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Cell evolution: immortality vs reproduction

Cell evolution: immortality vs reproduction


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Many sci fi movies produce interesting ideas and technologies that we seem to be able to realize in real life at some point. "Lucy" was not one of those movies.

But Morgan Freeman's speech in the movie on cell evolution did interest me.

The speech claimed that cells in harsher environments evolve towards immortality, while cells in favorable environments evolve toward reproduction.

Is this idea accurate?


You'll see that in many cases, when any sort of cell enters a zone of intolerance or zone of physical stress, the replication machinery gets put on the backburner (and thus replication). Expression of stress-response proteins like heat shock proteins is increased as a result (1). If a cell isn't within acceptable parameter to undergo division at G1 or G2 (anoxic environment, etc.), you'll find mechanisms like G0 phase or sporulation are preferred until the environment returns to something less stressful (2). I wouldn't say cells would rather be immortal, per se, but longevity or even apoptosis/entosis/etc. would be preferable to replication if nothing is going right (3, 4).

To be clear, when we're talking about evolution that's a tough one. Sure, some sort of stress-response transient signal could induce some lasting cell memory selecting toward a specific function. I simply don't have the data to quote you in that aspect, however.

  1. Biology of the heat shock response and protein chaperones: budding yeast (Saccharomyces cerevisiae) as a model system.

  2. Slonczewski, J., & Foster, J. (2011). Microbiology: An evolving science (2nd ed., p. 143). New York: W.W. Norton.

  3. DNA damage-induced apoptosis

  4. Cellular Stress Responses: Cell Survival and Cell Death

As a footnote, while replication does occur in sporulation, the replicated chromosome is destroyed in the process of forming the actual spore.


The evolutionary biology of aging, sexual reproduction, and DNA repair.

The phenomena of aging and of sexual reproduction are surely among the most counterintuitive and puzzling of widespread outcomes to have evolved under the influence of natural selection. Why should individuals of most species senesce and die when Darwinian selection seemingly would favor any genetic predisposition for greater longevity and continued reproduction? And why should individuals engage in sexual as opposed to asexual reproduction, when by so doing they not only expend time and energy in finding a mate, but also dilute (by 50%!) their genetic contribution to each offspring? Evolutionary biologists have long pondered these issues, and the theoretical and empirical results recently have been summarized eloquently in three landmark books. This commentary will address primarily the contribution by Bernstein and Bernstein (1991) on DNA repair as it relates to the evolution of aging and sexual reproduction, but for useful background some comments first will be made about the important volumes by Rose (1991) on aging and by Michod and Levin (1988) on sex.

Under Rose's evolutionary definition, aging is "a persistent decline in the age-specific fitness components of an organism [survival probability or reproductive output] due to internal physiological deterioration" (Rose 1991, p. 38). The central thesis of Rose's book is that the mathematical framework of evolutionary genetics has solved the paradox of aging in age-structured populations by showing that the phenomenon is an inevitable outcome of the declining force of natural selection through successive age classes. Under the formal theory that Rose cogently summarizes, natural selection is simply indifferent to problems of somatic deterioration with advancing age, because as measured by effects on fitness (representation in successive generations) these problems are trivial compared with those that might appear earlier in life. Thus, aging and death exist not for any ineluctable physiological cause, but because of "a failure of natural selection to 'pay attention' to the problem". Particular genetic mechanisms of aging are not specified by this evolutionary theory, but two leading candidates for which explicit theoretical treatments are available are (1) antagonistic pleiotropy, in which alleles tend to evolve that have beneficial effects at early ages of life but antagonistic deleterious effects later, and (2) age specificity of gene action, in which alleles with age-delayed deleterious somatic effects accumulate in evolution simply because they are nearly neutral in terms of fitness because of weak selection in later age classes. Regardless of the means by which aging is played out from the basic evolutionary script, the take-home message is that "given age-structured populations and genetic variation in life histories, aging is a straightforward corollary of population genetics theory". This theory should apply to all organisms in which there is a clear distinction between somatic cells and germ-line cells.

Having established a conceptual primacy for the evolutionary theory of aging, Rose then chastises the field of gerontology for lack of this orienting foundation. For example, according to the evolutionary view, "the search for an ultimate physiological cause of aging is no more cogent than a search for a physiological cause of evolutionary adaptation would be. . . . This implies that one of the basic goals of gerontology, that of finding the physiological cause(s) of aging, is misconceived". Rose provided extended reviews of the experimental evidence for several physiological theories for aging previously advanced (involving "wear and tear," rate-of-living considerations, hormonal influences, metabolic pathologies, and a host of others), and finds all to be wanting as universal explanations. Although many of these factors no doubt play proximate roles in the aging process, none provides the ultimate explanation for aging that is embodied in the evolutionary view.

From experimental findings as well as comparative aspects of aging across life forms, Rose concluded that there are multiple causes for aging and that these can be arranged hierarchically with regard to explanatory power. The ultimate (evolutionary) cause is the attenuation of the force of natural selection with respect to the age of gene effects in species with soma. At the penultimate level are the population genetic explanations of antagonistic pleiotropy and mutation accumulation, and at the bottom tier are the highly idiosyncratic molecular, cellular, and physiological pathways by which the genetic underpinnings of aging happen to have been executed in a particular population or species.

Rose's book is a seminal contribution because it provides one of the clearest, most coherent, and forceful documentations of why aging is not incompatible with natural selection after all. This new perspective should revolutionize the conceptual framework of gerontology, which as a discipline had remained one of the last bastions of biology relatively untouched by evolutionary thought. However, I don't quite share Rose's enthusiasm that this new theoretical orientation will revolutionize the day-to-day practice of gerontological research (any more than did Darwin's [1859] classic "On the Origin of Species by Means of Natural Selection, or the Preservation of Favored Races in the Struggle for Life" change the day-to-day practice of naming and describing species). Thus, an important empirical task in gerontology will remain the identification of particular molecular or cellular events involved in the aging process, idiosyncratic as they may be. This effort is especially important in humans or other species in which ameliorative efforts might then be contemplated. Furthermore, if the arguments by Bernstein and Bernstein (1991) are correct, Rose's sounding of the death knell for global molecular mechanisms underlying aging may have been premature.

Sexual reproduction entails the generation of new combinations of genes by the mixing of genomes, or portions thereof. In most evolutionary definitions, sex is synonymous with genetic recombination, although some authors emphasize usual components of the process, such as physical recombination (the breakage and reunion of two different DNA molecules), and outcrossing (the mixing of DNA molecules from separate individuals). Why should various mechanisms for genetic mixis have evolved so nearly universally across life? Michod and Levin's edited book brings together authoritative and stimulating contributions on this topic from most of the major architects of recent theories on the evolutionary significance of sexual reproduction.

These diverse hypotheses can be divided into two categories that are nearly opposite in orientation, though not necessarily mutually exclusive. The first category of theories perceives a benefit per se for sex, either at the immediate level of individual fitness or at the evolutionary level of group persistence. Thus, genetic mixis itself is the object of selection. Theories of this type are united by the theme that genetic variability arising from mixis and molecular recombination must somehow be advantageous in an ecological or evolutionary theater, such that the benefits to individuals (or perhaps to extended groups) outweigh the rather obvious and substantial costs of sex to individuals. Three advantages classically proposed for sexual reproduction are as follows: (1) to facilitate the incorporation of beneficial mutations into an evolutionary lineage (2) to facilitate the removal of deleterious mutations (i.e., to overcome Muller's ratchet, the ineluctable process by which the mutational load in strictly asexual lineages can remain only the same or increase through time) and (3) to allow adjustments to spatial or temporal changes in the physical and biotic environment. Several chapters (by Bell, Crow, Ghiselin, Maynard Smith, Seger and Hamilton, Williams, and others) formalize and elaborate these hypotheses, all of which can rationalize the prevalence of sexual modes of reproduction. However, some of the arguments are less than fully convincing, particularly when it comes to proposed short-term benefits of sex that are required under a strictly individual-selectionist framework.

The second category of theories proposes instead that sex is a coincidental evolutionary by-product of other primary consequences for mixis. For example, Hickey and Rose propose that sex is an outcome of subgenomic selection on parasitic DNA sequences that "imposed" biparental sexual reproduction on host genomes to favor their own spread. Another set of scenarios in this category (chapters by Bernstein et al., Holliday, Levin, and Shields) proposes that the evolution (and perhaps maintenance) of sexual reproduction involved selection pressures favoring mechanisms for the correction of genetic errors. This leads us finally to discussion of the DNA repair theory of sex and aging, as further elaborated by Bernstein and Bernstein (1991).

AGING AND SEX AS RELATED PHENOMENA

A fundamental tenet of the Bernsteins' theory is that damages to genetic material are a universal problem for life. These damages, defined as structural irregularities in DNA that cannot be replicated or inherited (unlike mutations), are of many types: single- and double-stranded breaks, modified bases, depurinations, cross-links, and so on. They arise inevitably from insults both endogenous and exogenous to the organism (e.g., oxidative damage from the molecular by-products of cellular respiration, and UV irradiation and DNA-damaging environmental chemicals, respectively). From empirical evidence, the cumulative numbers of such damages are astounding: for example, a typical mammalian cell experiences tens of thousands of DNA damages per day! These damages, if unrepaired, interfere with gene transcription and DNA replication and can cause progressive impairment of cell function and eventual cell death. The deterioration of somatic cellular function in turn leads to organismal senescence and death.

Damages to DNA can, however, be recognized and repaired by cells (though not necessarily at a rate that keeps pace with their production). Enzymatic machineries for repair of DNA damages are evolutionarily widespread, and their molecular details have been worked out to varying degrees in several model organisms ranging from viruses and bacteria to mammals. DNA repair processes almost invariably require the replacement of damaged genetic material through use of the intact information derived from a redundant copy. One source of redundancy is the complementary strand in double-helical DNA, which can serve as a template for repair when damage is confined to a single DNA strand. For example, all known forms of excision repair that occur regularly in somatic cells involve removal of the damaged section from one DNA strand and replacement by copying from the complementary undamaged strand.

A second source of redundancy for repair is the presence of another duplex DNA molecule with information homologous to that of the original copy. Such undamaged template appears necessary for the recombinational repair of double-stranded DNA damage. The Bernsteins argue that the exchange of genetic information between multiple infective phages, as well as the process of transformation whereby some bacterial cells actively take up naked DNA from the surrounding medium, are examples of primary adaptations for DNA repair in these microbes. So too they argue is meiosis in higher organisms, which is viewed as an adaptation for promoting recombinational repair of the DNA passed on to gametes. In general, all mechanisms for molecular recombination are interpreted by the authors as evolutionary adaptations that originated and are actively maintained by natural selection explicitly for the functions they serve in recombinational repair of DNA damage. Furthermore, in diploid multi-cellular reproductive systems with recombination, the Bernsteins suggest that outcrossing is favored because it promotes the masking of deleterious mutations. Thus, "DNA damage selects for recombination, and mutation in the presence of recombination selects for outcrossing".

According to the DNA repair theory, aging processes resulting from DNA damage should occur in all organisms, and not just those with a clear distinction between somatic tissues and germ-line cells. There appears to be a conflict of opinion (or perhaps merely a semantic distinction?) about whether senescence occurs in unicellular creatures such as bacteria, and in vegetatively reproducing multicellular creatures such as some plants and invertebrate animals. Rose concludes that "species that unequivocally lack such a separation of the soma, such as some sea anemones, some protozoa, and all known prokaryotes, appear to lack aging". However, the Bernsteins suggest that although populations of cells may survive indefinitely (e.g., in clonally reproducing trees and bacterial colonies), nonetheless "one would not expect to find old cells in a tree any more than one would find old cells in a growing culture of bacteria". To account for the persistence of such asexual populations of cells, the Bernsteins also introduce the concept of cellular replacement, in which lethally damaged cells are replaced by replication of undamaged ones. This strategy should work in any cell population in which "the incidence of unrepaired lethal damages is low enough at each generation to permit replacement of losses". Thus, the Bernsteins propose that there are two possible pathways to immortality for a cell lineage: (1) recombinational repair of DNA damages (which applies to germ cells) and (2) cellular replacement (which applies to predominantly clonal cells as in many bacteria).

In summary, the joint pillars of the Bernsteins' theory are that aging is a direct consequence of the accumulation of DNA damage, and that sex where it occurs is a consequence of the need to transmit damage-free genetic information to progeny. The theory as presented does not imply that the production of allelic variation through recombination and outcrossing is unimportant for long-term evolution: "Infrequent beneficial allelic variants generated by recombination undoubtedly promote long-term evolutionary success, just as infrequent beneficial mutations do." Nonetheless, "the tendency toward randomization of genetic information that occurs with recombination and outcrossing, under general conditions, has a negative effect on fitness in the short run, just as mutations, in general, do".

I think that the DNA repair theory as expounded by the Bernsteins is extremely important for several reasons. First, it provides a conceptual framework for linking the widespread phenomena of aging and sex, two evolutionary subjects that more typically have been dealt with separately (as in the Rose and Michod and Levin volumes). Second, the theory appears both logically consistent internally, and eminently plausible empirically--at least as much so as many of the traditional theories on sex and aging. Indeed, much of the Bernsteins' book constitutes a detailed compilation of observations and experimental data that appear either consistent with or positively supportive of the DNA repair view. Third, the DNA repair theory envisions immediate selective advantages that apply to individuals and their offspring and not merely to longer-term group benefits.

Finally, the DNA repair theory represents a dramatic and refreshing (to me) conceptual departure from the more traditional evolutionary theories of sex, which sometimes seem to go to rather great lengths in attempts to identify short-term benefits for the genetic variability generated by recombination. Under the Bernsteins' view, genetic variability is an immediate curse rather than a blessing, with any long-term benefits derived from recombinational variation being fortuitous epiphenomena of cellular and molecular processes that evolved under selection pressures to repair DNA damages and mask deleterious mutations. In this regard, I am reminded of the opposing world views on genetic variation expressed in another evolutionary arena--the debate between the selectionists and the neutralists. When extensive genetic variation was first uncovered in protein-electrophoretic and other molecular assays, many evolutionists assumed that the variability must be actively maintained by natural selection, and they sought hard to identify the balancing selective forces involved. But from the neutralist perspective [which grew out of the "classical" school in which genomes were perceived as heavily burdened by mutational load (see Lewontin 1974)], the overall magnitude of molecular variation was actually much lower than expected, given suspected mutation rates and effective population sizes. Thus, under the neutralist (and classicist) world views, if selection was involved appreciably in molding molecular genetic variability, it must act primarily in a diversity-reducing rather than diversity-enhancing fashion (Nei and Graur 1984).

Where does the DNA repair hypothesis fall within the hierarchical framework of causes for aging as advanced by Rose? If correct, the theory cannot be placed at the bottom of the hierarchy as just another idiosyncratic physiological mechanism for aging, because it is general, and an explicit selective force is involved. Indeed, the hypothesis is in some respects more universal than that of the declining force of natural selection with advancing age, because it applies to all forms of life, including those without a clear distinction between somatic and germ cells. However, for organisms with soma, the DNA repair hypothesis does not appear incompatible with Rose's evolutionary view: the declining impact of natural selection with age would mean that any organismal benefits to accrue from DNA repair processes in the later cohorts of an age-structured population would provide insufficient selective force to circumvent the evolutionary appearance of senescence and somatic death.

Having heartily applauded the Bernsteins' contribution, I must add however that I seriously doubt it tells the whole story on the significance of genetic variation. Once recombinational processes had evolved (for whatever reason, of which the need for DNA repair must now be considered a leading candidate), it seems probable that the genetic variability thereby generated would have been exploited for other functions as well. For example, the extensive molecular variability in the repertoire of the immune response in higher animals is in part recombinationally derived, and undoubtedly fosters enhanced disease resistance that often must be of immediate fitness benefit. Furthermore, the increased genetic variance stemming from recombination might well allow sexual reproducers to outpersist asexual reproducers in changing environments, despite the fact that such explanations tend to be group selectionist. Finally, as emphasized by several authors in the Michod and Levin volume (e.g., Brooks, Felsenstein, Maynard Smith, Trivers, Uyenoyama, and Williams), rates and patterns of genetic recombination (and the linkage disequilibria that they entail) can vary remarkably: across different regions of the genome, between the sexes, temporally within the life cycle (e.g., in taxa with an alternation of generations between sexual and asexual modes), across populations and species, and spatially across habitats. Many of these differences have been interpreted as adaptive adjustments to varying selection regimes. As stated by Ghiselin (Michod and Levin 1988, p. 20), "The eukaryotic genome turns out to be very highly organized, and the whole apparatus shows every indication that the amount, kind, and timing of recombination, and also the release of variability, are adaptive. . . . [T]he DNA repair hypothesis suggests that there should be little correlation between what goes on and when and where it happens. Such a correlation definitely does exist."

NEGLECTED OR UNDEREMPHASIZED TOPICS

In any event, I would like to stimulate further thought and discussion about two general considerations that seemed grossly underrepresented in all three books.

(1) Cytoplasmic genomes.--There are two major reasons why a relative neglect of mitochondrial (mt) genomes in these volumes was surprising (similar sentiments could also be expressed about chloroplast DNA). First, in organisms as diverse as fungi and humans, elsewhere there has been a tremendous resurgence of interest in the possible roles of mitochondrial DNA (mtDNA) damage in the aging process (e.g., Griffiths 1992 Wallace 1992a). In humans for example, this interest has been prompted by empirical findings that specifiable defects in mtDNA accumulate with advancing age in somatic cells, and that these defects tend to compromise physiological functions particularly in tissues and organ systems with high energy demands (e.g., the central nervous system, optic nerve, heart and skeletal muscle fibers, kidney, and liver). These are also the organ systems commonly associated with degenerative diseases and chronic illnesses of the elderly, thus suggesting a possible cause and effect relationship between mtDNA damage and the aging process (Wallace 1992b).

Further empirical and conceptual reasons exist for postulating that mtDNA might play a disproportionate role in aging. Mitochondrial DNA molecules are housed in an intracellular environment where they would seem to be especially prone to damage from oxygen radicals generated by oxidative phosphorylation (Bandy and Davison 1990). Indeed, mammalian mtDNA receives about 16-fold more oxidative damage on a per-nucleotide basis than does nuclear DNA (Richter et al. 1988, as quoted in Bernstein and Bernstein 1991). Yet ironically, animal mitochondria are thought to possess only limited DNA repair systems, and indeed this provides one conventional explanation as to why animal mtDNA evolves so rapidly at the nucleotide sequence level (Wilson et al. 1985). Animal mtDNA is packed tightly with genes crucial to the energy metabolism of cells, and for this reason, too, it would seem highly desirable for organisms to have evolved refined mechanisms for the repair of mtDNA damage. The paradox is heightened further because there are many copies of mtDNA within most cells. Thus it would seem that any repair capability should in principle be especially workable, because of the many available templates against which DNA damages might be corrected. (The hypothesis that an immunity from selection pressures stems from mtDNA redundancy and a possible excess metabolic capacity seems gratuitous and is also probably untenable evolutionarily.) Perhaps eukaryotic organisms have evolved more highly refined mtDNA repair mechanisms that, despite intensive searches, thus far have remained undiscovered. But if not, why not? And how can organisms have persisted evolutionarily without such enzymatic repair services for the crucial cytoplasmic genomes they depend upon for energy supplies?

A second reason for surprise over the relative neglect of mtDNA in these volumes relates to mtDNA's asexual inheritance. The transmission of mtDNA in most higher eukaryotes is predominantly uniparental, with effective genetic recombination between maternally and paternally derived molecules unknown. If meiosis and the recombinational aspects of gametogenesis provide evolutionary benefits, as surely they must (either via repair of DNA damages, and/or through generation of advantageous recombinational variation), then why doesn't mtDNA play by these rules? The entire answer cannot simply be that mitochondrial elements have been physically confined to the cytoplasm and hence unable to avail themselves of meiosis, because transfers and successful incorporations of some mitochondrial genes to nuclear chromosomes are known to have occurred over evolutionary time (see Avise 1991).

If meiosis is primarily a process for correcting DNA damages (as proposed by the Bernsteins), then mtDNA damages must be overcome by some process other than meiotic recombinational repair. One possibility is that mtDNA molecules might occasionally undergo (nonmeiotic) recombination or gene conversion within the germ line, perhaps in such a way that damage-free mtDNA templates correct faulty ones. The relatively few experimental attempts to uncover physical recombination in animal mtDNA through use of genetic markers have been hampered by the usual predominance of only one or a few detectable mtDNA clones within most individuals. More intensive searches for mtDNA recombination should be launched. Promising systems for further study involve species such as some mollusks, in which extensive paternal leakage of mtDNA into zygotes (e.g., Zouros et al. 1992) is known to have generated cell lineages jointly housing distinctive maternally and paternally derived mtDNA molecules that should provide useful genetic markers for detecting potential mtDNA recombination. Another possibility (elaborated beyond) is that processes of mtDNA replication and sorting during gameto-genesis provide an alternative, strictly nonrecombinational pathway for circumventing the accumulation of genetic damages.

(2) Cellular autonomy.--Another issue that was underemphasized in these volumes concerns the evolutionary ramifications of varying degrees of cellular autonomy. The somatic cells of an individual usually are interdependent, both structurally and functionally, whereas gametes are relatively autonomous (except perhaps in rather "trivial" respects such as the collaborative efforts required of sperm in penetrating the eggs of some species). In other words, gametes tend to be cellular free agents, whereas somatic cells (particularly in tightly organized creatures with determinate growth, such as many higher animals) are trapped in a web of interdependencies. Crow (Michod and Levin 1988, p. 68) raised an important question: "Is passing through a single-cell stage itself important? . . . Starting with a single cell, sexual or asexual, permits each generation to begin with a tabula rasa largely unencumbered by the somatic mutations from previous generations." Crow went on to lament that "I have never heard the importance of going through a single-cell stage expressed before, and would welcome comments . . . as to its possible merits."

It seems to me that many of the fundamental distinctions commonly made in discussions of aging and sex--senescence versus immortality, sexual versus asexual reproduction, somatic versus germ-line tissue, unicellularity versus multicellularity, and individuals versus groups--are inextricably related, and might profitably be viewed through a common denominator revolving on the concept of cellular autonomy, as described next.

EMBELLISHMENTS TO THE DNA REPAIR THEORY OF AGING AND SEX

Here I would like to propose some possible extensions to the Bernsteins' theory of DNA repair, and by so doing suggest how concepts of cellular and molecular autonomy might usefully be added to future discussions on aging and sex.

As mentioned above, two potential pathways to immortality seem available to life. The first is predominantly or exclusively asexual and is exemplified most clearly by unicellular organisms such as bacteria. Here, cell proliferation apparently can outstrip the rate of accumulation of DNA damages and deleterious mutations, with the net result that Muller's ratchet is circumvented and an indefinite continuation of the population occurs via cellular replacement. The second pathway is sexual and is exemplified most clearly by germ-cell lineages in multicellular organisms such as vertebrates. Here, repair of nuclear DNA damages by genetic recombination supposedly operates in conjunction with cell proliferation and intercellular selection to counter the accumulation of nuclear DNA damages and deleterious mutations that would otherwise be expected.

In both routes to immortality, many cells (bacteria or gametes) may die genetic deaths (e.g., from the inevitable imperfections of any DNA repair mechanism), but these deaths do not compromise the continuance of cell lineages that happen to have escaped or repaired DNA damage. Thus, the efficacy of both pathways to immortality would seem to depend critically on the autonomy of the proliferating cells. To emphasize why this is so, consider the prospect of somatic immortality for a multicellular organism such as a vertebrate. Even if some somatic cells and tissues could keep pace with DNA damage via the nonsexual strategy of cellular replacement [as may essentially be true for epithelial cells of the digestive tract of mammals, or for hemopoietic stem cells (Bernstein and Bernstein, p. 165)], these replacements are to no avail in conferring immortality, because the final fate of these cell lineages remains inextricably tied to the remainder of the individual's soma (which as a whole inevitably senesces, as predicted by Rose's evolutionary theory). However, autonomous gametes and the genomes they contain can escape the sinking somatic ship.

This line of reasoning also illustrates the difficulty (semantically and otherwise) of disentangling the issue of immortality from that of the distinction between somatic and germ-line cells. Without the presence of somatic tissue, the evolutionary theory of Rose predicts no age-structure in a population, and hence no aging but without aging, there is no compelling evolutionary stimulus for the escape of autonomous cells from a soma that inevitably deteriorates (either from DNA damage or other causes). These ruminations also point out why the distinction between an individual and a population can become rather vague in discussions of aging and immortality in unicellular taxa. A bacterial colony may survive indefinitely, but without a distinction between somatic and germ cells, what is the organismal entity to which this immortality refers? In truth, what persists are certain cell lineages, but in this sense the "individuals" or "populations" are no more well defined than are the potentially immortal germ-cell lineages in higher taxa. Furthermore, many bacterial cells inevitably die genetic deaths but without somatic benchmarks to assess chronological age, it is debatable whether this should properly be referred to as an "aging" phenomenon.

In many plants and invertebrate animals with various asexual modes of reproduction, the usual distinctions between individuals and populations, between somatic lines and germ lines, and between aging and immortality, all become even more ambiguous (Rose). For example, vegetative cell lines of some plants can be maintained indefinitely (perhaps by the strategy of cellular replacement), whereas others appear to senesce (perhaps because cellular replacement cannot keep pace with DNA damage). The former might well be considered potentially immortal, but according to Rose they do not violate the evolutionary theory of aging because specification of germ-line tissue in these cases is problematic. Whether this is a definitional slight of hand or a bona fide consideration is unclear to me, but in any event a more critical factor may be degree of cellular autonomy displayed. Diploid cells or collections thereof that have a capacity to survive and reproduce mostly independently of other cells exhibit considerable cellular autonomy (by definition). Thus, to a vegetatively spreading plant or coral, death of a portion of the "soma" may have relatively little influence on survival and reproduction of the remaining cells of the genet (a given clonal genotype, regardless of how it is physically partitioned). This contrasts with the situation in vertebrates, in which the death of a critical tissue dooms all somatic cells within each well-demarcated individual. Thus, any cell lineages characterized by increased levels of functional and replicative autonomy carry the potential for indefinite evolutionary persistence. Whether this potential could be realized then depends on additional factors, including whether the available processes of cellular repair and replacement are adequate to control DNA damages and to circumvent Muller's ratchet.

One important consideration on whether such cellular processes are workable indefinitely concerns genomic size. Formal models indicate that Muller's ratchet may well set an upper limit on the size of the genome in asexual organisms, particularly when their populations are small (Crow, Felsenstein, and Maynard Smith in Michod and Levin 1988). Bell notes that the small size of mtDNA molecules in higher animals ([is congruent to] 16 kilobases) may be a reflection of Muller's ratchet, and furthermore the somewhat larger mtDNA molecules of yeast and plants "would have to recombine in order to maintain the integrity of their genomes, as seems to be the case". From this perspective, nuclear genomes are vastly too large for long-term effectiveness of a cellular proliferation strategy acting alone to compensate for accumulation of DNA damages and deleterious mutations, hence the additional requirements for sexual reproduction and recombination. Crow and others have regarded this as an important factor accounting for why species with obligate parthenogenesis or other forms of asexual reproduction "are the twigs on the phylogenetic tree, not the main stems and branches".

I would like to propose that elements of both the recombinational repair and replacement strategies are employed simultaneously within the germ-cell lineages of higher organisms. Under this view, recombinational repair helps purge the nuclear genome of DNA damages, and a molecular-level analogue of cellular replacement ("molecular replacement") facilitates the purging of both DNA damages and deleterious mutations in nonrecombining cytoplasmic genomes. The immediate effect of these collaborative processes is to increase the probability that at least some gametes are produced that are free from genetic defects that had accumulated during the lifetime of the parent. In turn, the zygotes and early embryos produced by such "cleansed" gametes have a higher initial likelihood of being unburdened from the load of parental DNA defects.

The molecular replacement process is proposed to operate through the replicative segregation of mtDNA molecules in the lineages of germ cells (particularly oocytes). Unlike nuclear genes in diploid organisms, each of which exists as a single allelic copy per gamete, thousands of mtDNA molecules populate most cells, and several hundred thousand copies may cohabit a mature oocyte (Michaels et al. 1982). As cells undergo mitotic or meiotic cytokinesis, particular mtDNA mutations may fluctuate in frequency because of intracellular selection (differential replication) and genetic drift. Notably, the many mtDNAs in mature oocytes probably stem from a vastly smaller pool of mtDNA molecules that survive the process of replicative segregation in earlier cytokinetic divisions of the germ-cell lineage. Evidence for this conclusion comes from the empirical generality that the vast majority of the heterogeneity in mtDNA genotypes is distributed among rather than within individuals [implying relative mtDNA population bottlenecks in germ lines (Chapman et al. 1982)], and from observed rates of mtDNA clonal sorting in the gametes and progeny of heteroplasmic females (review in Avise 1991). In any event, mtDNA molecules that survive and replicate to populate a mature oocyte presumably have been rather scrupulously screened by natural selection for replicative capacity and functional competency in the germ-cell lineages they inhabit.

To the extent that these two damage-repair processes (recombinational repair of nuclear DNA, and molecular replacement of cytoplasmic DNA) fail during gametogenesis, the metabolic functions of some germ cells will be compromised, and there will be gametic deaths. These gametic screening processes would appear to have considerable scope and impact, for at least two reasons. First, germ-line cells are highly active metabolically (Hastings 1989), such that any functional defects likely would be exposed to cellular-level selection. Second, gametes are produced in prodigious quantities by most species (e.g., males produce billions of sperm, and the number of oocytes present in a human female at birth is approximately 2,000,000 Baker 1963). Furthermore, subsequent rounds of selective screening no doubt occur at the zygotic stage and during embryonic development, as genomes from the surviving functional gametes are called upon to interact properly in diploid condition. Failures at this level would be registered as embryonic abortions, which also are known to occur at high frequency (e.g., the loss of all human conceptions has been estimated at nearly 80% Roberts and Lowe 1975). In general, the Bernsteins interpret such observations to indicate that DNA damage is so pervasive that "recombinational repair during meiosis, as well as other repair and protective processes, may be just barely able to cope with DNA damage".

The Bernsteins' DNA repair theory by itself probably cannot account for all of the variety and nuances of sexual reproduction and aging processes. Nonetheless, it represents an exciting and important piece of a jigsaw puzzle whose other elements are summarized so eloquently in the Rose and Michod/Levin volumes. Furthermore, in this puzzle's emerging picture, aging and sex can be seen more clearly as interrelated phenomena, both evolutionarily and mechanistically. Undeniably, certain cell lineages in all extant life-forms have solved the problem of innate mortality (at least over the 4 billion yr of life on earth), and the strategies of genetic recombination, cellular replacement, and molecular replacement by which this has been accomplished are coming into sharper focus.

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Wallace, D. C. 1992a. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256:628-632.

-----. 1992b. Diseases of the mitochondrial DNA. Annual Review of Biochemistry 61:1175-1212.

Wilson, A. C., R. L. Cann, S. M. Carr, M. George, Jr., U. B. Gyllensten, K. M. Helm-Bychowski, R. G. Higuchi, S. R. Palumbi, E. M. Prager, R. D. Sage, and M. Stoneking. 1985. Mitochondrial DNA and two perspectives on evolutionary genetics. Biological Journal of the Linnean Society 26:375-400.

Zouros, E., K, R. Freeman, A. O. Ball, and G. H. Pogson. 1992. Direct evidence for extensive paternal mitochondrial DNA inheritance in the marine mussel Mytilus. Nature 359:412-414.


Oogenesis similar to spermatogenesis

I think I have found a biological solution to prevent menopause. My Kepler Bb humanoids don't get more frail with old age so aging is not a cause of death for them. They can survive well past 100 years if the conditions are just right. Because of this, I figured "If they don't die of old age, what is the point of menopause?"

This led me to my biological solution that involves adding differences to human anatomy.

In particular, there are 2 pairs of ovaries connected by small tubes. These are the primary and secondary ovaries.

The primary ovaries are closest to the fallopian tubes and are where meiosis takes place. Once meiosis is complete and thus the egg is haploid, ovulation takes place.

The secondary ovaries are closer to the uterus and are where mitosis takes place. Oogonia are like stem cells here. 1 becomes the next oogonium while the other becomes an egg cell. This primary oocyte that results from mitosis migrates into the primary ovaries where a follicle starts forming around the oocyte.

The only way menopause can happen in these females is if the secondary ovaries are surgically removed or become dysfunctional and stop producing eggs. Otherwise, the female will continue ovulating every month until death.

But is my biological solution plausible? I mean yes, lifetime ovulation does mean higher chance of pregnancy mortality and ovarian cancer. But considering that these humanoids don't die of old age, is it a good solution?

An Old Friend

Females stay fertile for their full lifetime.

Consider that the whole reason for reproduction is a form of immortality.
A lifeform that is immortal requires no reproductive ability.
Reminds me of the film
Lucy (2014)

You'll see that in many cases, when any sort of cell enters a zone of intolerance or zone of physical stress, the replication machinery gets put on the backburner (and thus replication). Expression of stress-response proteins like heat shock proteins is increased as a result (1). If a cell isn't within acceptable parameter to undergo division at G1 or G2 (anoxic environment, etc.), you'll find mechanisms like G0 phase or sporulation are preferred until the environment returns to something less stressful (2). I wouldn't say cells would rather be immortal, per se, but longevity or even apoptosis/entosis/etc. would be preferable to replication if nothing is going right (3, 4).

To be clear, when we're talking about evolution that's a tough one. Sure, some sort of stress-response transient signal could induce some lasting cell memory selecting toward a specific function. I simply don't have the data to quote you in that aspect, however.

Biology of the heat shock response and protein chaperones: budding yeast (Saccharomyces cerevisiae) as a model system.

Slonczewski, J., & Foster, J. (2011). Microbiology: An evolving science (2nd ed., p. 143). New York: W.W. Norton.

DNA damage-induced apoptosis

Cellular Stress Responses: Cell Survival and Cell Death

As a footnote, while replication does occur in sporulation, the replicated chromosome is destroyed in the process of forming the actual spore.

Prolonging the reproduction cycle may have unknown effects on your Kepler Bb humanoids. The effects will not be restricted to just body specifications. They will impact emotional and society stability.
This will impact your story greatly. Common associations with your characters will need to be closely monitored and written to include these changes in every way possible or the reader will pick up on the inconsistencies.

Why is she excited to get pregnant if she has her whole life to do it.
Why hurry to build a home and create a family atmosphere if there is plenty of time?
The reproduction urgency is changed. There is no longer a sense of urgency if the reproduction ability lasts as long as she lives.
This is going to be transmitted to all aspects of society.
Its going to change the very fiber of emotional state.
Its important to consider the butterly effect of changes in a story.
Readers of science fiction are pretty smart and notice things that are out of place in a story.
Often, it makes them put the book down and move to the next.

There is a difference between casually stating that women no longer experience menopause due to their long lives and going into great detail of the physical changes to justify the statement.

In one, the reader is inspired to wonder about the details.
In the other, the reader is forced to accept the details no matter if they understand the implications or not.


CONFLICT MEDIATION

We think that conflict and conflict mediation are fundamental to the emergence of individuality at a higher level, irrespective of the type of ecological interaction (mutualism, competition or exploitation) associated with the initial formation of the group ( Michod and Nedelcu, 2003). Both antagonistic (as may have been the case during the origin of the eukaryotic cell) and mutualistic interactions involve conflict the former, because of their very nature, and the latter because all cooperative types of interaction create the opportunity for the spread of defection. As discussed below, adaptations that restrict the opportunity for conflict between higher and lower-levels (what we term “conflict modifiers”) are instrumental in the conversion of the group to a new evolutionary individual.

In the transition between interacting genes and the first cell, an example of a conflict mediator is the chromosome because it aligns the interests and evolutionary prospects of linked genes with each other. In the case of the cell associations that pre-dated the eukaryotic cell, conflict mediation may have involved the amelioration of the initially exploitative interactions such as predation or parasitism ( Michod and Nedelcu, 2003). Ultimately, uniparental inheritance is thought to mediate conflict among the genetic interests of organelles coming from different cells ( Hastings, 1992). In the case of multicellular groups, conflict mediation may involve the spread of conflict modifiers producing self-policing, maternal control of cell fate, decreased propagule size, determinate growth of the organism, apoptotic responses, or germ line sequestration discussed below ( Michod, 1999, 2003).

To study how evolution may shape development and the opportunity for selection at the two levels we assumed a second modifier locus that affects the parameters of development and/or selection at the primary cooperate/defect locus. These conflict mediators are the first emergent functions that serve to turn the group into a new higher-level individual. Conflict mediators are assumed to be determined by a genetic modifier locus that may affect virtually any aspect of the model, such as propagule size ( Michod and Roze, 1999, 2000 Roze and Michod, 2001), and adult size (whether it is determinate or indeterminate, Michod and Li, unpublished results). To study the evolution of self policing, we assumed the modifier affects the parameters of selection at both levels, reducing the temptation to defect at some cost to the group ( Michod, 1996 Michod and Roze, 1999). In the case of the evolution of programmed cell death, we assume the modifier directly decreases the replication rate of mutant cells ( Michod and Nedelcu, 2003). In the case of the evolution of germ/soma differentiation, we have considered a two step process ( Michod, 1996, 1997 Michod and Roze, 1999). The first step is the evolution of costly forms of cooperation, interpreted as the evolution of somatic-like functions, in which the cooperative somatic-like cells replicate more slowly (and so cost the group in terms of fecundity) but benefit the survival of the group. The evolution of the modifier allele takes these cooperative groups and converts them into groups with two cell lineages: germ cells which beget the next generation and somatic cells which benefit the group but do not contribute genes to the next generation. Initially, we assumed in our models that the germ-line developed from a single cell that was sequestered very early (after the first cell division) during the formation of the group. Using similar two-locus population genetics techniques, we have relaxed this assumption, and have studied the effect of the time of separation of the germ and soma (early versus late in development) and number of cells that are sequestered ( Michod et al., 2003).


Is 80% of the Genome Functional? Or Is It 100%? Or 40%? No Wait …

So far, we have seen that as far as functionality is concerned, ENCODE used the wrong definition wrongly. We must now address the question of consistency. Specifically, did ENCODE use the wrong definition wrongly in a consistent manner? We do not think so. For example, the ENCODE authors singled out transcription as a function, as if the passage of RNA polymerase through a DNA sequence is in some way more meaningful than other functions. But, what about DNA polymerase and DNA replication? Why make a big fuss about 74.7% of the genome that is transcribed, and yet ignore the fact that 100% of the genome takes part in a strikingly “reproducible biochemical signature”—it replicates!

Actually, the ENCODE authors could have chosen any of a number of arbitrary percentages as “functional,” and … they did! In their scientific publications, ENCODE promoted the idea that 80% of the human genome was functional. The scientific commentators followed, and proclaimed that at least 80% of the genome is “active and needed” ( Kolata 2012). Subsequently, one of the lead authors of ENCODE admitted that the press conference mislead people by claiming that 80% of our genome was “essential and useful.” He put that number at 40% ( Gregory 2012), although another lead author reduced the fraction of the genome that is devoted to function to merely 20% ( Hall 2012). Interestingly, even when a lead author of ENCODE reduced the functional genomic fraction to 20%, he continued to insist that the term “junk DNA” needs “to be totally expunged from the lexicon,” inventing a new arithmetic according to which 20% > 80%. In its synopsis of the year 2012, the journal Nature adopted the more modest estimate, and summarized the findings of ENCODE by stating that “at least 20% of the genome can influence gene expression” ( Van Noorden 2012). Science stuck to its maximalist guns, and its summary of 2012 repeated the claim that the “functional portion” of the human genome equals 80% (Anonymous 2012). Unfortunately, neither 80% nor 20% are based on actual evidence.


Reproduction

Production of Germ Cells . The germ cells are the male spermatozoon and the female ovum (secondary oocyte ). The secondary oocyte (mature ovum) is a large round cell that is just visible to the naked eye. Spermatozoa, on the other hand, can be seen only under a microscope, where each appears as a small, flattened head with a long whiplike tail used for locomotion.

In the female, maturation of an ovum is a remarkable process controlled by hormones secreted by the endocrine glands. The menstrual cycle is ordinarily 28 days long, measured from the beginning of one menstrual period to the beginning of the next. During the first 2 weeks of the usual cycle, one of the ova becomes mature enough to be released from the ovary. At the time of ovulation this mature ovum (secondary oocyte) is released and at this point can be fertilized. If fertilization occurs, the fertilized ovum ( zygote ) is then discharged into the abdominal cavity. Somehow, by mechanisms that are not clear, it moves into a fallopian tube and begins its descent toward the uterus. If the ovum remains unfertilized, menstrual bleeding occurs about 2 weeks later.

In the male there is no sexual cycle comparable to the cyclical activity of ovulation in the female. Mature sperm are constantly being made in the testes of the adult male and stored there in the duct system.

Fertilization , or Conception . During coitus, semen is ejaculated from the penis into the back of the vagina near the cervix uteri. About a teaspoonful of semen is discharged with each ejaculation, containing several hundred millions of spermatozoa. Of this enormous number of sperm, only one is needed to fertilize the ovum. Yet the obstacles to be overcome are considerable. Many of the sperm are deformed and cannot move. Others are killed by the acid secretions of the vagina (the semen itself is alkaline). The sperm must then swim against the current of secretions flowing out of the uterus.

The sperm swim an average of 0.4 to 2.5 cm (0.1 to 1.0 inch) per minute. When one or more vigorous sperm are able to reach the ovum, which is normally in the outer half of the fallopian tube, fertilization occurs. The head end of the sperm plunges through the thick wall of the ovum, leaving its tail outside. The genetic materials, the chromosomes, are injected into the ovum, where they unite with the chromosomes inherited from the mother (see heredity ). The sex of the child is determined at this instant it depends on the sex chromosome carried by the sperm.

If by chance two ova have been released and are fertilized by two sperm, fraternal (dizygotic) twins are formed. Identical (monozygotic) twins are produced by a single fertilized ovum that divides into two early in its development.

Pregnancy . The ovum, now known as a zygote , begins to change immediately after fertilization. The membrane surrounding it becomes impenetrable to other sperm. Soon the zygote is dividing into a cluster of two, then four, then more cells, as it makes its way down the fallopian tube toward the uterus. At first it looks like a bunch of grapes. By the time it reaches the uterus, in 3 to 5 days, the cells are formed in the shape of a minute ball, the blastocyst , which is hollow on the inside with an internal bump at one side where the embryo will form. The blastocyst quickly buries itself in the lining of the uterus (implantation). Occasionally implantation takes place not in the uterine lining, but elsewhere, producing an ectopic pregnancy .

As soon as the blastocyst is implanted, its wall begins to change into a structure that eventually develops into the placenta . Through the placenta the fetus secures nourishment from the mother and rids itself of waste products. Essentially the placenta is a filtering mechanism by which the mother's blood is brought close to the fetal blood without the actual mixing of blood cells.

During the early stages of pregnancy, the fetus grows at an extremely rapid rate. The mother's body must undergo profound changes to support this organism. The muscles of the uterus grow, vaginal secretions change, the blood volume expands, the work of the heart increases, the mother gains weight, the breasts prepare for nursing, and other adjustments are made throughout the mother's body.


Disposable Soma Model of Aging

This model of aging states that a finite amount of nutrients can be extracted from the food we eat and the environment we live in, which must be allocated effectively to optimize our evolutionary fitness (Kirkwood, 1977). In nature, reproduction is energetically costly and risky for survival. There are time, energy and monetary (for humans) costs of searching for a viable partner. There are disease risks when interacting with others as well as mating injury risks that must be considered, including the strange phenomenon of female consumption of unsuspecting males post-copulation, or more relevantly domestic violence for humans.

Based on this model of aging, species that experience a higher extrinsic mortality rate (i.e. high levels of predation or a harsher environment – nutrient scarcity and extreme weather) will exhibit reproduction-centric adaptation. To visualize this idea, consider two mammals with similar body weights but very different lifespans: mice and bats. [Check out a plot of longevity vs body weight for a range of animals here.]

Bats are unusually long-lived for their body weight. Credit: CraigRJD

Mice will typically expend their energy reproducing at the earliest possible stage before they die or are killed. This occurs at the expense of cellular maintenance later in life. The latter isn’t much of an evolutionary concern because of the likelihood that mice will have been killed before they reach late life anyway. Mice having an average lifespan of 2-3 years (even when taken out of the wild and grown in a controlled environment).

Meanwhile, bats have very few natural predators. They have much lower selection pressure to reproduce as soon as possible early in life, but rather have evolved their genetic machinery to allocate resources towards survival, having an average lifespan of approximately 30 years! [Editor’s DYK: Bats are also resistant or immune to many viruses that are deadly to humans, like Ebola.]


Why Are Cells the Way They Are, and Why Aren’t They Perfect?

Although it is easy to marvel about the refined features of cells and their robustness to perturbations (1), the field of bioengineering imagines and even implements more efficient cellular mechanisms in extant organisms. What, then, limits the levels of molecular/cellular refinements that have been achieved by natural selection?

To What Extent Is Cell Biology Beholden to Historical Contingency?

We have learned an enormous amount about the genetic mechanisms of evolution since Darwin, and it remains true that evolution is an opportunistic process of “descent with modification,” working with the resources made available in previous generations. Once established, useful features cannot be easily dismantled and reassembled de novo unless there is an intermediate period of redundancy.

One remarkable example of how history continues to influence today’s cell biology is the near universal use of ATP synthase as a mechanism for energy generation (2). Embedded in the surface membranes of bacteria and organellar membranes of eukaryotes, this complex molecular machine uses the potential energy of a proton gradient to generate a rotational force that converts ADP to ATP, much like a turbine converts the potential energy of a water gradient into electricity. However, the proton gradient does not come for free: cells first use energy derived from metabolism to pump protons out of membrane-bound compartments, creating the gradient necessary for reentry through ATP synthase. Even assuming that ATP production is an essential requirement for the origin of life, it is by no means clear that the path chosen for ADP-to-ATP conversion is the only possibility.

Rather, the universal reliance of all of life on this mechanism of energy conversion may be a historical relic of the exploitable energy source present at the time of life's foundation: e.g., a precellular period in which energy acquisition derived from a natural proton gradient between overlying low-pH marine waters and the alkaline interiors of vent mounds (3, 4). Despite the central significance of ATP synthase to bioenergetics across the Tree of Life and the invariance of the basic mechanism of ATP regeneration, many examples are known in which the structure of the complex has been modified with respect to the numbers and types of subunits (2, 5, 6).

How Is Cell Biology Constrained by the Laws of Physics and Chemistry?

Although cataloging and explaining biodiversity are central themes of evolutionary biology, deciphering the roles by which biophysical/biochemical barriers channel cellular characteristics into a limited range of alternatives is equally important. Like the near-universal genetic code, the laws of physics endow cells with specific properties, but, unlike the nucleotide sequences of genes, these laws are immutable and have potential impacts at all levels of biological organization.

Examples of relevant organizing principles at the molecular scale include the role of the hydrophobic effect in protein folding and assembly and constraints imposed by intracellular molecular crowding. For example, rather than operating as monomers, the majority of proteins self-assemble into higher-order structures such as dimers, tetramers, etc. Remarkably, however, unlike the strong, general trend toward dramatic increases in gene structural complexity from prokaryotes to unicellular eukaryotes to multicellular species (7), higher-order structural complexity of proteins does not noticeably scale with organismal complexity across the Tree of Life (8). Comparative biochemical and protein-structural analysis within a phylogenetic framework has great potential to address many outstanding questions in this area, including whether variation in the multimeric states of proteins is a simple consequence of stochastic mutations of adhesive interface residues, with minimal effects on catalytic efficiency.

Similar questions arise about the biophysical properties of supermolecular structures, such as microtubules, actin filaments, and the endomembrane systems of eukaryotic cells (9). The self-assembly of lipid bilayers emerges spontaneously from the biophysical properties of amphiphilic molecules, and recent origin-of-life research suggests that some of the key first steps in the origin of life, such as the assembly and division of vesicles, are inevitable consequences of the behavior of organic molecules in water (10, 11).

Finally, general biophysical phenomena are undoubtedly involved in the patterning of phenotypes at the whole-cell level. For example, constraints on surface:volume scaling may have been involved in the establishment of internal membranes and their above-noted associations with bioenergetics (12). Such constraints may also have played a central role in the evolution of cell size and features of the nuclear envelope (13). The emergence of the nuclear envelope may have, in turn, had secondary evolutionary consequences, such as the establishment of a permissive environment for intron proliferation (7), which requires efficient pretranslational splicing of transcripts.

Although the preceding observations suggest that the emergence and diversification of numerous cellular features may be predictable on biophysical grounds alone, the imposition of constraints on a complex trait need not preclude substantial opportunities for modifying the underlying components, as previously discussed with respect to ATP synthase. For example, although there are common organizational principles in diverse regulatory, signal-transduction, and metabolic pathways, dramatic cases of rewiring have been revealed with the expansion of molecular and cell biological investigations to multiple species. Such examples include aspects of mating-type specification (14, 15), meiosis (16), cell cycle (17, 18), biosynthetic pathways (19 ⇓ ⇓ ⇓ –23), protein transport (24), nuclear organization (25), and ribosome production (26, 27). These kinds of observations imply that there are often numerous degrees of freedom for reorganizing the underlying determinants of otherwise constant cellular processes.

How Much of Cellular Complexity Is the Result of Adaptation?

A commonly held but incorrect stance is that essentially all of evolution is a simple consequence of natural selection. Leaving no room for doubt on the process, this narrow view leaves the impression that the only unknowns in evolutionary biology are the identities of the selective agents operating on specific traits. However, population-genetic models make clear that the power of natural selection to promote beneficial mutations and to remove deleterious mutations is strongly influenced by other factors. Most notable among these factors is random genetic drift, which imposes noise in the evolutionary process owing to the finite numbers of individuals and chromosome architecture. Such stochasticity leads to the drift-barrier hypothesis for the evolvable limits to molecular refinement (28, 29), which postulates that the degree to which natural selection can refine any adaptation is defined by the genetic effective population size. One of the most dramatic examples of this principle is the inverse relationship between levels of replication fidelity and the effective population sizes of species across the Tree of Life (30). Reduced effective population sizes also lead to the establishment of weakly harmful embellishments such as introns and mobile-element insertions (7). Thus, rather than genome complexity being driven by natural selection, many aspects of the former actually arise as a consequence of inefficient selection.

Indeed, many pathways to greater complexity do not confer a selective fitness advantage at all. For example, due to pervasive duplication of entire genes (7) and their regulatory regions (31) and the promiscuity of many proteins (32), genes commonly acquire multiple modular functions. Subsequent duplication of such genes can then lead to a situation in which each copy loses a complementary subfunction, channeling both down independent evolutionary paths (33). Such dynamics may be responsible for the numerous cases of rewiring of regulatory and metabolic networks noted in the previous section (34, 35). In addition, the effectively neutral acquisition of a protein–protein-binding interaction can facilitate the subsequent accumulation of mutational alterations of interface residues that would be harmful if exposed, thereby rendering what was previously a monomeric structure permanently and irreversibly heteromeric (8, 36 ⇓ ⇓ –39). Finally, although it has long been assumed that selection virtually always accepts only mutations with immediate positive effects on fitness, it is now known that, in sufficiently large populations, trait modifications involving mutations with individually deleterious effects can become established in large populations when the small subset of maladapted individuals maintained by recurrent mutation acquire complementary secondary mutations that restore or even enhance fitness (40, 41).

One goal of evolutionary cell biology should be to determine whether these general principles involving effectively neutral paths of molecular evolution extend to even higher-order biological features, such as intracellular architecture (37). Is natural selection a sufficient or even a necessary explanation for the evolution of the complex features of the ribosome, the spliceosome, the nuclear-pore complex, and the Golgi apparatus? Or is a march toward increased, and potentially irreversible, cellular complexity an inevitable outcome of mutation pressure and the inefficiencies of selection processes in finite populations?

The points raised above are not meant to suggest that structures as complex as ribosomes or ATP synthase are maladaptive. Certainly, today’s cells cannot survive without such molecular machines. However, the existence of complex cellular features need not imply that each of the myriad of changes that sculpted such structures over evolutionary time was adaptive at the time of establishment. The determination of whether it is even feasible for a cellular innovation to have been promoted by purely adaptive processes cannot be made in the absence of information about the population-genetic environment: i.e., the magnitudes of the power of mutation, recombination, and random genetic drift. All three features vary by orders of magnitude across the Tree of Life and can only roughly be inferred for ancestral species. Uncertainty in this area is a major challenge for evolutionary cell biology (30, 42).


The Phases

Prophase: A cell gets the idea that it is time to divide. First, it has to get everything ready. You need to duplicate DNA, get certain pieces in the right position (centrioles), and generally prepare the cell for the process of mitotic division.

Metaphase: Now all of the pieces are aligning themselves for the big split. The DNA lines up along a central axis and the centrioles send out specialized tubules that connect to the DNA. The DNA (chromatin) has now condensed into chromosomes. Two strands of a chromosome are connected at the center with something called a centromere. The tubules actually connect to the centromere, not the DNA.

Anaphase: Here we go! The separation begins. Half of the chromosomes are pulled to one side of the cell half go the other way. When the chromosomes get to the side of the cell, it's time to move on to telophase.

Telophase: Now the division is finishing up. This is the time when the cell membrane closes in and splits the cell into two pieces. You have two separate cells each with half of the original DNA.

Interphase: This is the normal state of a cell. We suppose that when it comes to cell division, you could call this the resting state. It's just going about its daily business of surviving and making sure it has all of the nutrients and energy it needs. It is also getting ready for another division that will happen one day. It is duplicating its nucleic acids, so when it's time for prophase again, all the pieces are there.


Teleonomy and Evolution

In a new paper, “Evolutionary Teleonomy as a Unifying Principle for the Extended Evolutionary Synthesis,” in the journal BIO-Complexity, Jonathan Bartlett of the Blyth Institute revisits an old idea first proposed by Ernst Mayr and Colin Pittendrigh. It is a way around biologists’ continued use of teleological (goal-directed, functional) language, despite the supposed lack of teleology in the Modern Synthesis (neo-Darwinsm). Bartlett writes:

For more than a century, biology has struggled with the concept of teleology. Teleology is the orientation of objects (often organisms) towards ends. That is, organisms have purposes which are reflected in their behaviors. What makes biology unique as a subject is that while the study of rocks or atoms rarely makes reference to purpose, the study of biology is almost exclusively concerned with purpose….

[T]he idea of evolution by natural selection seemed to remove teleology from biology as well. There was nothing in natural selection that referred to purpose — only to reproduction. The whole of evolution was therefore devoid of purpose. If teleology was not needed in physics, and now it is not needed in biology, then it seems like there is no need for it at all.

Thus, the whole concept of purpose fell out of favor with biologists. It was thought of as an old-fashioned concept — a leftover relic that would soon go the way of alchemy. By the beginning of the twentieth century, biologists were actively avoiding any sort of purpose-oriented language, sometimes to the point of ridiculousness.

As reported by Pittendrigh,

“Biologists for a while were prepared to say a turtle came ashore and laid its eggs, but they refused to say it came ashore to lay its eggs [emphasis in original].”

Pittendrigh and Mayr sought a way to deal with the problem of apparent function in biologists’ use of language:

In order to alleviate the situation, Pittendrigh and later Mayr suggested using the term teleonomy instead of teleology to describe this sort of purposive behavior.

Mayr suggested that we can use the term teleonomy to represent something that operates according to a purpose because of a program. Specifically, Mayr says, “It would seem useful to restrict the term teleonomic rigidly to systems operating on the basis of a program, a code of information. Teleonomy in biology designates ‘the apparent purposefulness of organisms and their characteristics,’ as Julian Huxley expressed it.”

That is, to the extent that organisms operate according to their genetic programming, “purpose” can simply refer to the actions of the program behind the organism. [Emphasis in the original.]

And of course, the program was, to their minds, an inherited program, the result of variation, natural selection, and drift. Mayr was concerned that the idea of teleonomy might be turned back toward the idea of design or purpose, so he made it abundantly clear:

Only three processes are known to [change the genetic pool]: mutation, fluctuation in genetic frequencies, and differential reproduction. The first two of those processes are not oriented toward adaptation. They are in that sense essentially random, and are usually inadaptive, although they may rarely and coincidentally be adaptive. By “differential reproduction” is meant the consistent production of more offspring, on an average, by individuals with certain genetic characteristics than by those without those particular characteristics…

If an organism is well adapted, if it shows superior fitness, this is not due to any purpose of its ancestors or of an outside agency, such as “Nature” or “God,” who created a superior design or plan.

“Note that here, Mayr explicitly decries not only the influence of outside purposes (i.e., divine teleology) in evolution, but also the influence of inside purposes (i.e., biological purposes present within ancestors),” says Bartlett.

But ideas sometimes morph into new forms. As our understanding of evolutionary processes has grown, it has become apparent that sometimes change happens too fast, or in a seemingly directed fashion, much more than a purely neo-Darwinian process can account for. Enter the Extended Evolutionary Synthesis (EES), a scientific program that seeks to explain longstanding evolutionary problems that the Modern Synthesis hasn’t been able to successful address.

In a paper published in Nature in 2014, “Does evolutionary theory need a rethink? Yes, urgently,” a number of EES proponents came together to list the features that they think make the EES distinct. These include:

  1. Extended inheritance: organisms inherit more than just genes and more than just by physical inheritance. Organisms not only have genetic and epigenetic inheritance, they have inheritance of behavior based on the nurturing of parents and biological communities.
  2. Reciprocal causation: organisms shape their environment, which then acts on themselves.
  3. Non-random phenotypic variation: organisms are biased in certain evolutionary directions rather than others, as reflected by available evolutionary phenotypes.
  4. Variable rates of change: the effects of mutations are non-linear, and therefore have the potential for saltational effects.
  5. Organism-centered perspective: organisms themselves have a larger causal role in the Extended Evolutionary Synthesis, as opposed to the gene-centered approach of the Modern Synthesis.
  6. Macro-evolutionary processes: the additional modes of inheritance will also lead to additional macro-evolutionary processes.

Says Bartlett, “This list maintains the cautious approach typically taken by those favoring the Extended Evolutionary Synthesis, making it unclear whether it deserves to be treated as a new synthesis. Is this really new, or are they merely tweaking around the edges? The architects of the Extended Evolutionary Synthesis are adamant about the need for a new synthesis but highly cautious about how it is described.”

There are differences, though, that open up the EES to teleonomy. One of the primary areas where the Extended Evolutionary Synthesis differs from the Modern Synthesis is in the number of modes of inheritance available for evolutionary action. These modes of inheritance each appear to incorporate some amount of teleonomy in their operation.

These modes include niche inheritance, sexual selection, epigenetics, and developmental processes.

Another concept common to EES is evolvability. Bartlett writes:

Shapiro, Caporale, and Noble [three of the main EES proponents] show that many systems within organisms can direct the evolution of specific genes. These evolvability systems are encoded by the genome, targeted by gene products, and produce effects that benefit the evolution of offspring. In every way they match the concept of Evolutionary Teleonomy.

If one considers the idea that there is an internal program governing each of these processes, and directing the organism’s response to its changing environment, then one has arrived at the idea of teleonomy. Bartlett says, “As is evident, Evolutionary Teleonomy plays a central, unifying role in nearly every aspect of Extended Evolutionary Synthesis.”

Is the idea of teleonomy actually useful to biology? According to Bartlett, teleonomy works well with the way biology is analyzed and described: “In nearly every other aspect of biology, the presumption of function is used as a heuristic for understanding how biological systems work.” That is, except in evolutionary biology, where up until now any hint of goal-directedness was barred by the Modern Synthesis. However, perhaps it is time for that to change. Bartlett explains: “[F]urther developments in the theory of evolution over the last several decades show that Evolutionary Teleonomy should be returned to a central place in evolutionary thinking.”

For example, it might make a difference in Dan Graur’s analysis of the percentage of our genome that is functional. It certainly makes a difference if you think that mutations are teleonomic or not, in how his calculations work out. See Bartlett for an explanation.

It would indeed be useful to have an idea that links together the many evidences that organisms respond to challenges in apparently goal-directed means. The difference that matters, though, is where those goal-directed systems actually came from. Did they evolve, pushing the problem back a step or two, or were they designed? Bartlett leaves that question unanswered.

Photo: Leatherback turtles hatching, by Elise Peterson (Own work) [CC BY 3.0], via Wikimedia Commons.