How does programmed cell death work

Too much apoptosis in an otherwise normal human being will result in a number of so-called neurodegenerative diseases where cells die when they're not supposed to die. And they get messages from some place, most of which we don't understand, to tell them to die, so in a certain part of the lower part of the brain, that's what causes Parkinson's disease.

This also characterizes Huntington's disease, and Alzheimer's disease, and Lou Gehrig's disease, and a number of other neurodegenerative diseases. Christopher P. Austin, M. Featured Content. Introduction to Genomics. This important question as to whether the emergence of an apoptotic death program in a kinetoplastid may be related to its obligate parasite nature may be addressed by investigating the closely related kinetoplastid Bodonids that include both parasites and free-living non-parasite single-celled organisms.

In summary, it is possible that the ancestors of the nine present day single-celled eukaryotes that are endowed with the capacity to undergo programmed cell death were initially devoid of the ability to self-destruct, and that programmed cell death became selected in different branches of the phylogenic tree in response to selective pressures that may have involved competition, interaction and cooperation with more recently diverging eukaryotes.

Such a process of parallel evolution leading to a somehow recent acquisition of programmed cell death may have happened either through horizontal gene transfer, through the building of similar cell death machinery by using a common molecular framework of conserved proteins of shared ancestry, or through the building of different cell death machinery by using diverse proteins through a process of convergent evolution.

But, whatever the molecular nature of such effectors may be, how did unicellular organisms select for the complex genetic programs allowing self-destruction, as well as for the coupling of cell survival to the repression of self-destruction? This is the question that I will now try to address.

I will now argue that there are ways to look at the nature and role of programmed cell death that are very different from those we have been accustomed to by thinking in the context of multicellular organisms.

The first example that I will discuss concerns various forms of regulated cell death that have been described in various bacterial species for several decades, but that were not considered, until recently, , , , , as potential examples of programmed cell death. Such primitive forms of programmed cell death had been described not only, as mentioned above, in circumstances that include the terminal differentiation of Myxobacteria , Streptomyces and Bacillus subtilis , but also, in several circumstances that involve competitions between bacterial colonies from different species, as well as competitions between plasmids or viruses and bacteria within a given bacterial colony.

When competing for the control of environmental resources, several bacterial species use strategies based on the killing of other bacterial species. They do this by secreting toxins antibiotics that induce the death of other bacteria. Such toxins include colicin E1, colicin E7, microcin Mcc B17, and streptomycin, and act either by inserting pores in the bacterial membrane, or by damaging bacterial DNA through direct or indirect mechanisms, involving the modulation of the activity of enzymes that participate in the modification of DNA topology, such as DNA gyrases.

These genetic modules bear surprising resemblance to the basic core of the genetic modules that allow, in cells from multicellular organisms, the regulation of programmed cell death. In other words, the ability to self-destruct may have simply evolved as a consequence of a capacity to kill others.

But there are other important aspects of an evolutionary arms race in bacteria that also pertain to the potential evolutionary origin of programmed cell death. In the prokaryote world, competition for environmental resources is not restricted to competition between different bacterial species. Infectious agents, such as plasmids and bacteriophage viruses, also compete with bacteria: in this case, it is the bacteria itself that is the resource, and the evolutionary arms race involves the spreading of the heterogeneous mobile genetic elements in the bacterial colony.

Strategies allowing plasmids and bacteriophages to propagate in the bacterial colony involves various mechanisms that allow spreading from one bacteria to another. Thus, the first targets of the toxins are the uninfected neighboring bacteria from the colony. This strategy allows a dramatic propagation of the plasmid in the colony, since it couples infection with survival, and induces the elimination of all uninfected bacteria.

Such strategy not only enforces efficient propagation, it also induces some level of irreversibility. But there are still more extreme forms of plasmid-mediated addiction strategies. Several plasmids achieve this by encoding both a toxin and an antidote. There are various forms of toxins and antidotes involved, but they all share two similar features: firstly, neither the toxin nor the antidote are secreted by the infected cell; secondly, the toxins are stable and long-lived, the antidotes are unstable and short-lived.

The usual view of symbiosis is that of a cooperation process, whereby the merging provides mutual benefits to the partners.

Here we see that a symbiosis can be achieved in a different and more radical way, by coupling separation with obligate death. What is the nature of the toxins and antidotes encoded by the addiction modules, and how is their respective half-life determined? All toxins are long-lived proteins; antidotes come in two kinds. Surprisingly, in all the known models, the protease is not encoded by the plasmid, but the plasmid addiction module relies on constitutively expressed bacterial chromosomal-encoded proteases, which include the Lon- or the ClpP-ATP-dependent serine proteases.

The reason why these bacterial serine proteases are constitutively expressed in the bacterial targets of the plasmid is that they appear to perform essential roles in bacterial survival, that will lead to the counterselection of protease loss of function mutants that may have otherwise escaped plasmid addiction. In some bacterial species, some of these essential roles performed by the Lon and ClpP proteases have been uncovered.

In both instances, they enforce the propagation of these genetic modules by inducing the elimination of the bacterial cells that do not express them. Natural selection can favor the propagation of given genes for the sole reason that they are successful at propagating themselves, while being of no advantage, or sometimes while even being detrimental, to the fitness of the organisms that carry them. A bacterial chromosome-encoded addiction module has been discovered in Escherichia coli.

The MazE protein antidote is short-lived because it is constantly cleaved by the constitutively expressed bacterial ClpP ATP-dependent serine protease. In appropriate environmental conditions, the MazF toxin, the MazE antidote and the ClpP proteins are constitutively expressed, leading to a constant de novo synthesis of the toxin, and to a constant de novo synthesis and cleavage of the antidote, a dynamic equilibrium that allows bacterial survival.

The ClpP protease continues to be expressed, the residual MazE antidote continues to be cleaved, and bacterial self-destruction occurs, as a consequence of MazF toxin-mediated irreversible DNA damage. Such a self-destruction process does not only provide the surviving cells with a greater share in the available external resources, but also with the additional nutrients represented by the dying cells.

Because the bacterial cells constitutively express the executioner protein allowing induction of cell suicide, cell survival constantly depends on the expression of a dominant but short-lived antidote protein that prevents activation of the executioner.

Accordingly, a surprising view of programmed cell death emerges when one fully realizes that it is not the expression of the programmed cell death module that induces cell suicide, but its repression; self-destruction in Escherichia coli is a phenotype that results from the regulated repression in response to environmental signals of a self-addiction genetic module encoding a toxin and an antidote.

But the coupling of such a repression of the addiction module to given exogenous signals could have become selected only if it allowed the concomitant survival of at least some members of the colony. In other words, such a program has to be socially regulated at the level of the colony population in order not to lead to the indiscriminate self-destruction of all the bacterial cells in response to adverse environmental conditions.

How may such a decision become integrated at the level of the bacterial colony? How may bacteria decide, at a single-cell level, when to die and when to survive? Although this is often neglected, the ability to differentiate is a feature of most, if not all, single-celled organisms, including prokaryotes. In bacteria, as in single-celled eukaryotes, coordinated changes in gene expression lead to changes in cell cycle regulation, in morphology, and in intercellular signaling.

Several other forms of differentiation have been described in bacteria, including the SOS stress and repair response, and the formation of biofilms that constitute complex multicellular communities. Upon nutrient shortage, a developmental program is triggered in most bacteria species, that leads to the concomitant induction of cell differentiation in a part of the population, and of cell death in the rest of the colony.

In Myxobacteria , Streptomyces and Bacilli , nutrient shortage induces the terminal differentiation, followed by the death, of a part of the cells from the colony; these terminally differentiated cells helping the other part of the cells from the colony to differentiate into long-lived non-cycling and highly resistant spores. Although environmental changes represent the initial and necessary trigger for the complex set of modifications that will lead to this process of alternate and complementary differentiation, the environmental signals by themselves are not sufficient: an additional step of intercellular signaling is required, that will lead to a coordinated set of changes in gene expression.

Quorum factor binding induces gene expression only when a threshold concentration of quorum factor is reached, that greatly exceeds the quantity of quorum factor that can be synthesized by any given cell. Such a process provides an interesting model for understanding how important changes that will affect the future of the whole colony are not taken at the level of any individual cell, but integrated at the level of the colony.

I will now argue that there is a striking example that illustrates how such a complex process can be achieved. A cell suicide program will become counterselected unless it is regulated in such a way that the sacrifice of some individuals in a unicellular colony will benefit or at least will not prevent the survival of other members of the colony. As mentioned above, a coupling of programmed cell death regulation to that of cell differentiation and of intercellular signaling represents one of the essential steps towards such a solution.

But how is this solution achieved? Bacillus subtilis provides a spectacular and extreme example of how such a major theoretical problem concerning the evolution of programmed cell death in unicellular organisms can be solved.

In favorable environmental conditions, Bacillus subtilis undergoes vegetative growth through symmetrical cell division. In adverse environmental conditions, such as nutrient shortage, Bacillus subtilis undergoes a complex developmental program whose initiation depends, as mentioned above, on cell density and on the concentration of released quorum factors. The septum cannot anymore be positioned at the middle of the cell as during vegetative growth but only closer to one pole of the developing cell.

Cell division, however, is not completed: the polar septum separates the cells in two different territories, and the two asymmetric future cells remain attached one to the other. In other words, the initiation of a process of asymmetric cell division allows Bacillus subtilis , at the level of each single cell, to undergo a developmental program leading to the emergence of the simplest possible form of a transient multicellular organism, made up of two cells that have respectively differentiated into the equivalent of a somatic cell the mother cell and into the equivalent of a germ cell the spore.

Because each single cell in the colony becomes the coupling unit, differentiation will obligatorily lead in the colony to an equal number of self-destructing cells and of surviving cells. Such a sophisticated temporal and spatial regulation of gene expression provides a spectacular example of how the coupling of programmed cell death to intercellular communication can avoid the death of the whole colony in adverse environmental conditions, by ensuring that the sacrifice of one half of the progeny will be coupled to the survival of the other half of the progeny.

Sporulation occurs only in some bacterial species, but as previously mentioned, cell differentiation associated with cell death is a usual response of most bacterial species to adverse environmental conditions. The view that I have proposed is that Bacillus subtilis represents an example rather than an exception of the intercellular communication that may operate maybe in a more stochastic manner in most single-celled organisms, and may allow the breaking of symmetry required for the coupling of programmed cell death to survival at the level of the colony.

While asymmetric cell division is an important and conserved mechanism involved in cell differentiation in bacteria , and single-celled eukaryotes, , it is not the sole mechanism allowing the breaking of symmetry at the level of a colony. In the single-celled eukaryote Dictyostelium discoideum , for example, independently of the numbers of the cells that have initially aggregated in response to adverse environmental changes and will develop a multicellular body, the respective proportions of cells that will become surviving spores and dying stalk will be conserved.

In contrast to Bacillus subtilis , however, the numbers of cells that will survive is not equal to the number of cells that will die, the former representing two-thirds of the cells, and the latter one-third.

It seems that each cell of the Dictyostelium colony, at the moment it begins to join the others, has the same initial stochastic probability to become a dying or a surviving cell. During a few hours, intercellular signaling, acting on initially random differentiation choices, seems to achieve a fine tuning of the respective proportion of future spore and stalk cells, through the release of molecules that, upon reaching threshold, influence the differentiation process in neighboring cells.

In summary, the evolutionary scenario that I have outlined above suggests a multi-step process for the emergence of programmed cell death in bacteria. Most eukaryote cells — from single-celled eukaryote organisms to multicellular animals and plants — harbor at least two genomes: the nuclear genome, that contains most of the cellular genes, and the cytoplasmic organelle genomes, that are small circular DNAs present in the mitochondria single-celled plants and multicellular plants contain an additional organelle genome, the plastid chloroplast circular DNA.

Numbers of mitochondria per cell also greatly vary depending on the organism, ranging from a giant unique mitochondrion kinetoplast in the kinetoplastid protozoan single-celled eukaryotes, such as the trypanosomes, to several hundred mitochondria per cell in several single-celled eukaryotes and in multicellular animals.

Mitochondria play an essential role in eukaryote cells from single-celled and multicellular organisms: they perform aerobic metabolism, that allows energy production through ATP synthesis by a respiratory process that involves an electron transport chain and a chemiosmotic process. Loss of mitochondrial function forces cells to rely only on anaerobic metabolism, which may be lethal in most cells from multicellular animals but mature human erythrocytes, that lack mitochondria, represent an interesting exception and, probably, from most single-celled eukaryote but Giardia and Microsporidia , that lack mitochondria, represent interesting exceptions.

Each mitochondrion is bound by two highly specialized membranes that create two separate compartments, the internal matrix space and the intermembrane space. All these features strongly suggest that mitochondria are of ancient bacterial origin, and support the hypothesis that mitochondria arose from symbiosis between bacteria able to perform aerobic metabolism and ancestors of eukaryote cells.

Present day mitochondria and eukaryotic cells are condemned to live together, and this symbiotic equilibrium is usually viewed as a consequence of a mutual cooperation process between the ancestors of the eukaryotic cells and the aerobic bacteria they captured.

This is true of some of the pathogenic bacteria,such as Ricketsia , Listeria and Schigella , that invade mammals and replicate in their cells by subverting host cell signaling processes. First, the amoebae palomyxa palustris , one of the rare single-celled eukaryotes that lack mitochondria, is a symbiont that contains aerobic bacteria in its cytoplasm; and it is these bacteria that perform the respiratory activity required for the aerobic metabolism of the amoebae.

If these situations are to be considered as examples of intermediate evolutionary steps towards endosymbiosis, they strongly suggest that the evolution of the present day eukaryote cell may have resulted as much from an initial bacterial manipulation of their host, than from the opposite situation. In present day mitochondriated eukaryotes, most of the genes encoding mitochondrial proteins are located in the cell nucleus and seem therefore to have been progressively transferred from the mitochondrial genome to the nuclear genome.

These proteins are synthesized on cytoplasmic ribosomes, and are then imported into the organelle. Once they have been synthesized and imported into the mitochondria, these proteins are believed never to leave the mitochondria, at least as long as the cell survives.

Interestingly, the transfer to the nucleus of the whole mitochondrial genome may have been rendered impossible at some time point by changes in the mitochondrial genetic code that may have prevented the transcription and translation of these mitochondrial genes from the nucleus. Such complex interactions may be better understood if considered in the context of a conflict resulting in an addictive form of enforced endosymbiosis, similar to the addictive enforced endosymbiosis between plasmids and bacteria that I have previously discussed.

On the one hand, eukaryotic cells from most organisms are condemned to retain mitochondria, since they have become dependent on aerobic mitochondrial respiratory metabolism; on the other hand, mitochondria cannot leave the cell since most of the proteins that constitute them have become encoded by nuclear genes.

The actual outcome of such an ancient evolutionary battle, the present day eukaryote cell, may result from a process of reciprocal addiction between the host and its former pathogen, whereby the survival of the cell depends on the homeostasis and presence of the mitochondria, and the survival of the mitochondria on the homeostasis and presence of the cell.

Interestingly, all these players, whether located inside the mitochondria or on its outer surface, are encoded by nuclear genes, and none by mitochondrial genes.

This is consistent with previous findings that the mitochondrial DNA contained in the organelle is neither required for the induction of the effector phase of programmed cell death, nor for its prevention by the bcl-2 gene product, a finding that was initially interpreted as suggesting the possibility that mitochondria may not be involved in the regulation of programmed cell death.

Although now located in the cell nucleus, such genes encoding mitochondrial proteins have homologues in bacteria and are thus presumed to be of ancient bacterial origin.

On the other hand, the genes encoding the Bcl-2 family proteins that participate in the suppression of programmed cell death, are presumed to be of eukaryote origin.

In other words, the involvement of an organelle of bacterial origin the mitochondria in the effector phase of programmed cell death is regulated by a family of genes of apparent eukaryote origin bcl-2 , through three dimensional features that they share with bacterial toxins.

This scenario provides a general framework for the evolution of programmed cell death that extends from prokaryotes to single-celled eukaryotes, and from single-celled eukaryotes to the multicellular animals and plants. This scenario raises additional interesting, yet unanswered questions. For example, some present day single-celled eukaryotes that lack mitochondria, such as the diplomonads, parabasalids, microsporidia, and entamoebae that include, respectively, the human pathogens Giardia , Trichomonas vaginalis , Encephalis tozoon and Entamoeba histolytica appear to have lost their endosymbiotic organelle after having transferred several genes of mitochondrial origin to their nuclear genome.

And, if this is the case, do their nuclear genes of mitochondrial origin play a role in the regulation of programmed cell death? Another question concerns plant cells, that have, in addition to mitochondria, another endosymbiotic organelle of cyanobacterial origin, the chloroplast. Do chloroplasts play a role in the regulation of plant programmed cell death?

And since an AP-ATPase, a metacaspase and a TIR domain have been identified in cyanobacteria as in some other bacterial lineages , 92 did plants acquire their putative homologues of the apoptotic machinery through this endosymbiotic process?

The scenario that I have outlined above may not be the only possible one for the evolutionary origin of programmed cell death. I have proposed an alternative scenario that has at least three interesting aspects.

Secondly, it removes the need for postulating a multistep process in the emergence and selection of the genetic modules allowing the regulation of self-destruction. It postulates that the origin of the capacity to self-destruct may be as ancient as the origin of the very first cell. The hypothesis I have proposed is that effectors of the cell survival cell cycle and cell differentiation machinery may have had an intrinsic and ancestral capacity of inducing the self-destruction of the cell in which they operate.

Accordingly, if effectors of the cell survival machinery can also be effectors of the self-destruction of the cell in which they operate, then the requirement for coupling cell survival to the prevention of self-destruction may be as old as the origin of the first cell. Is it possible to envision the molecular pathways and the gene products that participate in cell metabolism, cell cycle or cell differentiation as potential executioners?

Let us consider, in a putative ancestor cell of the prokaryotes, the topological manipulations of DNA required for replication, transcription and recombination; the DNA repair mechanisms involved in the correction of DNA damage; the cell membrane repair mechanisms; and the segmentation process of the cell required for cell division; and let us consider in a putative nucleated ancestor of the eukaryotic cell, the processes of rearrangement of chromatin organization, of remodeling or dissolution of the nuclear membrane, and of chromosomal migration required for cell division.

And in both prokaryote and eukaryote cells, the regulation of ionic channels, involved in the control of cell metabolism, volume, density and permeability. All cellular processes have intrinsic error rates; and most, if not all, the processes mentioned above involve enzymatic activities that, if not tightly regulated, have the intrinsic potential to lead to cell death.

If we attempt to continue this thought experiment in the first living cells, it is tempting to propose that genes encoding molecular tools allowing cell metabolism, differentiation, division and repair could become selected only if they were associated to genes that encoded inhibitors able to control the activity of the former by restricting their error rate. In mammalian cells, numerous gene products involved in the control of cell cycle and cell differentiation, including protooncogenes, tumor suppressor genes, cyclins, cyclin-dependent kinases, have also been shown to participate, at various levels, in the regulation of programmed cell death.

Indeed, in yeast, as in mammalian cells, mitotic catastrophes resulting from the uncoordinated activation of cyclins have a phenotype similar, or identical, to apoptosis; , in some bacteria species, the autolysins that are required for cell division by breaking the peptidoglycan bacterial wall, can also induce self-destruction in adverse environmental conditions; and we have seen that the ATP-dependent serine proteases Lon and Clp are involved in both the induction of self-destruction and the regulation of cell cycle in bacteria.

An interesting aspect of this scenario is that it does not postulate the existence of any real evolutionary transition between single-celled organisms unable to undergo regulated self-destruction and single-celled organisms able to achieve programmed cell death. I have argued that in the context of such an hypothesis, the evolution of programmed cell death would share similarities with the evolution of genetic diversification.

In other words, such a model implies that evolution has led to a continuous fine-tuning of the regulation of self-destruction, rather than to the emergence, at a given time point, of a cell suicide machinery. Such a model provides a simple mechanism for the selection of upstream inhibitors of self-destruction that enhanced the efficiency of cell metabolism, cell cycle, and cell differentiation. At the same time, such a model provides a simple mechanism for the selection of upstream inducers of programmed cell death that allowed enhanced fitness of the colony through the rapid dismissal of altered cells, and provided a selective advantage to the best adapted cells in adverse environmental conditions.

Therefore, the evolution of programmed cell death and the evolution of genetic diversification may share more than similarities: they may have deeply influenced each other from the onset, and exerted an important constraint on the process of natural selection. If the capacity to self-destruct represents an unavoidable intrinsic consequence of the capacity to self-organize, a basic property of life, then there may exist as many different pathways allowing self-destruction as they are allowing the establishment and maintenance of self-organization.

Rather, self-destruction would result from various usages of different gene products that each also participates in various pathways involved in cell metabolism, cell differentiation, cell cycle and, more generally, cell survival.

The first prediction is that there should not exist a single family of executionary molecules that is both necessary and sufficient in all instances to induce cell death. The second one is that there should be no effector involved in the execution of cell death that does not also participate in some vital cell function. Recent findings suggest that these predictions may have some validity.

But, concerning these mitochondrial proteins, it has been recently reported that in some instances, cell death may proceed in the absence of mitochondrial permeabilization. Indeed, when localized inside the mitochondria, cytochrome c plays an important role in cell survival through oxidative phosphorylation, ATP production and energy production. Once released from the mitochondria into the cytosol, however, it participates in the activation of caspases that may result in cell death.

Similarly, when localized inside the mitochondria, endonuclease G seems to play an important role in mitochondrial DNA replication, and once released from the mitochondria, it seems to participate in caspase-independent cell death. But we might even attempt to go one step further.

While such a view may seem to only raise theoretical questions, it also has obvious therapeutic implications. Firstly, if there are indeed several different self-destruction pathways, the targeting of a given effector for inhibition may not be sufficient to prevent unwanted pathological cell death in all circumstances, and selective, adapted, therapeutic approaches will be required. Secondly, since inhibition of a given effector, when not preventing cell death, may change the death phenotype from apoptotic to necrotic, for example , such a therapeutic manipulation of the cell death phenotype may either lead to deleterious effects or provide new opportunities concerning the modulation of inflammation, autoimmunity and effector immune responses to infectious or tumor antigens.

Finally, if effectors of self-destruction also participate in vital cell functions, the therapeutic activation or inhibition of a given effector may not only influence cell death regulation, but also, depending on the circumstances, cell differentiation and cell cycle. The nematode Caenorhabditis elegans has provided the paradigm i that a single molecular pathway, involving a small number of gene products, is both necessary and sufficient, in all instances, for the induction of cell death, and ii that gene products involved in the regulation of programmed cell death have no other possible effect than the induction or repression of programmed cell death.

In Caenorhabditis elegans , genetic mutants with a loss of function in the ced-3 gene, encoding the Ced-3 caspase, or in the ced-4 gene, encoding the Ced-4 adaptor protein required for Ced-3 activation, undergo no developmental cell death and are therefore born with additional somatic cells.

These additional cells do not show any obvious defect, consistent with the proposal that Ced-3 and Ced-4 have no other effect than inducing cell death. But things may not be so simple, for several reasons. The first one is that it is debated whether Caenorhabditis elegans truly represent an evolutionary simple ancestral metazoan, or rather a stripped down version of an initially more complex multicellular animal ancestor, through a process of reductive evolution leading to secondary simplification.

Consistent with these findings, overexpression of CEP-1, the recently identified Caenorhabditis elegans homologue of the mammalian p53 tumor suppressor protein induces widespread cell death in ced-3 and ced-4 loss of function mutants, implying the existence of a caspase-independent death program. The third reason is that CEP-1, in contrast to Ced-3 and Ced-4, does not seem to solely function as an executioner, but to have several additional properties.

Indeed, it may be required for both DNA damage-induced death and normal meiotic chromosome segregation in the germ cells; and also plays a role in the regulation of the whole animal life span in response to environmental stress. Caenorhabditis elegans has four genes that have seemingly been selected for only one effect: the control of developmental cell death.

But developmental cell death by itself appears to have no function in Caenorhabditis elegans. Indeed, the ced-3 or ced-4 loss-of-function mutants that have additional somatic cells seem to have no significant defects.

This may be consistent with the reductive evolution process hypothesis, as mentioned above. Alternately, it is possible that Ced and Cedmediated cell death provides some advantages in a wild-type natural environment that are not detected in a laboratory environment.

But if this is the case, then it is also possible that additional effects of Ced-3 and Ced-4, unrelated to cell death induction, may also become apparent in a wild-type environment. Finally, different domains of a given protein may be involved in different pro-death or pro-survival effects.

To come back to the example of the effects of cytochrome c in mammalian cells, the molecular domains that participate in caspase activation are not the same as those ensuring its crucial role in mitochondrial respiratory activity. In this respect, as far as I know, all ced-3 loss-of-function mutants in Caenorhabditis elegans studied to date are the consequence of point mutations and not of gross insertion or deletion processes ; therefore, I believe that, in order to assess whether the Ced-3 caspase in Caenorhabditis elegans may have effects other than execution of programmed cell death, that may be independent of their proteolytic activity, it would be important to perform Ced-3 knock-out experiments and to investigate their phenotype.

But we are not obliged to choose between them. We will now see that these two hypotheses are not antagonistic, but can be seen as complementary and even synergistic. An extreme implication of this view is that bacterial antibiotic toxins such as those involved in membrane permeabilization, in DNA fragmentation, or in the modulation of enzyme activity involved in DNA topological changes such as DNA gyrases may also exert important vital functions other than killing cells. But there is another level of heterogeneity.

The chromosomal genome is made of a congregation of genes that propagate if, and when, the proteins they encode achieve the minimal degree of cooperation that allows the survival of the cells that harbor them.

In principle, the propagation of a given genome results from selective advantages that such a cooperation provides to the cells that harbor it. In summary, each cell can be viewed as a heterogeneous environment involving both competition and cooperation between different genetic modules in a given genome; and each colony of single-celled organisms as an environment involving both competition and cooperation between different cells harboring similar or mutant genomes.

By coupling cell survival to the nature of interactions between different gene products in a given cell, and to the nature of interactions between different cells in a given colony, the modules allowing both regulated self-organization and self-destruction that become selected in prokaryotes and in eukaryotes led to multiple variations on the theme of enforced cooperation. I believe that this is the main reason why the regulation of premature cell death may have represented, since the emergence of the first cell, one of the driving force in the evolution of life towards complexity.

Deciphering these ancient and intricate relationships between the regulation of cell survival, cell renewal and cell death, and understanding to what extent these processes may be selectively modulated by therapeutic intervention will probably represent one of the new frontiers of biology and medicine in this century.

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Robert Horvitz, an expert on apoptosis at the Massachusetts Institute of Technology, gives a brief response: "In short, the question of why programmed cell death occurs should be subdivided into two related questions: Why are cells that die by programmed cell death generated?

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