be under the same complex, combinatorial control as the expression of terminal differentiation genes. This review will highlight these findings and will suggest why such complex control evolved.

ChemBioChem, 2004

Mutation Research/Reviews in Mutation Research, 2003

One of the hallmarks of multicellularity is that the individual cellular fate is sacrificed for the benefit of a higher order of life-the organism. The accidental death of cells in a multicellular organism results in swelling and membrane-rupture and inevitably spills cell contents into the surrounding tissue with deleterious effects for the organism. To avoid this form of necrotic death the cells of metazoans have developed complex self-destruction mechanisms, collectively called programmed cell death, which see to an orderly removal of superfluous cells. Since evolution never invents new genes but plays variations on old themes by DNA mutations, it is not surprising, that some of the genes involved in metazoan death pathways apparently have evolved from homologues in unicellular organisms, where they originally had different functions. Interestingly some unicellular protozoans have developed a primitive form of non-necrotic cell death themselves, which could mean that the idea of an altruistic death for the benefit of genetically identical cells predated the invention of multicellularity. The cell death pathways of protozoans, however, show no homology to those in metazoans, where several death pathways seem to have evolved in parallel. Mitochondria stands at the beginning of several death pathways and also determines, whether a cell has sufficient energy to complete a death program. However, the endosymbiotic bacterial ancestors of mitochondria are unlikely to have contributed to the recent mitochondrial death machinery and therefore, these components may derive from mutated eukaryotic precursors and might have invaded the respective mitochondrial compartments. Although there is no direct evidence, it seems that the prokaryotic-eukaryotic symbiosis created the space necessary for sophisticated death mechanisms on command, which in their distinct forms are major factors for the evolution of multicellular organisms.