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Retrograde evolution of invertebrates during major extinction periods and Haeckel’s terminal addition rule

By Jean Guex (1) and Alexej Verkhratsky (2)

  • University of Lausanne, Switzerland , (2) University of Manchester UK

This review presents in a very condensed form the detailed results of a recent book by Jean Guex (2016; with references therein; see also Torday 2015, 2016) with a foreword of Alexej Verkhratsky on the retrograde evolution of invertebrates during major extinction periods.

The first chapter of the book concerns the most common evolutionary trends described in the literature, showing more or less gradual geometrical and ornamental transformations occurring over long periods of ecologically stable periods. The most frequent is the increase of the size during the evolution of several phyla. It is commonly observed in foraminifera, ammonoids, nasselarian radiolarians, nautiloids and vertebrates.

In ecologically stable periods, the transformations of the skeletons are often characterised by an increase of shell curvature, corresponding to an increase in the apparent geometrical complexity

During massive extinction periods occurring through the Phanerozoic we observe major evolutionary jumps in several invertebrate groups. In such cases, the jumps are characterised by the appearance of primitive forms resembling remote ancestors of their immediate progenitors which can be defined as atavistic. The homeomorphic species generated during sublethal environmental stress can be separated from the ancestral group by several millions of years. The evolution of silicoflagellids is discussed as an example of application of artificial stress to modern organisms.

In this paper we summarize a new theoretical model of retrograde evolutionary changes during major extinction periods, first published in the recent book mentioned above (Guex 2016).

A diagrammatic presentation of the evolutionary patterns of some planktonic foraminifera, radiolarians, nautiloids, conodonts, corals and ammonoids is given in fig. 1. That diagram shows that the evolutionary complexifications of those invertebrates, lasting for very long periods, follow roughly the rules of Haeckel (1902). Reversals in the evolutionary patterns are observed during short periods of major crises.

Fig 1 Simplified and diagrammatic representation of the evolutionary lineages mentioned in the main text and their reaction to catastrophic events. Not to scale. Silicoflagellids (Cretaceous – recent). Foraminifera (Ticinella-Thalmanninella lineage – Cenomanian anoxy). Radiolarian (Saturnalids at the Cretaceous – Caenozoic boundary). Corals(Zardinophyllum lineage at theTriassic-Jurassic transition). Nautiloids (Domatoceras-Gyronautilus around the Permian Triassic transition. Ammonoids ( uncoiling during Jurassic and cretaceous crises). Conodonts (Evolution of the “Neospathodus” group during the Permian Triassic transition). From Guex 2016.

Fig.1 summarizes in an extremely simplified way the evolutionary cases discussed in our book. It shows that most of the evolutionary innovations are accumulated peramorphically (by “terminal addition” in the haeckelian terminology) over long periods of time (Guex et al 2012) It is precisely these newly acquired characters which are generally lost during periods of sublethal stress that are always much shorter than the recovery periods (a few thousand years vs several millions of years). The more generalized (=plesiomorphic) characters are also much more stable. This suggests that another possible mechanism could involve the genetic switching of Schlichtling and Pigliucci (1998) (see also Badyaev 2005). If this were true, we could speculate that some regulatory genes controlling the development of the newly acquired characters could be switched off at certain concentrations of pollutants (or under some sublethal temperature conditions) and switched on at normal concentrations. However that hypothesis cannot explain the usual cases where atavistic forms generated under extreme environmental stress are indeed giving rise to completely new lineages that are not identical to the ancestral one. Whatever the cause (genetic or biochemical) of the reversal processes discussed in our book, we note that it is very easy to inhibit the development of morphological novelties accumulated over several millions of years and to “reinitialize” the evolutionary clock of organisms submitted to high environmental perturbations leading to extinctions.

Our examples demonstrate clearly that multicellulars follow basically the same kind of evolutionary transformation (peramorphoses or atavisms) as their unicellular ancestors by accumulating new characters in an haeckelian way (see also Torday 2015).In other words the basic morphogenetic rules are the same as in unicellulars but they are spreading all along the ontogeny of the multicellulars.

In summary we can say that in both, unicellular and metazoans, most of the anagenetic evolution occurs by addition of new characters during long periods of time (several millions of years).

Retrograde evolution is catastrophic in the sense of Thom (1972): in our above mentioned book we use the cusp catastrophe to represent the evolutionary retrogradations occurring during extreme environmental stress (instantaneous in geological time). These diagrams show one simple thing: we can note that the retrogradations occur in exactly the same way in protists/unicellular and in metazoans. In other words it seems that the problem can be reduced to isolated cells communicating only with the external marine environment, the morphogenesis and phylogeny being strictly controlled by intracellular signals, which are not yet well understood.


Jean Guex (2016). Retrograde evolution during major extinction crises. Springerbriefs in Evolutionary Biology. (Personal copies:  write to

Torday JS (2015). Pleiotropy as the Mechanism for Evolving Novelty: Same Signal, Different Result. Biology (Basel). doi:10.3390/biology4020443

Torday JS (2016). Heterochrony as Diachronically Modified Cell-Cell Interactions.
Biology (Basel). doi: 10.3390/biology5010004

Cognition, Information Fields and Hologenomic Entanglement: Evolution in Light and Shadow

William B. Miller Jr.
 Independent Researcher –

AbstractAs the prime unification of Darwinism and genetics, the Modern Synthesis continues to epitomize mainstay evolutionary theory. Many decades after its formulation, its anchor assumptions remain fixed: conflict between macro organic organisms and selection at that level represent the near totality of any evolutionary narrative. However, intervening research has revealed a less easily appraised cellular and microbial focus for eukaryotic existence. It is now established that all multicellular eukaryotic organisms are holobionts representing complex collaborations between the co-aligned microbiome of each eukaryote and its innate cells into extensive mixed cellular ecologies. Each of these ecological constituents has demonstrated faculties consistent with basal cognition. Consequently, an alternative hologenomic entanglement model is proposed with cognition at its center and conceptualized as Pervasive Information Fields within a quantum framework. Evolutionary development can then be reconsidered as being continuously based upon communication between self-referential constituencies reiterated at every scope and scale. Immunological reactions support and reinforce self-recognition juxtaposed against external environmental stresses.

Keywords: hologenome; cognition; entanglement; quantum evolution; holobiont; zygotic unicell; self-organization; Darwinism; niche construction; information field
1. Introduction
The premise of this special issue is an enlarging perception that despite many appended forms, the Modern Evolutionary Synthesis does not represent a full account of eukaryotic evolution. For the last 150 years, as expanded into the Modern Synthesis and beyond, Darwinism has remained the unshakable center of standard evolutionary thought. More recent attempts at modification, such as the Extended Evolutionary Synthesis, still remain firmly anchored within the presumption of an obvious dominance of selection and random variation [1,2]. There is a tendency within that debate to wage deeply into details of theory, mechanism, nomenclature, and any perceived weaknesses or strengths of contemporary research. Yet, the issues as properly considered are actually few, and can be easily defined. Is evolution stochastic or not? If not random, is there a purpose? If there is a purpose, can it be considered a creative process at any scope or scale? Whether random or not, where is the central action of evolution, that is, where and what are its precise targets? Derivative to these primary issues are four further considerations. First among these is the one most vigorously debated: is natural selection ultimate causation, one factor among many, or mere tautology? Secondarily, is heredity primarily a vertical phenomenon or something other? This leads then to the third aspect so critical to the Modern Synthesis. Is evolutionary development best understood through the metric of gene frequencies or not? Lastly and little considered, how might eukaryotic organisms, as the endpoint of these processes, be best understood?
In order to gain a better perspective on these issues, it is fortunate that new research has revealed aspects of eukaryotic life that were not fathomed until quite recently. Eukaryotic life is holobionic by definition [3]. Its microbial fraction has only very recently been revealed through metagenomic sequencing and other advanced technologies and is much more elaborate and intimate than previously imagined [4]. Further yet, the complexities and extent of cell-cell communication that underpin cellular cognition have been generally recognized only in the last decades [5,6]. Lastly, there is now rapid progress in exploring the full extent of epigenetic impacts and their heritable transmission [7,8,9]. It is therefore contended that the impact of these relevant discoveries impels a thorough rethinking of evolutionary development with a decidedly changed focus.
As part of this shift, several concepts indicative of quantum systems can be included in the discussion. In particular, this includes the evaluation of biologic phenomena as existing in simultaneous states of ambiguous expression or probabilities of outcomes in genetic and cellular terms. In physical systems, this quantum duality is considered a superposition of probabilistic outcomes and chronologies in which a quantum state is considered a summation of two or more differing ones. A similar concept in biologic terms can be useful in understanding the deployment of epigenetic impacts and cellular responses to homeostatic stress [10,11]. Although these quantum phenomena properly dwell within the purview of quantum statistical mechanics and its rigorous use of statistical averages to define ensemble functions, general concepts based on quantum phenomena can still be deemed applicable. Such quantum principles include the inter-convertibility of physical thermodynamic principles into biologic action, quantum coherences that enable amplifying oscillatory phenomena in cellular activity, and non-local correlation through quantum entanglement (action at a distance). In each of these circumstances, biologic molecules and biologic expression do not necessarily exhibit one-to-one relationships and biologic molecules can entwine states at a distance without apparent direct connections [12].
Until recently, evolutionary theory has largely concentrated on the macro form. There has been relatively little attention to the unseen microscopic sphere or the immunological rules that govern it. The tendency has been to dwell upon the macroscopic aspect of our eukaryotic whole that dazzles in the light with much less scrutiny of the shadowed microscopic details. In the Renaissance, great artists such as Caravaggio used compositional chiaroscuro, sharply drawn lights and countervailing areas of darkness, to create compelling images. Close inspection of any canvas of that type reveals that these master artists instinctively understood that the complexity of the shadows and their detail is as consequential to the whole as any portion that is vividly illuminated. The shadows are filled with texture, gradation, and variety. Indeed, if the shadows were withdrawn from that form of image, it would be rendered lifeless to our eyes. Our prior understanding of evolutionary processes has been based on rigorous examination of biological light with little emphasis upon two vital aspects of biology that deserve further inspection: the microbial fraction of eukaryotic life and the essential duality of information as both representation of physical actuality within context and a corresponding source of ambiguity. When both sides are fully honored, evolutionary biology can be productively reappraised in an entirely consistent and differing frame as a complex hologenomic entanglement, always predicated upon and faithfully rooted within cellular origins throughout eukaryotic evolutionary development [13].
2. Darwin, the Modern Synthesis, and Beyond
When Charles Darwin offered his seminal work, he was unaware of the existence of genes. Backed by scrupulous observation, he proposed that evolution proceeded by the gradual modification of heritable variations through a process of natural selection. Notably, Darwin was not the first to proffer the concept of natural selection, although he was its most capable advocate. The theory of natural selection had been advanced earlier by Patrick Matthew, a Scottish horticulturist, in 1831 [14] and Darwin was familiar with his work. It is also remarkable that the lively debates about evolutionary mechanisms of his time have a continuing familiar refrain. In particular, in the early nineteenth century, Lamarck’s proposal that individuals can acquire characteristics based upon the patterns of use of the various faculties had many advocates [15]. Even Darwin had countenanced a variant of Lamarckism that he termed “pangenesis” in his 1868 text, Variation in Plants and Animals under Domestication [16]. Indeed, the debate about the primacy of selection and whether evolution has direction or is random has been ever ongoing and vigorous.
In the later part of the 19th century extending into the early part of the 20th, a variation of Lamarckism, known as orthogenesis, was propounded by Wilhelm Haacke and then promoted by the German zoologist Theodore Eimer. They believed that an organism held towards a fixed course by internal forces. In their view, variation was not random and selection was not a powerful force since a species is carried forward automatically by inner dynamics [15].
The integration of genetics into Darwinism began in 1900 when Bateson translated an obscure paper by Mendel into English and began asserting its findings as fundamental to understanding heredity and evolution [17]. By the early 1920s the pioneering work of Fisher, Haldane, and Wright had developed into population genetics, the formal study of genetic variation and the distribution of gene frequencies under natural selection. A further critical contribution was Mayr’s identification of reproductive isolation as the cornerstone of speciation [18]. George Gaylord Simpson’s work then reconciled this new landscape with paleontology [15].
From those beginnings, through myriad contributors and continuing until today, the Modern Evolutionary Synthesis has itself evolved as the unification of Darwinian natural selection theory with the burgeoning science of genetics. Yet, its primary principles have remained stable: heritable variation is random and natural selection is the main evolutionary mechanism. Changes in genetic diversity and Mendelian segregation are best understood within the context of populations through vertical descent, and its occurrences are necessarily gradual [19,20].
In discussing the long journey from Darwinism to the Modern Synthesis, Massimo Pigliucci observes that when Darwin was writing his volumes, two major questions were considered paramount; how can the diversity of life and its history be explained, and then further, how might that account for the apparent match between form and function in organisms [21]? Prior to any explicit knowledge of genetics, evolution theory was, in its earliest stages, a theory of forms. In contrast, during more recent decades, evolutionary theory has become nearly exclusively a theory of genes. Much of this perspective is due to the seminal work of Haldane, Fisher, Dobzhansky, Sewall Wright, and Mayr in exploring statistical methods within population genetics. Each was attempting to account for variation through the integration of Mendelian genetics into both the micro and macro evolutionary landscapes [22]. Of major concern was whether the microevolutionary changes that could be cataloged in local populations might be explicitly reconciled with the novelty and morphological inventions seen within macro evolutionary trends, and yet, remain in allegiance to a presumption of the primacy of natural selection that exerts its force over geologic intervals [23]. The neutral theory of molecular evolution proposing genetic drift as a major evolutionary driver was a consequential revision. Most mutations were envisioned as selectively neutral and not directly affecting the fitness of organisms [24]. Therefore, the understanding of selection shifted. It was not just a positive action, but instead, a purifying one through the elimination of the most harmful mutations with fitness accumulating by drift [25,26].
Over time, a trend emerged to accommodate a more pluralistic narrative compared to the major tenets of the Modern Synthesis [27]. Although not the first to champion it, Margulis [28,29] became a vigorous proponent of incorporating symbiogensis and endosymbiosis into the evolutionary narrative by outlining an organelle genesis theory [30]. McClintock played a similar crucial role with her illuminating work on transposable elements [31]. In particular, the discovery of the homeotic Hox master genes in the 1980s, highly conserved across many phyletic divisions and over a vast continuum, has gradually altered the focus of research towards regulatory complexity compared to the composition of genes [32,33].
Others researchers have stressed aspects felt to be essential parts of genetic evolvability though still maintaining coherence with overarching natural selection. Radman et al. stressed genomic variation, recombination, and mutation [34]. Caporale reviewed molecular biological mechanisms within a pleiotropic genome that responds to stress in a non-random and strategic manner [35,36]. Fodor and Piattelli-Palmarini in 2010 offered that natural selection in and of itself cannot explain evolution and emphasized what they appraise as extraordinary creativity in genetic evolution [37]. Jablonka, Lamb, and colleagues have reconsidered the Modern Synthesis by concentrating on Lamarckian epigenetic factors, suggesting environmental impacts are of major importance beyond intrinsic genes and random variation [8,38,39]. Others, such as McFadden [40] and Ho [12] have attempted to reconcile evolution with the natural sciences and quantum physics.
As part of the crosscurrents of thought, and starting in the 1960s, the Williams revolution shifted the frame of reference from population genetics towards models of natural selection through kin selection. The focus became the gene as a fundamental unit of self-preservation, accounting for both fitness and altruistic behavior through the inclusive fitness of a larger gene pool. This concept was further expanded by Dawkins [41], Doolittle and Sapienza [42], and Orgel and Crick [43]. It was maintained that genomic expansion was largely due to the repeats of selfish elements within a genome thereby accounting for “junk” DNA.
In 2007, Rose and Oakley offered an extensive critique of the Modern Synthesis. Certain aspects were no longer tenable, such as viewing the genome as a “well-organized library of genes” [27] that have single functions shaped by natural selection. They offered a greater emphasis on horizontal gene transfer, gene duplication, symbiogenesis, and differential lineage assortment. In a review of evolution from the perspective of new findings in genomics in 2009, Koonin contended that these studies indicate that natural selection is not the only force that shapes evolution and may not even be dominant. Non-adaptive forces might be the greater fraction. Even further, Koonin suggests that there is “hope for the discovery of simple ‘law-like’ regularities” [20] that underpin evolutionary development.
Others have distanced themselves from the Modern Synthesis to an even greater extent. Woese and Goldenfeld in 2009 urged casting away the Modern Evolutionary Synthesis to permit a fuller reconsideration of the last century of dogma in favor of a full integration of evolutionary theory with microbiology and molecular biology [44]. Shapiro has provided a link towards that goal, calling for a critical rethinking of evolution with natural genetic engineering rather than natural selection as the major mechanism [19].
Perhaps the most comprehensive attempt at a full and comprehensive alternative to the Modern Synthesis has been the promulgation of an Extended Evolutionary Synthesis (EES) [1,2]. This represents a pluralistic approach that views the center of action in evolution as developmental or phenotypic plasticity enabling an organism to change its phenotype in response to the environment. In this frame, heredity extends beyond genes to encompass the heritable transmission of other developmental resources between parent and offspring that can be both bioactive and behavioral in nature. Significantly, such effects are not merely confined to germ to germline transmission, but can also extend soma to germ, or germ to soma. Through these mechanisms, there is a tendency towards mutual reinforcement through niche construction, i.e., reciprocal causation between the capacities of the organism and the outward environment with each impacting the other. In this manner, an organism can shape its own developmental trajectory by adjusting both internal and external states along constructive developmental paths. Therefore, adaptations arise by both natural selection and a separable process of internal and external constructive development in reaction to epiphenomena.
Yet, EES still represents another pluralistic adjustment to the Modern Synthesis rather than any revolution. The targets of selection are changed and limits are imposed, but the underlying narrative receives no definitive challenge. By what means might evolutionary theory be fully reconsidered so that natural selection is no longer its centerpiece? The requirements would include a complete reappraisal of the targets of natural selection and then, even more importantly, a fundamental change in the means by which biological organisms are construed. Further too, it would require an ecobiological construct that is not merely a direct reduction to allele frequencies [45].
3. Cognition is Fundamental
In effecting any disassociation from the standard evolutionary narrative, contemporary resources from the emerging fields of hologenomics, metagenomics, and epigenomics can be productively applied. However, as important as those disciplines are in any attempt to suggest a new synthesis in apposition to Neodarwinism, one decided advantage is the opportunity to begin where Darwin could not. That differentiated platform is the centrality of cognition to life [19,23,46,47]. In 2011, James Shapiro stated it plainly, “Life requires cognition at all levels.” [19]. Beyond metaphysical speculations, Darwin did not have any concept of its biological ubiquity nor did any of the theorists of the early through mid-20th Century. Yet, even when the last few decades of research have revealed that self-referential cognition underscores all life on the planet [48,49], and further, that it might be productively considered and dissected apart from metaphysics, it has attracted the interest of few evolutionary biologists.
In 2007, Shapiro wrote, “Forty years’ experience as a bacterial geneticist has taught me that bacteria possess many cognitive, computational and evolutionary capabilities unimaginable in the first six decades of the twentieth century.” [50]. That assertion is based upon the extraordinary range of metabolic cellular processes exhibited by bacteria and used to evaluate and monitor their own internal environment. It can thereby be advanced that each living entity accomplishes these activities for the maintenance of self-identity, and further, that these actions are reinforced through willing cooperation. It is now well established that the engagement of bacteria in the colonial form results from abundant multicellular collaborations under girded by sophisticated mechanisms of intracellular and cell-cell communication [51,52]. As Lyon [47] observes, bacteria have an extensive cognitive toolkit that includes a wide range of faculties: advanced sensing, communication, autoinduction via the indirect use of information gathered by proxies, some elements of sociality, various forms of motility including complex swarming behaviors, and memory. Given the variety and sophistication of these actions, there is specific evidence of some elemental level of cognitive function at every scope and scale applied towards the maintenance of self-awareness that, in turn, permits such levels of collective sensing, cooperation, and interdependence. All these functions require levels of memory and information processing and are positively directed towards problem solving [53].
Ample complex cooperative strategies are clearly demonstrated throughout diverse eukaryotic cellular ecologies. The human gut and other tissue sites demonstrate that the depth of those interrelationships is great enough to promote specialization in the production and use of resources [4]. Therefore, microbes and individual cells send, receive and interpret information and importantly, put such outputs to use according to their scale to enact and maintain both individual and collective homeostatic preferences. They do so not merely based on their own immediate and explicit environment but based upon cues that are responsive to more global concerns that emanate from entire cellular networks [54]. The level of sophistication of these communication and feedback mechanisms provides an instructive comparison with our own human economic framework [55]. As such, economic equilibrium theory has been applied to the cellular biotic realm based upon bacterial metabolic exchange vis-à-vis the trading of resources to create a general equilibrium model that is useful for understanding both bacterial and human reactions. It is, therefore, implicit that widely disseminated intercellular processes lie at the center of a complex chain of cooperative cellular behaviors that characterize the biosphere and are then reiterated at every scope and scale to even include our own human proclivities. This discrete interaction helps explain why auxotrophs, or highly specialized cells unable to produce essential metabolites, are prevalent in symbiotic and free-living bacteria and appear to drive biosynthetic gene depletion as a fitness adaptation [56]. In sum, they have staked themselves upon trading for resources and an existence through cooperation and the exchange of information. That such cells exist indicates an expectation of entangling reciprocity as an inherent biological reality and then further, underscores an underlying biologic imperative for cooperative action as a centerpiece of biological activity. It can, therefore, be asserted that cooperation is the conditional basis for the construction of new levels of organization implicit to all evolutionary development [57]. Cooperative interchange exists throughout biology, whether at the level of individual cells or eukaryotic multicellular organisms. Mutual reciprocation between biological entities and the external environment is omnipresent [58]. These expectations and dependent phenomenon are so commonplace that it exists beyond communal circumstances and is also known to be evident among free living bacterial cells [56].
Such interactive behaviors are not exclusive to the unicellular side of the microbial sphere. It is now widely acknowledged that viruses are an essential element of our evolutionary narrative [20,59,60]. All of the critical functions of cells such as replication, translation, and repair are of viral origin. Our genome has thousands of endogenous retroviral sequences [61] and it has been a more recent surprise to identify that there are also large numbers of viral sequences that have impacted eukaryotic evolution [62]. The impact of the virome extends well beyond pathogen and host interactions and extends into every aspect of eukaryotic life to such depth that it is has been proposed that this component might determine our “normal” transcriptional state [63]. Further, it is clear that viruses and sub-viral particles exhibit a range of intelligent behaviors. They are efficient problem––solving entities, capable of overcoming the most sophisticated cellular mechanisms. They can evade or change cellular immune systems to meet their requirements and participate in and control the transmission of information between other biological entities [64]. Viruses cooperate with each other to determine cell fates [65], and there is complex communication and exchange of information between phage and bacterium that determines survival, reproduction, and movement [66]. Their actions as bacteriophages require sophisticated highly coordinated mechanisms for entering cells requiring the recognition of a wide range of bioactive molecules [67,68]. Therefore, it is clear that communication between all microorganisms is widely distributed and abundant [69] to such an extent that Visick and Fuqua liken its pervasiveness to “chatter” [6].
There is no doubt that all microbes including bacteria, viruses, and even prions have discriminatory preferential states. It is the reliable partialities of specific microbes for certain tissue types that form the definable criteria of infectious disease dynamics upon which the clinical practice of medicine is based [23]. Lyon has queried whether extensive signaling transduction pathways that have been demonstrated in microbes form a coherent adaptative response [47]. Direct observation asserts that microbial responses are indeed predictable and reliable in many instances. Lyons offers this, “Biological cognition is the complex of sensory and other information-processing mechanisms an organism has for becoming familiar with, valuing, and [interacting with] its environment in order to meet existential goals, the most basic of which are survival, (growth or thriving), and reproduction.” [47] However, those capacities are not exclusive to bacteria, or viruses, but have been shown to exist within all living entities including the individual cells of any eukaryote as they experience stress and make individual coping decisions [70]. Importantly, therefore, all biological mechanisms such as physiological traits underscore abilities that are best understood as direct exaptations of the unicellular state [71,72].
If it is then granted that cognition is a consistent element of microbial and cellular life, how might such a faculty have arisen? Since cells and microbes are entities that have some form of awareness of condition and are bounded compartments, it might be considered that in order for any awareness of condition to supervene, boundaries must exist. Obviously, without such perimeters, there is only one continuous state. Hence, borders are crucial for awareness and it might be surmised that it arises as a phenomenon of coherence induced by the bounded state in which physical forces are entrained, perhaps as a special case thermodynamic quantum coherence [73]. In that regard, there is research that supports that quantum processes are essential to life [74,75]. Such activity appears to be demonstrable within eukaryotic cells. In particular, the intracellular components of the cytoskeleton appear to be dependent upon quantum phenomena. Microtubules demonstrate coordinated vibrational beat frequencies that may produce quantum coherences [76]. Tubulin, actin filaments, collagen, non-polar protein interiors or membrane lipid peroxidation processes interact with the vibratory capacities of microtubules either directly or via serotonin production promoting quantum signaling that permits the collapse of the superimposition of possibilities inherent to quantum phenomena [77,78,79,80].
Therefore, it can be surmised that awareness is both knowing something has entered its space and the awareness of it as information that can be channeled through quantum inferences that devolve towards the physical realm and can then be used to resolve cognitive ambiguities [81]. Coherence actualizes the ability to discriminate preference within a frame that might otherwise remain ambiguous. Under such conditions, cognition is then the ability to purposely attempt to resolve ambiguity and, at a higher level, becomes the faculty of maintaining higher levels of ambiguity prior to initiating action even if resolutions can be sensed.
Yet, an awareness of condition or any self-referential capacity can be separated from other aspects of intelligence. One person may be better at solving certain problems than another, but our assessment of intelligence is not enlarged to presume that any basal sense of “self” of one individual is greater than another. It is, therefore, possible to consider “self” as separable from other aspects of cognitive discrimination and ability. It is can then be asserted that bacterial and cellular self-awareness exists as a condition of life but is still distinguishable from overall intelligence. Yet, bacteria are far from simple. As Shapiro points out, “The first point is to recognize that bacteria are far more sophisticated than human beings at controlling complex operations.” [50]. Bacteria use chemotaxis to find nutrients, avoid toxic chemicals, sense pH, and extensively interact with others. Therefore, the origins of cognition must originate in the physical world as an impulse that transmutes into biological form and is capable of refinement dependent upon scope and scale. However, self-awareness is better understood as a condition of life as a first principle upon which all resultant life rests.
In that regard, De Loof [82,83,84] has suggested that life should not be considered a noun, but a verb. In those terms, life must be regarded as the sum total of all executed acts of communication at any moment, at all levels of any compartmental organization, and as a summation of all that activity. Furthermore, all of that life activity is directed towards problem-solving. De Loof asserts that communication/problem-solving precedes selection and should therefore be considered a universal element of evolution.
Proceeding within the context of life as a verb, it can, therefore, be represented that life consists of the active use of information to sustain change towards preferential conditions for any living entity. In this regard, De Loof maintains that communication is the handling of information in a system that is organized as a “sender-receiver communicating compartment”. Yet, information is not merely data to any receiving entity. Upon being decoded by any receiver, it becomes part of the stored energy within the receiver that can be mobilized towards action as work. Therefore, for De Loof, the cell concept should be changed from the strictly material towards a larger consideration of the cell as a “sender-receiver” universal unit of structure and function of all living matter from which complexity then builds from level to level.
In such a system, a natural bridge exists between thermodynamic considerations and a biological one that is best appreciated through quantum phenomena in which energy and information are considered essentially equivalent stipulations that are dependent upon receiver status in biological contexts. Although it is typical to consider biology in terms of organization in violation of the 2nd Law of Thermodynamics, the flow of information that is inherent to life processes with all the ambiguities that it creates is not usually part of that account. Considerations of entropy in living systems are by no means direct. For example, although it is common to consider information as concrete, communication is otherwise, generally pervasive, and often not directed towards any specific receiver. Instead, it is a generalized attribute of cognitive life and largely noise. Since the sending of information requires the release of energy, the amount of entropy in a system consistently transitions and is dependent upon the reception of information that is used to resolve ambiguities versus the quantity that remains noise.
Jacob et al. examined Schrödinger’s ideas about the fundamental requirements for life from the perspective of contemporary observations about bacterial self-organization and the emerging understanding of gene network regulation mechanisms and dynamics [85]. Schrödinger proposed that consumption of negative entropy requires the further context of an organism’s ability to extract latent information embedded within any environment from its complexity [86]. By acting together, bacteria efficiently perform this task through cooperative behavior and thereby prove their biotic cognitive ability and that of any basic cellular unit. When viewed in this manner, there are then direct links between thermodynamics and self-referential cognition. Even though biological organisms can be considered secondary to entrained thermodynamics, energy is merely in transit despite any temporary storage for work. Therefore, it is appropriate to consider all biologic organisms, either at the unicellular or multicellular levels as transient intermediary manifestations of energy flux in which information is part of that same phenomenon. In such a context, energy as information may be best framed as a phase transition in the physical order, such as water to steam. In our biological system, such a phase transition has been validated experimentally through calculations of the probability of a fluctuating neuronal membrane voltage exceeding certain activation thresholds that define neural coding [87].
A similar phase transition has been previously applied to the origin of life which has been likened to a physical transition such that information is transformed to achieve context-dependent causal efficacy over the matter from which it was instantiated [88]. Even though biological organisms can be considered secondary to entrained thermodynamics, energy is merely in transit. Contemplating such a transition requires our distancing ourselves from the manner in which we have traditionally considered any organism and accept the same dynamical frame of Walker and Davies [89]. In this circumstance, living organisms are way stations of entropic and enthalpic flux in which information as energy gains efficacy over matter. Further, since any such entity radiates energy via heat, it is then also continually effecting information transfer insofar as it is always radiating heat or other by-products of life processes. Among living things, this is ever ongoing and includes metabolic products as waste, cast off cells and particulate matter that have never traditionally been considered information but decidedly are. In this manner, all living things are dynamical agencies contributing to entropic flux on a steady basis towards the large universal entropic sink as entities that dissipate heat and information. In quantum circumstances, all such activities proceed from the superimposition of possibilities that is inherent in the biological sphere [90].
Therefore, any living organism is a temporary non-equilibrium dissipative entity a fleeting manifestation of the collapse of the superimposition of possibilities of a variety of entropic and enthalpic moments as rates of change that are reflective of homeostatic status. A number of variables determine that state: temperature, volume, pressure as well as entropy and enthalpy. Each are state functions and cellular life and homeostatic status depends upon them. Such variables may be difficult to measure, but there are natural bridges between thermodynamic exchanges and biologic entities that employ all of these factors. Photosynthesis for the direct conversion of energy from sunlight to sugars required for metabolism and growth by phototrophs is an obvious instance. Chemotrophs extract energy for the manufacture of sugars by taking electrons from substances in their surrounding environments—a process called chemosynthesis. Other biologic entities, chemolithoautotrophs, get their energy from the oxidation of inorganic substances. Shewanella loihica PV-4, a metal reducing bacterium, can self-organize as an electrically conductive network becoming a long distance electron transfer conduit using outer membrane proteins and semiconductive minerals [89]. Instead of energy from the sun, or the inorganic molecules from deep sea thermal vents, these bacteria seem to represent a third different type of energy ecosystem in which microbial activity is sustained by the direct use of electrons available in the environment [91].
Such bioenergetic solutions can be productively regarded as fundamental principles of physics channeled into biologic expression. It would seem reasonable assume then that any system of cognition is energy dependent, and that energy flows via those quantum processes that represent that particular union along a continuum of physics as biology expression. The cusp can thereby be considered an inherent duality incorporating both the exchange of information and the reciprocal transfer of energy between receptive entities. Consequently, this can be properly represented as a first- order entanglement between the physical realm and the biologic one. A further supposition would suggest that cognitive self-awareness, as a quantum state, arises as a phenomenon of coherence induced by any bounded state in which the appropriate resonant energy is entrained. Within the eddies and flows of the varied gradients within the cell, or even within a viral capsule, when “life” supervenes within cohering physical boundaries, the resonant energy of awareness simply exists. Furthermore, then, as Whitehead conceptualized, it might not necessarily be invested only in bioenergetic molecules [92]. Whatever the reality, it is enough that it is evident in all that are regarded as “living”. However, as energy transfer is an oscillating function of frequency and amplitude, there must be zones of coherence (amplification or resonance) or decoherence that occur across gradients within any boundary condition. In biological terms, this can be considered regions of more or less ambiguity in which the superimposition of possibilities is either broader or more constrained. These can be considered as points of intersection of energy/information transfer within the cell as they overlap energetic inputs emanating from outside cellular margins. Within the cell, such zones of coherence can be regarded as foci of discrimination and preference enacted in biologic form as cognition, perhaps centered within cellular microtubules as has been suggested by Hameroff and Penrose [76]. Since information is energy transfer, information becomes a gradient function subject to harmonics and resonances that instantiates or promotes a spectrum of awareness of status. Therefore, each cellular unit is a coherent and discrete cognitive entity in which information becomes another form of resonant energy both within and without the cell. Energy becomes information within the bounded resonating chamber of the cell achieving the coherence necessary to become information to both sender and receiver. The difference between energy and information can then be assumed to be based on specific energetic coherences that permit its use by an apt receiver to settle specific biological ambiguities.
Life is best defined as the property of self-awareness that permits the use of information to either sustain or change conditions. Further, life as self-awareness is thereby imbued within everything that is regarded as living. It necessarily follows then that self-awareness exists independently of the number of steps required to enact it. Therefore, self-awareness is properly considered a state function. From that inherent base, its variability exists as a reiterative conditional function based upon discriminated preferences within varying frames of ambiguity. Under such circumstances, cognition can, therefore, be understood as the ability to purposely attempt to resolve ambiguity through the use of information. As a derivative then, at reiterative levels beyond the unicellular domain, cognition can be considered as the self-organizational ability to permit higher levels of ambiguity prior to the initiation of action, even if earlier resolutions can be sensed. Certainly, it must continuously be based upon basic thermodynamic principles of energy utilization and information transfer. Under such circumstances, however, free energy in thermodynamic terms becomes uncoupled from variational minimal free energy in biologic information space [93]. Others have upheld the statistical power of Markov blankets. In a Bayesian network, a Markov blanket is a set of nodes that consist of parents, its children, and any other parents of its children in which the probability distribution of each node is conditionally independent of the other nodes in the network. A set of such nodes of diverse parentage that connects to neighboring nodes can be considered a pertinent depiction of the means by which cellular membranes uphold their intracellular matrix as opposed to extracellular influences [94]. In those systems, inputs are based on Bayesian inferences of random inputs and typically too, local coupling [95]. However, within a context of self-referential cognition, there are direct biological limits placed upon the bounded dispersion of sensed states by which cells experience epiphenomena and the outward environment. Any inevitability of self-organization as a form of active Bayesian inference is thereby empowered as the means by which biological uncertainties are resolved through inputs that are not necessarily random and also through quantum biologic phenomena that are subject to both local coupling and non-local correlations [96]. Therefore, higher levels of intelligence can be understood as permitting an organism to resist the collapse of the superimposition of possibilities to improve decision-making within its environment. Intelligence is, therefore, discrete problem-solving that is context dependent, but is still separable from self-awareness.
If all living units are considered sender/receiver units, then all organic systems register information and further yet, transform it as part of inherent information systems. Intelligence as problem-solving beyond self-awareness might then properly be considered as an emergent property of an information system [97]. Further yet, intelligence should be more fully considered as the purposeful use of information which has been argued exists even at the level of a small protein [98]. Even so, intelligence is difficult to localize within any one structure of any macroorganism and might be better understood as an emergent property of any living entity as a part of a cellular network that both sends, receives, and interprets information. As Pookottil notes, jellyfish have no brain, but are self-aware and intelligent, demonstrating wide-ranging behaviors and advanced problem-solving abilities [97].
Therefore, it is best to consider intelligence as problem solving that has additive and emergent properties that extend from self-awareness but is also separable from it. Such capacities are much more widely present than previously understood. For example, Shomrat and Levin demonstrated that Planarian flatworms are able to reiterate their entire body including their brain if segmented, and will still demonstrate some intact memories from the initial brain structure [99].
Most discussions of intelligence have concentrated on an in-depth examination of animal behavior. Yet, plants have been considered nearly passive and their cognitive abilities have received little attention. However, they have memory and intelligence, and clearly demonstrate cognitive awareness through solving problems such as optimal light acclimation, transpiration, and resisting immunological transgressions [100]. Plants are capable of learning complex signaling behaviors, acquire large amounts of information and have the capacity to memorize and organize learned responses [101]. For example, Mimosa pudica exhibits clear habituation, suggesting some elementary form of learning. Unexpectedly, Mimosa can display this learned response for more than a month between stimuli. This relatively long-lasting learned behavioral change as a result of previous experience matches the persistence of habituation effects observed in many animals.
Nor have we understood the varieties of intelligence or its distribution. Cephalopod intelligence seems unlike our own. Cephalopods such as squid, demonstrate a form of highly distributed intelligence with independent motor control distributed to each of their arms and a system of highly sensitive chromatophores in their skin [102]. These cells demonstrate activity that is independent of the central nervous system and can be considered separate cognitive centers [103].
Therefore, cognition can be regarded as the purposive use of information and communication as represented across the entire microbial sphere and widely distributed in different cellular ecologies within multicellular eukaryotic organisms. Naturally then, it exists beyond any centralized brain structure. It is important to emphasize that the purpose of cognition is not merely reaction to stress. In biological organisms, information is also used for prediction that can also be understood in the context of resolving biological ambiguities towards biological expression. Such predictive capacity is universally distributed and is clearly exhibited by bacteria in which it has been demonstrated as a form of associative learning that has typically been attributed only to metazoan nervous systems [104,105].
With these considerations, an assertion can be made that self-awareness is a condition of life as a state function derivative from physical processes. Consciousness as awareness of an external environment is conditional to all forms of life and represents the specific differentiating junction between the biotic and abiotic realms [106,107]. In that frame, self-awareness is the deployment of information as another form of energy. Since life is self-awareness by definition, and further yet, since information is a form of energy transfer purposed towards settling biological ambiguities, then life, and then too, self-awareness, are properly regarded as a specialized form of energy transfer. The preservation of self-awareness is then best considered as a quantum process. Derivatively then, the subjective assessment of “self” becomes fundamentally related to the status of the participant/observer relative to others [108]. Under such circumstances, as Fingelkurts et al. assert, consciousness as we experience it becomes a neural collective phenomenon dependent upon a “nested hierarchy of electromagnetic fields of brain activity” in which subjective and objective reality represents a “unified metastable continuum guided by the universal laws of the physical world such as criticality, self-organization and emergence.” [109]. Therefore, within this quantum framework, it can be advanced that “self” is a quantum phenomenon experienced through the continuous collapse of the superimposition of possibilities that constitute the resolution of biological ambiguities inherent to the manner in which biologic organisms obtain information.
Therefore, a new beginning permits distancing from Darwinism as a precondition of any further evolutionary narrative. Self-referential awareness as a state function from the inception of life forward has its base value independent of the history of the system. Its broader expression as intelligence implies a wider range of problem-solving tools and remains an emergent phenomenon that is context dependent and causally related to its historical path. Self-awareness must arise from the physical system that preceded it and is thereby best understood as a function of entrained thermodynamics. It is likely then that awareness is based upon energetic coherences enacted primarily within the requirement of cellular boundaries including membranes or viral envelopes that permit conditions for any phase transition by which energy becomes information.
Since eukaryotes, bacteria, viruses and virions, and even prions are separable from inanimate entities through a reactive awareness of status, they too exhibit a property of self that is “life” by definition. Therefore, all known life and its consequent evolutionary course should properly be considered as based upon self-referential awareness, dependent upon contextual energy transfer as both information and communication with its attendant layers of uncertainty. Self unites with thermodynamics through these quantum uncertainties as the continuous resolution of ambiguities into biological expression. Furthermore, since the purpose of information transfer and communication is problem-solving and further yet, that this impulse originates with cellular mechanisms, it can be expected that evolutionary development would remain faithful to cellular imperatives throughout its course [71,72]. Specific evidence for this is available, as shown in the recent elucidation of the structure of the ribosome from its origination 3.8 billion years ago, with layers of accreted complexity as terminal additions extending forward continuously from an initiating central core [110].
4. A Differing Endpoint
At least as important as any new point of origination may be to any reconsideration of the Modern Synthesis, a fuller understanding of evolution is necessarily dependent upon an accurate perception of the current endpoint of these processes. In this regard, the general Darwinian appraisal of macroorganisms as unitary beings is no longer contemporary. No accurate current assessment of evolution can be undertaken without a thorough appreciation of the essential nature of all eukaryotic organisms as holobionts. There are currently estimated to be at least 100 trillion microbes that are in and on us—bacteria, viruses, fungi and others. They outnumber our primary cells by a factor of 10 to one or more [111]. Further yet, if the entire genetic fraction of any holobiont were to be considered, then the full genetic cohort of the associated microbiome outnumbers our innate genetic complement by 100 to one or more [112]. Although there has been a movement toward revision of the raw numbers [113], the conclusions about the nature of eukaryotic multicellular organisms as functional holobionts remains steady.
Research is now underway to properly define our dependencies upon our microbial partners for the proper function of our gut [114], brain, and central nervous system [115,116] and immunesystems [117]. In view of these interrelationships, Gilbert et al. have discussed considering all eukaryotes as multi-species units [118]. However, any complete understanding of evolution requires a complete separation from our prior subjective notions. Indeed, the entire model of “host” and “guest” should be revised. Rather than regarding any macroorganism as an inherent singularity, a more accurate comprehension restates eukaryotes as vast collaborative enterprises of co-linked, cooperative, co-dependent and competitive ecologies merged together so seamlessly as to seem one discrete entity [23]. All multicellular eukaryotes are holobionts. There are no exceptions and its implications must be considered in any appraisal of evolutionary development.
The concept of the hologenome has been championed by Eugene Rosenberg and Ilana Zilber-Rosenberg [119,120], although it was originally advanced by Richard Jefferson years earlier [121]. The hologenome theory of Rosenberg and Zilber-Rosenberg maintains that the actual object of natural selection extends beyond any macroorganism as “host”. Instead, it extends to encompass the entire symbiotic community with which it is associated. However, within their theory, the traditional concepts of “host” and “guest” are strongly maintained even as they consider this duality as a conjoined unit of selection. Furthermore, their evolutionary narrative remains an entirely traditional Darwinian one. Conceptually then, their approach is not specifically different from the Synergism theories of Maynard Smith and Szathmáry in which the object of selection is the synthesis of collaborative components at many levels and at major transitions [122]. With these theories, the object of selection is shifted by an enlarged pluralistic bandwidth beyond the central genome of a macro-organism but remains centered within selection theory.
Chiu and Gilbert regard multicellular eukaryotes as holobionts with multiple species of persistent symbionts [123]. Whereas they do appreciate the anatomical, physiological, developmental and immunological unity of holobionts, their interpretation is that it is best understood as an instance of “reciprocal scaffolding” in which species share relationships. Therefore, symbionts are more than mere appendages and are part of a “superorganism”. However, Miller asserts that the intimacy of the relationship is intimate enough that holobionts are beyond reciprocal scaffolds, or even superorganisms, but are instead better understood as assemblages of linked cellular and viral ecologies as distinct merged confederacies into a unique complex integrated entirety [23].
Therefore, the combination of eukaryotic “us” and “other” must be reappraised within a consensual “we”. In this manner, macroorganisms are no longer evolutionary singularities but are always the product of the mutually collaborative and competitive needs of conjoining cellular action in a transient arc of life that to our casual human appraisal is “personhood”. Such oneness is merely seamless integration. Necessarily, such consensual links require the backdrop of two inter-related features of cellular life: Information sharing among the variety of confederated mixed cellular ecologies that must be constrained within immunological rules foundational to the maintenance of mutual co-alignment.
When multicellular eukaryotes are reconsidered as always anchored within cellular mechanisms that extend across many mutually co-linked life forms, information systems and information transfer become the logical framework for any deeper understanding. In 2002, Lloyd introduced the concept of the Pervasive Information Field (PIF) in order to attempt to define a system of self-organization that is universal and scale free upon which many inter-related disciplines could be based [124]. Such an information field offers insight into information storage and its usable and accessible distribution and has been used as a model for the description and modeling of social systems [125]. Clearly, life is a unique type of information management system that is distinguished in character from theoretical measures such as Shannon information. The difference centers on context as apart from raw data [88]. It is certain that information is being sent and received within and across the cell at all times, reverberates externally and has further reciprocal effects. The context of information transfer across a vast multicellular constituency is obviously complex and based upon receiver and sender characteristics which is perforce a function of velocity that depends upon the medium of transfer and information type. Further yet, a great deal of it might be regarded as noise. The appropriate means of assessing its summation might be best considered as a complex information field, and in turn, such an active informational field has its epicenter within and overlaps every cell and projects beyond it. This is simply analogous to the more familiar concept of any cell having its own energy field that consists of its gradients and fringe effects. In the case of an information field, it is the summation of all the sources and receptors of information within the cell and extends outward into the external environment. In this regard, the concept is similar to the summation of communication approach of De Loof [84].
The term “field” is appropriate since there is no reason to suspect that there is any exclusivity for reception of information within any purported “network”. Some players might be privileged based on field effects, e.g., amplitude or frequency, but it is likely an open system, more like a broadcast than a direct line. When a virus enters a cell, it is able to tap into the information field and utilizes it to begin its intracellular purposes. Furthermore, since information has velocity and degrades over distances, then it is a gradient phenomenon with fringe effects and distortions. This becomes a primary source of ambiguity within biologic systems substantiating the contention that life can only be understood as the continuous resolution of uncertainties within context.
Any concept of a Pervasive Information Field can be easily reconciled with self-awareness. It is an actualization in biologic terms of an informational set. Within this definition, it rationalizes the non-intuitive requirement of cellular boundaries towards purposive self-awareness. The cellular boundary delimits the informational field, shielding it from some distortions or deformations caused by external environmental variables and adjacent cellular field effects. The cell membrane creates the environment in which the integrity of the information field can be protected and coherently projected. Therefore, our typical biological frame of reference of material form can be redirected towards a larger concept of information space. Phenotype becomes a manifestation of biological substrates resolving the inherent ambiguities within energy and information fields into material form. Holobionts no longer reduce to only innate cells and obligatory microbial companions but are instead considered as aggregations of overlapping Pervasive Information Fields (PIFs) wherein each constituent cell has its own basic self-referential life property. All link together enabling larger PIFs, as localized cellular ecologies and then again reiterating, in series as holobionts. Each extends in information space along its own developmental arc, experiencing and gaining vital information about the outward environment from the exchange of bioactive molecules, genetic transfers and epigenetic impacts.
5. An Alternative Endpoint Requires Different Mechanisms
Once biologic organisms are reconsidered as specialized forms of information fields, the linkages between the unicellular realm and eukaryotic multicellular life become more apparent. Certainly, it is understood that bacterial organisms exist in complex social and reciprocating communities [126], that are dependent upon communication and the transfer and use of information. This consequent interplay leads to complex colonial forms in which individual cells can demonstrate specialized behaviors. Ben-Jacob has determined that this effect is attributable to problem-solving via collective sensing and the use of information based upon shared environmental experiences and stored information as memory [126]. Such distributed information processing is shared throughout the information field of an estimated 109–1012 bacteria in the colony, that transforms “sense” into a form of collective overarching intelligence. Bacteria utilize what they can to enact these changes, such as quorum-sensing, chemotactic signaling and plasmid exchange [127]. Complex colonial forms emerge through the self-organizing interplay between each individual bacterium and the colony, which can now be further pictured as systems of overlapping and reiterating individual Pervasive Information Fields inherent to each of the interacting constituents. In this manner, novel features can arise and be put to use, based upon collective problem solving that extend beyond any level of previously stored information capacity. The manner in which this occurs is best understood through the concept of stigmergy.
Stigmergy is a type of feedback loop in which any action leaves some kind of trace in a medium. Each trace, consequent to any action, incites a further action either by the individual leaving the first trace or others that follow [128]. Heylighen defined it as “an indirect, mediated mechanism of coordination between actions, in which the trace of an action left on a medium stimulates the performance of a subsequent action.” [128]. In the macro world, the best studied case is the self-organization demonstrated by the building of termite mounds.
This type of process requires some minimal level of intentionality, but only insofar as the actions are appropriate to environmental conditions. However, there need not be any explicit goals. The only base requirement is that the participants in a stigmergic system are able to send and receive information as communication.
Importantly, in such systems, there is no need for planning or anticipation, memory, intentional communication, mutual awareness, simultaneous presence, imposed sequence or division of labor, or centralized control or supervision. Stigmergy illustrates a realistic means through which information is used towards self-organization. Although stigmergy assumes that any participating agents are individually goal directed, it is independent of the goal itself. So any living entity whose goal is to maintain self-identity by sustaining a preferred homeostatic boundary condition would satisfy that requirement. Since the individual participants can have independent goals in any mixed cellular ecology, there is a natural division of labor. The variety of these participants working together build complexity, in sequence or in parallel, based on this continuous stream of information from both within any niche or shared information field, such as a bacterial colony. Since the information that is available is both direct and indirect within any PIF, under conditions in which neither sender nor receiver is necessarily clear cut, conflicts are diminished as the participants mutually edge towards consensual outcomes by always striving to remain within their own limits. This can realistically be offered as the origin of the synergy through which all tissue ecologies evolve. The hallmark of self-organization is the emergence of global order from local actions [129]. Since this organization arises spontaneously from local activities, and there is no central plan or planner, or external control, there is no organized resistance in any one specific direction and there are no actual errors being made. Only actions that constitute a general drift towards consensual outcomes in continuous reaction to epiphenomena emerge. This can result in surprising outcomes and can be considered a creative means in terms of biological expression. Furthermore, increasing collaboration becomes an effect of collective stigmergy, as an emergent phenomenon based on individual self-awareness and the reciprocity that underscores the cooperative impulses inherent within biological systems.
There is an important difference between individual self-awareness and the collective self-awareness that emerges from a stigmergic PIF. In stigmergic systems, in which information is continuously deposited as traces in the environment, the processing of information extends beyond any individual participant and extends outward into the larger environmental PIF. An example is the stigmergic organization of bacteria termite mounds with cues that extend throughout the extracellular matrix [130]. Since the information does not lie within the individual itself, yet exists within its entire sphere, stigmergic interactions exemplify the advantage of considering biological development as based on information space and Pervasive Information Fields.
One singular advantage of considering cognition as foundational to evolutionary development is that the processes by which complexity can build in the cellular realm can be compared to the manner in which humans engineer within our own sphere [19,23]. Witzany considers such natural engineering type actions as a product of communication processes within and among cells that proceed along combinatorial, context, and content specific paths through rules that have some similarity to language-like text [131]. All organisms use signs by which they can distinguish self from non-self and exchange information. RNA-based regulatory networks interact in complex ways with patterns of gene expression that can be linked to epigenetic impacts, to such a degree that it can be asked whether “evolution has learnt to learn.” [132]. It is clear then that a path exists between the cognitive aspects of unicellular life that permits its reiteration in eukaryotic multicellular organisms. Ancient and fundamental links therefore extend backward to unicellular capacities so that problem-solving at the level of our own neural capacities derive from those same processes [46]. In that way, natural engineering processes can be seen as a continuum from the origin of life forward.
A number of models have been utilized to underscore the principle that individual cells and other life forms can engineer solutions to environmental stresses. Agnati et al. emphasize several basic principles that underscore any process of natural engineering [133]. This includes reiteration, self-consistency, and mosaic formulation by which reiterative patterns diverge to arrive at differing endpoints [133]. An additional such precept is termed the principle of Biological Attraction, an inherent drive for association based upon an “attractive” field. The effects of such a field are asserted to extend throughout biology to include interactions that are not typically considered in that manner, such as infectious interchanges [23].
Criticisms of natural engineering are generally focused on a lack of agreement as to the extent of the influence of the horizontal transmission of both genic and non-genetic materials [134]. However, heritable genetic transfers at the eukaryotic level are clearly demonstrated, including retroviral endogenizations of HIV [135], Koala retrovirus [136] or the transmission of heritable DNA from bacteria to eukaryotes [137]. Wang et al. have demonstrated that LTR class I endogenous retrovirus (ERV) retroelements, a distant relative of HIV, have considerably impacted the transcriptional network of human tumor suppressor protein p53, a master gene regulator crucial for primate differentiation [74]. These results demonstrate how retroelements can significantly shape the regulatory network of a transcription factor in a species-specific manner. In fact, the adaptive value of retrotransposon activation secondary to environmental stresses is frequent and contributes to the functional regulatory machinery of the cell [19] Furthermore, eukaryotic development is strongly dependent upon viral properties and impacts [131]. Such viral incorporations can be considered the long-term “domestication” of such elements and their subsequent conscription into holobionic function. Accordingly, Frank Ryan, the physician-author of Virolution [60], favors the term “symbionts” for such retroelements rather than parasites; his term implicitly acknowledges the often beneficial roles of retrotransposons.
The general reluctance to accept the primacy of natural cellular engineering might be attributable to a common assumption that honors selection as a near exclusive agency. Yet, no rejection of selection is needed. Instead, there is only a requirement to accede that there are limits to selection within a re-framed evolutionary narrative. Further, when cellular engineering is empowered as a mechanism through the agency of self-awareness as an implicit property of all living things, then evolutionary development can be viewed as the consensual enactment of cellular purposes directed towards maintaining fundamental self-referential awareness within delimiting boundaries. Retroelements then become tools, as the residual effect of infectious exchange as a form of information exchange, from which phenotypic competencies can then emerge [138]. It is known that at least half of our human genome is a legacy of past retroviral encounters, which has been termed “plague culling” by Ryan [139]. In fact, it is not merely culling as selection that matters for these infectious exchanges. They are better understood as part of a continuum of biological effects as the common currency of biological interchange on this planet. Depending on circumstances of amplitude, target, and extent, infectious interchange extends beyond the typical considerations of infectious illness to include diverse outcomes ranging from individual infection, epidemic infection, parasitism, symbiosis, mutualism or infectious latency. Occasionally, that same process yields heritable change that can then become an evolutionary event purposed towards future phenotypic alteration if the appropriate vector intersects a susceptible organism. The mechanism of all such manifestations is similar [20]. All these processes, both genic and not, become part of cellular means towards engineered solutions to environmental stresses in collaboration and competition with others. This includes the intracellular life cycle of the virome that permits the creation of new genetic paths to manipulate the environment and enact novel biological solutions according to universal self-awareness [140]. These biological combinations reverberate throughout complex genomes. By this mechanism, creative potential is fueled through the union of transposable elements and retroviral genetic sequences or LTRs with vertebrate genomes [141,142].
In such circumstances, natural selection becomes a post facto filtering agency of phenotypic differences and morphological novelties that emerge from very different impulses. Contrary to selection, hologenomic evolution considers the primary impulse of evolutionary development to be embedded information within PIFs to enable a natural and self-organizing form of cellular engineering to solve problems. Phenotype is its product. Through competitive and consensual cellular engineering processes, phenotype emerges as the reciprocating output of cellular ecologies as they reiteratively meet environmental stresses, in deep collaboration and competition with other cellular ecologies.
In any such assertions, epigenetic impacts are of salient importance. Over the last few decades, there has been a significant countering shift against the prior ingrained belief that all important genetic activity is random mutational variation within a generally static central genome [2]. This earlier viewpoint has yielded to our contemporary understanding of the larger scope of the epigenome [38,143,144,145] and its wide range of effects on genomic plasticity [146]. The functioning genetic complement of any multicellular organism is an ever-ongoing and dynamic interrelationship between any species innate cellular ecologies and an agitating epigenetic realm. A fuller extent of this epigenetic influence is now acknowledged throughout evolutionary development that fundamentally changes the epicenter of control of multicellular eukaryotic organisms beyond traditional Darwinian means [147,148]. All transgenerational genic and non-genetic heritable effects are information [149]. This is the feedstock of natural engineering processes, that then proceed by becoming a part of the Pervasive Information Field that constitutes all organisms.
6. Discussion
If it is considered that natural selection is not an exclusive driver of evolution, any simple assertion that evolutionary development is pluralistic suggests differences but does not represent sufficient progress. That consequential differential can be the recognition that cognition is both a point of origination as a permanent enabling mechanism and source of countervailing constraint. This standpoint is premised upon self-awareness as a state function as the conditional aspect of life on this planet. With this as its base, evolutionary development becomes the further elaboration and reiteration of self-referential cognition sustained against the stress of epiphenomena. Cognition with its own boundaries and limitations provides both release and imperative limits. Selection pertains but operates differently than typically assumed.
When cognition is the base, then the sustenance of any organism and its survival are information dependent. In the context of eukaryotic organisms, this is best conceived as a Pervasive Information Field (PIF) as the summation of the use of information to sustain self-awareness among the myriad constituents that constitute any holobiont. As opposed to our obvious material form, it is the primacy of information that matters in evolution. Information underscores self-recognition and maintains homeostasis at every scope and scale. Information space then collapses into biologic form to sustain self-referential status between necessary boundaries. Pervasive Information Fields are the systematic background through which the problem-solving matrix of eukaryotes is directed toward that goal. Derivatively then, the integrity of the information field must be deemed most consequential. It is a necessary requisite that the information field of any organism must be continuously re-centered and matched against a stream of epigenetic impacts. Without this, the information field becomes chaotic. Therefore, it can be assessed that this essential stability is achieved through the agency of the zygotic eukaryotic unicell and thereby provides the rationale for its obligatory recapitulation [150].
Within any Pervasive Information Field, the issue is not having too little information. Just as in our own lives, the disquieting reality is that most information is useless noise with respect to our own needs or purposes. In a world of pervasive information or “chatter”, in which most information is not necessarily directed towards any specific receiver, the self-organizational and cooperative impulse of stigmergic systems provides the practical mechanism for self-organizing activities within the mixed cellular ecologies that constitute all holobionts. In stigmergic systems, there need not be any directed coordination among individual players. It is sufficient that they have a means of identifying preference and act in conformity with its sustenance. Through the stigmergic feedback loop, indirect information that might be merely detritus from sender/receiver units ultimately becomes useful to one or more of the constituent players and can be utilized towards consensual outcomes without any necessity for correspondence with the intentionality of the sender.
In this manner, coordination emerges within tissue ecologies through both direct and indirect means among a wide assortment of constituencies. Most importantly, unless information is expressly directed and received, it becomes a primary form of biological ambiguity. The status of information is always uncertain and context dependent. Any sender/receiver unit must contend with that lack of clarity. Information that is directed may not necessarily be received. If received, it may never be understood. Even further, it is not necessary that any information that has been received and comprehended will necessarily yield a reaction. In that situation, ambiguity remains unless that information collapses into a response on the part of the receiver, at which point the chain of uncertainties is resolved in only one aspect and simply begins anew in another. Further too, what is noise to one entity may be actionable information to differing ones that intersect with the PIF and may not be any intended receiver. Therefore, the status of any receiver is almost always unclear with respect to the sender. As humans, musical notes as aural information are collapsed into musical appreciation in our own subjective manner. What may be noise to some is music to others. Therefore, the continuous collapse of the superimposition of possibilities is settled through a collective emergence of the resolution of those ambiguities.
Contingency is therefore contained within the variety and specializations of the individual constituents of the system, and is thereby dependent upon the flow of internal traces and external stimuli of epiphenomena. In such circumstances, stigmergy can be offered as a unifying mechanism between the quantum ambiguities in any information system and their collapse into biological expression as it reprises at every scope and scale. Physiology then becomes an enactment of self-awareness as repeatedly reinforced through multicellular stigmergic networks as a framework for maintaining both individual and collective “self” through protective homeostasis, reiteratively accomplished by the ready transfer of information.
Furthermore, it is clear that thermodynamic levels both within and outside of any cell are themselves forms of information. For example, thermal microscopy can be utilized to understand intracellular metabolism or disease incidence or the effectiveness of new cancer drugs [151]. Furthermore, the mechanical and structural properties of cells play a pivotal role in many cellular processes. While DNA may be resistant to heat, even small changes in physiological temperature compromise the mechanical integrity of the cell nucleus. Therefore, there is a reciprocal interplay between thermal cues and mechanical attributes of the cell. In this manner, physiology is properly understood as another form of information, and becomes then, part of any PIF. Physiological paths are thermodynamically efficient and lead to cellular self-organization through information transfer. At every scope and scale, self-organization becomes a directed means of protecting physiological homeostasis according to thermodynamically efficient pathways which include an entropic open system and energy dissipation [152]. Any such circumstance requires abundant information. Therefore, the ability to efficiently meet those compelling thermodynamic requirements is directly correlated to the use of that information and then manifests as the emergence of physiology from its unicellular roots [72]. As mixed cellular ecologies can be both properly defined as an informational agency and dependent upon the continuous flow of information, there is a concomitant impulse to extract an optimizing amount of energy (as the counterpart of information) within homeostatic limits from the surrounding ecosystem. In terms of cognition, this is enacted as the minimization of variable free energy [93]. Through reciprocal action, and within boundary constraints, phenotype as form and function emerge based upon cell-cell interactions [153], that is directed towards the minimization of variable free energy and the suppression of surprise (unpredictable outcomes).
When information is considered the backbone of any evolutionary frame, then information quality becomes paramount. It becomes clear then that the manner in which homeostasis is reiteratively maintained at every scope and scale requires the intercessory function of the eukaryotic unicellular zygote through which all multicellular eukaryotes recapitulate. Although not obvious, multicellularity need not have been any necessary evolutionary outcome. Intracellular engineering might have led to enormously large, efficient and capable single eukaryotic cells. Yet, that is not our known biologic outcome in the cellular realm even as it is evident in the virome. [154,155]. The question, therefore, arises as to the reason that evolution has not led to single large efficient eukaryotic cells as the dominant biologic players.
That answer lies within physiologic mechanisms based upon thermodynamic constraints that extend forward from unicellular roots. These processes are perpetually based on stable cellular principles of evolutionary development that include empowerment and constraint [84,150]. It is known that there is a crucial modulation of transgenerational epigenetic inheritance through the obligate intermediary of the zygote [156,157]. As a consequence, it can be asserted that the recapitulating zygotic unicell is the actual centrality of eukaryotic development as an enduring Pervasive Information Field that assesses current environmental epigenetic impacts within the constraints of any intrinsic genome. An essential aspect of this obligatory recapitulation occurs during meiosis as dynamic modification of transcriptional activity of sex chromosomes, histone modifications, and regulation of epigenetic programming and chromatin dynamics [158]. Epigenetic reprogramming in germ cells is critical and extends into early embryological development [159]. The variety of these mechanisms includes meiotic trans-sensing and meiotic silencing acting within their molecular role in protecting transgenerational genomic integrity. These mechanisms have not been fully elaborated but seem to be directed towards the prevention of the expression of rogue retroelements as novel epigenetic insertions [160]. Furthermore, those marks that are inconsistent with development and homeostasis are eliminated during morphogenesis through networks of epigenetic specificities [161]. Yet, it is also known that other epigenetic impacts continue and can affect phenotype and health [162]. Therefore, the concept of a static genome throughout the life of any organism can no longer be sustained. It is now known that there are Developmentally Regulated Genome Rearrangements (DRGRs) that alter genomes either in specific cells or during particular life cycle stages. Furthermore, these processes are widespread throughout eukaryotes [163,164]. It is, therefore, apparent that maintaining overall fidelity to a base genomic structure is necessary and this is increasingly understood as highly dynamic on both a genic and epigenetic basis [165]. As it is now accepted, dynamic genomes are the rule across the Tree of Life [166]. Nevertheless, genomic order and integrity must be still be assured, which then implicitly defaults into the unicellular eukaryote zygotic phase as the necessary intercessory agency of the self-referential unicell directed towards the resolution of quantum ambiguities against epigenetic stresses. As a derivative then, it can be asserted that selection is no longer random since there is a reciprocating interaction between constituents of the environment in a highly integrated and iterative process that prevails in evolutionary terms.
The conspicuous role of obligatory rechanneling through the eukaryotic unicellular state relates directly to the unicell as an adjudicating moment governing replication errors and the epigenome. Asano et al. suggest that the unicell conforms to a quantum-like master equation governing the information state of the cell [10]. In any information network, noise must be regulated to avoid chaos. Therefore, the expression or down-regulation of epigenetic marks either through meiosis, the zygotic unicell, or subsequent embryological development is the biological resolution of the quantum superimposition of possibilities stirred by ambiguous epiphenomena. Within this framework, the eukaryotic macro phase becomes something different from that which has been previously supposed. Its explicit purpose is directed towards the acquisition of epigenetic experiences that will then be placed in the context of the perpetuation and sustenance of a perpetual eukaryotic unicellular form. When considered in this manner, eukaryotic reproduction becomes the reconstitution of that eukaryotic unicellular form which has a new and potentially more flexible full range of implicates and explicates in juxtaposition to the outward environment consequent to its prior macro-organic excursion. In essence, evolution proceeds from zygote to zygote [150]. In this manner, space and time for the unicell are different from our conventional view of biological space-time. The unicell is gaining information about the external environment through a transient elaborating context within its macro form, but utilizing it according to the proscriptions of its own “self”, to which it has permanent adherency that extends over geologic time.
The eukaryotic unicell expresses only a portion of the heritable transmissions that it has received into its next macro elaboration. In so doing, it is storing information from its past. Crucially, this can become its future based upon further information that exists in biological form as the latent compaction of the superimposition of biological possibilities as opposed to those epiphenomena that may never be collapsed into biological expression. In this way, the zygotic unicell achieves a unique status as both observer and participant that privileges it to collapse the superimposition of latent states into those that are best equipped to sustain its homeostatic “self” over very long-term environmental cycles. Any re-elaborated macro form is therefore equipped to deal in flexible terms with widely shifting though temporary environments. By this means, the unicell escapes any rigid or traditional view of biologic space-time through the entanglement of pervasive information systems that are both its own but also part of the outward environment with which it has contact through both direct communication and non-local correlation. This intersection of both inner and outer information spaces is reiterated in the macro form and explains a wide range of biological actions. For example, the avian magnetic sense organ used to detect magnetic fields operates on a quantum basis via entanglement with molecules acting simultaneously at a distance. The final state of one molecular action of that type is determined after the fact by a subsequent one without apparent connection [96]. Monarch butterflies and fruit flies use similar quantum effects in navigation, and plants are dependent on quantum processes for photosynthesis. Instantaneous muscle coordination over a scale of distances over nine orders of magnitude by the coordinated splitting and release of 1020 molecules of ATP in all animals is another example of non-local correlation in biologic form [12].
This entanglement principle is further exemplified through overlapping information fields in the context of complex interrelationships between the unicellular zygotic phase, the post-zygotic embryonic development, and the macro form. Recent research has elucidated both the importance of the unicellular phase in the frog embryo (Xenopus tropicalis) and overarching maternal control of frog embryonic transcription [167]. That overlapping control network is depicted through epigenome reference maps within the unicellular zygote that are partially formed by the maternally defined epigenetic regulatory space, instilled within islands of hypomethylation enacted by deliverable proteins and maternal RNA that are part of maternal cytoplasm. This maternal overlap predominantly controls gene regulation in the frog embryo through the first twelve divisions but its influence also extends into the later regulatory space. A similar process is present in mammalian embryos, though the exact timing patterns differ. In all instances, however, information undergirds development. Therefore, information space is a property of the state function of self-awareness implicit to all living things and exists as a crucial entanglement between variational free energy as self-organization derivative of thermodynamics that eventually resolves into biological form.
In like manner, the concepts of information space are essential to understanding embryonic development. Kirschner and Gerhart detail embryonic spatial mapping and developmental compartmentalization as keys to regulatory control [168]. Since there are no simple anatomic boundaries, biological expression results from highly coordinated communication among linked developmental compartments in a system that is best understood as consisting of overlapping transient developmental environments. Further yet, such communication could only exist within the context of an overarching information field that controls the timing of that development. The obligatory recapitulation of the eukaryotic unicell is therefore a crucial centering of that essential PIF to regulate the expression or down regulation of epiphenomena accumulated during the prior macro elaboration. Absent such a mechanism over successive generations, there would be heritable chaos. There would be a similar potential for damage within any intrinsic genome if there was no superbly efficient mechanism for faithful DNA replication and the policing of replication errors. It can, therefore, be asserted that there is an information field, continually centered and adjusted, that permits the elaboration of the linked compartments that are both contiguous and distant that enables embryological development.
Under these circumstances, the connection of the macro form to its re-elaboration is changed. The macro form, as its own PIF with its exclusive environmental experiences and acquisitions, is a contributory essential to the unicellular zygote. However, its next macro-organic elaboration is altered through the adjudication of the self-referential zygotic phase whose residual influences redound throughout the embryological arc and beyond. As a corollary then, the concept that evolution relates to simple gene frequencies can no longer be sustained. The obstacles to this assumption are now many, not the least of which is that our entire concept of the composition of a gene as an anatomically discrete zone of DNA has been completely reappraised since the formulation of the Modern Synthesis [169]. Furthermore, epigenetics is entirely centered upon a discordance between simple gene frequency and further genetic expression in biologically active systems. Nor does any simple notion of gene frequency realistically incorporate holobionts into its purview as evolutionary entities in which microbial genetic material is at least 100 times greater than the innate genetic information of any macro form [170]. Nor does it incorporate any theory of complex limiting behavior of multi-locus genetic systems as that relates to the interactions of ecosystems or constituencies within ecosystems [45]. Therefore, it can be maintained that the differing contributions of genic and non-genetic inheritance impose a necessary fresh conceptual framework that is not merely related to raw genetic frequencies, or even to genes alone. The alternative requirement requires an understanding of the flow of energy as information in biologically active materials harnessed and constrained into a consistent and inclusive framework [171]. As such then, genes can be understood as not merely “units of inheritance” but as an emergent expression of information space reciprocally dependent upon cellular processes and dependent upon information inherent in bioactive molecules and extrinsic epiphenomena [172]. In such circumstances, everything depends on everything else, and phenotypes then become emergent properties of a larger overarching biologic information system that is inclusive of heritable proteins, lipids, and cytoplasm and largely extends beyond nuclear DNA [173]. Therefore, when energy and information are considered as differing aspects of an entangled equivalency, then any PIF is thereby inter-related with any bioactive energetic field with which it has contact, in a construct that might be considered an enhanced Markov blanket as interconnected nodes of diverse parentage, connected to the network but still retaining conditional independence. In this manner, the nodes in any specific PIF retains some aspects of conditional individual intentionality in reaction to stress, while remaining within other overarching fields. In hologenomic organisms, energetic processes such as heat dissipation minimize variable free energy and propel self-organization which can then be understood within a context of entanglement between information, energy and biologic substrates. An explicit example is the propagation of neural activity by endogenous electric fields [174].
It can then be maintained that within pervasive information systems based upon self-referential cognition, genes serve to maintain the information system and then, in turn, are also reciprocally being served. Any explanation of biological evolution in terms of gene frequency refers to outcomes rather coherent process when cooperative mechanisms, collaborations, and reciprocity have sway [175]. Therefore, it can be asserted that it is not merely genomic integrity that is re-centered through the recapitulating unicell, but more accurately, an overarching Pervasive Information Field that enables every organism. It is during this phase that those permissive and involuntary modifications acquired during the re-elaborating macro phase are readjusted towards the longer-term moving average of the dominant environment trend. Absent such a process, any genome, all cell processes and the information fields that control them, would become increasingly chaotic. The easily overlooked implication of our contemporary understanding of the large extent of the epigenetic influences experienced in every phase of our life trajectory is that a re-centering mechanism towards a longer term environmental average is essential. Absent this, organisms fatally skew towards temporary aberrations.
A crucial question then applies. Can the concept of a Pervasive Information Field substitute within biology for actual physical form? Certainly, such an overarching field exists since its activity is clearly apparent in the developmental stages emanating from the delimited form of the unicellular zygote. As an example, the embryological spatial map has no anatomic correlation with subsequent form [168]. It is clear then that information content has primacy over form throughout the recapitulating reproductive cycle and its immediate postzygotic development. Therefore, it requires only a little imagination to consider a dominant PIF that is its own specific form of sender/receiver space-time whose existence is implicit as an overarching archetypical entity entraining energy. In such an instance then, any physical organism becomes a manifestation of biologic expression as a transient flux agent of a particularized information field. In essence, all multicellular eukaryotic organisms become transient informational subsets of a larger dominant eukaryotic PIF. Each extends outward into the environment and intersects with other information sets as a reciprocating constituent of the larger environment.
Within this model, fitness is a transient enforcement of one of the superimposed possibilities of any PIF, as part of a subset of the full spectrum of a dominant eukaryotic PIF. This bandwidth subset then gets briefly expressed as phenotypic form. Natural selection is a tautology since its action is a post facto concentration on phenotype that is a derivative expression of a larger encompassing overlapping Pervasive Information Field. Any macro form is merely a temporary fraction. Therefore, at any moment in time, current biologic form is the settling of the superimposition of possibilities from a larger dominant unicellular eukaryotic information set as a temporary manifestation of a narrow range of specific informational subsets. Therefore, whatever set is not currently expressed or has been eliminated is by definition, “fit”.
Therefore, it can be asserted that there is a dominant Eukaryotic Pervasive Information Field inherent to that fundamental cellular form as opposed to that of Bacteria or Archaea, and further, that is not a direct object of selection. It exists above our ordinary understanding of selection. However, any PIF subset expressed as a eukaryotic macroorganism is acted upon by selection. Therefore, selection is an agency of temporary bandwidth flux of a larger information set that is perpetual as a Eukaryotic life form. Selection becomes the temporary settling of a range of implicates within the PIF of that master Eukaryotic cellular domain as an information subset of latent potentials resolved into biological explicates.
Therefore, reproduction is more than a means towards reiterative phenotypic expression. Sexual reproduction is the best means of re-centering any PIF through meiotic averaging. Eukaryotic multicellular organisms are a representation of a bandwidth of an overarching PIF as a derivative thermodynamic entity and information subset. Therefore, any organism as a material entity is the physical embodiment of a unique PIF subset that must stay centered within a long-term environmental trend even as it flexibly deals with shorter term and transient environmental circumstances. It can be suggested that any transient macro elaboration is a necessary and limited environmental taste akin to the difference between daily weather and long-term climate trends. That longer term consistency channels through the self-referential agency of the zygote unicell and its own PIF subset.
In any system of nested ecologies that are constitute holobionic organisms, it is plain that order must be maintained. In biologically active terms, this is an immunological expression [23]. Undeniably then, the only means by which holobionts can exist as an explicit reality is through an active immunological compact. Further, the core purpose of immunology is self-recognition against “other”. Therefore, cognition as a condition of life is dependent from its inception upon immunological means to maintain “self” within an active biological frame that must continue in a reiterative manner throughout evolutionary development. Indeed, this is obvious. Without effective immunologic mechanisms, there would be only a single biologic organism undifferentiated from any others. Yet, the impact of immunology on the entirety of any evolutionary narrative and the centrality of holobionts as multigenomic consortia governed by immunological imperatives has only just been recognized [3,23].
7. What Does This Mean for the Modern Synthesis
In 2010, Lewontin noted that the standard formulation of evolution by natural selection does not explain the actual forms of life that have evolved and further contended that there is an immense amount of biology that is missing from Neodarwinism [176]. Any proposed justifications must, therefore, grapple with the central dogmas of the Modern Synthesis and provoke essential questions. Is evolution primarily a narrative of natural selection? Does it proceed according to strict gene frequencies? Is it a merely random process? Does Crick’s Central Dogma asserting a unilateral direction of the flow of biological information from DNA to RNA apply? Any worthy answer must concede that any facile assertion of exact opposites is also inappropriate. As with all complex and well-calculated concepts, the inherent depth of their profundity is that simple contradictions are not themselves necessary absolutes. Therefore, any oppositions are not unyielding negations but are instead directed towards a fuller understanding of evolutionary development within a complex schema.
For some, the search for satisfactory answers has been to recast dogma into a more flexible form. Müller suggests that evo-devo is “a causal mechanistic approach towards the understanding of phenotypic change in evolution” [177] and is no longer just about gene frequencies. Yet, that frame is still deeply selection dependent, even as it denies that genes work in a linear fashion and are subject to extensive feedback from many associated players within developmental constructs. Mattick emphasizes the importance of intergenerational epigenetic inheritance and a prominent role for RNA regulation of the epigenetic state [132]. He conclusively dismisses Biology’s Second Law, known as the Weismann barrier. Somatic cells and germ cells are not exclusive from one another. Further then, since RNA editing can alter genetic code in a context dependent manner as an epiphenomenon, then phenotype becomes that dynamic product. Therefore, any long-held belief about the absolute centrality of DNA must be set aside.
The concept of “facilitated variation” has been proposed as one solution to the problem of developmental pleiotropy [168]. In that perspective, core processes remain intact but the regulatory components determine the extent of variation, which is still based upon random mutations and subject to standard selection mechanisms. Since only the regulatory side experiences that variation, theoretically then, only a few mutations in that space would be needed to generate novelty. In effect, the number of unlikely steps is theoretically reduced. Somehow, organisms are considered “poised response systems” ready to make changes that they are “prepared to make”. Still, however, within facilitated variation, those changes are not still directed or enumerated beyond selection and random variation.
The Predictive Adaptive Response hypothesis has been offered as a differing alternative [178]. This is a form of developmental plasticity in which early life environmental experiences can influence fitness later in life, and could theoretically induce fixation of epigenetic markers. This is a more pluralistic form of Neodarwinism, still centered on selection and limited in scope as an explanation of developmental novelty. Yet, its base assumption importantly construes that organisms have the capacity to anticipate future fluctuating environmental conditions and act upon that forecast. In Predictive Adaptive Response, the delay between the incursion of epigenetic impacts and the induction of phenotype is a form of “forecast about the future conditions of the external world.” [178]. Hologenomic evolution also asserts a predictive capacity but offers a differing interpretation. In cellular terms, predictive power is offered through the agency of the recapitulated zygotic unicellular form that permits the adjudication of epigenetic markers to meet long-term environmental stresses as opposed to transient ones. In this circumstance, the “forecast” is a prediction of the future environment only insofar as it recognizes that there is a dominant longer term environmental trend that will ultimately reassert itself compared to transient environmental extremes. The predictive capacity of the unicell can, therefore, be understood as its ability to match the shorter term environmental exigencies into the context of the more consequential and enduring longer term trends. In that sense, the zygotic unicell contains information from both the past and future. The latter remains in latent form within the PIF of the unicell and is then used to discern the activation of epigenetic marks or the down-regulation of others.
In a review of the integration of evolutionary biology and physiology, Noble et al. provides an overview of the burgeoning extensions to the Modern Synthesis [179]. In particular, the role of epigenetic horizontal transmission is now viewed as displacing the absolute primacy of vertical descent. Further, the traditional congruence between genotype and phenotype implicit within the Modern Synthesis is no longer regarded as tenable against a broader understanding of heredity in which concepts such symbiogenesis and natural genetic engineering are now offered as consequential adjustments.
Each of these constructs nudges evolution in more contemporary directions in which a gene-centered and selection dependent formalization of the Modern Synthesis must yield. What might be considered instead? Shapiro clearly outlines one essential difference [180]. Certainly, the flow of genetic information is not exclusively from DNA outward, thereby vitiating Crick’s Central Dogma. Additionally, the concept of the gene as a discretely localized region of DNA code is inaccurate. Further yet, any specific “lock and key” mechanism between molecules and biological interactions must be reappraised in light of the flexibility of molecular subdomains [19]. It is also becoming apparent that genetic mutations do not account for genomic change compared to other processes such as natural genomic engineering. But even this is not a sufficient. The cell should not be viewed in purely mechanistic terms [181]. Instead, the entire cell must be regarded as an informational system in which decision-making is its central function. An important aspect of this reconsideration is that intracellular decision-making processes or decisions among cells are resolutions of biological ambiguities sustained from environmental stresses in furtherance of critical homeostatic balance. Information transfer is the backbone of cellular processes and takes forms that have not been typically considered as such. For example, horizontal gene transfer is commonplace and not restricted solely to prokaryotes as assumed under the prior dogma of separation. Examples of transfers from prokaryotes to eukaryotes, such as the horizontal transfer of terminal proteins between prokaryotes and the eukaryotic nucleus are documented [182], as well as the horizontal transfer of genetic material across species boundaries as a form of niche construction [183]. Therefore, as a necessary correlate, the underlying rules governing information transfer between cells is dependent upon immune status represented through major signaling molecules as part of the information system that governs all aspects of cellular well-being [184,185].
Once it is understood that information fields rather than phenotype underlie evolutionary development, it follows that the biological rules in the unicellular and viral realms do necessarily apply to the eukaryotic one. The fundamental information spaces are perpetual. It is therefore not surprising that developmental strictures are based upon the disciplining agency of obligatory recapitulation through the eukaryotic unicellular form and the consistent imposition of overarching immunological rules that also recenter within that unicellular phase. From this, it follows that despite macro appearances, our planet has remained firmly anchored in cellular life across eons and remains so even now [71,72,150]. Examples include ribosomal translation [110] or the glucocorticoid receptor protein whose ancestral form permits modern conformational flexibility [186]. Therefore, the past perpetually recapitulates through the unicellular form, whose forecast of the future is its knowledge of the past in geological space-time. Within this greater narrative, genes serve, and then as constituents with their own biologic “selves”, are in turn being served. In consequence, it becomes apparent that there is a suppleness to evolution that eludes any mere conformity to a narrative based upon selection as an effective exclusive agency.
In an evolutionary system predicated on information exchange derived from energy transfers, selection is a byproduct of that information system, not its driver. Placing information at the center of biology is not unique [88], nor is considering communication as universal to life and or as a directed means towards problem solving [83]. However, placing it within the context of an overarching awareness of preferential status as a derivative of homeostatic imperatives represents a significant differing perspective [23]. Differing too is an appreciation that biologic form is preceded by information space, derivative of energy transfers, as its own matrix both intrinsic to and still distinguishable from any material biologic entity.
Also separate from prior theory is the assertion that information space and any resultant self-awareness are intrinsic properties of a system in which ambiguities are consistently resolved by consensual and collaborative holobionic players as the proper end point of eukaryotic development. Implicit in this differing viewpoint is the acknowledgment of macro-organic structures as a unique adherency of confederated life united through information space. This extends beyond presuming that microbial life is merely affixed to a host scaffold but is instead predicated upon a framework of such organisms as intimate and profound seamless interconnections of cellular and non-cellular constituencies. Therefore, any microbial eukaryotic cohort is not simply appended as a scaffold. Instead, all participants are part of a complex, transient, and dynamic life form arc. It is our instinct to appraise the differences between microbe and innate cells of any eukaryote and dismiss the requisite dependencies. In a reiterating manner, eukaryotic evolutionary development becomes a comprehensive whole. Its common currency is the flow of information as communication towards the preservation of self, that is reciprocally then in service to all cohabiting living entities in eukaryotic cellular confederacies. Our biological interactions on this planet are all directed towards those mutual non-exclusive aims.
The dynamic patterns through which these biologic principles are entwined are well known though typically casually misunderstood as merely infectious interchanges or dispassionately denoted as “horizontal genetic transfers”. Instead, the broad range of infectious interactions, encompassing individual infection, epidemics, parasitism, mutualism, symbiosis, latency and evolutionary genetic interchange are means by which self aware biological entities communicate, collaborate and compete. All biologic manifestations then become derivative of a singular overarching principle of information transfer directed towards the maintenance of self-referential preference [23]. Within this necessary linkage, it is also clear that the rules are always immunological. Such a declaration is actually self-evident. Successful reproduction depends upon self-similar recognition through immunological compatibility as opposed to dissimilitude. Reproduction, upon which natural selection depends, is absolutely under girded by immunological phenomena [23]. Clearly, in any modern context, immunological factors determine reproductive success more than access to mates or any other macroscopic metric. Therefore, immunological distinctions, rather than traditional measures of fitness, define the operating characteristics of our biologic system. Of course, immunology is also simply a variant expression of a larger organismal information system. Natural selection certainly pertains, but only as a reproductive post facto filter. Therefore, selection is a derivative function of the immunological enforcement of self-awareness as the essential property of an information system in which immunological action is itself simply another form of information and communication. Further too, it is indisputable that immunological recognition is itself a differing aspect of cognition that guides cellular decision-making within any information matrix [187].
There is another differing feature of any information matrix that impacts evolutionary development as a problem-solving mechanism. All creative cellular inter-reactions are purposed towards the resolution of biological ambiguities. However, the context in which this can occur is one of biological relativity in which neither causation nor observer status is fixed. Within such a system, control is iterative and disseminated, enacted layer upon layer. Consequently, decisions are enlivened across linked networking constituencies to reach consensual solutions to environmental stresses. This is the process by which separable living entities become holobionts. Therefore, in hologenomic evolution, causation and observer status simultaneously exist at multiple levels in a manner that confounds any simplistic Darwinian narrative. The proper frame is then clarified, a perpetual sphere of Bohmian implicate and explicates [188] pre-testables both expunged and renewed, always in transit towards its further self, ever arriving, never leaving, overlapping transient losses and gains, constructions and deconvolutions, but always a perpetual cellular/viral realm of self aware entities in service to self and eukaryotic wholes. Within this construct, it would be mistaken to assume that all information is useful as opposed to noise. And further, it would be equally incorrect to assume that all information is welcome. Indeed, many infectious interchanges are explicitly the latter unwelcome information that returns to the eukaryotic unicell among survivors and then becomes a critical aspect of the recapitulating information field.
What then is the creative aspect of evolution within that frame? Biology uses its own tools in the selfsame manner that we, as humans demonstrate within our own frame: collaboration, co-dependency, and competition are directed towards solving ongoing stresses in a continuous stream of enacted preference. This is our own human narrative, just as we construct cities, resolved at the cellular level [19,23]. Necessarily then, our human use of both inorganic and organic materials is our particular biological manifestation of cellular impulses brought forward from eukaryotic unicellular origins and then expressed within our boundaries. Plainly, we, as humans, are cellular, creative and cognitive entities, derived from and faithful to our evolutionary roots.
Might all this be random? When that answer is properly framed, it becomes quite clear. Any system in which creativity is a means towards environmental problem solving is primarily non-stochastic. However, it is not that random inputs are of no consequence. Crucially, though, in the context of the intimate and shared connections of any holobiont, random inputs are channeled towards problem-solving. Therefore, random epiphenomena can be utilized in some cases or resisted in other circumstances at many levels and then, most particularly, at the level of the adaptive immune system. Yet, other epigenetic incursions cannot be resisted and demand a place. They must, therefore, be accommodated and then may become yet another addition to a capacious eukaryotic genome and adjust its particular PIF. By this process, and at each moment, the range of implicates consequent to any variety of epigenetic incursions as experienced by any multicellular entity is directed beyond random towards resolving present and future cellular biological ambiguities in the face of environmental stresses. When that process settles into any explicate form, natural selection then has its sway.
Any dispute about the relative importance between Lamarckian forms of horizontal acquisition of heritable information as opposed to vertical descent considered primary within Darwinism is also then re-framed in this new construct. Each serves and differs, but both are purposed towards cellular needs and imperatives. Most particularly, though, the central action of evolution is no longer invested in the macro form but instead remains constituted within the cellular one. The eukaryotic life form remains anchored within its cellular origination as an iterative form in which it transiently seeks information from the outward environment and then returns it to the unicell. In that manner, terminal addition becomes non-stochastic and a form of cellular creativity. Phenotype emerges through this narrative.
Newman and Müller have defended that major evolutionary developments such as the origin of the vertebrate limb emerge through a “bauplan” based on an interplay of genetic and epigenetic processes that should be considered as self-organizing properties [189]. If this perception is endorsed, then a further aspect can be advanced. That “bauplan” is the Pervasive Information Field that defines any form of life. In the eukaryotic life form, that PIF “bauplan” is perpetually adjudicated through the obligatory unicellular zygote as it spills through the embryological compartment map and undergoes sequential developmental reiteration. As Newman and Müller note, selection has its part but does so secondary to other originating processes by adjusting and stabilizing forms. Selection then, according to Newman, is not needed so much as thermodynamics and self-organization. In the hologenome, cognitive constituents make decisions between implicates and explicates, according to their homeostatic needs as a further reflection of their self-referential state. In so doing, new homeostatic boundary conditions are set, at their limits, that become the thresholds of creativity. Evolution then flows from bounded sets of implicates based upon internal cellular dynamics and epiphenomena into explicates as biologic expression. Evolutionary development elaborates and reiterates from that in the continuous process of sustaining cognitive self-awareness against the stresses of epiphenomena of all types. As De Loof [84] has stated, it is problem-solving activity that precedes selection. However, crucial to any such problem solving is the information field that permits communication that can be directed towards resolutions. This is the means by which interactions are enforced between agents that have traditionally thought to be uncoupled [125].
With the foregoing as a central perspective, a fresh synthesis can be discerned that is distinguished from the biological materialism of natural selection theory and must be directed towards quantum concepts. Such a thorough reconsideration can be regarded as a cognitive entanglement theory. If there is to be any acceptance of this contention, there is only a single requisite. There must be an acknowledgment of an inherent entanglement between physics and biological entities through the thermodynamic state function of self-awareness. In a manner yet to be determined, energy acquires the faculty of information by which it senses both its direction and its preferred state within a given set of boundaries. In its most basic terms, this is a vectorial function, that is not dissimilar to Feynman’s Path Integral Formulism of Quantum Field Theory as indicated in his conceptualization of time as a vectorial sum of histories [190,191]. In this construct, any particle (or entity) can travel between points along an infinite number of paths, all of which has a certain probability that can be described as a wave function. As these wave functions spread through space, they can cohere or interfere with each other, and the sum of all the resultant amplitudes results in the final discrete path that it eventually follows [192]. If a similar line of inferential reasoning is used in biological terms, biologic space-time represents overlapping information fields. It thereby proceeds through quantum entanglement with other energetic vectors, each a sum of its histories as implicates and explicates. It is through this entanglement that self is derived and then, ever and always, continues to define the biological interactions between the self-referential entities that are then, by definition, alive.
It has certainly been skillfully maintained by others that biological processes can only be understood within a quantum frame. Ho has emphasized that thermodynamics in biologic terms fundamentally differs from the linear thermodynamics of Boltzmann [193]. In those terms, it is not dependent upon the acknowledged genetic or biochemical processes, but rather upon quantum coherent fields through which biological action coordinates. Life has been pictured in that frame as a far-from-equilibrium coherent photon field in a range of frequencies. The differing components of the organism, each with their unique characteristics, nevertheless synchronize together through quantum coherent fields. McFadden too emphasizes quantum effects through decoherence and the ability of cells to measure their quantum status [192]. In information space, these quantum thermodynamic field considerations unite into a faculty of quantum assessment of energy through a phase transition whereby energy becomes information by knowing its direction and status instantiating self-awareness as a condition of life. There are, however, substantial inherent differences between the means by which information systems in living things can be compared to theoretical models. Shannon information systems presuppose random variables as they pertain to the source of information independent of the object; Kolmogorov Complexity (algorithmic information theory) maps objects through sequence length seeking to determine the shortest sequence that transmits the information and then comes to a halt [194]. The limitations of theory can be readily appreciated in biological circumstances since information may not be random nor is there any necessity for information to follow either the shortest path or proceed by the most efficient means. Yet, a framework of Shannon information is still important: information is understood as inversely related to ambiguities and the extent to which they are resolved. This fits extremely well into any concept of an informational field as a probabilistic subset in which some aspects settle into biologic form and others do not. Further too, both theoretical models attend to mutual information processing providing for shared information; one object offers information about another, whether random variables in Shannon theory or sequence information in algorithmic theory. However, there is an important implication of both models with respect to that sharing and transfer; reciprocation is its implicit derivative. As Grunwald and Vitányi assert about information systems, “In an appropriate setting, the former notion [one object offering information about another] can be shown to be the expectation of the latter notion.” [194].
That such quantum processes underscore human cognition has been advanced as essential [195]. The advantage of this frame is that these processes are being actively researched both within neuroscience and physics [75,196,197]. Therefore, a full range of experimentation and research can be devised, yielding the predictability to evolution that others, such as Morris have sought [198]. It is only in this manner that any open-ended and indeterminate process such as Neodarwinism is subject to testing and refutation.
When entanglement as information sharing is considered as the base circumstance, niche construction can be better understood as its reiteration at every scope and scale in which the traditional concepts of proximate versus ultimate causation might be forsworn [199]. Although niche construction is traditionally considered as the expression of genetic and acquired semantic information, it is also seen as a process through which organisms discriminate and adjudicate environmental stresses [200]. It is a clear imperative of niche constructions that organisms must modify environmental states in a systematic and directional way. The critical point is that niche construction endorses organism–environment complementarity and not simply the Darwinian selection of genes. Niche construction is specifically a concept of the entanglement of living entities with each other in reciprocation with environmental impacts. It is through this responsive interaction that directionality derives [1]. In this manner, niche construction theory in its varied forms is the bioactive representation of cognitive entanglement theory.
It is certainly understood that our perceptions of the external environment or the internal environment are not absolute. Our structure is that of entangled constituencies, with complex internal and external surfaces as part of our organic makeup. Indeed, within any frame of entanglement within the complexity of holobionts, the concept of causation itself becomes entirely artificial and any divide between proximate and ultimate causation must yield. As Noble asserts, there is no privileged level of causation and the concepts of proximate-ultimate are best understood as metaphors [201]. The macro form is a linked confederacy. Cause and effect are disseminated among cognitive players both in direct and intimate contact but also through non-local correlation though separated by distance. Yet all are still in contact through a system-wide flow of information. In these terms, genomes do not exclusively determine any organism but participate as entangled ensemble players among others in which the Pervasive Information System is the overarching conductor. It is not genes alone, nor any “milieu intérieur”, or the environment as exclusive agents, but an entangled interplay, based upon individualized self at all levels executed through immunological rules within a world whose only consistency is ambiguity.
Therefore, hologenomic evolution is not merely another terminal addition to Darwinism. Nor is it an antipode. It is both differing and complementary, describing the limitations of natural selection, but acknowledging that selection influences reproduction and population frequencies. It accepts that variation underscores our evolutionary narrative but insists that its mechanisms and means are beyond random circumstance. It originates from its own platform of self-awareness as a condition of life, but also embraces replication as a reiteration of self while noting an entailing necessity; self-awareness as an intrinsic property must precede it. There is room then within contemporary evolutionary biology for creativity and determinism. Not towards any explicit outward endpoint, only toward the continual perpetuation of primal unicellular forms. The discomfiting issue is plain. To what can we ascribe the perpetuating success of the eukaryotic form? Random or not? A creative response to environmental exigencies or not? On a theoretical basis, this is the entire crux. If we absolutely knew the answer to those two questions, then the rest is detail. Cognitive-based hologenomic evolution suggests its answer. There are non-stochastic forces that can be identified in evolutionary development. Therefore, even though random actions remain crucial, the system is then, by definition, no longer random. That reason can be directly ascribed. Eukaryotic evolution is determined by cognitive eukaryotic cells responding according to their scope and scale to environmental stresses. Their reiterative cooperative and reciprocating reaction at separable, yet interlinked scales is our macro-evolutionary narrative.
8. Conclusions
Since cognition is everywhere apparent among biologic organisms, then any biological system must be built upon it. Any organism as a thermodynamic dissipative entity becomes an information transfer mechanism that resolves into physical expression by minimizing its variable free energy based on the settling of ambiguities according to quantum proscriptions [96]. The center of all such activity is information transfer, enacted through biological organisms as communication among self-aware participants. Evolution can then be properly defined as an information transfer system and can no longer be represented as primarily related to either material biological form as phenotype or natural selection acting upon it.
The line of reasoning that extends to this conclusion is quite direct. Energy comes first. Information is its derivative as a specialized form of energy in context. Physical form then follows. Necessarily then, physical space is subordinate to information space. DNA, RNA and all the various transcription factors and bioactive molecules are intermediaries of information storage and transfer, just as macro-organisms are acknowledged forms of energy storage and transfer. Since the epicenter of communication as information transfer is ever and always enacted at a cellular level, cellular imperatives become the primary driver exerted towards the maintenance of self in homeostatic concert with the environment. Any information set that produces self-awareness is a unique Pervasive Information Field. From that moment of delimiting instantiation as a circumscribed set, any PIF then becomes the sum of the histories of that field and also the summation of its latent potentials to meet environmental stresses.
It has been recently demonstrated that the history of a photon is not one of fixed chronologies but is instead its simultaneous multiple chronologies that are all intertwined as if all had been experienced [202]. In biological terms, the zygotic unicell is the sum of its chronologies that always represents more than its current physical form. It is ever the summation of latent markers that might have permitted the probabilistic settling of alternative actualities. All can exist coincidentally within the zygotic unicell in near equal terms, some expressed and others not. Some of these implicates are in fact prior histories that had yielded prior phenotypic manifestations. They were transient biological actualities as specific phenotypic forms but are no longer so. In the unicell, their equality is that they are each simply differing quantum paths and alternative resolutions within a field set that represents the summation of all those possibilities and thereby simultaneously includes its past and its future. Crucially, physical form as any might apprehend it with our own senses is subordinate to that information space as the sum of both the light and shadow of every living thing.
In the circumstances of the hologenome, the entanglement is more complicated. Each of the constituents that form a holobiont has some degree of independence. Each has its own Pervasive Information Field and is, therefore, its own unique sum of histories replete with its own individual latencies and actualities. This is precisely the type of entanglement that can yield biological creativity. Potentials and actuals entwine in problem-solving through creative solutions to meet exogenous and endogenous environmental stresses. The sum of all histories is within each and can be rendered from thermodynamic principles into active biological expression or latency, both of which are well represented in biological systems. Latent markers remain as unexpressed potentials that might blossom only when specific triggers and criticalities eventuate. In iterations then, holobionts are enacted as linked cellular ecologies whose constituents are themselves self-aware participants with their own intrinsic PIFs. The maintenance of the perpetual and superimposed eukaryotic PIFs supports these macro entities through the assurance of the continual re-centering of the basal integrity of a dominant Eukaryotic PIF through an obligatory unicellular form. Indirectly then, genomic integrity is maintained versus the outward environment. Importantly too, the holobionic nature of all multicellular eukaryotes and its vast interlocking relationships with the microbial sphere are governed by immunological interactions upon which self-recognition and the integrity of biological information depend.
Therefore, eukaryotic evolutionary development is properly considered a self-referential creative process in opposition to the persistent onslaught of epiphenomena. It is expressed in terms of communication, collaboration, and cooperation, just as well as competition. In hologenomic entanglement, it is not natural selection at the macro whole as our senses contend that is the controlling agency of evolution but a differing impulse: preservation of self-referential information fields at every scope and scale, as mediated by states of homeostatic preference. Reproductive frequency still pertains but is only one aspect.
Morris emphasizes that evolution tends to converge towards similar forms and structures, despite differing points of origin and even using differing biological substrates due to adaptive constraints [203]. Any such channeling is best understood when those limitations are imposed upon information fields and their subsets that exist within their own countervailing restraints. This enables the unification of quantum concepts with emergence and convergence into a single comprehensive whole. Order in biological terms is spontaneous, but only in the sense that it derives from an instantiation of a property of self-awareness that is a part of the thermodynamic scale according to a harmonic that is not comprehensible in our current terms. The origin of self- organization may not yet be absolutely clear, but its existence is not in doubt throughout our biological system insofar as both divergence and convergence are simply differing aspects of the flow of information of any adaptive landscape [204].
What then is the differential crux between standard evolutionary theory and any hologenomic transformative one? Perhaps this is best appreciated through the illustrative manner in which Adam Smith, in The Theory of Moral Sentiments, (1790) discusses the operating presumptions of any human governmental or legislative “man of system”. He states “(such a person) does not consider that in the great chess-board of human society, every single piece has a principle of motion of its own, altogether different from that which the legislature might choose to impress upon it.” [205].
Contemporary research justifies an assertion that human society demonstrates many echoed reflections of its entire evolutionary journey. Consonant with that principle, as enacted at every scale even to the present moment, we remain in a continuous struggle against any invariable imposition of any “man of system”. If that dynamic is deemed accurate, then there is no permanent overarching Darwinian “man of system” operating in any macro plane. Otherwise then, we too, would be its perseverating reflection and accept its imperative control to rule our lives. Instead, it is our individual human impulses that govern our creative capacities that permit our collaborative endeavors. In like kind then, individual self-aware cellular and non-cellular constituents unite towards confederacies of creative expression through the perpetual agency of the eukaryotic cellular macro form, either tentatively or intimately, and collaborate in an outward elaboration to taste the environment. In so doing, all the co-aligned participants are thereby changed through that transitory embodiment. They return through obligatory reiteration to the eukaryotic unicell as a mediator of a larger hologenomic emergent “self” in both willing and obligatory co-alignments that form all macroorganisms. This perpetuation is assured through the eukaryotic unicell as a reiterating continuous loop from macro form to unicell and back once again, thus preserving the same self-referential exactitude from which it emerged. This is eukaryotic life properly appraised. Associated constituencies of individuals, each with their own “principle of motion”, participate in mutual concert and apposition in a transient arc of conjoined life. Phenotype thereby emerges as consensual form. It is the creative biologic expression of the aggregated homeostatic requirements of the individual constituents as they serve themselves and the linked constituencies of confederated ecologies that together represent a holobiont. Each constituent has its own “principle of motion” in service to itself and, in turn, in service to the whole. That hologenomic reality, as the product of co-linked bioactive individual entities, provides a consistent impulse that can be united into conjoining force yielding biological expression that is always schooled by the reactive imperatives of endless epiphenomena. At every scope and scale, this quantum summation is reiterated through contrasting shades of collaboration, codependency and competition and reciprocation. Constraints are present too: immunological boundaries reinforce self-recognition and are further resolved through the consistent disciplining filter of selection.
So then, what is hologenomic evolution if not a further appendage of Darwinism and competitive natural selection theory? The primary differences are clear. Hologenomic evolution, in which cognitive entanglement has primacy, is the settling of ambiguities that arise from self-awareness. Living entities utilize information and communication to temporarily resolve ambiguities to sustain self-awareness that arises as a state function derived from thermodynamic principles. This is both the condition of all living things and the property through which it can be defined. All further evolutionary steps are then subsidiary. Importantly, though, self-awareness perpetually dwells in uncertainty. In contradistinction, the Darwinian frame assumes “knowing” concrete form and discrete place in apposition to others. Cognitive entanglement theory of which hologenomic evolution is subordinate embraces the altered frame. In all biological circumstances, uncertainty is the ruling biological constant. Therefore, any system of evolutionary development must specify a process that enables the resolution of quantum ambiguities into biological expression against the restraints imposed by the constant buffeting of an agitating external environment. Signals of all kinds, whether molecular or beyond, are information as energy. Each is derived from thermodynamic imperatives and both propel and compel biological results in reiterating levels of cellular entanglement. Biologic form emerges from that extension outward into the environment and back in a consistent reciprocation. Yet, the center of this decision matrix is always at the level of the self-referential cell whose identity is defined by a circumscribing Pervasive Information Field. As such, it is always both participant and enactor of further iterative environmental responses. All the mechanisms of communication that our research has identified sustain this perspective. Therefore, eukaryotic evolution is now understood as the means by which self-referential individual “principles of motion” collaborate through entanglement based upon information transfer whose communicative purpose is organized problem-solving. From this essential form of interchange, phenotype emerges as self-organizing cellular solutions in biologic form. If it is asserted that any good theory must be testable and falsifiable, then this definition becomes a direct research manifesto.
Evolution is decidedly an assertion of creativity that always dwells within both light and shade. Although creativity is certainly information based, it is unclear whether it skips along its interfaces or as phase transitions of contextual information. Yet in biologic terms, one aspect of information is necessarily true; it is both actualized information as physical state and concomitant ambiguity. Life is the dual faculty of using information and sensing its uncertainties and limitations, which in the same instantiation becomes its self-referential status. Those cellular actions that manifest as collective and emergent cellular solutions are achieved despite ambiguities towards the perpetual sustenance of a self-referential center at every scope and scale. Therefore, just as with our own thought processes that jostle within a realm of complex quantum entanglement, the discrete connections between those steps may always remain elusive. Yet, even within those necessary impediments, biology can now be better defined. In evolution, the past is ever prologue and is always a continuous enactment of quantum relativity, related to the subjective status of the observer/participant, and then settled. The process is perpetual. Quantum uncertainties are inherent to epiphenomena and flux against a bounded thermodynamically derived state function of “self”. The cusp of life is the ability to use information to sense ambiguities, and then settle them for better or worse. The ability to use information as another form of energy, and thereby actively discharge a range of implicates, defines life. In that sense, biology becomes metaphor and evolutionary development thereby reduces. At every scope and scale, it is the reiterative entangled property of living entities to use information to resolve environmental ambiguities into explicate self-referential biological solutions.
The author is grateful to John S. Torday, (Evolutionary Medicine, University of California, Los Angeles) for critical discussions and the opportunity to contribute this article.
Conflicts of Interest
The author has no conflicts of interests.
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Pre-Biotic Evolution: Part V. The Evolutionary Importance of Chemi-Osmosis, Ion and Electron Transport

Joseph H. Guth*
Published by the
Society for the Advancement of Metadarwinism

One Scientist’s Overview and Perspectives


The traditional definition of biological evolution usually involves the interactions within and between an organism, their genetic apparatus and the conditions of their environment. In this series of articles the author has extended the concepts and principles of evolution to include the purely inanimate, chemical world that had to have preceded the formation of the first partially-to-completely self-sustaining rudimentary cells (i. e.,protocells). Once such cells began growth through mass increases and a primitive self-propagation of their basic matter and simple structure, this narrative posits how the complex chemistry that operated within them helped them continue changing in further ways to enhance their chances towards more durable structure and wider-ranging functioning should there be future existential stressors and challenges.

The first three parts of this series1, 2, 3 have described the time-dependent processes that provide a plausibly likely pathway from the production and evolution of various atomic and molecular species through the formation of huge collections of varying complex chemical mixtures under suggested early earth conditions. In the fourth installment,4 the story continued with application of common physical phenomena and various chemical constituents that would have generally led to their packaging or capture within various simple membrane-enclosed volumes of such mixtures along with their initial adsorption of available amphiphiles into the ever-increasingly asymmetric membranes. Some amphiphiles would have been initially richer in the internal surface with others richer at the external membrane surfaces. Thus not only were the aqueous internal and external fluids asymmetric in their dissolved components, providing initial electromotive potentials across such membranes, but the embedded molecular species statistically presented at the two surfaces of such membrane vesicles would also have become more

uniquely and separately displayed. Many new kinds of functions involving membrane- related phenomena could have been tested or explored at this transition stage for their utility or at least survivability under those current conditions. Those that conferred any advantages tended to last longer than those that remained inert, maladaptive or impaired. Ultimately in this “combinatorial protocell self-selection” process, the more optimized combinations began to thrive. Various more successful yet still early protocellular platforms, in astronomically large numbers and variations, now took center stage. Such an early starting point reflects the stage of early protocellular development that must have preceded the more conventional Darwinian and subsequent views on evolution in which one traces back the branches of life through branch-points involved to the Last Universal Common Ancestor (LUCA).

Note to Readers

My apologies to the reader for using antiquated phraseology in this part of the story. I do not intend to convey any sort of directed or intelligent involvement in a purely physical pre-biological process. Such a process only operated according to the inherent chemical and physical properties of the atoms and molecules as dictated by the physical forces and chemical species and their reactivities that were present. I do not use the terms “Nature” or “Natural Laws” in their original sense that implies something omnipotent had placed or dictated these properties be what they are. My definitions only define that they are as they are found. Nothing more. In my sterile views, atoms, molecules, subatomic particles, fields and all non- vacuum state space simply exist and possess the measurable properties we can observe or measure. This is but one story of their collective habits and proclivities.

We now can examine this transition stage even more closely. Simply capturing some rather uninteresting simple and non-biogenically made macro-molecules in aqueous solution within a lipid-like bimolecular-or-multilayered vesicle would not, by itself, be sufficient to provide a path towards a stable, long-term, operational framework. Also keep in mind that we use the term “lipid-like” and “amphiphile” at this early stage because modern day phospholipids, sterols and hopanoids may not have been abundant enough to become the predominant membrane-forming class of molecules. But such a framework could house and support a more rudimentary set of chemistries whose combined output resulted in the continuous self-generation of new protocell mass, including new membrane mass.

It would have to be at least complex and productive enough to result in the net syntheses of adequate new membrane components within which to contain the ever-increasing internal water-based chemistry. Within such an ever-expanding volume, this framework housed the generated pools of various intermediates and end products. At earlier stages, the collection was richer in mineral particles, metalloids, and organo-metallics. Though transitional in all likelihood, some may have diversified to other modern forms while retaining their earlier inorganic requirements. Several examples could include barium sulfate crystal production in desmids, strontium sulfate crystal formation in radiolaria and acantharia, silica wall formation of radiolaria and diatoms, and hydroxyapatite formation within osteoblasts. Later, many such early inorganic steps were likely supplanted and replaced with more catalytically specific, more coupling-capable, organic-based species that performed equivalent functions based on differing atomic content. In our carbon and hydrogen rich environment, that would lead to the involvement of abiotically made polypeptides, proteins, carbohydrates, and transmembrane transporting molecules. Early transmembrane transporting molecules (both passive and active) could also have been mineral-based, rather than more complex, purely organic molecules. Such a rudimentary transport capability is an absolutely necessary step needed to provide dynamic machinery to a collection of otherwise thermodynamically-challenged assemblies of molecules. Without such evem inefficient machinery becoming initially available, it would be almost impossible to transit the chasm from an inanimate to an animated state or condition. Assisted membrane transport capabilities are possessed by all present day living cells.

What we are also presenting is a picture of such vesicular packages being generated in uncountably large numbers over a long span of time and occurring in many locations and environments with varying chemical and physical conditions. Some locations like undersea alkaline hydrothermal vents could generate quite simplified versions of the first protocells,5.6 while hydrothermal geyser and mud pot fields in surface geothermally active areas could have been harbingers of a somewhat different version of such early protocells. Groups of vesicles formed in one location with a particular complex mixture of captured molecules, molarity, pH and temperature resistance (such as high phase transition temperatures) eventually mix with other ones containing other complex mixtures, molarities, pH and temperature resistance values. The innumerable encounters and mergings created many unique combinations of reaction capabilities and this could ultimately have led to more than one kind of proto-life starter form being generated. Life may not have just occurred from a single source protocell that then went on to take over and form the biosphere we know today

Figure 1. Multiple types of protocells originating from different chemical and physical conditions create astronomically high numbers of literal “experiments” within which some combinations may then have become simple, self-growing, and capable of taking in and utilizing high energy chemistries. This latter ability allowed those to indefinitely maintain the rest of the chemical reaction activity while continued energy-rich reactants were present. This linking of a few higher energy chemical reactions involving oxidation-reduction electron transfers and the release and taking up of protons became the main driving force for creating the narrow conditions needed for the internal chemical reactions to operate optimally.

Oxidation-reduction chemistry does not require oxygen as the only possible end electron receptor. Any abundant chemical element or oxidizable molecule could have initially provided such a sink for those lost, de-energized electrons. When the catalysts eventually became membrane-bound in their photocells and transferred either the electrons or protons across the semi-permeable membranes, active transport and other directed molecular movements then became possible. At that seminal moment, active transmembrane transport, long-term energy storage and retrieval and energy recharge-ability was born. Osmotically- driven water movements across membranes helped maintain stable protocell sizes and prevention of bursting as the numbers of dissolved solute molecules and ions changed during such energy cycles. A chemi-osmotic energy storage and management capacity was now part of the story leading to a truly permanently self-propagating state.

Taken together, these represent a multitude of naturally-occurring trial and error combinatorial experiments in the stability, longevity, durability and survivability of one or more combinations of chemical structures and functions.

Such a period of pre-biotic earth, with all of its niches where protocell formation and co- mingling took place, would have been akin to a collection of scenes conjured by Dante Alighieri’s Divine Comedy and portrayed through the art of Hieronymous Bosch. Some niches were fiery hot while others were submerged deep in the new ocean depths or at the edges of shallow surface waters. At some waters’ edges, rapidly cooling volcanic lava blistered with high temperatures, cooking the water-born molecules and protocells that were caught too close. Chemical reactions and high temperature reaction products that only occurred at such higher temperatures would have become common in such niches. The end result of these new chemical actors would only have revealed itself after a further complex process of incubation, with further self-selection taking place. A competition eventually optimizing the abilities and characteristics of these new generations of early proto-life forms that would only flourish in those niche environments. Life from varied protocellular bases would thus arguably have sprung up along many differing initial designs. The subsequent self-selection would have been where the more robust survivors from each genesis center were shaken out of the mix and become the dominant forms. This would have been similar to Darwin’s views on survival of the fittest and natural selection that he theorized occurred much later in the story of life, but on a much more rudimentary level.

The internal milieu of such vesiculated self-growing protocells would have been quite varied from one to another. Smaller sized protocell units would have possessed an internal aqueous environment that would have been necessarily smaller in volume. Smaller volumes would have reacted more quickly to changes in internal concentrations of various dissolved species. Larger protocell units would have taken longer for diffusion-limited equilibration and internal concentration changes to affect the reaction rates of various internal chemical reactions as might have been inadvertently cloistered within them during initial packaging or subsequent protocell-to-protocell fusions. These two opposing effects, each with some potential for the protocell’s survivability, would provide at least one basis for ultimately narrowing down the range of absolute sizes that subsequent living systems finally attained.

When these early protocells by chance contained catalytically active molecules that could, through various linked sets of chemical reactions, generate and build new ranges of designs of molecules not already produced abiotically, that would have boosted dramatically the possibilities for some of those ancient chemical factories to wind up producing needed molecules that we find in even the simplest of today’s unicellular organism’s structure and operations. Those in particular, having more robust structural stability, necessary but specific chemical reactivity, self-repair capabilities, and structural survivability or persistence, would tend to have preferentially accumulated in total mass and numbers over time. But a continued source of useful chemical energy would have been an absolute minimum requirement for these early entities if they were to become capable of growth. It should be noted that some of the earliest catalytic molecules may not have even been organic in nature. They may, in fact, have been partly or wholly inorganic in their composition, been microscopic-sized solid particles floating within the interior fluid or spanning the protocell’s membrane, or even large solid surfaces in synergistic chemical proximity to an adherent protocell, rather than being in true interior aqueous solution.

Many mineral surfaces have known chemically and even stereo-chemically reactive catalytic activity. Microscopic sized crystalline particles of various minerals, collecting within membrane-coated droplets, with the right pH and other dissolved substances would have begun to allow linked chemical reactions to occur within a single volume. Many such reactions that take place geochemically in nature are of the oxidation- reduction (“redox”) variety. Those reactions all involve a transfer of one or more electrons from one chemical species to another. When occurring in an aqueous environment, water molecules are almost always involved and are taken up or given off, along with changes in the free hydrogen ion concentrations. Changes in electric charges on different elements’ valence states are usually also always seen during such reactions.

Random generation of such uncommon reactive ensembles could become the zephyrs upon which mighty future changes in the subsequently available chemical species depend. If such linked, mineral-based or -aided, redox-type reactions collect in common ancestral protocell environments, we start to move towards a cast of actors that allows a rudimentary electron transport chain to begin forming within the same time-span and general niches as the protocell membrane vesicle formation occurs. Whether by surface droplet interactions, lava cooking, hydrothermal vent boiling, lightening strike, cometary or asteroidal impact, or by simple aerosolization, our earliest vesicle-enclosed chemical synthesis factories may have begun modestly, in terms of contents and somewhat electrochemically-energized condition. They would not have remained that weakly developed for long in a generally hostile environment. Chaos theory and thermodynamics operating along with selective forces for the more capable forms, once connected to somewhat reliable energy sources, allowed them to become more complex, varied, and extended in every direction possible within the physical limits of the environment they emerged from. Early proto-life bootstrapped itself out of the dead end world of inanimacy because that route gave it it’s first functional connections with its environment and its challenges

This earliest stage in the formation of the first protocells was likely to also include a concurrent, loosely-coordinated development of both organic and metallo-organic reaction chemistry coupling with redox chemical reactions that provided some of the earliest sources of electromotive force to kinetically drive certain kinds of chemical changes against their natural and spontaneous directions of flow. With redox chemical reactions that find themselves asymmetrically distributed across a protocellular membrane, electrons travel in one direction while protons travel in the opposite direction. Thus whenever these redox reactions became associated with thin, semi-permeable membrane structures that separate two separate aqueous phases, especially if these reactions self-organize across such a membrane with an initial oxidation step occurring on one side and final reduction step on the other, we then have met the basic plan of life’s bioenergetic operation. That basic plan at this early stage was for oxidizing half- reactions to occur on one side of the membrane while reducing half-reactions occurred on the opposite side. The membranes and their embedded “channeling” molecules served the function of a modern “salt bridge” connecting the two sets of half-reactions. And this also can be portrayed as the first electrochemical battery spontaneously being formed. From that point on, as long as the beginning reactants are supplied and physical conditions do not impair things, the system should always continue operating.

Figure 2. One of Many Means of Creating the Very First Protocells. Life springing from water droplets? A partly submerged surface rock collects water droplets on it. Some droplets had mixed with a cloud of dust blown up from the land and different types of catalytically-active, crystalline mineral particles were captured within some of the droplets. The rock, previously coated with keragen-type amphiphiles such as found on meteorites or formed on earth, would have thus picked up a hydrophobic coating only a few molecules thick during such contact with the rock’s oily surface. A smaller number of droplets may have collected multiple numbers of two or more types of mineral particles and out of that sub-population, some had the right ingredients to begin removing protons and electrons from the earliest chemical energy sources. They passed them onto the next mineral particle co-mingled with them and so on. At some final step, the last type of mineral particle reacted the penultimate intermediate and the final electron acceptor to release, for example, gaseous hydrogen. And that droplet began to collect hydrogen bubbles within it. And the bubbling action created separate membrane-bounded aqueous domains of the internal chemistry. Could this have acted as a primitive phenomenon that assisted this early chemical factory to replicate itself? It my not look like much. It certainly did not look like what most would call “life”. But that may very well have been a step very close to the final stage of turning this droplet sized chemical reactor into a self-expanding, self-repairing protocell which now became a new design in the sequence of ever-more complex chemical reactors leading to the first independently “living” cell. And so far these chemical, physical and behavioral features of life’s inanimate chemicals are commonly found today in the natural world.

Growth, the ability to increase the total mass and volume of this now self-expanding chemical factory plus the ability to repair or replace damaged or lost structure, would have to be the first important feature needed to be acquired. Such a new capability would take our protocells from a condition of needing a great deal of outside physical and chemical resource processing to internalizing that. That internalization literally lit the fuse that would lead these fore-runners of life towards an ultimately autonomous condition. Each component of this early “cell stuff” had to be synthesized internally for this early indefinitely growing protocell stage to become the next step in the early pre- biotic evolution of life. The creation of new cell-stuff was now moving from the external world into the internal one, and becoming more closely linked to the work capacity contained within the higher energy electrons present in their available fuel-source molecules.

As a preview to our actual course of subsequent evolution, we should ask about where the present day metabolic pathway complexity sprang from. In this theorized setting, uncountable numbers of protocell-like structures contained complex combinatorial chemical libraries. These consisted of broad-ranging collections of varied molecules, both in terms of structure and reactivity. Such complexity that resulted could in some cases have lasted relatively unchanged for long geological periods in some more static environments. There, structures that contained macro-molecular assemblies that had reaction sequence-catalyzing capabilities within them, became the predecessors for future super-complex branched and internally self-regulating branches of our current metabolic pathway enzyme sequences. Macro-molecular species could have finally found the environmental incubators within which to grow in places like the interstitial water residing in highly mineralized soils in contact with surface and subsurface water sources. These future metabolic pathway actors, often being amino acid-based poly-peptides formed through dehydration reactions possessed significantly different molecular structures and were capable of providing specificity to the underlying reaction chemistry. That specificity was asserted through molecular geometries such macro-molecular chains could provide. Many variants of these molecular “cherry-pickers” must have become available in this pre-biotic world and its countless niches. But out of each variant capable of carrying out the same catalytic functions that then existed, only the most catalytically productive ones would have survived in the widely diverse branches of the tree of life of today. This may be another reason we often have the same function built into two quite different proteins that are structurally dissimilar when comparing members from different branches of taxonomic relevance.

Simple fusion of all possible combinations of such varying content protocells then could at times have created new levels of complexity in which multiple end-products of simple pathway operation would have been generated in proximity with one another. Picture this: One kind of protocell containing a short sequence of glycolysis-related enzymes, fusing with another protocell containing a different metabolic pathway’s main catalytic capabilities. Whether the fusion resulted in a single, co-mingled collection of those enzymes and catalysts or whether such fusion resulted in an internalized and compartmented final structure would subsequently lead to different ultimate behavior and capabilities of future generations derived from each. Overall though, this merged the outputs of one pathway to the inputs of others, all in a very tiny volume. Such concentration of multiple new metabolic end-products within single protocells now allowed larger scale leaps in the evolution of complex cell structure, design, operation and functioning. Thus the rate at which evolution of inanimate matter finally attaining a truly self-sustaining state greatly accelerated from some critical points within this pre- biotic epoch of growing complexity.

Figure 3. The Overall Process of Pre-Biotic Evolution Aided by Aerosol Formation. This is but one of many descriptions of such protocell generation. (a) Seas, lakes, ponds, pools and rivers created aerosols. Tiny droplets of water containing many different combinations of constituents, some of which have several types of linked chemical catalysts that cause coordinated chemical reactions that take simple molecules from the environment and add to and modify their structures into more useful forms. (b) Hydrocarbon-rich waters coated with multi-colored sheens of multi-layered, amphiphilic molecules collected everywhere. This natural and spontaneous separation of oil-from-water behavior with subsequent surface spreading presented huge areas of membrane-precursors awaiting the landing of small droplets of aerosols (c) from different sources. One alternative to aerosolization, as diagrammed in Figure 2, allowed protocell vesicle packaging through lipid-coated water droplets collecting and streaming down surfaces before slipping beneath the surface of larger bodies of water. (d) sometime well after vesiculation packaging of coupled catalytically-related mineral particles, macromolecules and similar active sites, feedback modulations would have had to become part of the most optimized modifications. Such a feedback design would impose a regulated, variable-control, processing speed that would have allowed switching on and off or partial down-regulation of the overall activity of such pathways. With those controls, better inter-pathway integration and intermediary pools of reactants and products provided even more refinements in the control and management schemes that such protocells would enjoy. The presence of such linked catalytic elements with feedback control would have created a processing cycle during its operation. From an exterior view, that would have behaved in a steady-state input-output flow design that could elicit oscillatory behavior at critical parametric values. It was capable of both classical as well as chaotic kinetics. That is represented in our diagram above by the final oscillating alteration of the colored protocells at the right. As long as new initial substrates remain available, able to be transported in and input into the beginning of such linked pathways, the final end-products of chemical synthesis would be generated. And if those end-products were simply new “cell stuff”, these protocells would simply continue to grow in size without the necessity for any further subdivision of the enclosed cell mass. Obviously physical forces that occasionally impacted upon such a growing protocell could stretch and force that very gel-sol-like entity to pinch off or be subdivided into smaller sized packages in an unprogrammed manner. These would be mostly conserved through the lipid membrane’s innate property for self-sealing during any hyper-distortion or over-stretching. And as the relatively slow scissioning of new protocell production through physical fragmentation occurred, each new resultant “daughter” protocell would itself become the next center of growth as long as there were adequate nutrients available. Such an early, but inefficient reproductive process is arguably a likely early beginning to the overall later mechanism of reproduction which would eventually evolve much more efficient and high fidelity features. Such features would include an information storage and management system (nucleic acids, genetic code, and chromosomes). Such a development will be considered in subsequent chapters of this re-examination of early earth.

Chemi-Osmosis Theory and Multi-Compartmented Cell Patterns

The Chemiosmotic hypothesis was first proposed by Peter Mitchell to be the operating form of bioenergetics in modern day living cells in 1961.7 It was one of two competing views attempting to explain why, if not how, energy-rich, naturally unstable molecules like adenosine triphosphate (ATP) were created in cells. Those views eventually merged to form the current biophysical energy management model of the cell. It was well appreciated that without a continuing utilization of, and replacement of ATP, all cells eventually died. And since most ATP was cyclically reformed in a majority of aerobic cells from glucose with the utilization of oxygen creating a major enhancement of this production, the mitochondria of eukaryotic cells, along with many kinds of Bacteria and even Archaea were probed for evidence of this.

Such was the case and this was even extended to the process of photosynthesis and ultimately the fixation of carbon dioxide. So what form of energy was tapped into to become the main “glue” for the attachment of the phosphate ion to the adenosine diphosphate precursor? It was ultimately demonstrated that intact semi-permeable vesicles with membrane-based catalysts and internalized electron carrier chemical species were at play in these operations. But the main initial form of energy that drove all this subsequent chemical synthesis, as described above and in the last installment of this series,4 was the production, maintenance and utilization of an electrochemical, or more accurately, a proton-motive gradient across those active membranes. The building up of proton gradients across a topologically enclosed, self-contained membrane vesicle resulted in the ability to store useful energy in the form of electrostatic charge separation plus concentration gradient/entropy-driven work whenever the opening of channels through that membrane provided a mechanism of tapping that stored energy for later usage. When the proton gradient generation and utilization were accomplished through the same set of transmembrane molecules, the birth of a longer lasting capacity to live through intervals of energy starvation was born. The protocells with such a built-inrecharge-ability could now actually live long and prosper! What was not so apparent in the early halcyon days of bioenergetics research was that this process might also be equally applicable to all other eukaryotic cell membrane-based systems and organelles as well to mitochondria, chloroplasts and bacteria.

The current view of the author is that in a modern day eukaryotic cell, each membrane- bounded compartment within the cell, from the intact interphase nucleus, to the mitochondria, lysosomes, peroxisomes, endoplasmic reticulum, Golgi complex, pinocytotic and exocytotic vesicles, contractile vacuoles, to other kinds of membrane- bounded storage vesicles, all of these subcellular membrane-bounded compartments exist and allow the creation and maintenance of disparate and incompatible chemistries to reside in close proximity. This proximity also allows their respective chemstries to be coupled, when appropriate, to one another. But existing between all of them is a complex synergy and set of symbiotic interrelationships that allow each to “supply” and “feed” off of its co-inhabitants, providing a modern day niche within which a “eukaryotic meta- evolution” continues to take place.

Regulated and controlled transmembrane movements of protons, sodium, potassium, calcium, magnesium and other ions as well as specific uncharged molecules across such semi-permeable barriers creates a much more highly choreographed control and interlinked framework. This also provides the connections to the primary energy storage of the cell for many other transmembrane transport of other molecules, both actively and passively. This higher-level, interlinked organization to accommodate multiple pathways, each of which produces different end-products, taken together, allowed life to utilize those various coordinated synthetic products towards building new mass as required for its newer, more complex architecture. And that allowed it to address and overcome even more challenges to its survivability when encountering new environments. This allowed the eventual multi-compartmented versions of protocells to become more elaborated into uncountable types of multi-compartmented, metabolically segregated versions of proto-eukaryotelike patterns in meeting ever more challenges to their development. This idea is partially explored by Gabaldon and Pittis.11 The present day eukaryotic cell design would have thus originated through the independent and/or concurrent or repeated incorporation of various preexisting protocells into the growing multi-compartmented forms, with each adding its individual and unique capabilities to the mix. Such heightened elaboration would aid in ultimately attaining the additional higher levels of structural organization, new function development, and thus, survivability. This latter aspect is what evolution in all its variations is really all about. It would be the final step just before trophic behavior (dynamic goal-seeking) and genetically-driven reproduction could become established as a endpoint universal pattern for terrestrial life. This was the step immediately before independent protocell motility could become possible. It was here that the ultimate coupling of the internal operating chemistry linked up with the external environmental’s chemical offerings and physical state.

Chemi-Osmosis is Created at Membrane Interiors and Surfaces

Dissolved ionic substances in bulk aqueous phase always have a series of coordinated shells of water molecules surrounding them, loosely attached through polar interactions and hydrogen bonding. This spreads their net charge out over a larger surface and thus their electric charge is less concentrated. Such an arrangement forms a compatible means of maintaining the solvated state. More water-soluble substances have more of this coordinated water around them than less water-soluble substances. But when those ions begin to interact with other kinds of molecules, such as proteins, some or all of those water molecules that immediately surround them are stripped off, replaced by various chemical and polar groups that are part of that larger molecule. Differences in polarizability and electronegativity of the replacing atoms creates stronger bond formations through decreased energy of solvation. Such a reversible “dehydration” step of the ion’s shell of water molecules transiently occurs as an ion passes through ion transport channels in semipermeable membranes. Once through the membrane, new water molecules assembly around the ion to resolvate it into the aqueous phase on the opposite side of the membrane.

Chemiosmotic behavior is initially created through the net movement of ions through open channels that span across a semipermeable membrane. Following the movements of those substances, water molecules must also move across the membrane to reestablish equal osmotic pressure across the membrane. Those water molecules are thought to mainly flow through and between the phospholipid molecules and their fatty acid tails where smaller sized “pockets” of space can exist due to the presence of internal membrane fluidity or liquid crystalline phase change behavior caused by the presence of non-rotating unsaturated double bonds plus rotatable single bonds involved between adjacent carbon atoms in the fatty acid chains. When this movement is passive, down- gradient movement of ions occurs (in the absence of an energy source). The ions are, in fact, spontaneously moving down their electrochemical (and concentration) gradient. This phenomenon requires a non-equal concentration of the substance or ion to begin with and then it will proceed when the transmembrane channels are opened. And as the number of such ionic particles move from the higher concentration side to the lower concentration side, similar to water flowing downstream over a dam, the potential energy originally stored in that water is converted to kinetic energy and then dissipated as frictional heat or transferred to the chemical or physical environment in another form. Humans have engineered the water dam to a greater extent than the original design created by the beaver. They did this by adding water wheels or turbines to convert the linear water flow’s kinetic energy into rotational kinetic energy. Through further connections to millstones, pumps, electrical generators and the like, we reclaim some of that energy in the form of useful work or more usable forms of energy. The early evolution of life created these energy-extracting designs at the molecular level billions of years earlier! And even more impressively, evolved the reciprocal means of regenerating such gradients and permanently maintaining them in a non-equilibrium state to handle all of life’s future energy needs through such an energy storage process.

An example of this would be the various membrane-based “ATPase” activities associated with many kinds of biological membranes as well as the overall generation of adenosine triphosphate (ATP) by the up-hill movement of hydrogen ions, from lower to higher concentrations, across a membrane during cellular respiration or photosynthesis.

An ion gradient has potential energy contained within it and can be used to power many other chemical reactions. When the ions pass through a molecular channel designed to link their movement to other coordinated molecular movements, electron transfers or changes in partially charged states will result.

Hydrogen ions, or protons, will preferentially diffuse from an area of higher proton concentration to an area of lower proton concentration, and an electrochemical concentration gradient of protons across a membrane can thus be harnessed to make ATP. The overall reaction takes the initial two negatively-charged reactants of adenosine diphosphate (ADP) and inorganic phosphate (PO4-3) and brings them together while concurrently removing a hydrogen atom and hydroxyl group, resulting in the formation of a higher-energy content covalent bond. This reversible, overall proton transport process is thus inextricably connected to the water movement through osmosis. That is why the entire phenomenon is called “chemiosmosis”.

In virtually all modern day cells, whether prokaryotic or eukaryotic, ATP synthase is the enzyme that makes ATP, energized through chemiosmosis. It allows protons to pass through the membrane and uses the free energy difference to phosphorylate adenosine diphosphate (ADP), making and reforming ATP in a cyclic fashion. In its many forms, ATP synthase involves rotational movements at the molecular level as well during operation.

Evolution has conserved the role and function of ATP. In many parts of the tree of life, it has been demonstrated to be the universal energy-transferring molecule utilized in so many cell dynamic and synthetic processes. The generation of ATP by chemiosmosis occurs in mitochondria, chloroplasts as well as in most bacteria and Archaea. We might suspect that ATP synthase is one of the first enzyme catalysts to have been formed as life emerged from inanimate matter within the first generation of protocells. I would have to take a much harder look at such a suggestion because it presumes a number of things that have little experimental evidence at this point. In fact, even though adenine and ribose are readily created from many common, simple early earth-/astrochemically-demonstrated chemical species, such conjugations on the earliest shores of primordial earth may have involved other, more simplified catalysis than large, multicomponent, macromolecular proton-transporting motors.8,9.10

With all of these different basic protocells floating about, merging together, co-mixing their interior contents while co-mixing their varied membrane compositions, mutually swapping chemical species, or alternatively taking smaller protocells with different internalized chemistries deep within them, what was this massive combinatorial world of protocells like? Our next installment looks at some of these more complex events to see how they could have formed the bridges to modern day life forms.

Next: Pre-Biotic Evolution. Part VI. From Protocells to Proto-Prokaryotes

*Scientific and Forensic Services, Inc., Delray Beach, FL. and Norfolk, VA


1.Guth, J. H. “Pre-Biotic Evolution: I. From Stellar to Molecular Evolution”.

Society for the Advancement of Metadarwinism, Volume 1, November 19, 2014. Accessible at

2.Guth, J. H. “Pre-Biotic Evolution: II. Pre-Biotic Chemical Oscillations and Linked Reaction Sequences”. Society for the Advancement of Metadarwinism,

Volume 2, June 12, 2015. Accessible at

3.Guth, J. H. “Pre-Biotic Evolution: III. Transitioning to Animacy”. Society for the Advancement of Metadarwinism, Volume 3, January 5, 2016. Accessible at animacy/

4.Guth, J. H. “Pre-Biotic Evolution: IV. The Development of Electrochemically- Generated Energy Linkage, Extraction and Storage in Protocells”. Society for the Advancement of Metadarwinism, Volume 4, 2016. Accessible at

5.Martin, W. and M. J. Russell. (2007) “On the origin of biochemistry at an alkaline hydrothermal vent”. Phil. Trans. R. Soc. B 362: 1887–1925

6.Herschy, B., A. Whicher, E. Camprubi, C. Watson, L. Dartnell, J. Ward, J. R. G. Evans, N. Lane. (2014) “An Origin-of-Life Reactor to Simulate Alkaline Hydrothermal Vents”. J. Mol. Evol. 79: 213–227

7.Peter Mitchell (1961). “Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism”. Nature. 191 (4784): 144–148.

8.Pasek, M. A., J. P. Harnmeijer, R. Buick, M. Gull, and Z. Atlas “Evidence for reactive reduced phosphorus species in the early Archean ocean.” Proc. Nat. Acad. Sci. (June 18, 2013) 110 (25): 10089–10094.

9.Pasek, M., B. Herschy, T. P. Kee (2015) “Phosphorus: a case for mineral- organic reactions in prebiotic chemistry.” Orig. Life Evol. Biosph. 45(1-2): 207- 218.

10.Wang, J., J. Gu, M. T. Nguyen, G. Springsteen, J. Leszczynski. (2013) “From Formamide to Adenine: A Self-Catalytic Mechanism for an Abiotic Approach.” J. Phys. Chem. B, 117: 14039−14045

11.Gabaldon, T. and A. A. Pittis. (2015) “Origin and evolution of metabolic sub- cellular compartmentalization in eukaryotes”. Biochimie 119: 262-268

©Copyrighted by Joseph H. Guth, 2017. All rights reserved.

Born to Choose: An Evolutionary Perspective

John H. Falk
Institute for Learning Innovation
Emeritus, Sea Grant Professor of Free-Choice Learning
Oregon State University

People were born to choose.  And choose they do, from birth to death each human being spends every second of his or her life making choices.[i] To be alive is to make choices.  Some choices are momentous and life-altering; most are tiny.  Collectively, choices define the trajectory of a person’s life. Few things are more characteristic of what it means to be alive and human than the choices a person makes, but surprisingly few aspects of choice-making are understood.  Despite thousands of years of wondering about why people make the choices they do, no one has yet developed a completely satisfactory answer, one that suitably accommodates all human choices,  choices large and small, those made by Americans, Chinese and Inuit, and those made consciously, as well as the innumerable choices a person makes unconsciously.

It is not the case that there are no theories of human choice-making.  There are many.[ii]  However most of these theories only operate within special circumstances or for certain groups of people.  In great part this is because virtually all have attempted to answer such questions based on a faulty assumption.  Specifically, most models of human choice-making have been predicated on the supposition that choice-making is a uniquely human process requiring a complex mind, largely involving conscious deliberation, what social scientists refer to as agency.[iii] However, choice-making is neither uniquely human, nor is it always or even typically driven by conscious processes. A more comprehensive model of choice is needed that accommodates fundamental findings from the neurosciences, physiology and evolutionary biology, as well as results from years of social science research.

Towards a Unified Model of Human Choice-Making

My major premise is that human choice-making is an evolutionarily ancient and complex process involving multiple biological as well as psychological processes.  At its core, choice is a mechanism for insuring survival using feelings of well-being as a proxy. All living things, from the tiniest microbe to the most complex social primate, strive to achieve well-being through functionally similar processes of choice-making.  Certainly some of the choices people make are distinctly human, influenced by culture, and in some cases, involving a measure of conscious thought, however a surprisingly large number of human choices are not specific to any particular human group or even to humans in general.  However the traditional emphasis placed on conscious agency is misplaced, particularly in light of recent research suggesting that at best 5%, and more typically less than 1% of all thought is available to the conscious mind.[iv] Even more importantly, even though a person’s presumed “big” choices, e.g., career choices or voting patterns, are highly salient and thus memorable, they are typically not the most important choices a person makes in any given day. Far and away the thousands of small, mostly unconscious choices a person makes over the course of each day – choices about diet, general health and social relationships – are much more likely to influence a person’s well-being. Whether “big” or “small” though, all choices share a common structure and pedigree.

The model I propose posits that human choice-making is a complex, adaptive system, where choices, as well as the actions they precipitate represent parts of a larger, highly integrated Well-Being System.  Choices are always self-referential and always focused on self-related needs; the satisfaction of which correlate with fitness and result in perceptions of well-being.

The Components of Well-Being

Well-Being Systems emerge from the complex interactions of four key components as illustrated in Figure 1 below.

Figure 1.  The Universal Well-Being System.

Before I define each of the key constituents of this model I need to provide some framing about my terminology. I purposefully tried to choose commonly used words for each of these constituents, rather than more “scientific,” jargon-laden terms.  I wanted words that might be readily recognized and understood by a wide readership spanning both the social and biological sciences. There is an obvious advantage to this approach.  The goal of language is effective communication; it is always easier to communicate with a person if he does not have to constantly refer to a glossary to understand the words used.  However, there also is an inherent danger in using common terms.  All these words already come with a variety of meanings, particularly key terms like Choice, Need and Well-Being. Each has a long history of vernacular use.  These terms also have a long history of use within the social sciences, humanities and biological sciences; though interestingly and significantly there are no universally agreed upon definitions for any of these terms.  I would implore the reader to try to set aside prior conceptualizations and understandings of these terms and think about them only in the specific ways I define them here.

Choice: Is the active response to Self-Related Needs and selection between options. I use the term choice to include selections that involve both conscious agency, but also those decisions processed unconsciously, including choices that other theorists have categorized as “instinct.”  Even “instinctual” choices arise through active selection of options and are subject to change and manipulation.  Also important to appreciate is that the most frequent choices people make are the “choices” to continue doing the same thing they are currently doing. In humans, choice-making typically though not exclusively involves some kind of neural processing.

Actor: Are structures, they can be nerves, muscles or a whole person that respond to choices. Actions typically involve physical responses, ranging from simple movements to more complex behaviors, but actions can and do happen at every organizational level, from the biochemical to the collective efforts of groups of people.

(Self-Related) Need: Is a perception of an underlying state; a threshold-like, regulatory “construct.” Perceived needs can be based on either an actual physical entity such as a molecule or possession, but they can also be based on totally abstract, entirely mental constructions such as a relationship or an idea.  Whether physical or mental, individual or social, Needs are always self-referential, always framed in relationship to the balance of a person’s perceived requirements as compared with some intended internal or external reality.

Sensor: Are bodily structures that take in information and are capable of perceiving the status of Self-Related Needs relative to the internal and external environment. Some sensors are externally focused such as eyes and ears but others are internally focused, attuned to electrical and biochemical signals coming from the gut or circulatory system.

Well-Being: Is a dynamic system, designed to sustain a balanced state representing an optimal satisfaction of Self-Related Needs, monitored by Sensors, regulated by Choice and maintained through Actions.  Well-being, in particular short-term well-being, has evolved as a perceptible proxy for fitness.  People perceive Well-Being when they feel they are healthy, part of and appreciated by their group, physically safe and secure and intellectually and spiritually satisfied. Perceived states of Well-Being generally correlate with enhanced survival.

The essence of this model is that all choices are designed to support survival, in the guise of perceived well-being. Typically a person strives to achieve a short-term sense of well-being. Typical short-term actions related to well-being include eating when one feels hungry, trying to get warm when feeling cold or trying to get the person one is conversing with to pay attention and respond positively. Occasionally well-being goals are longer term, resulting in actions such as saving money for college or retirement, or plotting how to get a date with someone just met. No matter the time-line of well-being, the process is always the same. Individuals are constantly attempting to optimize their state, their perceived as needs, relative to the world,.  Based on an appraisal of whether or not their needs are in balance, a choice is made which in turn precipitates a self-appropriate action (or inaction).  The purpose of the action is to effect the relative balance of the perceived need. So, for example, when a person first walks into a room full of people she knows, her first reaction is to greet each person with customary greetings, in both word and action. Choice-making is dynamic, responsive and typically reflexive.  In other words, the individual is constantly gathering feedback from the environment about their choices.  For example, in the above social situation, the individual is attuned to the others in the group to determine whether her greetings were appropriately received; to see how others respond to her actions. The feedback she receives, will determine her next set of choices. Over the course of a day, a person is bombarded by a constant flow of signals, emanating from both inside and outside of her body.  The individual monitors these signals and appraises them relative to the state of her self-related needs, making choices and initiating “appropriate” well-being-related actions.  Through these real-time, well-being related processes – processes occurring at the level of the phenotype not the genotype – humans actively manage their survival.[v]

Maintaining well-being is a continuous, never-ending process.  As dictated by Newton’s Third Law of thermodynamics, things always move towards entropy. Thus Well-Being Systems, whether supporting physiological well-being or social well-being, are always drifting away from equilibrium and constantly requiring corrective action.  Thus contrary to the way well-being has typically been conceptualized and measured in humans,[vi] perceptions of well-being are not easily reduced to some annual synoptic assessment.[vii]  Well-being is never stable.  It fluctuates, often widely over time; not only across a year but even over the course of minutes and hours.[viii]  Well-being is not a lake, it is a river, never totally static, but always dynamic.  Well-being is a judgment about experience, particularly the experiences happening in the immediate here and now.[ix]

Based on a range of experiments, psychologists have hypothesized that humans perceive their well-being, and hence make choices differently, depending upon the timeframe involved.[x]  Reinforcing this idea, brain research has shown that individuals process differing temporal conceptualizations of their self-related needs in different parts of the brain.[xi]  Even though people intellectually understand that the needs they will have in a month, the needs of their “future self,” will be affecting the same person that they are today, their “present self,” the present self appears to have little concern, understanding or empathy for the needs of that future self.[xii]  Thus, although people are more than capable of imagining a better future and acting in ways that would support a future well-being, this is not the norm.[xiii] The key to why this is so seems to be related to the fact that pleasure in general, and pleasurable memories in particular seem to be disproportionately connected with the “present self” part of the brain. This discrepancy in where positive emotional connections occur appears to have consequences.  It is hypothesized that the paucity of positive emotional connections to the future self negatively affects future choice-making.[xiv]  People most of the time selectively opt to make choices designed to satisfy short-term rather than long-term needs. This is because, based on prior experiences, people perceive that satisfying short-term needs are much more likely to result in feelings of positive well-being.  This is why people find it so hard to pass up that chocolate cake for dessert.  Even though they know the cake might create long-term issues such as weight gain or high blood sugar, the memories of short-term pleasure are screaming “do it!”

This bias towards the needs of the moment has been argued to exist in other species beyond humans.[xv] Although humans perceive and act upon well-being in a distinctly human way, Well-Being Systems themselves are anything but unique to humans.  Well-Being Systems are ancient and can be found in all life forms.

Origins of Well-Being Systems

The origins of Well-Being Systems seem to be connected to the evolution of a semi-permeable cell membrane, an event that likely happened at the very beginnings of life itself more than 3.7 billion years ago.[xvi]  A fundamental need of all living things is the maintenance of an appropriate chemical balance between the inside and outside of an organism; the ability to operate outside of, and often far from thermodynamic equilibrium.[xvii]  All living things satisfy well-being in this way through processes biologists have traditionally referred to as homeostasis. The fact that all living things – bacteria, redwood trees, insects and humans – possess these homeostatic systems has led scientists to conclude that this capability must have appeared very early in the evolution of life, at a minimum prior to the appearance of the last universal common ancestor.[xviii] Although life on earth shares a number of other common capabilities, the most celebrated example being DNA-based reproduction, some scientists believe that homeostasis was not only a critical first step on the road to life, but the critical step.[xix]  It is noteworthy that many of the most dramatic events in early evolution, including the formation of the first true cells, the origin of various bacterial groups and the emergence of the first eukaryotic cells were likely associated with and dependent on the evolutionary changes in non-genetic, inherited cellular structures.[xx] Even in complex organisms like humans, many critical Well-Being Systems are structurally rather than genetically inherited.[xxi]

From the beginning of life, homeostasis has functioned using the following basic process (Figure 2).

Figure 2. Textbook diagram of how homeostasis works.[xxii]

It is not an accident that this diagram of homeostasis looks surprisingly similar to my Well-Being System model; all Well-Being Systems are homologous with homeostatic systems.  Well-Being Systems, like homeostatic systems, are complex systems that evolved to phenotypically regulate the well-being of organisms by affecting appropriate responses to the perceived environment.[xxiii]  Although the evolutionary origins of homeostasis are hypothesized to have been mechanisms designed to maintain appropriate balances of single chemicals,[xxiv] life ultimately evolved a wide range of similar systems for dealing with ever more complex physiological needs; each new system functioning independently, yet interconnected within the larger complex of physiological regulating systems.[xxv] I assert that the evolution of homeostatic-like systems did not end with physiological processes.  Through successive exaptations,[xxvi] these Well-Being Systems evolved to support organismic regulation at every biological level – the molecular, cellular, organ, organism, social, community and potentially beyond.[xxvii]  This means that even the simplest cell is comprised of hundreds if not thousands of homeostatic/Well-Being Systems. Over evolutionary time, life utilized the basic genetic and biochemical machinery of homeostasis to build other well-being maintaining systems; each new system utilizing the same basic, multi-step process of sensing need states, making choices, effecting appropriate actions, and then judging the consequences of that cycle again on the state of some self-related need variable such as temperature, safety, belonging or a new solution to a problem.  The result is that life itself can be thought of as a complex adaptive system comprised of trillions upon trillions of highly interconnected, nested, functionally similar, but not identical Well-Being Systems.[xxviii]  The functioning of all such systems, from the simplest chemical regulation within a cell to the most complex control of an entire organism within a dynamic ecosystem across space and time, involve continuous adjustments in order to remain successfully attuned to the needs of an ever-changing environment.[xxix]  Thus it is that within every human, trillions upon trillions of Well-Being Systems are simultaneously cycling along, perceiving needs and enacting choices; virtually all happening outside of human conscious awareness.

My analysis, supported by research and theory in evolutionary biology, the social sciences and philosophy, suggests that all of these trillions of human Well-Being Systems can be categorized into seven basic modalities.[xxx]  These seven basic Well-Being System modalities are separable because each is the by-product of one or a series of major transitional events in human evolutionary history.  Each category of Well-Being System arose in response to specific environmental needs and selective pressures.  This is why it is possible to identify within most of these modalities numerous types of Well-Being Systems with ancient pedigrees serving similar functions in countless other organisms beyond humans.  Within each of these modalities, in particular those that are most recently evolved, it is also possible to identify entirely modern and uniquely human types of Well-Being Systems.  But whether ancient or modern, all Well-Being Systems within a modality bear evidence of a shared ancestry.

Human Well-Being System Modalities

Briefly summarized, the seven human Well-Being System modalities are:

  1. Continuity – the cluster of Systems that actively maintain a constant and self-sustaining physiological state; a main goal is stability.[xxxi]
  2. Individuality – Systems designed to protect and defend the whole organism by recognizing, avoiding and when necessary attacking others perceived to be “not self;” a main goal is security.
  3. Sexuality – Systems primed to recognize and respond to other selves, either positively or negatively depending upon species-specific sexual characteristics; a main goal is reproductive success.
  4. Relationality – the cluster of Systems that selectively foster associations with and cooperation between other entities perceived as part of the self; main goals are love and belonging.[xxxii]
  5. Social Awareness – Systems that enable conscious perception of the relative position of the individual relative to others within the group; main goals are status and esteem.
  6. Envisaging – Systems that utilize conscious awareness as a vehicle for projecting the self beyond immediate circumstances in time and space; main goals are improved understanding of the past and planning for the future.
  7. Creativity/Spirituality – Systems that enable abstract thought, and with it the ability to purposefully and imaginatively project one’s self into situations unfettered by immediate realities; main goal is personal fulfilment and building of identity.

Prima facie evidence for separating human Well-Being Systems into these seven modalities comes from current understandings of brain anatomy and function.  For example, the Systems responsible for Continuity, Individuality and Sexuality are disproportionately localized within the oldest parts of the brain, including and particularly the brain stem and limbic systems[xxxiii] while Systems responsible for Envisaging and Creativity/Spirituality are primarily localized in the most recently evolved parts of the brain such as the pre-frontal lobes.[xxxiv] However it is essential to understand that although the human brain plays a critical role in the processing and functioning of large percentage of human Well-Being Systems, such Systems come in a wide range of forms and sizes with some located entirely within the brain, e.g., the Systems involved with processing the content of this sentence, some entirely within individual cells, e.g., the Systems involved with the intracellular pH regulation, and others distributed across large areas of the body, e.g., the digestive system, writ large.

Whether distributed throughout the body or restricted to the boundaries of a single cell, complex vertebrates like humans have evolved multiple electrical and chemical processes in order to monitor and generally triage the competing needs of all the multiple “selves” of the organism.[xxxv] The result is that the brain regularly processes trillions of competing signals coming from both internal and external sources; each signal vying for dominance.  The “fittest” signals are selected, resulting in choices and actions, which in turn are monitored to determine whether or not well-being is enhanced and maintained.[xxxvi]  In large complex organisms such as vertebrates, sometimes actions are required that involve the mobilization and simultaneous coordination of large numbers of Well-Being Systems.  It appears that emotions evolved for just this purpose. Not only are signals with high emotional valence deemed worth attending to, they also have a galvanizing effect that helps to focus and coordinate otherwise competing needs.  In addition events with high emotional valence also make choices and actions more likely to be memorable and replicable; emotionally charged events are also more likely to be consciously discernable.[xxxvii]

As stated earlier, most of the activity involved in the functioning of Well-Being Systems operates below the level of conscious awareness.  Of course people seem to be aware of many things about themselves but these perceptions are rarely direct.  Whether feelings related to physiological states such as hunger or pain or psychological states such as love or curiosity, these perceptions are actually cued by secondary, parallel processes rather than direct perception of the actual Well-Being System.[xxxviii]  And language based descriptions of feelings, are yet another step removed.[xxxix] Thus people’s descriptions of their choice-making, including and particularly the reasons why they believe they made the choices they did, need to be viewed with appropriate skepticism.  Verbal descriptions about the nature of choices can provide useful clues about underlying processes but should never be viewed as fully accurate representations of core Well-Being Systems in operation.[xl]

However, whether conscious or not, typically all seven Well-Being System categories influence human well-being.  Even more importantly, one cannot fully understand the functioning of what some consider the “higher” modalities such as Envisaging and Creativity/Spirituality, without understanding the functioning of “lower” modalities, such as Continuity and Individuality.  Each successive type of modality evolved from earlier modalities; each subsequent modality re-purposing earlier pathways and processes in order to adapt to new challenges and opportunities, creating new, more complex manifestations of earlier systems in the process.[xli]  Importantly, normal human behavior nearly always reflects a blending of needs emanating from multiple modalities rather than the singular expression of the needs of a single modality.[xlii]

Human Choice-Making

So in summary, the following represents the key assertions of this new model as pertains to choice-making within humans:

  • People constantly make choices in an effort to satisfy self-related needs; collectively choices and needs and the sensing and acting that mediate between the choices and needs combine to form Well-Being Systems. Extant Well-Being Systems were selected for over evolutionary time because the perceptions of well-being generated by these systems were correlated with enhanced fitness.
  • Creating well-being is challenging, as is maintaining well-being. As a consequence, choice-making on behalf of well-being is primarily designed to achieve short-term well-being and is assessed phenotypically, moment by moment.
  • Well-Being is always framed through the lens of self-perception. Self-perceptions allow a person to distinguish and judge the quality of his reality relative to his surroundings, which in turn provides a concrete frame of reference for making actionable choices.
  • Every human is comprised of not just a single Well-Being System, but trillions upon trillions of Well-Being Systems.
  • Although these myriad Well-Being Systems all have distinct characteristics they all share a common, ancient origin and generally can be classified as falling into one of seven distinct modalities of Well-Being System – Continuity, Individuality, Sexuality, Relationality, Social Awareness, Envisaging and Creativity/Spirituality. Each of the seven modalities are reflective of both the unique needs they evolved to satisfy and the social and cultural milieu in which they currently are enacted.
  • Every human choice and every resulting action represents a response to the self-related needs originating from one or typically some combination of these seven core Well-Being Systems.
  • Human Well-Being Systems come in a wide range of forms and sizes with some located entirely within the brain, some entirely within individual cells and others distributed across large areas of the body.
  • Despite their varied size and distribution, signals from the vast majority of Well-Being Systems find their way to the brain where they are monitored and processed. The trillions of competing signals coming from both internal and external sources vie for dominance, the “fittest” are selected, resulting in choices and actions, which in turn are monitored to determine whether or not well-being is enhanced and maintained.
  • Emotion evolved as a device for facilitating the maintenance of Well-Being Systems. Signals with high emotional valence are deemed worth attending to.  High emotional valence also makes choices and actions more likely to be memorable and consciously discernable.
  • Most of the activity of Well-Being Systems, and thus most human choice-making, operates below the level of conscious awareness. Individuals typically only become aware of these processes through secondary, parallel processes, e.g., through emotions, which in turn trigger the language centers of the brain.  Thus verbal descriptions about choices are always inferential and should never be viewed as fully accurate representations of underlying processes.

In conclusion I assert that my proposed Well-Being Systems model provides a theoretically sound and evolutionarily plausible way to describe the fluidity and complex adaptability of living choice-making systems in general, and human choice-making systems in particular.  It is an integrative model that parsimoniously synthesizes findings from the biological and social sciences. The model offers a comprehensive way to understand macro processes affecting observable human choice-making behaviors, as well as the narratives humans use to describe how and why they choose to act in the ways they do.  Equally, if not more importantly, the Well-Being Systems model also provides explanations for micro processes since fractal-like commonalities exist across Systems at each biological level, from the biochemical up to the ecosystem and beyond.[xliii]  Unfortunately tools do not currently exist in either the biological or social sciences to fully decipher or describe the vast complexity of interlocking and synergistic Well-Being Systems at any of these levels.

My hope is that this new model will foster further synergies between the biological and social sciences, supporting new ways to make connections between what were historically viewed as disconnected life processes.  I look forward to any and all comments and suggestions.



The following represents a distillation from a forthcoming book, Falk, J.H. (in press). Born to Choose. New York: Routledge.


Leotti, L.A., Iyengar, S.S. & Ochsner, K.N. (2010). Born to choose: The origins and value of the need for control. Trends in Cognitive Sciences, 14(10), 457-463.


e.g., Nozick, R. (1990). A normative model of individual choice. New York: Garland Press.

Fernández-Huerga, E. (2008). The economic behavior of human beings: The Institutional/Post-Keynesian Model. Journal of Economic Issues, 42(3), 709-726.

von Neumann, J. & Morgenstern, O. (1972). Theory of games and economic behavior. Princeton, NJ: Princeton University Press.

Kahneman, D. & Tversky, A. (1972). Subjective probability: A judgment of representativeness. Cognitive Psychology, 3, 430-454.

Bell, D.E. (1982). Regret in decision making under uncertainty. Opinions Research, 30(5), 961-981.

Simon, H. A. (1956). Rational choice and the structure of the environment. Psychological Review, 63, 129-138.

Fishbein, M. & Ajzen, I. (1975). Belief, attitude, intention, and behavior: An introduction to theory and research. Reading, MA: Addison-Wesley.

Shiffrin, R. & Schneider, W. (1977). Controlled and automatic human information processing: II: Perceptual learning, automatic attending, and a general theory. Psychological Review, 84(2), 127–190.

Deci, E. L., & Ryan, R. M. (2000). The “what” and “why” of goal pursuits: Human needs and the self-determination of behavior. Psychological Inquiry, 11, 227-268.


e.g., Jeannerod, M. (2003). The mechanism of self-recognition in human. Behavioral Brain Research, 142, 1-15.


Wegner, D. (2002). The illusion of conscious will. Cambridge, MA: The MIT Press.

Edelman,G & Tononi, G. (2000). Reentry and the dynamic core. In T. Metzinger (ed.) Neural correlates of consciousness: Empirical and conceptual questions, pp. 121-138. Cambridge, MA: MIT Press.

Freeman, W. (2000). How brains make up their mind. New York: Columbia University Press.


cf., Torday, J.S & Miller, W.J. Jr. (2016). The phenotype as agent for epigenetic inheritance. Biology,  5, 30; doi:10.3390/biology5030030.

Torday, J.S. (2013). Evolutionary biology redux. Perspectives in Biological Medicine, 56, 455–484.


e.g., Ryff, C. D. (2014). Psychological well-being revisited: Advances in the science and practice of Eudaimonia. Psychotherapy & Psychosomatics, 83(1), 10-28.

Cloninger, C. R. (2004). Feeling good: The science of well-being. Oxford: Oxford University Press.

Eid, M. & Larsen, R. J. (Eds.). The science of subjective well-being. New York: The Guildford Press.

Diener, E. & Biseas-Diener, R. (2008). Happiness. Malden, MA: Blackwell Publishing.


A large number of wide-scale surveys and assessments of well-being, typically referred to in the psychological literature as “subjective well-being” have been developed.  These assessments have now been administered to individuals, groups and even whole nations (e.g., Hicks, S. (2012). Measuring subjective well-being: The UK Office for National Statistics experience. In Helliwell, J. F., Layard, R., & Sachs, J. (Eds.), World happiness report. New York: Earth Institute; Helliwell, J., Layard, R. & Sachs, J. (Eds.). (2016). World Happiness Report 2015.  New York: Earth Institute.  Retrieved December 8, 2016; Diener, E. (2015). Subjective Well-Being Scales.  Retrieved December 8, 2016.


Dolan, P. (2014). Happiness by design: Finding pleasure and purpose in everyday life. London: Penguin


Importantly, this idea of making a judgment, in essence taking abstract information and converting into actionable information is the very essence of all Well-Being Systems, from the most fundamental homeostatic systems all the way through the most complex creative systems responsible for driving scientists to try and understand the natural world. Defining biological systems using such seeming metaphorical definitions makes many scientists uncomfortable. For example, critiques by Tauber (Tauber, A.I.,(1994). The Immune Self: Theory or Metaphor?, New York and Cambridge: Cambridge University Press) and Pradeu and Carosella (Pradeu, T & Carosella, E.D. (2006). The self model and the conception of biological identity in immunology. Biology and Philosophy, 21, 235-252) have specifically taken issue with the longstanding use of the self-non-self metaphor to describe immunological processes. Although these authors raise some interesting issues, ultimately these and other critiques are predicated on the argument that something like self-perception cannot exist because it would require that living organisms, including simple one-celled creatures like bacteria were capable of dealing with abstractions, rather than the actual concrete realities of real life; in other words chemistry and physics.

I would argue that rather than trying to force living things into a mechanistic mode where all processes are based on absolutes, we should accept that life is actually quite creative and that flexible adjustments to an ever changing and variable world are not exceptions but the rule for living things.  So rather than seeing the inherently metaphoric nature of Well-Being Systems as a fundament flaw in how we think about life processes, we should see it as a fundamental strength.  The metaphorical and open-ended nature of the model actually quite accurately reflects the realities it is attempting to explain.  The fact is that perception of the self, and the Well-Being Systems those perceptions support are always abstractions, despite the fact that living things perceive and act upon them as if they were a concrete reality.  As accurately described by Preadeu and Carosella, living things are indeed open systems. [ix] But by necessity organisms act out their lives as if they were closed systems.  Doing so has been evolutionary selected for.  The boundaries of life cannot be absolutely defined.  However the best way to survive is to arbitrarily define boundaries.  In other words, a perceived boundary, even if it is not 100% real, is capable of being defended; open undifferentiated spaces cannot be defended.  Life is indeed continuous, but living things, including humans, prefer to see the world as discrete, defined by simple dichotomies – inside-outside, me-not me, good-bad, safe-unsafe.  Creating an association between two seemingly unrelated activities, such as perceiving a relationship between becoming violently ill and a food one might have eaten hours before is a huge intellectual leap but one that humans and many other organisms make every day. The essence of life is the ability to operationalize the metaphorical; the ability to treat abstract realities as if they were concrete and tangible. In so doing, organisms impose boundaries on the ephemeral and open-ended nature of life and make it possible to make choices and act as if there was permanence and continuity.


Blouin-Hudon, E-M. & Pchyl, T. (2015). Experiencing the temporally extended self: Initial support for the role of affective states, vivid mental imagery, and future self-continuity in the prediction of academic procrastination. Personality and Individual Differences, 86, 50-56.


Ersner-Hershfield, H. Elliott Wimmer, G. & Knutson, B. (2009). Saving for the future self: Neural measures of future self-continuity predict temporal discounting. Social Cognitive and Affective Neuroscience, 4(1), 85–92.


Ersner-Hershfield, H. Elliott Wimmer, G. & Knutson, B. (2009). Saving for the future self: Neural measures of future self-continuity predict temporal discounting. Social Cognitive and Affective Neuroscience, 4(1), 85–92.


Mischel, W. (2014). The marshmallow test: Conquering self-control. New York: Little, Brown.


Blouin-Hudon, E-M. & Pchyl, T. (2015). Experiencing the temporally extended self: Initial support for the role of affective states, vivid mental imagery, and future self-continuity in the prediction of academic procrastination. Personality and Individual Differences, 86, 50-56.


e.g., Vincent, T. (2005). Evolutionary Game Theory, Natural Selection, and Darwinian Dynamics. Cambridge, UK: Cambridge University Press.


Martin, W. & Russell, M.J. (2003). On the origin of cells: A hypothesis for the evolutionary transitions from abiotic geochemistry to chemoautotrophic prokaryotes, and from prokaryotes to nucleated cells. Philosophical Transactions of the Royal Society of London, B-Biological Sciences, 358(1429), 59–85.

Margulis, L. & Sagan, D. (1986). Microcosmos. New York: Summit Books.

Maturana, H. & Varela, F. ([1st edition 1973] 1980). Autopoiesis and Cognition: the Realization of the Living. In R.S. Cohen & M.W. Wartofsky (Eds.), Boston Studies in the Philosophy of Science, 42. Dordecht: D. Reidel Publishing.

Monnard, P.A. & Deamer, D.W. (2002) Membrane self-assembly processes: steps toward the first cellular

life. The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology, 268, 196–207.


Prigogine, I. & Nicolis, G. (1977). Self-Organization in Non-Equilibrium Systems. New York: Wiley.


Woese, C. (1998). The universal ancestor. Proceedings of the National Academy of  Sciences, USA, 95(12), 6854-6859.


Torday, J.S. (2015). Homeostasis as the mechanism of evolution. Biology, 4, 573-590.


Cavalier-Smith, T. (2004). The membranome and membrane heredity in development and evolution. In R. P. Hirt and D. S. Horner, eds., Organelles, genomes and eukaryote phylogeny: An evolutionary synthesis in the age of genomics, pp. 335–351. Boca Raton: CRC Press.


Jablonka, E. & Lamb, M. (2014). Evolution in four dimensions: Genetic, epigenetic, behavioral and symbolic variation in the history of life. Cambridge: MIT Press.


Cummings, B. (2006). Pearson Educational Publishing.


Torday, J.S & Miller, W.J. Jr. (2016). The phenotype as agent for epigenetic inheritance. Biology,  5, 30; doi:10.3390/biology5030030.


It is speculated that the first homeostatic mechanism was designed to regulate calcium concentrations in the primordial cell.  Kamierczak, J. & Kempe, S. (2004). Calcium build-up in the Precambrian seas. In J. Seckbach (Ed.) Origins, pp. 329-345. Dordrecht, The Netherlands: Kluwer.


[xxv] McEwan, B.S. & Wingfield, J. (2010. What is in a name? Integrating homeostasis, allostasis and stress. Hormones and Behavior, 57, 105–111.

Giordano, M. (2013). Homeostasis: An underestimated focal point of ecology and evolution. Plant Sciences, 211, 92-101.


cf., Gould, S.J. & Vrba, E.S. (1982). Exaptation – a missing term in the science of form. Paleobiology. 8(1), 4–15.


It should be noted that I am certainly not the first person to see a connection between homeostasis and higher order processes, including human psychological functioning (e.g., Cofer, C N. & Appley, M. H. (1964). Homeostatic concepts and motivation. In C N. Cofer & M. H. Appley, Motivation: Theory and Research (pp. 302-365). New York: Wiley).  But most of these early applications of homeostatic processing to human behavior were based upon Behaviorist frameworks and assumed that humans mechanistically and rigidly responded to the environment analogous to the way a thermostat responds to changes in temperature.  These early models also did not account for the diversification and radiation of these homeostatic-like processes into the wide array of new, evolutionarily connected but functionally novel forms that humans now display, including at the social and analytical levels.


It is not a stretch to think of Well-Being Systems as having fractal-like qualities, appearing as suggested by John Torday (Torday, J. (2016). The cell as the first niche construction. Biology, 5, 19-26.) at every level of biological organization, subcellular to cellular to tissue to organ to organism to social system, potentially all the way up to the Gaia-like level of ecosystems.


Torday, J. (2015). Homeostasis as the mechanism of evolution. Biology, 4, 573-590.


As stated above, these seven interconnected but functionally discreet modalities of Well-Being Systems reflect my best effort to build on previous theory and synthesize available evidence.  Four specific sources are discussed below.

I sought to accommodate the considered thinking of historian, Jerrold Siegel’s monumental analysis of 500 years of Western philosophical thought on the nature of the self in which he distinguished three basic types of self-perception – bodily, relational and reflective (Siegel, J. (2005). The idea of the self: Thought and experience in Western Europe since the eighteenth century. Cambridge: Cambridge University Press).

Psychologist Abraham Maslow’s five levels of human need, often represented as a pyramid of well-being has long been a dominant model for understanding human behavior (Maslow, A. (1943). A theory of human motivation. Psychological Review, 50(4), 370–396). Maslow’s five stages of well-being, often referred to as Maslow’s hierarchy of needs because each stage was thought to build upon the satisfaction of needs in the stage below, included: physiological needs, safety, love/belonging, esteem and self-actualization. I’ve also included for comparison a more recent version of Maslow’s hierarchy of needs developed by evolutionary psychologists, Douglas Kenrick, Vladas Griskevicius, Steven Neuberg and Mark Schaller (Kenrick, D. T., Griskevicius, V., Neuberg, S. L., & Schaller, M. (2010). Renovating the pyramid of needs: Contemporary extensions built upon ancient foundations. Perspectives on Psychological Science, 5, 292-314).  Kenrick, Griskevicius and Neuberg argue that although basically sound, Maslow’s hierarchy of needs was never accurately or appropriately anchored to evolutionary theory.  They proposed a new hierarchy, primarily based on findings from evolutionary psychology, including needs such as mate acquisition and retention and parenting.[xxx]

Finally, in what is now considered a classic work, evolutionary biologists John Maynard Smith and Eors Szathmary hypothesized that there were eight major transitions in the evolution of life, beginning with the compartmentalization of molecules, i.e., evolution of cell membranes to the evolution of societies and language (Smith, J.M. & Szathmary, E. (1995). The major transitions in evolution. Oxford, UK: Oxford University Press).

The following table how my 7 categories align with those developed by Siegel, Maslow, Kenrick et al., and Smith and Szathmary:

Kenrick, et al.
Smith & Szathmary
Physiological Needs
Immediate Physiological Needs
Populations of Molecules in Compartments
Unlinked Replicators to Chromosomes
Genetic Code
Prokaryotes to Eukaryotes
Physiological Needs
Mate Acquisition
Asexual Clones to Sexual Populations
Protists to Multicellular Organisms
Solitary Individuals to Colonies
Primate Societies to Human Societies/Language
Mate Retention
Primate Societies to Human Societies/Language
Creativity/ Spirituality

Reflectivity What should be apparent from this table is the close, though not perfectly alignment between the ways I categorize the human Well-Being Systems and the major categories proposed by these four other models. Perhaps not surprisingly, given my focus on humans, my model like that of Siegel and Maslow, adopts a more fine-grained view of later evolving modalities, while consolidating several of the important early evolutionary milestones noted by Smith and Szathmary, who were not primarily focused on non-humans.  At a minimum, these multiple lines of evidence drawn from philosophy of self, psychology of need and evolutionary biology support the basic premise that it is possible to distinguish categorical disjunctions in human evolutionary history; disjunctions I argue are reflected in the form and function of present-day human Well-Being Systems.


[xxxi] I selected the terms Individuality and Continuity to describe these first two fundamental Well-Being System modalities since they reflect what English Philosopher David Wiggins described as the two foundational and complimentary aspects of all human perceptions of self (Wiggins, D. (2001). Sameness and substance renewed, 2nd edition. Cambridge, Cambridge University Press).


Relationality is the generic term historian of philosophy Jerrold Siegel uses to describe this class of self-related perceptions (Siegel, J. (2005). The idea of the self: Thought and experience in Western Europe since the eighteenth century. Cambridge: Cambridge University Press.).


LeDoux, J. (2002). Synaptic self: How our brains become who we are. New York: Penguin.

Damasio, A. (2010). Self comes to mind. New York: Vintage.

Eagleman, D. (2015). The brain: The story of you. New York: Pantheon.


[xxxiv] LeDoux, J. (2002). Synaptic self: How our brains become who we are. New York: Penguin.

Damasio, A. (2010). Self comes to mind. New York: Vintage.

Eagleman, D. (2015). The brain: The story of you. New York: Pantheon.


Over the past few decades scientists have become aware of the fact that every human is host to a massive array of microbes living on the skin and throughout the body.  In fact, it is now estimated that there are more than ten times as many genetically unrelated “selves” living within a person than genetically related ones, and although each is microscopic and weighs virtually nothing, if combined they would weigh about 6 pounds.

cf., Wolfe, N. (2013). Small, small world. National Geographic, 223(1), 136-147.

Smith, P.A. (2015, June 23). Can the bacteria in your gut explain your mood? New York Times  Retrieved June 27, 2015.

            Ridaura, V.K., Faith, J.J., Rey, F.E., Cheng, J., Duncan, A.E., Kau, A.L., Griffin, N.W., Lombard, V., Henrissat, B., Bain, J., Muehlbauer, M.J., Ilkayeva, O., Semekovich, C.F., Funai, K., Hayashi, D. K., Lyle, B.J., Martini, M.C., Ursell, L.K., Clemete, J.C., Van Treuren, W., Walters, W.A., Knight, R., Newgard, C.B., Heath, A.C. & Gordon, J.I. (2013).  Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science, 341 (6150): 1214.


[xxxvi] e.g., Edelman, G. (1989). Neural Darwinism – The Theory of Neuronal Group Selection. New York: Basic Books.

LeDoux, J. (2002). Synaptic self: How our brains become who we are. New York: Penguin.

Eagleman, D. (2015). The brain: The story of you. New York: Pantheon.


LeDoux, J. (2002). Synaptic self: How our brains become who we are. New York: Penguin.

Damasio, A. (201). Neural basis of emotions. Scholarpedia, 6(3):1804.  Retrieved December 8, 2016.


LeDoux, J. (2002). Synaptic self: How our brains become who we are. New York: Penguin.

Eagleman, D. (2015). The brain: The story of you. New York: Pantheon.


Eagleman, D. (2015). The brain: The story of you. New York: Pantheon.


Wegner, D. (2002). The illusion of conscious will. Cambridge, MA: The MIT Press.


Adami, C., Ofria, C. & Collier, T.C. (2000). Evolution of biological complexity. Proceedings of the National Academy of Sciences (USA), 97, 4463–8.

Torday, J.S. (2015). A central theory of biology. Medical Hypotheses, 85, 49–57.


A fuller, more neurologically justified explanation is available in Falk, J.H. (in press). Born to Choose. New York: Routledge.


As also suggested by Torday (Torday, J. (2016). The cell as the first niche construction. Biology, 5, 19-26).

Retrograde Polymorphism during Sublethal Environmental Stress

By Jean Guex (ISTE, University of Lausanne, Switzerland)

A detailed discussion of the effect of sublethal stress on the evolution of invertebrates is given in the book of Guex (2016; review in Guex and Verkhratsky, this issue). In this paper we will present a brief description of the effect of major stress on the development and evolution of some foraminifera and ammonoids. In the two cases discussed below, we show that retrogradation does’nt generate only retrograde evolution but also retrograde polymorphism.

One notable case of polymorphisms was named “Buckman’s law of covariation”. Buckman first discovered that some extreme morphotypes of atavistic habitus with simple and archaic morphologies show a perfectly continuous morphological spectrum towards the most advanced forms in the same sedimentary beds (synchroneity of the ammonite population). One example given by Buckman concerns the beautiful and famous ammonite genus Amaltheus of the gibbosus group which first occur during the Upper Pliensbachian located at the transition between the Gibbosus and Spinatum zones in the Late Pliensbachian (see Guex 2016 for references). The evolute spinose zonal index Amaltheus gibbosus is an atavistic form generated from involute A. margaritatus which strongly resembles the ancestral morphology of the Sinemurian Eoderoceras.

We consider as fascinating the fact that some planctonic foraminifera (e.g. the lineage Ticinella Thalmanninella) display a covariation which is similar to that observed in some ammonoids. Foraminifera are well known to be extremely sensitive to environmental stress and several classical studies have shown that the variability of these organisms was polarized in function of thermal and chemical stress and by depth.

The evolutionary trend observed in the Ticinella Thalmaninella lineage illustrates the frequent evolutionary trend occurring in coiled shells (Fig.1): in the T. greenhornensisT. multiloculata plexus a strong keel is developed at the maximum lateral curvature of the chamber, demonstrating the relation between morphogen concentration and strong curvature of the membrane secreting the shell. During episodes of environmental stress such as anoxic events, a retrograde polymorphism is observed in these protists, which is perfectly similar to the case of Amaltheus described above, as illustrated in Fig.1.

The fact that Buckman’s First Law of Covariation applies to both unicellulars and metazoans proves that similar biochemical signals are at work in both types of organisms, the membrane of foraminifera functions in a way similar to the ammonoids’ mantle.

Fig.1 (a) Evolutionary lineage going from the simple and evolute ancestral planktonic foraminifera Ticinella (right) towards the involute and carinated Thalmaninella. The variability of a single synchronous population illustrated in Fig.1-a mirrors the evolutionary sequence observed in this group.

(b) Highly evolute “Eoderoceras-looking” (right) Amaltheus gibbosus showing a similar trend from evolute towards involute coiling (A.margaritatus) during a Pliensbachian environmental stress episode.

Technical Remark

Covariation depends on the internal shell geometry, namely the lateral and ventral curvature of the shell which controls the amount of morphogens present in the more or less curved mantle, the most salient ornamentation being present where the whorls are most curved, shells with slight angular bulges often being spinose or carinate and flat ones being almost smooth. Our empirical conclusion was that the covariation phenomenon could be explained within the framework of Gierer-Meinhardt’s reaction diffusion models. To prove that conclusion, we simulated the distribution of “morphogens” (in the physical sense) in a quadrangular body chamber and demonstrated that morphogens maxima are located, as expected, in the part of the mantle located in the angular parts of the shell. For this, we calculated a numerical solution of the Gierer-Meinhardt equations for a cross section through an ammonite shell, orthogonal to the growth axis. In the computation, the units of distance, time and concentration are arbitrary. The boundaries of the domains are supposed to be impervious for the inhibitor. The outer boundary (arc of circle) is unaffected by the activator whereas the other boundaries are susceptible to this factor. The choice of these boundary conditions is motivated by the following arguments: The activator is supposed to diffuse freely outside the mantle’s cells (or the membrane of foraminifera) into the environment (intercellular medium and sea water). The reaction-diffusion equations are solved numerically on a hexagonal mesh containing 1500 nodes corresponding to a hexagon radius of 0.23 units. The concentrations a(x,t) and h(x,t) are determined at each node of the mesh. The initial values of the concentrations at t = 0 correspond approximatively to the values taken from the (unstable!) homogenous stationary solution. We add small random deviations ε(x,0) to the concentrations of the activator to allow the system to leave the initially homogenous state. The stationary inhomogeneous solution is found using a standard iterative procedure (details in Guex 2016 with references). Similar conclusions were obtained by Newell et al. (2008) in their general study of phyllotaxy: “… buckling leads to a template for primordia, it is growth that leads to the visible primordial bumps and phylla. This growth is postulated to be a biochemical response, perhaps through chemical agents such as auxin, to the local stress or curvature inhomogeneities of the buckled surface …”. In our carbonate shelly invertebrates, the morphogens have obviously nothing to do with auxin but could simply be Ca2+ ions. The output of our calculation shows that the distribution of the activator and inhibitor in a bended shell displays very low concentration in the smooth part and very high concentration in the curved part, both in foraminifera and ammonoids. More recently, an alternative model leading to the same kind of conclusions has been proposed by Mercker et al. 2013 where the authors write that “biomechanical forces may replace the elusive long-range inhibitor and lead to formation of stable spatially heterogeneous structures without existence of chemical prepatterns. We propose new experimental approaches to decisively test our central hypothesis that tissue curvature and morphogen expression are coupled in a positive feedback loop”. It might be useful to note that a multitude of mathematical models can simulate the pattern formation in shelly organisms. To illustrate this we can mention the fact that phyllotaxy, a domain studied by botanists, has been formally described by models developed in three totally different fields of mathematics: pure geometry by Van Iterson (1907), pure physics by Douady and Couder (1992) and reaction-diffusion by Meinhardt et al. (1998). In other words it is clear that our model of spine formation in ammonites is obviously not the only possible (all refs. in Guex 2016).


Jean Guex (2016). Retrograde evolution during major extinction crises. Springerbriefs in Evolutionary Biology. (Personal copies: write to

How Deep is the Neuron?

By Tam Hunt

A conversation with Anirban Bandyopadhyay about new advances in neuroscience.

The study of consciousness is becoming more serious. From being a rather fringe field during the 20th Century it has in the new century become a more mainstream endeavor with substantial funding and many careers now being built on our effort to understand the mind, brain and their interactions.

Somewhat surprisingly, many large questions about the functioning of our psyches are still unanswered, including how memory works, or even where memories reside, why we sleep, why we dream, how free will works (or doesn’t) and many more.

And the biggest of our unsolved mysteries: what the heck is consciousness itself and how does it relate to matter and the brain?

We are on our way to answering these questions and key to good answers to these longstanding mysteries is a better understanding of how neurons work and how they interact. Neurons are the building blocks of the brain and our understanding of these specialized cells has improved immeasurably in recent decades.

As we’ll see below, however, there is much that we don’t know, including exactly how much computation goes on in each neuron. Some researchers, including Hameroff and Penrose, have highlighted the role of microtubules in adding many layers of complexity and computation to our current brain models. Others, like the researcher interviewed here, think that might just be the tip of the computational iceberg.

Anirban Bandyopadhyay is a senior researcher at the National Institute of Materials Science in Tsukuba, Japan, and an adjunct professor at the Michigan Technological University. He studies the brain and is creating a detailed unconventional model of the brain he calls the frequency fractal model. Anirban is on the cutting edge of research into the neuroscience of consciousness.

I met Anirban originally at the annual Science of Consciousness conference hosted by the University of Arizona, where he is a regular speaker. I interviewed Anirban by email for my upcoming book further examining the intersection of philosophy, science and spirituality.

My own thoughts on the nature of consciousness are detailed in a technical manner in a 2011 paper in the Journal of Consciousness and a book length treatment called Eco, Ego, Eros: Essays in Philosophy, Science and Spirituality.


  1. What are the most interesting questions in neuroscience today? 

The most interesting questions in neuroscience today are questions like what is information, what is memory and where is it located? The synaptic junction is widely believed to be the locus of memory storage, but it may not be true.

Neuroscience needs more effective eyes at the atomic scale to see what happens inside the neuron. The days of Hodgkin-Huxley and Sakman Neher, which led to the idea that information in a neuron is stored in the synaptic junctions only, are over. We are seeing more and more evidence that supports the idea that it is not the firing above threshold but below the synaptic threshold that plays the major role in information processing in the brain.

To reveal what is happening within neurons, we need to find elements that live inside the neuron and regulate sub-threshold firing in a sophisticated manner. So neuroscience is awaiting a major invention in the form of an “atomic eye” that would enable us to take the next quantum leap in understanding information processing in the brain at a deeper level.


  1. Do you find philosophical questions like the “hard problem” of consciousness intriguing or useful? Where do you fall on the spectrum from idealism to panpsychism to materialism?

Whether we tag this the “awesome problem” or “hard problem” or “jackass problem,” the fact remains that unless we better define what consciousness is, mere adjective tags don’t serve much good.

I don’t consider the various philosophical positions on the nature of consciousness that important when we consider that the universe and human minds are frequency fractals that generate frequency wheels. Thus, inside the giant frequency wheel of the universe, our human minds are a simple subset. This position may fairly be labeled panpsychism because mind exists at levels in this model of the universe.


  1. Do you have a preferred theory of consciousness, such as Hameroff and Penrose’s Orchestrated Objective Reduction (Orch OR) theory? Or do you have your own theory of consciousness? 

I am trying to derive a better definition of consciousness, and I prefer to experimentally verify sensible models of consciousness. I like Orch OR but I feel that it is too early to have a well-developed theory of consciousness because there still isn’t enough information to create one.


  1. You stated in a 2014 interview: “Evolution is just a march to capture material or matter from nature and enrich that resonance chain.” Could you flesh out what this means?

We have an experimental laboratory where we build organic supramolecular structures. Our structures grow differently than a normal crystal. They change their symmetry over time and at various stages look very different. We have seen that when material growth is mostly incomplete, we find some of the resonance chains or vibrations are un-occupied, they need oscillators to complete this growth. What interaction enables the structure to evolve their geometry and generate new ones? We found that coupled resonance of elementary components may drive a very complex growth process. Elementary component seed A forms B, then B forms C, with each becoming more complex. The resonant oscillations of A creates a coupled electric field, which enables a new arrangement constituting B, and so on.

More generally, the drive to become more conscious is the primary drive in the universe, and this drive to become more conscious thus drives evolution. To be more conscious or more profoundly resonating with the universe is the objective of a living system. This drive results in structural modifications and we call this process evolution.


  1. What are the most promising “atomic eyes” that are being developed for looking more deeply into neurons?

What skin is to our body, cell membranes are to a neuron. The membrane’s ionic signals are strong and cellular electromagnetic signals appear as noise in a patch clamp, for example. Most of the noise elimination is done in the hardware and software using extensive filters. Above threshold, due to strong ionic bursts, the subtle changes in the potential are not visible. Patch clamp techniques can capture ions and neutralize them to estimate the membrane potential. This is a slow process, however, so it fails to map faster signals. The technology is limited in this key way.

Atom probes can, however, capture faster electromagnetic signals and we are thus able to track and record in far more detail the signal produced in the cells with these new tools. The atom probe is our new invention. It is a needle whose front part is 0.1 nanometers sharp. We cover it with an insulated area. Then, on the top we place another metal layer, creating a three-layered nano structure. It is an advancement of co-axial cable at the nano-scale.


  1. Orch OR focuses on microtubules as the key locus for quantum processing that leads to consciousness. Do you agree with this idea or are there other structures in the neuron that also play a heretofore unknown role in information processing and thus consciousness?

Microtubule and tubulin are extremely important for the information processing in the sub-neuronal scale, there is no doubt about this. There are, however, many other protein complexes involved in computation in neurons. For example, clathrin-SNARE complex, ribosome, proteosome, NOS (n+e), apoptosome and spliceosome etc. These five proteins complexes are as rich as microtubules and generate equally complex electromagnetic resonance bands similar to microtubules. In a fractal structure, there are various elements that play a role in filling up the major gaps in the resonance chain of the human brain. The resonance chain connects the smallest atomic structure to the largest sub-organs of the brain.


  1. In terms of the information processing ability of the human brain, if Orch OR or a similar model that focuses on sub-synaptic information processing is accurate, how many orders of magnitude of computational ability do we need to add in terms of creating viable human brain models? 

We need a new information theory to explain the decision making of the biological system. If we consider the brain to be a computer and then calculate how many bits, and how fast is it, we may miss some key details about how the brain really works. We have proposed that the human brain does not follow a traditional Turing tape model of computation; rather, it follows a fractal tape computational model. Transitioning conceptually from a Turing tape to a Fractal tape is easy: just consider that every single cell of a Turing tape also has a Turing tape inside it.

In a fractal tape based machine, we have a single bit, and then there are bits inside of that bit. At any time when you count the number of bits, it is always one. In a fractal system, the counting is never done the way we see it in a von Neumann type computer. The ability to build a brain-like machine depends on how many frequencies make a wheel. How complex is the wheel required to include all layers of computation present in the human brain? We add layers of fractals one above the other in our model and for human brain there are 12 layers. We need at least 12 layers of wheels to model the complexity of the human brain.

All memories are geometric in nature; here is a very brief summary of twelve kinds of memories that we found in the brain and how to edit them:

  1. Periodic memory: a chain of guitar string we see mostly in DNA, proteins, period of periods in the nodes of the string. You can edit the memory by changing the periodic length of elementary point oscillators.
    2. Spiral of spiral memory, in DNA and proteins, also in microtubules. Edit the memory by changing the twists and the number of hierarchical periods by inducing more and more twists.
    3. Vector memory, orientation of helices to make cavities inside protein. 3D orientation makes it a multipolar complex 3D vibrational element. Edit the memory by changing the orientation of column oscillators.
    4. Lattice memory, microtubule, actin-beta spectrin network, protein complex. Change the lattice parameters to edit the memory.
    5. Chemico-electric memory, chemical transmission cycles. There are nested time cycles highly interconnected, to edit the memory, change the diameter, phase, delay or starting points.
    6. Leak density of Cavity memory, ion diffusion holes in the cellular membrane. To edit the memory change the leak density on the cavity surface.
    7. Spiral geometric memory, assembly of neurons etc. To edit the memory, change the pitch-diameter-length of the spiral.
    8. Vortex or fractal memory, memory stored in the geometric parameters of vortex. A vortex has divergence parameters and scale repeat unit, these two parameters are changed to edit memory.
    9.Nodal & polar memory: Nodes in the spinal cord brain network (nodes in a tear drop). Geometry of the shapes are changed among 8 different choices from teardrop to ellipsoid to edit nodes and polarity memory.
    10. Electromechanical phase memory: organs sync and desync like a giant molecule. This memory is edited by changing the bond length or wiring length and distribution.
    11. Multipolar loop in phase space loop memory constitutes a “hyperspace memory.” This memory is non-physical and hence not editable.
    12. Phase of phase duality generator memory: hierarchical assembly of reality sphere. This memory is also non-physical and hence not editable.


7a. Ok, so if we view the human brain as a fractal tape type of computer rather than a Turing tape computer how many orders of magnitude of computation do we need to add to account for these 12 fractal layers of computation? Hameroff 2013 estimated about 1016 additional operations per neuron per second, for a total of 1021 operations per neuron per second, and a massive 1037 total operations per second for the entire brain, which accounts for the additional sub-synaptic microtubular computational operations. Do you agree? Or are there even more levels of computation going on inside neurons than Hameroff accounts for?

When we consider the fractal tape model, we cannot count the number of bits involved. Rather, what we count is always one rhythm. Instead of bits, or 0s and 1s, you have time cycles. We proposed the frequency fractal model of the human brain and introduced a very new kind of computing that rejects the Turing machine model of computation as well as Bertrand Russell’s way of thinking (Ghosh, S.; Aswani, K.; Singh, S.; Sahu, S.; Fujita, D.; Bandyopadhyay, A. Design and Construction of a Brain-Like Computer: A New Class of Frequency-Fractal Computing Using Wireless Communication in a Supramolecular Organic, Inorganic System. Information 2014, 5, 28-100). In our approach, you have only one time cycle or rhythm, but when you go deeper inside any point you find another time-cycle. So, there is no total number of operations per second. Those kinds of terms are applicable to those who believe in the Turing model of computing. For us, it is just one.

We argue that a user can see only the one clock in any given system and this clock constitutes a triplet of information: a seconds tick, a minutes tick and an hour’s tick. We have triplet clocks everywhere in all the layers of the human brain. We have already identified 350 different classes of cavities in the brain distributed over 12 layers nested one inside another. If each cavity resonator is an octave musical flute, then nearly 2,800 frequencies and time cycles compose one nested rhythm and that constitutes our total brain power. The current idea that more number of operations per second is an accurate approach to brain modeling is not right. That is the Turing way of thinking.

Information for us is a time cycle that can be modeled in particular geometric shapes. It is all about one rhythmic vibration that arises through integration of geometries using 2,800 frequencies over 10^20 Hz. Each vibration includes a “bing” moment (Hameroff’s metaphor for the moment of conscious awareness) and also a “silence” period. The “silence” contains the “phase”, and this holds the true information about the geometric shape of the particular time cycle. A band of frequencies always make a circular strip as it always vibrates periodically. Several such concentric circles make a frequency wheel that is an integration of the included time cycles. Such a fractal like integration of information (FIT) is fundamentally different than other theories of consciousness such as Tononi’s Integration Information Theory (IIT). Just one bit is enough for us to model the brain’s operations.

It takes only the product of 12 primes (1X3X5X7X11X13X17X19X23X29X31X37=10^11) oscillators to generate all possible patterns of wheels at each layer. This is the mathematically largest number of components we need to generate our brain dynamics. Our brain dynamics model is also relatively simple, with only eight steps to convert a tear-drop shape into an ellipsoid. These eight steps are enough to replicate all cavity shapes and their dynamics in the brain. The simplicity of our approach is a major benefit when compared to other computational approaches.


  1. Can you flesh out what you mean by resonance chains with respect to human consciousness or consciousness more generally? 

Every single element in the brain is a cavity resonator and has an electromagnetic resonance band. When several materials come together their resonance bands overlap to form a chain. Since the number of cavities in a larger cavity is finite, the chain is finite in length and as the guest cavities process only the geometric information, the total phase lag is always two π. Hence there is a time cycle. So, we convert a resonance chain into a wheel layer. Many nested layers make a frequency wheel and that constitutes our model of this type of system.


8a. What do you mean by brain cavity resonators and the geometric shapes used to model them?

For example, a cortical column is a cavity resonator. A neuron is also a cavity resonator. Inside the neuron the microtubule is like a flute and that’s also a cavity resonator. Tubulin proteins are dumbbell-shaped cavity resonators, and the alpha helices inside surrounded by beta sheets form yet another cavity resonator. A column of alpha helices is itself a flute-like cavity resonator.  Similarly, we can consider self-assembly or neural columns forming vital components of the brain, like nucleus or even hippocampus. Therefore, the whole brain is a giant leaky cavity resonator and then if we open it up we find a large number of cavity resonators inside. Our journey to open up and find the new cavities at each level continues until we reach the molecular scale.


  1. You mention missing resonance chains in our current models. What level of physical structure are you referring to?

We consider that every single biological element is a cavity resonator or a flute. You can integrate the flutes in two different ways. First, you place them side-by-side. This is called an iterative function system type fractal. Or you can place them “one inside another. That is called an escape time fractal. We can generate an analogue of any biological structure using the elementary cavities like flutes and integrating them side by side and/or “above and within”. We proposed a fusion of these two kinds of fractals as a generic approach of nature to construct an analogue of a biological systems.

As described above, a fusion of escape time fractal and iterative function system type fractals made of cavity resonators are generated to create an analogue of a biological system. This analogue structure vibrates in sets of resonance frequencies. Resonance can happen in various ways, like, for example, a tuning fork vibrates resonantly following a mechanical vibration. We have identified twelve different kinds of resonance frequencies that might be operating simultaneously in the human brain to make rhythms or cyclic vibrations, as follows:

  1. Electromagnetic rhythms [carrier is photon or electromagnetic wave is trapped in a cavity to generate beating or rhythm].
  2. Magnetic rhythm [spiral flow of electrons or ions, they are the carriers editing the magnetic flux, geometry of path forms the periodicity].
  3. Electrical potential rhythm [change in the arrangement of dipoles editing the electric field, fractal distribution of local resonators generate a time function of potential]
  4. Solitonic & quasi particle rhythm [carriers are solitons, defect in the order flows in a ordered structure, the ordered structure is edited to make a loop].
  5. Ionic diffusion rhythm, [ions are carriers, tube like cavities are formed in a circular shape or continuous path to generate a loop]
  6. Molecular chemical rhythm [molecules like proteins, enzymes, etc., are carriers, tube like cavities are formed and sensory systems make sure a circular signaling pathway]
  7. Quantum beating [spin is the carrier, wavefunctions interfere in a squeezed excited photonic, electromagnetic or spin state]
  8. Density of states rhythm [orbitals coupling, wave function modulation, virtual carrier, a virtual continuous loop is made]
  9. van-der Waal rhythm [atomic thermal vibration is looped in a spiral pathway].
  10. electro-mechanical rhythm [classical beating with a mechanical beating like tuning fork]
  11. Quasi-charge rhythm polaron, polariton [topological fractured band based continuous loops]
  12. Mechanical rhythm, sound wave [similarly elastic pathways to make a circuit of sound waves].

Now, we can put the resonance frequencies side by side, say, from 1 micro Hz to 1 peta Hz to create a chain. To understand resonance chains, just imagine that the chain of vibrations that starts from 1 micro Hz ends at 1 peta Hz. The group of frequencies arranged in a sequence for a system is the resonance chain and when vibration in the chain is repeated many times, it is a rhythm. A loop is represented by a circle. For twelve kinds of rhythms, several such circles can be put together and we get integration of that information, or what we call a frequency wheel.


  1. How does resonance relate specifically to the nature of consciousness? Do all resonating structures have some associated consciousness?

Our mathematical model shows that when the resonance chains in the form of a frequency wheel are drawn for a system, as described above, we get a composition of rhythms. A rhythm means, say, a sinusoidal wave that propagates continuously for an infinite time. We represent it using a single frequency value, which is the inverse of the time period of the waveform. Now, how could we combine frequencies? Let’s do some simple math here. A rhythm should have at least two frequencies. Or it could have three frequencies. If it has four frequencies they can be played as a pair of two. In this way we can integrate frequencies to make various kinds of rhythms.

What are the elementary compositions? For basic rhythms, which cannot be divided into smaller loops, we need prime numbers of frequencies to couple. For example, take a pair of frequencies and combine with that seven-frequency rhythm. This is a unit now and no one could find a sub-rhythm. This is why groups of prime numbers of different frequencies link together to form the architecture of information in the biological system.

Now, let’s do some more math. Try to find how many ways one could deconstruct a rhythm made of 12 frequencies? 2X (3X2) or 3X (2X2)? Both solutions are equally possible. This is a remarkable situation: we have a giant cavity resonator, say, our brain and we have two sets of rhythms, which exist in parallel. This occurs when one hardware system generates two replicas of the particular information structure and both can edit each other. This is called the mathematical criteria for consciousness.


  1. How many years are we from having a good working model of the human brain and mind?

We are creating the model now. We have already built one, which will be perfected over time. We feel strongly that redefining “information” and creating a new type of “information theory” is the key to move forward. We will have a good working model by the end of this year. We are writing a manuscript, and of course we will upload the entire database freely in the website, where we regularly update our research activities.


  1. Once we have a good working model of the human brain how many years do you think it will be before we’ll be able to upload human consciousness into a computational substrate?

We are already building small machines to demonstrate the duality of frequency fractals as an essential feature of consciousness and we have achieved some good progress. Once we generate the two distinct information structures from a singular hardware setup it will improve rapidly. We project that within five years we will patent the most primitive conscious machine. Note that the definition of consciousness is only “self-aware” here, it means a hardware that analyzes the environment and continuously edits it’s intelligence, knowledge and learning rules.

We will never, however, be able to upload human consciousness because artificial structures cannot be a replica. It will be a new consciousness of its own, but not a replica of human consciousness. The principle that we use to build the conscious machine suggests superposition of various features one on top of another. Such an integration has a simultaneity prerequisite and that cannot be replicated in any construction process at the molecular scale. In the future, if human race masters the  regulation of simultaneity, then it may be possible. Otherwise, however, we will be able to make humanlike machines, but never a true replica of any particular human

Pre-Biotic Evolution: Part IV. The Development of Electrochemically-Generated Energy Linkage, Extraction and Storage in Protocells

by Joseph H. Guth*

Published by the

Society for the Advancement of Metadarwinism, Volume 4 


One Scientist’s Overview and Perspectives


The first three parts of this series1, 2, 3 have described the time-dependent processes that  provide a plausibly likely pathway from the production and evolution of various atomic and molecular species through the formation of huge collections of varying complex chemical mixtures under early earth conditions.  The story continued with the general application of common physical activities and phenomena that would have commonly led to their packaging within simple membrane-enclosed volumes of such mixtures and their dispersal into new extracellular aqueous media.  This current chapter in pre-biotic evolution looks more closely at that and begins to mate these energy-requiring functions with energy sources and the growing complexities of a fully competent, self-sustaining version of protocell.

Uncountable numbers of protocell-like vesicular structures containing complex combinations of molecules and macro molecules collected over millenia.  They were derived in the primary laboratory, namely primordial earth, from the most diverse range of combinatorial chemical reactions.  Without living organisms yet present seeking out a food supply, those molecular libraries could have lasted for long periods in some environments.  Adsorbed onto mineral surfaces deep within the water-filled interstices of submerged clays and sediments, they could have remained relatively protected for greatly extended periods.   There, structures that contained macro-molecular assemblies that had reaction sequences within them, became the macro-molecular platforms for future super-complex branched predecessors of our current, well-regulated metabolic pathways made of various enzyme sequences.  Closed, lipid-based membranes spontaneously formed around many kinds of collected macro-molecule assemblages.  The new physicochemical

rules of lipids in water became the method and means for future combinations of these sequential functions to extend their evolutionary story through.  Simple fusion of all possible combinations then could have created brand new levels of complexity in which multiple end-products of simple pathway operation would have been generated in proximity with one another.  Such concentration of multiple new metabolic end-products  within single protocells now allowed larger scale leaps in the evolution of complex cell structure, design, operation and functioning.  At that point the rate at which evolution of inanimate matter into a truly self-sustaining state must have greatly accelerated.  With multiple occurrences of such breakthroughs at each of those critical points, this pre-biotic epoch appeared unchanging to the naked eye while major microscopic and chemical changes in growing complexity sprung forth on earth.

Looking back in retrospect at different pathways within modern life’s biochemical pathways and sub-cellular structures, we might very well be seeing a journal of the most successful types of ancient protocells that ultimately produced the first self-sustaining “living” early cells.  For example, the glycolytic pathway, an important pathway in most anaerobic as well as aerobic procaryotes and eucaryotes, regenerates adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate in modern organisms as it breaks down six carbon carbohydrates down to 3 carbon forms in the initial stages of their complex energy-extracting metabolism.  This part of the modern cell’s overall metabolic pathway complexity, composed of a small number of sequentially-operating chemical catalysts (i. e., what are now called enzymes) could very well have developed through combinatorial chemistry followed by self-selection.  If then captured within liposomes as a “starter set” within a relatively few early pre-biotic protocells, this would have given them certain advantages over the many other kinds of protocells they were mixed in with in various niches around the early earth.  But some of those other types of protocells must have had their own fragmentary reaction sequences operating that, if combined within some future hybrid already possessing the glycolytic reaction sequence, then provides that evolutionary quantum leap to a new set of survival capabilities.  See Figure 1.

Figure 1.  Protein-rich protocells with differing sets of contained unitary functions produced in uncountable numbers must have been a common occurrence in many niches on early earth.  Examples might include an ocean foam collecting at the water’s edge on a beach or a kind of bubbling, floating pond scum.  Mixing of such collections in a somewhat random fashion would have been accompanied by all manner of fusion hybridizations between these different parental lines of biochemical and biophysical function-carrying units.
It is not so difficult to imagine that when a few of these functional pathways combined into a single protocellular package it could have generated a major enhancement in its survival properties and thus ability to persist.  And as those more successful hybrids out-performed and multiplied by simple physical scission in flowing rivulets and crashing waves, each resultant metabolizing vesicle regenerated more of its unique collection of molecules.  Their overall numbers then could preferentially increase over the less functional previous forms.  Once this new hybrid became dominant, further mixing and fusions with other functionally distinct protocells would allow subsequent quantum leaps of development to become the newest dominant forms.  At some distant step in this fusion recycling, the independently free-living protocell would have come into existence.

No one should ever expect the formative steps of life on earth to not have been hap-hazardous, chaotic but bordering on random, irrational or inelegant.  Nature is really messy that way.  The march to a living state had to be a very crooked one at best.  Though not the current prevailing view, this piecemeal building up of cellular complexity derived through a long series of steps involving protocellular fusions could also provide an even more important level of understanding.  This step-wise combining of already self-assembled and self-selected functioning protocell units presents a natural explanation for how the membrane-bound nucleus evolved in eucaryotes and even how multiple individual chromosomes came about in more complex asexually-reproducing modern uni-cellular types of free-living cells.  This evolution-controlled formation process could also be extended to explain how and from where other types of subcellular structures were derived.  It would explain the earliest origins of functionally separate sub-cellular structures such as lysosomes, peroxisomes, Golgi apparatus, ribosomes, microtubules, actin and myosin-related dynamic structures, endoplasmic reticulum membrane vesicles, and various kinds of storage, excretory and secretory vacuoles.  More elaborate and convoluted histories must have been followed however for the ultimate incorporation into early evolving protocells for the modern day, double-membrane chloroplast, mitochondrion and membrane-enclosed “super-control room”, the eucaryotic nucleus.  These subjects will be individually explored in future additions to these articles.

Such an incomplete picture then provides a somewhat mechanistic but still far-removed protocellular structure because no continuing energy-related processes are present or linked to the static metabolic schema that would have existed at that point.  Ultimately we need to now focus our attention on the energetics of what has developed in this picture to convert the finite existence of such protocells to a continuing, dynamic, persistent form we have come to know as organic-based terrestrial life.  This may not be the only such pathway but is argued to be a logical, consistent and realistic one that merits serious consideration.

In a previous part of this series, the author described the characteristics of a living system and alluded to the structural and mechanistic features that imbued that system with what we all must ultimately agree is the essence of the living state.  Life can be recognized as a persisting active, thermodynamically “uphill” set of processes contrary to what would happen if allowed to become depleted of energy sources and undergo normal spontaneous changes.  This has often been referred to as negatively entropic and focuses on the fact that instead of living cells slowly dissipating like a cube of sugar dissolving in a glass of room temperature water, they continuously work and function to hold together, repair and replace their losses in structural components and their non-random organization.  And here we are referring to the persistence of cells between their reproductive cycles.  That is an energy-requiring process.  Such behavior requires a continuing resupply of useful forms of energy and raw building materials to draw upon for this self repair behavior to out-perform Nature’s ever-present deteriorative influences.   So we might best be served in seeking a more detailed definition of the living state and how it is connected to energy sources.  Let us approach this by first defining the non-living, or dead state.

The most basic unit of life, an individual, free-living cell, can be in a living state one moment and dead in the next.  The difference is that the living version will persist indefinitely if continued to be supplied with all it needs to maintain its structure, composition and internal dynamic operations.  The dead cell will be irreversibly changed to a state where the structure and all organized and reorganizing processes cease.  It will no longer persist as that meta-stable processor of matter and energy.  In life, the cell behaved as a homeostatically-operating, steady-state flowing, chemical processing unit.   It is both a delicate and robust thing, the living cell.  And it has a continuing need for energy and raw matter input from which it maintains its overall structure.

To find the thing that physically defines that living state, one must closely observe, probe and analyze a living cell and follow the changes in it when a lethal injury is applied.  The simplest type of injury that can cause cell death is a rupture or uncontrolled leakage across the outer membrane of the cell.  Once such a breach of the plasma membrane occurs, extracellular fluid and its dissolved substances flows in at a much greater rate than it would if that membrane were intact.  At the same time, intracellular contents also uncontrollably leak out.

At the end of this injury scenario, the cell plasma membrane, like an empty burst balloon, floats away from the discharged dissolved cytosolic substances, the gelled cytosolic proteome, and sub-cellular debris.  The dead cell debris that used to be the nucleus, mitochondria, lysosomes, peroxisomes, endoplasmic reticulum, as well as any other specialized structures characteristic of the type of cell last only a short time before they also degrade.

In the living state, the semi-permeable plasma membrane completely enclosed and originally maintained a highly asymmetric set of concentration gradients, both inwardly and outwardly directed, in a permanent non-equilibrium condition.  It takes energy to maintain these gradients and part of the cell’s energy design is devoted to continuing to rebuild those gradient processes.

Thus the one thing that is always a marker for cell death is a loss of the ability of the cell to continue to maintain its internal milieu within very narrow and vital chemically-defined limits.  Internal dissolved calcium ion concentration in the cytosol compartment of modern eucaryotic cells typically ranges from about 10-8 up to 10-5 molar during various aspects of the cell’s life.  Important internal increases and decreases in cytosol calcium ion concentration are controlling features of the animal cell division cycle.  It is a key indicator of the biochemical activity patterns in operation.  But when approaching 1 millimolar in concentration, the cytosolic calcium concentration becomes a harbinger as well as agent for the cell’s death.  It directly causes loss of viability and the cessation of all its previous life processes.

The modern eucaryotic cell possesses multiple types of membrane-enclosed compartments.  Of course the outer plasma membrane provides this function for the cell as a whole, allowing it to maintain a different chemical milieu from the surrounding fluid.  Each type of sub-cellular organelle that has an uninterrupted enclosed membrane-bound volume also contains its preferred optimum milieu compatible with its unique chemical reaction sequences housed within.  All such membrane-bounded compartments must forever maintain the integrity and limited permeability of those internal compartments for the cell to remain in a completely viable condition.

Within a modern eucaryotic cell, the primary chemical reactions housed in various sub-cellular organelles frequently have quite different and conflicted optima for pH and other chemical reaction requirements.  The enzymes located in one compartment could rapidly destroy the enzymes or intermediates if they had access to the contents of other compartments.  The limited permeability and macro-molecular barrier functions of most cell membranes also provides protection and isolation of incompatibly self-destructive portions of the cell’s metabolic operating parts.   The semi-permeability of all such isolative membrane systems is also a long term requirement for generating and storing energy and creating each of its functional molecular parts.  In that sense it furthers the maintenance of the living state as well.

These facts are important to appreciate when looking for the clues to how life on earth began and then continued to evolve and improve its ability to persist, if not grow.  For without semi-permeable membranes and the necessary bioenergetic apparatus presenting itself in a life-compatible condition during the time of first capture, our protocells might form but not be able to persist.  In a somewhat literary sense, we can infer that the “vital energy” possessed by all living things can be biophysically defined in terms of chemical and electrical properties of the cell membrane and chemical gradients as produced through the asymmetric transport and longer duration storage of a multitude of differing chemical species.

The Origins of Bioenergetics

When biophysicists characterize modern cell plasma membranes, whether from procaryotes or eucaryotes, virtually all normal nutrients, specific cell secretory products and waste products transfer through such membranes by way of specific or relatively non-specific transport molecules or channels in those membranes.  If we begin with more of substance A on one side of such a membrane than on the other, the natural or spontaneous tendency is for such a gradient of concentration of A to flow in a net fashion from the higher to lower concentration until it arrives at final equilibrium concentrations. Those concentrations, or more formally, the chemical activities, becomes equal on both sides.  Even at equilibrium, the transfer of molecules or atoms of A continue, but the transfer rate in one direction would be equal to the back transfer rate in the other direction in a non-energized, permeable.

It is here that a series of seminal events took place during the early origins of life on earth.  These events must have occurred over a long period and many variations must have been present simultaneously.  In a very real sense, development of trans-membrane transport mechanisms must have followed a similar script through the genesis engine of  combinatorial chemistry.  That continuously operating agency would have led to the highly diverse molecular species that became available as the early building blocks of the membranes that formed the basic protocells.  These events included the development of passive, assisted and active transporting systems that not only spanned those protocell membranes, but were themselves asymmetrically co-orientated in a group fashion across such membranes.   These allowed dissolved substances that could closely interact with them to essentially move in one direction and not in the other direction, very much like a check valve or back-flow preventer in a water pipe.

So how could a collection of transport molecules get embedded in a phospholipid bilayer membrane all in the same trans-membrane orientation?  If combining in a purely random fashion, equal numbers of a given trans-membrane transporter could become embedded in a membrane oriented in opposing directions.  That would not only be self-defeating, it would eliminate the ability for that membrane to be able to generate a chemical gradient across it.

Transport molecules are typically protein in composition.  They are uniquely composed of chains made from a combination of varying length sequences of more highly polar amino acids joined to internally-connected sequences of lower polarity, lipophilic amino acids.  The lower polarity sequences  generally anchor the middle of transport molecules within the phospholipid membrane interior.  They control the way in which the secondary protein structure forms through folding of the more polar portions of the chains.  Those more polar regions are hydrophilic and closely connected to the aqueous medium on either side of the membrane.  The more polar sequences and regions of the protein’s amino acid sequences are usually found either extending out from the membrane surface and into the highly polar aqueous phases on either side of the membrane.  This makes them more “visible” or accessible to the kinds of molecules that are seeking passage through the membrane.  Such polar amino acids can also be found in a hollowed out, tubular interior of the protein.  These interior trans-membrane pipelines with polar groups projecting inwards, create trans-membrane channels possessing more selective size, charge polarity and geometric constraints for what kinds of substances can pass through them.  They are similar to the same chemical criteria found within an enzyme’s active site.

Such membrane-compatible protein molecules when free can form quasi-crystallized, weakly-aggregated films at or near air-water interfaces.  If phospholipids are also present, these amphiphilic molecules spontaneously form mono-, bi- and multi-layered membranes that spread across the surface of any available water-air interfaces.  Their appearance is quite like that of the black and multi-colored sheen of water contaminated by petroleum oil.  They have a strong tendency to keep spreading thinner and thinner and if the surface area is large enough, black single bi-layer membranes form.  The co-presence of what we might call proto-transport molecules floating as a regularly-ordered, two-dimensional, quasi-crystalline aggregate just under the bi-layer allows them to approach the bi-layer from one direction and become embedded in it in a uniformly oriented fashion.

An alternative means of accomplishing this same goal could utilize a solid mineral surface that presented adsorption sites for the proto-transport molecules to first attach to.   Following attachment to the mineral surface, the floating phospholipid bi-layer could be juxtaposed to that surface through direct contact streaming or evaporation of the water phase with deposition of the bilayer onto the protein-coated surfaces.  The result is a transfer of the proto-transport protein molecules from the mineral surface to a single side of the bi-layer membrane sheet.  And once this formation of an asymmetrically distributed collection of protein molecules is completed, uni-directional semi-permeability and asymmetric chemical reactions can take place across the membrane after enclosed vesicles are produced from such larger sheets through different types of physical agitation.

Such a mechanism for the formation of asymmetric membrane functions would ultimately be highly inefficient and lack stability and reproducibility.  This set of events are simply offered as a short term means to an end.  That end is the final bringing together of all the necessary structures, activities and components that are finally capable of indefinite persistence, and packaging them within a membrane-bounded, single small vesicular volume.  In other words, the crucial point in which they have the basic starting capabilities of life.

Electrochemistry and Life

Up until now we have only looked at the chemical complexity, reaction conditions and ability for a protocell membrane vesicle to concentrate and maintain a gradient across  its membrane.  The generation of the gradient, requiring an external source of usable energy, is very much analogous to a rechargeable battery.  The external energy source would be the recharger plugged into its energy source.  In the battery model, initially electrically net neutral chemical species are dissociated and actively separated or pulled into different fluids. The oppositely charged particles move to opposite sides of a semi-permeable, somewhat electrically insulative bridge or barrier.  If it is too highly insulative, it can store the charges for long periods but then they are greatly retarded in their movement back through the barrier.  That limits the rate that such a field can be subsequently utilized to perform other work.  So to operate properly, this barrier must still be slightly conductive in order to allow oppositely charged particles to pass through at a useful rate and allow the charged particles to rejoin and neutralize their free charges.

In cells, that barrier is the phospholipid portion of the bilayer membrane.  Thus, across various cell membranes, if such electrochemical reactions take place asymmetrically across those membranes, charges can be separated and stored for various amounts of time across a two-dimensional surface.  This becomes a direct simulacrum to an electrical capacitor.  If an electrically-charged capacitor is subsequently connected to an electric motor, that stored electrical field energy can drive the motor as the potential electric field energy collapses and the charges flow back together to reform electrically neutralized species again.  In a more fundamental fashion, electrochemically charged  membranes can provide a moderate amount of electrical charge storage and a means of tapping that stored energy into various types of useful work when the cell needs such input to extend its existence and persist.  The first free-living protocell was the original Walkman.

Useful energy storage can also be obtained through simply moving non-dissociable molecular or atomic species from one side of the membrane to the other, to form a simple concentration gradient of a neutral non-ionizable chemical compound.  Such a type of energy storage is more analogous to a dam that collects water and then can be linked to some energy-converting mechanism, such as a hydro-electric power station or a simple water wheel.   It is also analogous to the physical work generated within a growing plant as it rises out of the soil and gains new height against gravity through forces generated by osmotic pressure.  The usable energy, or work, in this latter example is performed from building up the potential energy by movement of water molecules from one side of semi-permeable membranes to the other.  That forces the water collected on one side of a fixed volume cell to be at higher pressure relative to the other side.  Thus osmotic pressure is also equivalent to stored potential gravitational energy.  The system’s natural tendency creates this type of energy storage whenever non-ionizable substances are actively transported across membranes.  The gradients they form have the natural tendency to spontaneously return to their equilibrium distribution of the various compounds and water of solvation while in earth’s gravitational field.

In our actual cell, the concentration gradient is driven by attracting more water to one side of a water-permeable membrane through addition of more non-dissociable particles  to that side.  This can be accomplished in several ways.  One simple way is to have a trans-membrane transporter move a single molecule from the outside of the cell to its interior where it is subsequently split into two molecules.  Osmotic pressure is based upon simple numbers of particles that are solvated.  The thermodynamic behavior of this extra energy is then stored in the form of the heats of hydration for each of the transported species plus net movement of extra water towards the side needing added water for solvation.  If the volume of that side is forced to be constant, that drawing in of the extra water would be converted to a physical force or pressure.  That is the fundamental cause of osmotic pressure.  And for completeness, it should be stated that osmotic pressure can be associated with either ionizable or non-ionizable soluble matter.

All living cells are involved with both kinds of energy storage.  Certain states can exist, such as within ungerminated spores and suspended animation, that do not necessarily preserve those qualities during such transient states.  Thus we can allow for a living system to become temporarily “non-living” during suboptimal conditions and re-start again after restoration of minimally supportive conditions.

For all of the functioning that we have previously been looking at, we have to still describe how chemical or physical energy taken in by the early protocells was first converted to a storage form, then stored for extended periods, and subsequently linked to and drawn upon to energize various life processes during energy-poor moments.  Those non-equilibrium concentration gradients spanning across membranes, and electrical fields located on the membrane surfaces, need to be able to be physico-chemically linked to molecular engines or processes that can only continue to operate by absorbing useful energy from the gradient and converting it into new cell “stuff”?  Let’s look briefly at the energy contained within chemical gradients.

The Nernst Equation

A well-known relationship was described by early electro-chemists between the relative difference for the concentration gradient existing for two aqueous solutions of a charged ion separated across a semi-permeable bridge and the strength of that species’ tendency to return to equilibrium through transference of negatively-charged electrons.  The physical form that this type of energy storage manifests is as an attractive electrical field created between oppositely charged species separated by the thickness of a relatively low-conductive dielectric membrane.   Different ions have different intrinsic dissociation energies based on the electronegativity and electron configurations of the atoms that compose them.

As the science of electrochemistry developed, electron transfers were found to occur not only between two identical-type ions simply based upon their relative concentrations in two different solutions, but also between different ionizable species.  But such phenomena have been occurring throughout the entirety of earth’s history without the intervention of Man.  Such electrochemical reactions existed before the first protocell was capable of forming on primordial earth.  As general features of such reaction chemistry, the following should be noted.

  1. All electrochemical reactions can occur in aqueous media (there are non-aqueous electrochemical reactions but those will be reserved for our future considerations regarding origins and evolution of extra-terrestrial life).
  2. As electrons are transferred from one ion to another, water molecules are included in the reaction steps. This leads to a simultaneous uptake or release of protons causing the reactions to also be affected by, and be capable of changing, the pH of the medium.
  3. Useful work can be effected if the two reacting species, also known as half-cell reactions, are first separated by a semi-permeable bridge (salt bridge) or membrane possessing selective channels connecting the two reacting solutions. Such a path is needed to allow the net flow of one type of ion in the appropriate direction, depending on whether the gradient is being recreated by an energy-utilizing regeneration mechanism or allowed to flow back spontaneously towards its equilibrium point by some kind of work-accomplishing process.  Such a system is mimicked by standard man-made rechargeable batteries.  Asymmetric chemical catalysts and electron carriers and their attendant reactions are commonly found embedded in and spanning biological membranes.
  4. If one has two such selective membranes separating three different solutions in tandem, this would increase the electrochemical potential in the same way that two standard batteries in series would double their combined output voltage. This pattern is also analogous to that of the eucaryotic cell in which the extracellular medium is separated by the plasma membrane from the cytosol and the cytosol is further separated from the inner mitochondrial matrix by the inner mitochondrial membrane.  Such a stacked strategy is also found in the electrogenic glands of the electric eel, Electrophorus, as well as in stacked flattened membrane vesicles in chloroplasts (thylakoids) and photosensitive retinal cells.  Synapses within the nervous system have a similar but less recognizable similarity to such stacked membrane vesicle packages.  But in each of these examples, gated flows of ions and non-dissociable chemical species flow into and out of those individual compartments while being apposed to other membrane-bounded compartments or cells.  This gives rise to the well-known action potential behavior of excitable membranes.  And that is also a commonly found trait of such electrochemically energized membrane phenomena.  For this reason, it might be reasonably expected that not only were simple membranes required at the dawn of the living state, but a low grade version of a gated, excitable membrane’s type of behavior would have presented exceptionally enhanced survival advantages to whatever protocells had developed it.

This multi-compartmented design of the eucaryotic cells however is much more complex than this.

(Certain terms must be used due to their universal meanings.  “Design”, “plan”, and “create” are such terms.  These have also come to be used in less rigorous non-scientific contexts.  For the sake of this subject matter, I will at times use them but caution the reader that nothing is implied in their use regarding extra-scientific meanings.)

Multiple chemical species are separated among these three aqueous compartments.  Each relatively impermeable to the phospholipid membrane framework but is transferred through the membranes by selective carrier or transport molecules embedded in the membranes.  The membranes also isolate and help maintain differing pH, chemical and ionic compositions between compartments that are optimized for the specific kinds of compartment-specific enzymology contained within those same compartments.  Osmotic pressures are relatively well-maintained across each type of membrane.  The membranes also isolate the biochemical reactions in one compartment from potentially incompatible reactions going on in another compartment.

Some of the reactions taking place across a given membrane are of an electrochemical nature.  For those reactions, the protons or electrons must pass through the membrane channels or transport molecules and during that passage, useful chemical work is capable of being coupled to them.  In energy-capturing membrane structures such as thylakoids in chloroplasts, this process works in the reverse direction under illumination and generates the pH gradients through electrons being first raised to excited states by photon absorption followed by linked chemical reactions being driven by them as they return to their ground states.  Those reactions are of the utmost importance in the evolution of life on earth.  For those reactions finally link all life on earth, directly or indirectly, to the main form of energy output of our nearest stellar neighbor, the Sun.  These will be considered in greater detail later.

The simple mathematical relationship describing energy storage for electrochemically active chemical species separated by a salt bridge or semi-permeable membrane was first offered by Nernst as follows:

E = (RT / zF) Ln [ion] outside  / [ion] inside

where E is the electromotive force in volts

R is the universal gas constant

T is the absolute temperature

z is the number of charges on the ion

F is Faraday’s constant

and the square brackets indicate concentration units

This relationship exists for each type of ion that can move across the membrane.  There are many kinds of ions that transport across membranes and this relationship exists for each type.  Other equations have been developed to better describe biological membrane potential.  The overall resultant electrical potential is the mathematical sum of each ion’s contribution.  In resting animal cells, the plasma membrane typically exhibits a resting electrical potential of about 70 millivolts, outside negative.  Whenever a cell becomes active, ions flow in and out of the outer membrane and the membrane potential changes in either a depolarizing direction or a hyperpolarizing direction.  All of these properties and variations are intrinsically part of and define the living state as  contrasted to a state of death.  The alternative, a state of pre-biosis in which life’s processes have never previously occurred within an early version of protocell, would also be found in a similar equilibrium or near equilibrium condition.

Osmotic Mechanisms of Energy Storage and Management: High Resolution

As any chemical species, ionizable or non-ionizable, moves through its preferred molecular channel from one side of a semi-permeable membrane to the other, water molecules to keep each ion or molecule in solution must follow.  As previously described, the phospholipid portion of the biological membrane has an important property in that at normal growth temperatures it allows the smaller water molecules to easily slip between the hydrocarbon chains making up the interior of the bi-layer.

Membranes have elasticity, plasticity and resilience.  This provides a back pressure to resist the continuing and unlimited movement of solutes across that membrane.  Biological membranes have some interesting behavior as they are stretched by osmotic swelling.  They become more non-specifically permeable to smaller ions and molecules.  As the membrane is further stretched, larger molecular weight ions and molecules and even macro-molecules begin to passively leak back down their concentration gradients.  When cells are osmotically over-stressed even further, macro-molecular solutes in the cytosol slowly exit the cell through the unbroken, but now more “porous” plasma membrane.  Even molecules and ions that normally move through specific transporter membrane proteins can also flow through these non-protein leakage pathways.  These capabilities are both important and useful to understanding how the self-assembled pre-biotic membranes must have behaved as the first “life-capable” membranes could have formed for the first time.

Combining All to Form the Living State

Our origin of life model must also include an adequate and plausible description of how all of the starter molecules necessary for a rudimentary metabolism were captured by the first pre-biotic liposomes.  Further, our narrative must also have a basic set of means (trans-membrane transporters) by which necessary substances move into and out of those early cells.  But even with all of that inventory list of life’s minimum necessary molecular content, we must also include a rudimentary energy-capturing and/or energy-converting mechanism that could collect, store, supply and recharge the necessary forms of energy needed to keep all of the internal chemical and physical activities continuing indefinitely thereafter.  It is here that our greatest challenge to life’s genesis will probably be found.

So how does one combine a set of uni-directionally selective, asymmetrically and uniformally disposed membrane transport molecules?  How can one understand the first genesis of sets of sequentially-operating enzyme complexes and then finally find a plausible and testable means of linking the internal reaction chemistry to the active transport of ions and molecules across the membrane against their concentration gradients?

Each of these collective functions embodies a number of types of molecules having to be maintained in close proximity and accurately juxtaposed to one another for extended periods of time.  The combined functions taken together creates an almost insurmountably complicated perception of a collection of components that behave with integrated complexity.  The whole seems much greater than the sum of its parts.  It is almost like trying to build a tall house of delicately balanced cards beginning at the top!  But remember, we have already described a relatively direct means of bringing all these functional units together.  It is through the prior formation and then subsequent hybridization of each functional type of protocell.  The first generation of protocells captured and utilized formative sequences of combinatorial chemical reactions.  Multiple liposomal formation captured differing collections of molecules, that is to say, different rudimentary but operating fragments of biochemistry.  The second generation of protocells then could form following fusions of different functionally distinct types of liposomal ensembles.  The more successful combinations self-selected and became the dominant types in their niches.  Life would not be held in abeyance for long.  It was trying to develop all over earth and at probably more than one location, it would finally become fully capable of unlimited growth of mass and able to begin actively sensing its chemical and physical environment.  And that sensing allowed it to become more tropic…  more able to seek out and meet its needs for energy, raw materials and optimal growth conditions.  At this point our protocells are beginning to “come alive”.  But there is much more to the story before they can be officially called alive!

Next:  Pre-Biotic Evolution.  Part V.  The Evolutionary Importance of Chemi-Osmosis and Electron Transport

Scientific and Forensic Services, Inc., Delray Beach, FL. and Norfolk, VA


  1. Guth, J. H. “Pre-Biotic Evolution:  From Stellar to Molecular Evolution”.  Society for the Advancement of Metadarwinism, Volume 1, November 19, 2014.   Accessible at
  2. Guth, J. H. “Pre-Biotic Evolution:  Pre-Biotic Chemical Oscillations and Linked Reaction Sequences”.  Society for the Advancement of Metadarwinism, Volume 2, June 12, 2015.   Accessible at
  3. Guth, J. H. “Pre-Biotic Evolution:    Transitioning to Animacy”.  Society for the Advancement of Metadarwinism, Volume 3, January 5, 2016.   Accessible at

© Copyrighted by Joseph H. Guth, 2016.  All rights reserved.

Phenotype as Agent for Epigenetic Inheritance

By  John S. Torday, MSc. PhD.  & William B. Miller, Jr, M.D.

Abstract: The conventional understanding of phenotype is as a derivative of descent with modification through Darwinian random mutation and natural selection. Recent research has revealed Lamarckian inheritance as a major transgenerational mechanism for environmental action on genomes whose extent is determined, in significant part, by germ line cells during meiosis and subsequent stages of embryological development. In consequence, the role of phenotype can productively be reconsidered. The possibility that phenotype is directed towards the effective acquisition of epigenetic marks in consistent reciprocation with the environment during the life cycle of an organism is explored. It is proposed that phenotype is an active agent in niche construction for the active acquisition of epigenetic marks as a dominant evolutionary mechanism rather than a consequence of Darwinian selection towards reproductive success. The reproductive phase of the life cycle can then be appraised as a robust framework in which epigenetic inheritance is entrained to affect growth and development in continued reciprocal responsiveness to environmental stresses. Furthermore, as first principles of physiology determine the limits of epigenetic inheritance, a coherent justification can thereby be provided for the obligate return of all multicellular eukaryotes to the unicellular state.

Keywords: phenotype; Darwin; Lamarck; germline; epigenetic; life cycle; niche construction

  1. Introduction

The recognition that the cell is the basis for eukaryotic evolution [1] as a manifestation of perpetual cellular principles renders phenotypes as epiphenomena, i.e., subordinate to the actual event. Such a perspective alters many otherwise dogmatic aspects of evolutionary biology. In particular, the systematic error of the perception of evolution as a stochastic phenomenon yields instead to phenotypes as mechanistic products, always directed towards identifiable cellular needs [2]. Such a change of focus is similar in type to David Bohm’s insight into dual explicate and implicate orders in the physical realm [3]. He stipulated that our evolved senses mislead us into regarding our conscious experience as an explicate ordering of an entire reality. Instead, a truer reality is a continuous stream sustained by both explicates and an additional set of subjective implicates of which we are not typically aware. Similarly then, in biologic terms, it can be presented that an explicate phenotype is fully dependent upon a steady flow of epigenetic implicates in a cellular continuum that mechanistically interconnects evolutionary development with the larger environment across space and time.

  1. Background

In conventional terms, any phenotype is assumed to be the end result of descent with modification through Darwinian random mutation and natural selection [4]. However, with the emergence of a contemporary re-appraisal of the importance of Lamarckian inheritance, the role of phenotype must be reconsidered as the effective primary means by which all organisms acquire information from the environment in the continuous maintenance of essential cellular requirements. These necessities are

expressed through all the cellular mechanisms that are directed towards sustaining cellular activity within homeostatic limits, defending cellular integrity and self-recognition. Thus, in eukaryotic multicellular organisms, phenotype becomes an agent promoting and incorporating epigenetic inheritance, rather than a simple manifestation of the concordance of intergenerational vertical genetic transmission exclusively based on selection.

This perspective on the significance of the phenotype is consistent with Niche Construction Theory [5,6] critically enacted at the cellular level. When cellular imperatives or principles such as maintenance of preferential homeostatic status and self-protection in both individual and collective terms are subjected to environmental stresses through epigenetic inheritance, evolution is understood as much more dynamic and environmentally interactive than via any filtering mechanism of Darwinian evolution. Importantly, this perspective faithfully reflects evolution’s origin as a self-organizing, self-referential mechanism that originates within the unicellular domain, and always remains contingent on it [6]. In this manner, phenotype becomes a directed product of cellular activities in response to epiphenomena rather than a mere result of random forces [7].

Perhaps even more importantly, the impact of epigenetic inheritance on the cell, and its physiologic limits, is amenable to hypothesis testing and falsification in a manner beyond any generally accepted Darwinian evolutionary narrative [8]. Selection still applies, but its precise role and its center of action are deeply reconsidered.

  1. The Water-Land Transition as the Epitome of Epigenetic Inheritance

There is evidence that life was initiated and then propelled on its evolutionary course in response to the physical constraints imposed by the environment [9], and therefore evolved in response to such major effectors as gravity [10], carbon dioxide [11], oxygen [12] and calcium [13] as epiphenomena to the cell [1].

The vertebrate transition from water to land was caused by the evaporation of water globally about 300 million years ago due to the accumulation of carbon dioxide in the atmosphere, causing a “greenhouse effect” [14]. An essential set of evolved traits was necessitated for the transition from water to land, critically dependent upon the lung as homologous with the swim bladder of bony fish [15]. This is particularly the case for physostomous fish [15], which have the homolog of a trachea (called the pneumatic duct) connecting the esophagus to the swim bladder. The swim bladder is derived from the foregut in both fish and land dwelling vertebrates [16]. Functionally, the effective inflation and deflation of both the swim bladder and lung are dependent on the production of surfactant by the gas gland epithelium lining the bladder lumen [17,18]. In the case of the swim bladder, the surfactant has been speculated to be necessary for preventing self-adherence of the walls of the bladder [19]. In the case of the lung, surfactant is necessary for preventing atelectasis, or alveolar collapse [20]. Alveoli are very small in diameter, thereby generating high surface tension based upon the Law of Laplace [21]. The physiologic stress of hypoxia forced selection pressure for the remodeling of the alveoli. The cell-cell interactions between the epithelial and mesenchymal components that mediate surfactant production [22] were modified through phylogeny and ontogeny in order to allow for the reduction in alveolar diameter, increasing the surface area-to-blood volume ratio for efficient gas exchange [23].

This mechanism for facilitated gas exchange, ever-dependent upon lipids, refers to the inception of cholesterol synthesis and its critical insertion into the cell membrane [24]. The facilitation of gas exchange through this cellular example of niche construction exemplifies how first principles of cellular requisites are put in service for oxygenation in unicellular organisms, exapted over billions of years through the implementation of homologous genetic motifs [25].

Starting from its origins, the spontaneous generation of micelles as lipids immersed in water [26], the reduction in entropy [27], in combination with chemiosmosis [28] and homeostasis [29] are assumed to have fostered life [30]. Unicellular life dominated the Earth for the first 4 billion years [31]. Then, fewer than 500 million years ago, multicellular organisms evolved from unicellular forms, likely

due to competition among prokaryotes able to mimic multicellularity through traits such as Biofilm [32] and Quorum Sensing [33]. Rising levels of oxygen in the atmosphere put selection pressure on prokaryotes, producing hopanoids that caused increased order within the cell wall [34], making it more permeable. The generation of oxygen by bacteria was hypothesized to have given rise to cholesterol, given that eleven atoms of oxygen are required to form one molecule of cholesterol [35]. The presence of cholesterol in the cell membrane of primitive eukaryotes promoted metabolism, oxygenation and locomotion, the basic principles of vertebrate evolution [36]. There was also an increase in atmospheric carbon dioxide [37,38], which dissolved in the oceans to form carbonic acid [39]. That acidity leached calcium out of the bedrock, threatening life due to the denaturing effects of calcium on proteins, lipids and nucleic acids. In response, unicellular organisms formed peroxisomes, organelles that use lipids to buffer intracellular calcium [40]. In such a scenario, the formation of calcium channels from lipids for the excretion of calcium was exapted to protect burgeoning eukaryotes. During the Phanerozoic Era, the greenhouse effect of rising levels of carbon dioxide [13] forced some evolving vertebrates to transition from water to land [4143], marking the beginnings of terrestrial life [44]. The adaptation to land gave rise to novel physiologic traits that had their origins in fish. The increased force of gravity on land [45] put great selection pressure on the skeletal system, altering it at least five times based on the fossil record [44]. Rising, fluctuating oxygen levels in the atmosphere necessitated remodeling of the internal organs, though there is no fossil evidence for these events. For example, we now know that the same genes that determine the swim bladder of bony fish determine the development of the lung [14]. Functionally, both the swim bladder and lung depend upon surfactant for their function [19,22], and the mechanisms that facilitated the evolution of the lung alveoli from the swim bladder delineate how and why these structures became smaller and more numerous [23] due to cellular interactions fostering evolutionary change. Moreover, the genes responsible for both skeletal and pulmonary evolution are involved in the evolution of the skin, kidney and brain. These adaptive changes were the net result of physiologic stress mediated by cellular-molecular damage to specific tissues and organs due to shear stress on microvessels generating radical oxygen species causing gene mutations and duplications [46]. This epigenetic remodeling pathway based upon the water-land transition exemplifies how phenotype becomes a product of environmental stress based upon cellular requisites in the cellular context of niche construction.

As apart from these deeply rooted cellular/molecular developmental mechanisms, there are now many direct examples of epigenetic factors influencing phenotype. The phenotypic differences between human monozygotic twins are now ascribed to epigenetic factors [47]. As an outgrowth of twin studies, there is a greater understanding of that link between epigenetics and phenotype. Such studies on genetically identical organisms suggest that studying the effects of epigenetics on phenotypic outcomes can yield discrete molecular pathways and mechanisms [48]. Therefore, an exploration of the effect of contemporary epigenetic impacts on phenotype can be expected to integrate with deep evolutionary experiences along the same types of molecular pathways that have been outlined above.

Certainly contemporary impacts can have substantial phenotypic results. In humans, maternal body mass index and blood pressure directly correlate with fetal birth weights [49]. Neonates born to obese women are larger and at a higher risk of birth complications. A similar association exists for elevated maternal fasting blood glucose, whereas elevated maternal systolic blood pressure has been directly linked to low birth weight infants. Starvation is now known to have profound intergenerational effects on phenotype, fitness and health in many animals. In C. elegans, generations of progeny of starved animals demonstrate smaller size, diminished fecundity, smaller brood size, a greater number of male progeny, and an increased tolerance to heat [50]. These transgenerational starvation effects in C. elegans have been demonstrated to be due to small RNAs that persist for at least three generations [51]. Such effects are now acknowledged in humans with starvation-induced neonatal adiposity and an increased incidence of diabetes in progeny [52]. Gluckman and Hanson [53] include the periconceptional, fetal, and infant environments among those aspects of particular significance in the future incidence of adult human disease. They further stress the dependence of the mature

phenotype upon both any individual genome and its epigenome, which then, together and iteratively, influence subsequent responses to environmental stresses and disease incidence [54]. This emphasis on the reciprocating balance between the environment and phenotype via epigenetic intermediaries is a form of interrelating niche construction through which any particular organism receives feedback from the environment, is shaped by it in some manner, and then correspondingly affects the outward environment that it occupies.

Furthermore, the influence of epigenetic impacts on phenotype extends beyond those forms that are typically considered. The mammalian placenta represents an example of epigenetic interactions and their critical impact upon mammalian development that achieve complex phenotypic form. Mammalian placental development is partially dependent upon crucial reproductive protein expression that does not emanate from within any central genome. Instead, it is the product of early epigenetic impacts as a co-option of retroviral proteins. Such retro-elements are largely responsible for the formation of the placental syncytiotrophoblast [55]. The development of maternal immunosuppression enabling viviparity is itself critically dependent on proteins produced in response to accumulated retro elements as infectious epigenetic impacts on central genomes [56]. Furthermore, retrotransposon activity or suppression are now acknowledged as epigenetic mediators of phenotypic variation in mammals producing variations between genetically identical individuals [57]. Nor are such impacts of little consequence to genomic integrity since retrotransposons are the principal component of most eukaryotic genomes and alter the expression of a wide variety of genes in animals and plants [58]. Beyond these distant considerations, epigenetic impacts are actually now contemporaneously evident. The endogenization of HIV [59], Koala retrovirus [60], and the direct demonstration of heritable transmission of bacterial DNA [61] are crucial examples. Importantly, these transfers are emblematic of the self-same processes in which epiphenomena are either employed or withstood, within both the eukaryotic and prokaryotic realms [62]. Self-same processes is the descriptive term used to indicate that our evolutionary system is based upon cellular activities in which there are consistent adherencies to basic cellular principles. These basic mechanisms guide cellular interactions and reactions and are consistently reiterated at every scope and scale. In every circumstance, these physical and bioactive epiphenomena can now be appreciated as directing responses to environmental stress through reiterative means.

  1. Predictive Value of Phenotype as Epigenetic Agent

Based upon these considerations, niche construction, either as beaver dams or cities, and then even further as phenotypes, can be productively assessed as consequences of elemental cellular first principles and epigenetic underpinnings. When considered in this manner, even our protracted human infancy and childhood can now be understood as a necessary phase through which crucial environmental epigenetic marks are assimilated to foster human brain development.

With these clarifications, all phases of the life cycle can be understood as derivative of cellular needs and imperatives that determine the timing and expression of each developmental and life cycle stage of which, arguably, the endocrine system has primacy. Crucially though, the endocrine system itself is a cellular phenomenon that is its own summation of epigenetic marks and their differential activation, ever-dependent upon environmental stresses [63].

  1. Conclusions

In any typical Darwinian narrative, phenotype is an output of selection experienced through differential survival and reproductive success. However, heritable epiphenomena are now better understood. Therefore, it can be argued that epigenetic mechanisms are a primary means by which organisms evolve in matched reciprocation to environmental stresses best exemplified by niche construction. Phenotype can then be reappraised through a non-intuitive Bohmian shift [3] within biologic terms of co-existent implicates and explicates. Phenotype is a transient explicate upon which a series of epigenetic impacts gather, as a set of implicates, to be enacted according to

cellular imperatives. The obligatory return of eukaryotic multicellular organisms to the unicellular form becomes the critical phase for the settling of those implicates towards biological expression as phenotype. Thus, a renewed evolutionary narrative can be considered that centers upon the primacy of epigenetic inheritance within deeply rooted cellular mechanisms. In such circumstances, perpetual cellular imperatives determine our evolutionary course. Phenotype is no longer merely a result but is instead a means through which organisms explore the outward environment and its stresses. Those impacts are brought back to the eukaryotic unicell and then, upon reproductive elaboration, enable the reiterative extension of phenotype into the environment to experience a subsequent series of environmental impacts towards its next set of adjustments. It is this consistent reciprocation that shapes phenotype. When fully considered, this new concept becomes a novel and testable route towards further progress in evolutionary theory and biomedicine.


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Published with permission, courtesy Biology (Basel)

Citation:  Torday, J. S., & Miller, W. B. (2016). Phenotype as agent for epigenetic inheritance. Biology, 5(3), 30.

Man is Integral to Nature

By John S. Torday, MSc. PhD.  & William B. Miller, Jr, M.D.

“It is a country . . . with innumerable lakes and rapid streams, peopled with trout.”

                                                                                    —H.D. Thoreau, The Maine Woods

In the Beginning

The traditional perspective for physiology, as portrayed by Galen and Harvey, is like Lego Blocks, with one biochemical process linked to another until an entire biochemical structure is revealed. In contrast to that post facto narrative, a predictive approach can be asserted—there actually are founding first principles for physiology that originated in and emanate from the unicellular stage of life. Einstein’s insight to relativity theory emerged from a dream in which he traveled in tandem with a light beam, seeing it as an integral particle and wave. Similarly, viewing physiology as a continuum from unicellular to multicellular organisms provides fundamental insight to ontogeny and phylogeny as an integral whole, directly linking the external physical environment to the internal environment of physiology, and even extending beyond, to the metaphysical realm, bearing in mind that the calcium waves that mediate consciousness in paramecia and in our brains are one and the same mechanism.

Life probably began much like the sea foam that can be found on any shoreline, since similar lipids naturally form primitive “cells” when vigorously agitated in water. Algae, for example, are 90 percent lipid. Such primitive cells provided a protected space for catalytic reactions that decreased and stabilized the internal energy state within the cell, and from which life could emerge. Crucially, that cellular space permits the circumvention of the second law of thermodynamics. (The entropy of an isolated system such as a cell never decreases since such systems always decay toward thermodynamic equilibrium as a state of maximum entropy.) That violation of physical law is the essential property of life as self-organizing and self-perpetuating, always in flux, staying apace with, and yet continually separable from a stressful, ever-changing external environment.

Even from the inception of life, rising calcium levels in the ocean have driven a perpetual balancing selection for calcium homeostasis, mediated by lipid metabolism. Metaphorically, the Greeks called it Ouroboros, an ancient symbol depicting a serpent eating its own tail.

Ouoroboros, an ancient symbol depicting a serpent eating its own tail. (Image by Abake, Wikimedia Commons).
The Ouroboros embodies self-reflexivity or cyclicity, especially in the sense of something constantly re-creating itself. Just like the mythological Phoenix, it operates in cycles that begin anew as soon as they end. Critically, the basic cell permits the internalization of factors in the environment that would otherwise have destroyed it—oxygen, minerals, heavy metals, micro-gravitational effects, and even bacteria—all facilitated by an internal membrane system that compartmentalized those factors within the cell to make them useful. These membrane interfaces are the biologic imperative that separates life from non-life—“Good fences make good neighbors.”

The Advent of Multicellularity

Unicellular organisms dominated the earth for the first 4.5 billion years of its existence. Far from static, these organisms were constantly adapting. From them, the simplest plants evolved first, producing oxygen and carbon dioxide that modified the nitrogen-filled atmosphere. The rising levels of atmospheric carbon dioxide, largely generated by blue-green algae, acidified the oceans by forming carbonic acid, progressively leaching more and more calcium from rock into the ocean waters, eventually forcing a proliferation of life from sea to land.

The existence of a protected space within primitive “cells” allowed for the formation of the endomembrane system, giving rise to chemiosmosis, or the generation of bioenergy through the partitioning of ions within the cell, much like a battery. Early in this progression, the otherwise toxic ambient calcium concentrations within primitive cells had to be lowered by forming calcium channels, composed of lipids embedded within the cell membrane, and the complementary formation of the endoplasmic reticulum, an internal membrane system for the compartmentalization of intracellular calcium. Ultimately, the advent of cholesterol synthesis facilitated the incorporation of cholesterol into the cell membrane of eukaryotes, differentiating them (our ancestors) from prokaryotes (bacteria), which are devoid of cholesterol. This process was contingent on an enriched oxygen atmosphere, since it takes six oxygen molecules to synthesize one cholesterol molecule. The cholesterol-containing cell membrane thinned out, critically increasing oxygen transport, enhancing motility through increased cytoplasmic streaming, and was also conducive to endocytosis, or cell eating.

All of these processes are the primary characteristics of vertebrate evolution. At some point in this progression of cellular complexity, impelled by oxygen-promoting metabolic drive, the evolving physiologic load on the system resulted in endoplasmic reticulum stress, periodically causing the release of toxic calcium into the cytoplasm of the cell. The counterbalancing, or epistatic mechanism, was the “invention” of the peroxisome, an organelle that utilizes lipids to buffer excess calcium. That mechanism became homeostatically fixed, further promoting the movement of ions into and out of the cell. Importantly, the internalization of the external environment by this mechanism reciprocally conveyed functional biologic information about the external surroundings, and promoted intracellular communication—what Claude Bernard referred to as the “internal milieu.”

Walter B. Cannon later formulated the concept that biological systems are designed to “trigger physiological responses to maintain the constancy of the internal environment in face of disturbances of external surroundings,” which he termed homeostasis. He emphasized the need for reassembling the data being amassed for the components of biological systems into the context of whole organism function. Hence, in 1991, Weibel, Taylor, and Bolis tested their theory of “symmorphosis,” the idea that physiology has evolved to optimize the economy of biologic function; interestingly, the one exception to this theory was the lung, which they discovered was “over-engineered,” but more about that later.

Harold Morowitz is a proponent of the concept that the energy that flows through a system also helps organize that system. West, Brown, and Enquist have derived a general model for allometry (the study of the relationship of body size to shape, anatomy, physiology, and behavior). They proposed a mathematical model demonstrating that metabolism complies with the 3/4 power law for metabolic rates (i.e., the rate of energy use in mammals increases with mass with a 3/4 exponent). Back in 1945, Horowitz hypothesized that all of biochemistry could be reduced to hierarchical networks, or “shells.” Based on these decades of study, investigators acknowledge that there are fundamental rules of physiology, but they do not address how and why these rules have evolved.

As eukaryotes thrived, they experienced increasing pressure for metabolic efficiency in competition with their prokaryotic cousins. They ingested bacteria via endocytosis, which were assimilated as mitochondria, providing more bioenergy to the cell for homeostasis. Eventually, eukaryotic metabolic cooperativity between cells gave rise to multicellular organisms, which were effectively able to compete with prokaryotes. As Simon Conway Morris has archly noted, “First there were bacteria, now there is New York.” Bacteria can act like multicellular organisms through such behavioral traits as quorum sensing and through biofilm formation, thus behaving, even at this primitive stage, as a pseudo-multicellular organism. The subsequent counter-balancing selection evolution of cellular growth factors and their signal-mediating receptors in our vertebrate ancestors facilitated cell–cell signaling, forming the basis for metazoan evolution. It is this same process that is recapitulated each time the organism undergoes embryogenesis.

This cellular focus on the process of evolution serves a number of purposes. First, it regards the mechanism of evolution from its unicellular origins as the epitome of the integrated genotype and phenotype. This provides a means of thinking about how and why multicellular organisms evolved, starting with the unicellular cell membrane as the common origin for all evolved complex traits. Further, it offers a discrete direction for experimentally determining the constituents of evolution based on the ontogeny and phylogeny of cellular processes. For example, it is commonplace for evolution scientists to emphasize the fact that any given evolved trait had its antecedents in an earlier phylogenetic species as a pre-adapted, or exapted, trait. These ancestral traits can then subsequently be cobbled together to form a novel structure and/or function. Inescapably, if followed to its logical conclusion, all metazoan traits must have evolved from their unicellular origins.

Evolution, Cellular-Style

Moving forward in biologic space and time, how might such complex traits have come about? Physiologic stress must have been the primary force behind such a generative process, transduced by changes in the homeostatic control mechanisms of cellular communication. When physiologic stress occurs in any complex organism, it increases blood pressure, causing vascular wall shear stress, particularly in the microvascular beds of visceral organs. Such shear stress generates reactive oxygen species (ROS), specifically at points of greatest vascular wall friction. ROS are known to damage DNA, RNA, and proteins, and to particularly do so at those sites most affected by the prevailing stress. This can result in context-specific gene mutations, and even gene duplications, all of which can profoundly affect the process of evolution. So we should bear in mind that such genetic changes are occurring within the integrated structural-functional context of that tissue and organ. However, understanding the biochemical processes undergirding the genetic ones equips a profound and testable mechanism for understanding the entire aggregate of genetic changes as both modifications of prior genetic lineages, and yet “fit enough to survive” in their new form.

Over evolutionary time, such varying modifications of structure and function would iteratively have altered various internal organs. These divergences would either successfully conform to the conditions at hand, or failing to do so, cause yet another round of damage-repair. Either an existential solution was found or the organism became extinct; either way, such physiologic changes would have translated into both phylogenetic and ontogenetic evolution. Such an evolutionary process need not be unidirectional. In the forward direction, developmental mechanisms recapitulate phylogenetic structures and functions, culminating in homeostatically controlled processes. And in the reverse direction, the best illustration lies with the genetic changes that occur under conditions of chronic disease, usually characterized by simplification of structure and function. For example, all scarring mechanisms are typified by fibroblastic reversion to their primordial signaling pathway. This sustains the integrity of the tissue or organ through the formation of scar tissue, albeit sub-optimally, yet allowing the organism to reproduce before being overwhelmed by the ongoing injury repair.

The Water-Land Transition and Vertebrate Evolution

Nowhere are such mechanisms of molecular evolution more evident than during the water-land transition. Rises in oxygen and carbon dioxide in the Phanerozoic atmosphere over the course of the last 500 million years partially dried up the oceans, lakes, and rivers, forcing organisms to adapt to land through remodeling of tissues and organs, or else become extinct. There were two known gene duplications that occurred during this period of terrestrial adaptation—the parathyroid hormone-related protein (PTHrP) receptor and the β adrenergic receptor (βAR). The cause of these gene duplications can be surmised from their effects on vertebrate physiology. PTHrP is necessary for a variety of traits relevant to land adaptation—ossification of bone, skin barrier development, and the formation of alveoli in the lung. Bone had to ossify to maintain the integrity of skeletal elements under the stress of higher gravitational forces on land compared to relative buoyancy in water. PTHrP signaling is necessary for calcium incorporation into bone. We know from the fossil record that there were at least five attempts to breach land by fish ancestors based on fossilized skeletal remains. Those events would have been accompanied by the evolution of visceral organs, based on both a priori reasoning, and the fact that the genes involved in skeletal development are also integral to the morphogenesis of critical internal organs, particularly PTHrP. In the aggregate, the net effect of shear stress on PTHrP-expressing organs like bone, lung, skin, and kidney may have precipitated the duplication of the PTHrP receptor, leaving those progeny best able to adapt to land. These, then, were the founders of the subsequent terrestrial species.

As a result of such positive selection pressure for PTHrP signaling, its genetic expression also evolved in both the pituitary and adrenal cortex, further stimulating adrenocorticotrophic hormone and corticoids, respectively, in response to the stress of land adaptation. This pituitary-adrenal cascade would have amplified the production of adrenaline in the adrenal medulla, since corticoids produced in the adrenal cortex pass through the microvascular arcades of the medulla on their way to the systemic bloodstream. This passage of corticoids through the medullary labyrinth enzymatically stimulates the rate-limiting step in adrenaline synthesis, catechol-O-methyltransferase, or COMT. Positive selection pressure for this functional trait may have resulted from cyclic periods of hypoxic stress. Episodes of intermittent large increases and decreases in atmospheric oxygen over geologic time, known as the Berner Hypothesis, may have triggered lapses in the capacity of the lung to oxygenate efficiently, demanding alternating antagonistic adaptations to hyperoxia and hypoxia as a result. The periodic increases in oxygen gave rise to increased body size, whereas hypoxia is the most potent vertebrate physiologic stressor known. Such intermittent periods of pulmonary insufficiency would have been alleviated by the increased adrenaline production, stimulating lung alveolar surfactant secretion, transiently increasing gas exchange by facilitating the distension of the existing alveoli. The increased distention of the alveoli, in turn, would have fostered the generation of more alveoli by stimulating stretch-regulated PTHrP secretion, which is both mitogenic for alveolarization, and angiogenic for the alveolar capillary bed. This would allow for iterative evolution of the alveolar bed in the interim through positive selection pressure for those members of the species most capable of increasing their PTHrP secretion.

And it is worthwhile highlighting the fact that the increased amounts of PTHrP flowing through the adrenal may also have been responsible for the evolution of the capillary system of the medulla. Such pleiotropic effects typify the positive selection that has occurred during the evolutionary process.

This scenario would also have explained the duplication of the βARs. The increase in their density within the alveolar capillary bed was necessary for relieving a major constraint during the evolution of the lung in adaptation to land. The βARs are required for a ubiquitous mechanism for blood pressure control in both the lung alveoli and the systemic blood pressure. The pulmonary system has a limited ability to withstand the swings in blood pressure to which other visceral organs are subjected. PTHrP is a potent vasodilator, so it had the capacity to compensate for the blood pressure constraint in the interim. But eventually the βARs evolved to coordinately accommodate both the systemic and local blood pressure control within the alveolar space.

The glucocorticoid (GC) receptor evolved from the mineralocorticoid (MC) receptor during this same period through a third gene duplication. Since blood pressure would have tended to increase during the vertebrate adaptation to land in response to gravitational demands, there would have been positive selection pressure to reduce the vascular stress caused by the blood pressure stimulation by the MC aldosterone during this phase of land vertebrate evolution. The evolution of the GC receptor would have placed positive selection on GC regulation by reducing the hypertensive effect of the MCs by diverting steroidogenesis toward cortisol production. In turn, the positive selection for the GC cortisol would have stimulated βAR expression, potentially explaining how and why the βARs superseded the blood pressure–reducing function of PTHrP. It is these ad hocexistential interactions that promoted land adaptation through independent local blood pressure regulation within the alveolus. This integration of blood pressure control in the lung and periphery by catecholamines represents allostatic evolution.

The net result of PTHrP-mediated pituitary-adrenal corticoid production would have fostered a more potent “fight or flight” mechanism in our amniote ancestors. These were small, shrew-like organisms that would have been advantaged by such a mechanism, making them “friskier,” able to more likely survive the onslaught of predators during that turbulent era.

Moreover, increased episodes of adrenaline production in response to stress may have fostered the evolution of the central nervous system. Peripheral adrenaline mediates and limits blood flow through the blood-brain barrier, which would be expected to cause increased adrenaline and noradrenaline production within the evolving brain. Both adrenaline and noradrenaline promote neuron development. One might even speculate that this cascade led to human creativity and problem solving as an evolved expression of that same axis as an alternative to fight or flight, since it is well known that learning requires stress.

The duplication of the βAR gene may also have been instigated by the same intermittent cyclical hypoxia resulting from the process of lung adaptation, subsequently facilitating independent blood pressure regulation within the alveolar microvasculature; both of these mechanisms would have been synergized by the evolution of the GCs during this transition.

The bottom line is that all of the molecular pathways that evolved in service to the water-land transition—the PTHrP Receptor, the βAR, and the GC Receptor—aided and abetted the evolution of the vertebrate lung, the rate-limiting step in land adaptation. Perhaps that is why Weibel, Taylor, and Bolis observed that the lung had more physiologic capacity than was necessary for its normal range of function (see above), since only those organisms fit to amplify their PTHrP expression survived the stress of the water-land transition. The synergistic interactions of the lung and pituitary-adrenal axis producing adrenaline relieved the constraint on the lung through increased PTHrP production, fostering more alveoli. Perhaps this is the reason why the lung has excess capacity—either that, or become extinct.

The Cellular Approach to Evolution Is Predictive

This reduction of the process of evolution to cell biology has an important scientific feature—it is predictive. For example, it may answer the perennially unsolved question as to why organisms return to their unicellular origins during their life cycles. Perhaps, as Samuel Butler surmised, “a hen is just an egg’s way of making another egg” after all. It is worth considering the proposal that since all complex organisms originated from the unicellular state, a return to the unicellular state is necessary in order to ensure the fidelity of any given mutation with all of the subsequently evolved homeostatic mechanisms, from its origins during phylogeny through all the elaborating permutations and mutational combinations of that trait during the process of evolution. One way of thinking about this concept is to consider that perhaps Haeckel’s biogenetic law is correct after all—that ontogeny actually does recapitulate phylogeny. His theory has been dismissed for lack of evidence for intermediary steps in phylogeny occurring during embryonic development, like gill slits and tails. However, that was during an era when the cellular-molecular mechanisms of development were unknown. A testament to the existence of such molecular lapses is the term “ghost lineage,” which fills such gaps in the fossil record with euphemisms. We now know that there are such cellular-molecular physiologic changes over evolutionary time that are not expressed in bone, but are equally as important, if not more so in other organ systems. In all likelihood, ontogeny must recapitulate phylogeny in order to vouchsafe the integrity of all of the homeostatic mechanisms that each and every gene supports in facilitating evolutionary development. Without such a fail-safe mechanism for the foundational principles of life, there would be inevitable drift away from our first principles, putting the core process of evolution in response to environmental changes itself at risk of extinction. S.J. Gould famously wondered whether an evolutionary “tape” replayed would recapitulate. In this construct, the answer would resoundingly be yes, at least qualitatively, since all of the same components—bacteria, oxygen, minerals, heavy metals—are still present, and it would be expected that first principles would still remain as they are.

One implication of this perspective on evolution—starting from the unicellular state phylogenetically, being recapitulated ontogenetically—is the likelihood that it is the unicellular state that is actually the object of selection. The multicellular state—which Gould and Lewontin called “Spandrels”—is merely a biologic probe for monitoring the environment between unicellular stages in order to register and facilitate adaptive changes. This consideration can be based on both a priori and empiric data. Regarding the former, emerging evidence for epigenetic inheritance demonstrates that the environment can cause heritable changes in the genome, but they only take effect phenotypically in successive generations. This would suggest that it is actually the germ cells of the offspring that are being selected for. The starvation model of metabolic syndrome may illustrate this experimentally. Maternal diet can cause obesity, hypertension, and diabetes in the offspring. But they also mature sexually at an earlier stage due to the excess amount of body fat. Though seemingly incongruous, this may represent the primary strategy to accelerate the genetic transfer of information to the next generation (positive selection), effectively overarching the expected paucity of food. The concomitant obesity, hypertension, and diabetes are unfortunate side effects of this otherwise adaptive process in the adults. Under these circumstances, one can surmise that it is the germ cells that are being selected for; in other words, the adults are disposable, as Dawkins has opined.

Hologenomic evolution theory provides yet another mechanism for selection emerging from the unicellular state. According to that theory, all complex organisms actually represent a vast collaborative of linked, co-dependent, cooperative, and competitive localized environments and ecologies functioning as a unitary organism toward the external environment. These co-linked ecologies are comprised of both the innate cells of that organism and all of the microbial life that is cohabitant with it. The singular function of these ecologies is to maintain the homeostatic preferences of their constituent cells. In this theory, evolutionary development is the further expression of cooperation, competition, and connections between the cellular constituents in each of those linked ecologies in successive iterations as they successfully sustain themselves against a hostile external genetic environment. Ontogeny would then recapitulate phylogeny since the integrity of the linked environments that constitute a fully developed organism can only be maintained by reiterating those environmental ecologies in succession towards their full expression in the organism as a whole.

Another way to think about the notion of the unicellular state as the one being selected for is to focus on calcium signaling as the initiating event for all of biology. There is experimental evidence that increases in carbon dioxide during the Phanerozoic era caused acidification of the oceans, causing leaching of calcium from the ocean floor. The rise in calcium levels can be causally linked to the evolution of the biota and is intimately involved with nearly all biologic processes. For example, fertilization of the ovum by sperm induces a wave of calcium, which triggers embryogenesis. The same sorts of processes continue throughout the life cycle, until the organism dies. There seems to be a disproportionate investment in the zygote from a purely biologic perspective. However, given the prevalence of calcium signaling at every stage, on the one hand, and the participation of the gonadocytes in epigenetic inheritance on the other, the reality of the vectorial trajectory of the life cycle becomes apparent—it cannot be static, it must move either toward or away from change.

By using the cellular-molecular ontogenetic and phylogenetic approach described above for the water-land transition as a major impetus for evolution, a similar approach can be used moving both forward and backward from that critically important phase of vertebrate evolution. In so doing, the gaps between unicellular and multicellular genotypes and phenotypes can realistically be filled in systematically. But we should bear in mind that until experimentation is done, these linkages remain hypothetical. Importantly, though, there are now model organisms and molecular tools to test these hypotheses, finally looking at evolution in the direction in which it occurred, from the earliest iteration forward. This approach will yield a priori knowledge about the first principles of physiology and how they have evolved to generate form and function from their unicellular origins.

We Are Not Just in This Environment, We Are of It

The realization that there are first principles in physiology as predicted by the cellular-molecular approach to evolution is important because of its impact on how we think of ourselves as individual humans and as a species, and on our relationship to other species. Once we recognize and understood that we, as our own unique species, have evolved from unicellular organisms, and that this is the case for all of the other organisms on earth, including plant life, the intense and intimate interrelationships among all of us must be embraced. This kind of thinking has previously been considered in the form of genes that are common to plants and animals alike, but not as part of a larger and even more elemental process of evolution from the physical firmament. This perspective is on par with the reorientation of man to his surroundings once he acknowledged that the sun, not the earth, was the center of the solar system. That shift in thought gave rise to the Age of Enlightenment! Perhaps in our present age, such a frame-shift will provide insight into black matter, string theory, and multiverses.

In retrospect, it should have come as no surprise that we have misapprehended our own physiology. Many discoveries in biomedicine are serendipitous, medicine is post-dictive, and the Human Genome Project has not yet yielded any of its predicted breakthroughs. However, moving forward, knowing what we now do, we should countenance our own existence as part of the wider environment—that we are not merely in this world, but literally of this world—with an intimacy that we had never previously imagined.

This unicellular-centric vantage point is heretical, but like the shift from geocentrism to heliocentrism, our species would be vastly improved by recognizing this persistent, systematic error in self-perception. We are not the pinnacle of biologic existence, and we would be better stewards of the land and our planet if we realized it. We have learned that we must share resources with all of our biological relatives. Perhaps through a fundamental, scientifically testable and demonstrable understanding of what we are and how we came to be so, more of us will behave more consistently with nature’s needs instead of subordinating them to our own narcissistic whims. As we become deeply aware of our true place in the biologic realm, such as we are already witnessing through our increasing recognition of an immense microbial array as fellow travelers with us as our microbiome, we may find a more ecumenical approach to life than we have been practicing for the last five thousand years.

Bioethics Based on Evolutionary Ontology and Epistemology, Not Descriptive Phenotypes and Genes

By definition, a fundamental change in the way we perceive ourselves as a species would demand a commensurate change in our ethical behavior. Such thoughts are reminiscent of a comment in a recent profile of the British philosopher Derek Parfit in The New Yorker magazine, entitled “How to be Good,” in which he puzzles over the inherent paradox between empathy and Darwinian survival of the fittest. These two concepts would seem to be irreconcilable, yet that is only because the latter is based on a false premise. Darwin’s great success was in making the subject of evolution user-friendly by providing a narrative that was simple and direct. Pleasing as it may be, it is at best entirely incomplete. Think of it like the transition from Newtonian mechanics to relativity theory. As much is learned about the unicellular world with its surprising mechanisms and capacities, new pathways must be imagined. It is clear that we as humans are hologenomes, and all the other complex creatures are, too. In fact, there are no exceptions. The reasons for this can only be understood properly through a journey from the “Big Bang” of the cell forward, with all its faculties and strictures. By concentrating on cellular dynamics, an entirely coherent path is empowered. Tennyson’s line about “Nature, red in tooth and claw” is only the tip of what the iceberg of evolution really constitutes. As pointed out above, we evolved from unicellular organisms through cooperation, co-dependence, collaboration, and competition. These are all archetypical cellular capacities. Would we not then ourselves, as an example of cellular reiteration, have just those self-same and self-similar behaviors?


In summary, by looking at the process of evolution from its unicellular origins, the causal relationships between genotype and phenotype are revealed, as are many other aspects of biology and medicine that have remained anecdotal and counter-intuitive. That is because the prevailing descriptive, top-down portrayal of physiology under Darwinism is tautological. In opposition to that, the cellular-molecular, bottom-up approach is conducive to prediction, which is the most powerful test of any scientific concept. Though there is not a great deal of experimental evidence for the intermediate steps between unicellular and multicellular organisms compared to what is known of ontogeny and phylogeny of metazoans, we hope that the perspectives expressed in this essay will encourage more such fundamental physiologic experimentation in the future. 

Pre-Biotic Evolution: III. Transitioning to Animacy

Joseph H. Guth

Published by the

Society for the Advancement of Metadarwinism, Volume 3 2015

One Scientist’s Overview and Perspectives


In the first two parts of this series1,2, we have attempted to describe and summarize the steps and processes that in the author’s view, provide an almost invariably likely pathway from the production and evolution of various atomic species, formation of huge varying complex chemical mixtures under early earth conditions, and predictable interactions that then could lead to a high probability for the self generation and self-selection of complex dynamic, chemically-reactive systems and processes that ultimately we would come to define as organic-based terrestrial life.  This may not be the only such pathway but is argued to be a logical, consistent and realistic one that merits serious consideration.  Most would consider the ultimate occurrence of such a completely integrated process as highly unlikely, as one of very low probability.  That would be true if the universe only worked with one pair of molecules at a time and in a linear, sequential, trial-and-error fashion.  But if these molecular “experiments” occurred in parallel and simultaneously, and in uncountable high numbers of combinations and permutations for such events, as occurs in combinatorial chemistry, but which extended over very long timeframes while under a wide variety of operating conditions, the unlikely could then become the inevitable.  This is not unlike the old posit of having an infinite number of monkeys typing on an infinite number of typewriters eventually by random chance and accident being able to create all of Shakespeare’s novels.

Up through this point, we have collected a set of basic chemical and physical facts and allowed them to be blended into a plausible story of genesis of the first set of chemical species and energy sources that are thought by many to exist throughout the universe.  It provides a certain compelling argument for expecting similar living processes and organisms being likely to have developed throughout the cosmos.  But it also provides us with a more specific set of targets and signs to scan and search for other life in our extra-terrestrial explorations now and into the far future.

Animacy, one of life’s most useful characteristics when it occurs, is the ability to engage in some kind of movement, relocation or translocation.  Such movements are not always present or apparent at the individual organismal level but can usually be found if not individually, then collectively in colony-forming species or multicellular organisms.  Even rooted, as well as non-rooted single-celled or colony-forming plants, have the ability to move or reorient themselves in response to their environmental needs (e. g., phototaxis, water seeking tap root growth, gravitaxis, specialized food-trapping structures and flagellated motion).  It is hard to overstate how great an evolutionary advantage was gained when living systems of all types finally were able to react to environmental conditions and the presence of other living organisms by development and self-selecting for directed translocation.

From Molecules in Random Motion to Functional Movements in Evolving Protocells

Motion, reorientation or other movement can be found in different functional modalities in modern day living systems.  For instance, the movement  of the outer eukaryotic cell membrane as it pinches off at the end of the mitotic cycle performs a different function than the pinching off of membrane vesicles during phago-, endo- and exo-cytosis.  Such membrane-based movements are further expanded on with the ruffling leading edge of the plasma membrane in certain types of amoeboid movement.

Figure 1.  Both mammalian cells are demonstrating membrane edge ruffling behavior.  In this animated gif image file, the cell on the left is stationary because the entire 360 degree perimeter is involved.  The cell on the right is rapidly moving from left to right with the leading hyaline edge on its right side ruffling strongly.  In such directional motility, the cell’s underlying cytoskeleton plays a major role in its ability to keep it moving in a continuous fashion in one direction.  (Taken from  Accessed 12/2/2015)

Of course many of these modern day capabilities are also greatly assisted by underlying intracellular structures and molecular processes3 such as microfilament-microtubule interactions4 and the concurrent visco-elasticity changes through reversible cytoplasmic gel-sol modification, the internal relocation of mitochondria and increased rates of intra-cytoplasmic streaming and mixing of chemicals and enzyme complexes (Figure 2).

Figure 2.  Cytoplasmic flow generated by microfilaments and microtubule polymerization-depolymerization cycles is seen in this animated image as a mechanism for internal cytoplasmic mixing, relocation of subcellular organelles and for generating the underlying forces for formation of pseudopodia, ruffling edges and other mechanical movements by the cell.  The efficiency of such an evolutionary development represents a highly efficient use of structure and function for the early cells. (From Dr. R. Wagner,, accessed 12/6/2015)

But there has been a well-demonstrated ability by various purified synthetic lipid membrane model systems preparations to also spontaneously possess very similar behavior and capabilities.5  Figure 3 provides a still record of this behavior but microscopic videos have recorded it as a dynamic budding process that is sometimes surprisingly rapid.  So the first protocells composed of these chemical compounds simply incorporated the natural tendencies of the self-organized chemicals they were made up of.  It was simple, undirected, relatively low-functional movement, but movement and change, nevertheless.  And from any kind of change comes the opportunity to evolve into something more adapted to the existing conditions.

Figure 3.  Spontaneous microsphere formation, pinching off and fusion behavior occurs in synthetic preparations and is intrinsic to both lipids, like lecithin, and to proteins with higher contents of less polar amino acid compositions.  (Taken from, accessed 12/6/2015)

Thus we likely actually have the initial seed for cellular mobility and animation actually built into the molecular properties of the membrane matrix.  It can be enhanced with other underlying molecular machinery, such as microfilament and microtubule structural and dynamically-changing mechanical frameworks, but the primary basics for animacy are built into the physical properties of the lipids, and to a narrower extent, the membrane proteins and carbohydrate-containing molecules that compose such structures in later protocells as well as up through modern cells.  For more highly developed mechanisms and structure emerging in cell evolution, such as flagella and cilia, we will have to wait until we discuss the developments after the first prokaryotic and eukaryotic cells transitioned into existence in a later installment.

With the intrinsic capability for limited movement already inherent or built-in at the molecular level in protocellular membranes, directed movement could provide a dramatic improvement in survival potential for more successfully composed protocells.  For instance, the ability to avoid damaging conditions, such as excessively high or low temperatures (thermotaxis), or seek out better sources of nutrients or avoiding toxic substances (chemotaxis), or find optimal levels of illumination (phototaxis) would be indispensable for enhancing the growth rate, reproduction rate, and survival potential of protocells as it does in modern living cells.  In this sense, one might extend the idea of Darwinism and survival-of-the-fittest to the basic animation processes deriving from the molecular properties of various molecules making up the cell membranes.

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Figure 4.  An animated image providing an example of a directed chemotactic response by a white blood cell that is tracking and phagocytizing bacteria in blood.  (Taken from and attributed to David Rogers, Vanderbilt University.  Accessed 12/2/2015)

This capability is well-recognized to confer a significant modern advantage to present day life as exemplified in the above figure, but such a capability would have profound advantages to a simpler protocell that was only getting its initial nutrition through soluble compounds.  Such dissolved nutrients were rate-limited by slow passive diffusion rates through the surrounding medium.  Non-soluble sources of nutrients would have been unavailable to such passive cells.

Membrane Basics and Molecular Bases for Membrane Dynamic Behaviors

Many things can modify those animation-related properties of modern cell membranes.  Such membranes all have a basic common design.  The major framework is composed of various phospholipids that preferentially auto-assemble into two-dimensional sheets in aqueous media in the temperature range allowing fluid behavior.  One of the most abundant membrane phospholipids, lecithin, is composed of three bonded components.  Those are a phosphate moiety, glycerol, and one or two fatty acid molecules (see Figure 5).

Figure 5.  The most common molecule that provides the basic framework for modern day cell membranes is the phospholipid, lecithin.  It is made of a phosphate group (blue ball) covalently bonded to a glycerol molecule to which two fatty acid molecules (elongated downward legs) are also attached.  This diagram also demonstrates the saturated fatty acid molecule on the left is flexible but can become linear while the fatty acid molecule on the right has a permanent kink in it due to its being unsaturated (that is, containing a double bond between two adjacent carbon atoms in it).  Not all phospholipid molecules contain the same fatty acids nor the same proportions of saturated to unsaturated fatty acids.  The lengths of the fatty acid chains and the number of unsaturated bonds within the unsaturated fatty acids also modify the temperature at which that part of the membrane transitions between its more fluid to less fluid state, and thus its deformability and fusibility in that same region.  (Taken from Wikipedia, “Phospholipids”. Image authored by Ties van Brussel .  Accessed 11/30/2015).

The elongated phospholipid molecules always have a highly polar end, that is attracted to other polar molecules such as water, and a low- or non-polar end that is not bondable with polar molecules.  Those hydrophobic ends tend to become more stably associated with other non-polar molecular regions.  When these phospholipid molecules finally finish their segregating and reorientation in a bulk water phase, they initially can form a monomolecular layer at the air-water surface interface, with the polar phosphate ends bonding downwards with water molecules and their non-polar, hydrophobic ends pointing upwards towards the less polar molecules making up air.  In this “head down” orientation, the fatty acid hydrophobic tails are stabilized by lower strength van der Waal forces.  But that is still sufficient to hold them in a closely packed two dimensional sheet.  But in any average suspension of such phospholipids in aqueous media, these monolayers will tend to spontaneously form bilayers in which two monolayers pair up with their hydrophobic fatty acid tails directed inwards towards each other and their more polar, electrically-charged phosphate heads oriented outwards and in intimate contact with the water phase.  Water molecules are polar and can hydrogen bond with each other as well as other, more polar molecules.  Because of the stronger electrical charge fields existing around the phosphate moiety, water molecules tend to strongly interact with this end of the phospholipids and arrange themselves in a loose cage-like structure surrounding each phosphate group.  This overall electrical charge repulsive force and clathrate structure interaction is what generates the natural but slight rigidity in a molecular aggregate that is only two molecules thick!  It generates a physical back-resistance to membrane deformation that allows there to be different flexibility between different zones of the membrane.  This is energetically a more stable arrangement for a sheet-like structure.

In an aqueous phase there are edges where phosphate groups are absent that are exposed to the more polar aqueous environment and those seek to lower their energy state even more by minimizing the exposed internal hydrophobic interior.  To minimize this disruption to the water structure surrounding the flat sheet of bilayer membrane, the membrane edges continue the self association process ultimately resulting in an even lower energy arrangement, a closed vesicle shape with no exposed edges.  Thus the simplest bilayer membrane geometry that is most stable at normal temperatures is the single bilayer, membrane-enclosed vesicle.  Studies have demonstrated that multiple- layered bilayers are also capable of forming.  These are not as rapidly permeable as a single bilayer under normal circumstances so it is unlikely that such added barriers between the internal life chemistry and the external medium would confer greater advantages to the newly created protocells.  Though we will revisit this thought in a later installment.

Analytical and synthetic chemists have a rule of thumb that is based upon this difference in solubility based on the polarity and charges of the molecule’s bonds.  Termed the Solubility Rule, it is well known and stated that “like dissolves like”.  What this means is that when looking at a molecule’s structure, one can make a fairly accurate prediction of what kinds of solvents would best be useful to dissolve such a compound in. Many kinds of chromatographic and affinity separations of complex mixtures use this relationship as well.  It is based upon the thermodynamic properties and bond strengths of intermolecular bonding and rearranging the positioning and orientation of electrically charged and uncharged molecules (or portions thereof) with respect to one another.  Its applicability also extends one level further in that when dealing with two or more types of molecules within a single category, such as hydrophobic molecules, that molecules with identical structure tend to further segregate themselves into regions with others of the same structure.  Such pooled regions of identical composition in a larger background of molecules of similar low charge and polarities is essentially what is found in modern day biological membrane structure.  This has also been termed membrane microenvironments.  A good example is the “raft-like” behavior of cholesterol and other steroidal molecules that cluster around embedded and transmembrane proteins within a broader area of bilayer phospholipid membrane (see figure 6).

Figure 6.  A cross-section of a modern animal cell plasma membrane illustrating the different microenvironment regions of such a membrane.   Phospholipid molecules showing the two fatty acid hydrophobic tails (light blue) attached to the hydrophilic heads (darker pink circles) align in two monolayers to form a bilayer framework within which many other molecules associate and function.  Region 1 is the microenvironments where no other molecules are present.  Region 2 is a raft region which is enriched in cholesterol content (number 7 in light pink) and membrane proteins (numbered 3 and 4 in dark green) as well as other kinds of functional molecules (numbered 5, 6 and 8).  The raft regions provide a more physically and chemically unique microenvironment within which membrane-bound, multi-protein complexes are attracted and operate.  Phase transition temperatures within these regions are expected to be somewhat different than those in region 1 zones.  Physical deformability and fusion/membrane coalescence capabilities would also be expected to be modified in those regions as well.  (Taken from  Wikipedia.  “Lipid Raft”.  Image authored by Artur Jan Fijałkowski.  Accessed 11/30/2015).

One purpose of such segregated regions within a phospholipid bilayer is to provide regions of differing solubility for other lower polarity transmembrane molecules, such as transmembrane proteins, to reside in.  Such transmembrane molecules can provide specialized transmembrane functions, such as semi-permeability, electrochemical reaction platforms, cell signalling, intracellular communication, and catalysis-assisted processing and transport of specific substances.  Obviously, the appearance and conservation of cholesterol-rich, self-associated membranes during protocell evolution would also be a major advantage to increasing the likelihood of more potential functions being able to be added to the developing protocell membrane in our evolutionary story of the perfecting of cells from protocells.

Under typical biologically favorable conditions, these phospholipids tend to aggregate together in different packing geometries and with different bonding energies defined, in part, by the kinds of fatty acids that are part of their composition.  Regularly-shaped saturated fatty acids tend to “crystallize” into more tightly packed arrangements at some pseudo-solidification temperatures while the presence of unsaturated bonds tends to keep them from crystallizing at those temperatures.  What this means is that bilayer membrane lipids will have regions in their 2 dimensional surfaces at any given temperature where the internal, more saturated fatty acids will be more tightly packed and less fluid.  Lower fluidity necessarily hinders molecular motions and transmembrane processes while at other, more unsaturated locations those transmembrane processes occur more quickly and with larger scale molecular motions.  In such higher fluidity regions of the membrane surface, the packed membrane components can quickly reconfigure to allow surface-localized transport to occur.

Other concurrent membrane properties that are affected by the rafting and saturated/unsaturated behavior of the lipid components are membrane flexibility, folding and fusibility/pinch-off potential.  Such are the physicochemical foundations for modifying the fluid/semi-fluid/nonfluid behavior potential of all membranes.  In studies using modern cell types, the fatty acid compositions of biological membranes actually changes in a single cell type as a function of the growth temperature.  This is an active homeostatic control mechanism of cells that is linked to their lipid metabolism.  The membrane fatty acid composition is continually readjusted so that the fluid transition temperature is maintained just below the actual growth temperature, assuring transmembrane processing will remain fully functioning.  Because these membrane lipids can have several different transition temperatures that can modify both the packing geometries of a single kind of lipid as well as the fluidity and flexibility of that part of the membrane it is found in, membranes are considered liquid crystalline in nature.  This provides for thermal transitions between several different phases and thus allows a wide variety of fluidity-based functions to co-exist within a single membrane at the same time at a given temperature.

Each transition temperature built into a particular membrane’s lipid framework confers both mechanical and transport limitation ranges as well as the optimum temperatures for each kind of membrane-based process or movement.  When one looks at cells that are undergoing some directed dynamic process or behavior, it is tempting to envision that such a large scale movement is caused by or connected to highly localized transmembrane molecular events underlying and inseparably-linked to the overall function being carried out.  As an example, if one views the formation and extrusion of pseudopodia in a modern day amoeba moving along a surface towards a nutrient-laden particle, it would be greatly aided in its food-seeking chemotaxis if the concentration of soluble nutrient substances diffusing from that particle be the first event that triggers the amoeboid cell movement in that direction.  This first event entails recognizing that a source of food is closely present and can be reached by moving in the direction closest to the point on its membrane where the greatest flux of soluble nutrients are passing through.  Areas of this closest approach would become enriched in more fluid-like lipids that concurrently would allow a greater degree of deformation at a given temperature while the other parts of the membrane are reduced in their fluidity.  They would take on a somewhat more deformation-resistant quality and give the cell a better way of maintaining its directionality of overall translocation or movement.  And embedded within the differing functional and structural micro-areas of this food-seeking cell’s membrane are other translocation molecules, like proteins, that are further enhancements to connect the overall membrane alterations with internal biochemical changes needed to capture and process the food source once it is physically encountered.  Not only higher fluxes of soluble nutrient molecules would be expected in this initiation of a chemotactic movement, but active triggering of internal cellular motility machinery through localized increases of calcium ion influxes would be coordinated at the same time.  Such localized increased calcium concentration just below the deforming membrane surface would also activate microfilament movement creating an internal current of cytoplasmic flow in that same region.  That flow would further deform the membrane in that location leading to a general cellular movement in that direction.

In protocells, we do not yet have that level of functionality and complexity built in but the co-presence of other lipids with differing transition temperatures and self-association energies can begin to provide such infant cells with a beginning blush of chemotactic potential.  Darwinian evolution must then follow to increase rates and improve performance of such a complex set of molecular events found in modern day cells.  One very basic aspect of cell animacy is likely to have sprung from the molecular structure and properties of the membrane lipids that are to be found in modern cells and likely in early earth protocells as well.

The Evolutionary Impact of Cell Membrane Fusion and Scission

Experiments with both phospholipids have demonstrated that when the temperature was above the phase transition temperature for membrane fluidity, the closed membrane vesicles were capable of two overall actions.5,6  The first was of a scission or budding process in which a vesicle could pinch off and separate into two or more smaller vesicles without loosing, leaking or diluting its internal fluid content or otherwise modifying that internal compartment chemistry noticeably (See Figure 7).  That is an extremely useful built-in behavior for such a packaging that needs to indefinitely maintain its complete integrity and uncompromised contents.Figure 7.  This greatly magnified phospholipid vesicle can exhibit bud formation and ultimate scission into smaller vesicles without any additional internal mechanical or chemical assistance. This example is indistinguishable from an identical behavior in modern organisms’ cell membranes.  (Taken from E. Sackmann, “Physical Basis of Self-Organization and Function of Membranes: Physics of Vesicles”, Chapter 5 in Handbook of Biological Physics, Vol. 1, R. Lipowsky and E. Sackmann, eds., Elsevier Science B. V., 1995)

Figure 7.  This greatly magnified phospholipid vesicle can exhibit bud formation and ultimate scission into smaller vesicles without any additional internal mechanical or chemical assistance. This example is indistinguishable from an identical behavior in modern organisms’ cell membranes.  (Taken from E. Sackmann, “Physical Basis of Self-Organization and Function of Membranes: Physics of Vesicles”, Chapter 5 in Handbook of Biological Physics, Vol. 1, R. Lipowsky and E. Sackmann, eds., Elsevier Science B. V., 1995)

The second action is that of the coalescence and fusion of two or more different vesicles into one larger vesicle, again without loosing or modifying their contents through external medium leakage into them.  The fact that such actions are naturally found to occur in most living cells provides us with a directly observable behavior of cells that is based upon the inherent molecular properties of phospholipid membrane composition, internal membrane component rules of association, and the overall tendency to form vesicular structures in aqueous environments.

What these two properties allowed the earliest protocells to accomplish was to provide a rather robust and putatively permanent housing for the complex chemical processes that were developing and occurring in the locations on early earth where the building blocks of life were being endlessly and spontaneously generated and modified.  These properties of membrane fusion and scission allowed the large pre-protocellular bulk liquid phases containing the various combinations of linked reaction sequences to not only be initially captured, but even more important, to give each micro-collection of complex reactive chemistry the ability to resist dissipation and to remain longer-lasting.  It provided the desirable internal environments to maintain the reactants in a more concentrated fashion within small protected environments.  With this increased longevity, these reactive vesicles could combine their contents together in a multitude of different trials-and-errors while conserving the higher internal concentrations of ingredients.  Such a design would improve the chances for development of even faster and more controlled internal chemical kinetics.

But another and even more valuable evolutionary capability was inherent in this protocellular membrane design.  The ability to become permanently self-sustaining through the spontaneous scission and generation of vesicular copies of more successful protocell compositions would be drastically improved if the more rapidly growing versions could bud or pinch off into independently growing units.  Multiple backup copies of successful versions would be a strategy to conserve a new and more suitable species of protocell.  And retaining a smaller vesicular size (i. e., surface-area-to-volume ratio) increases the transmembrane flow of metabolites into and out of the protocells without becoming limited by internal diffusion rates or increased thickness of membrane surface diffusion-limiting solvent boundaries.  The forces occurring in natural fluid settings that abound in nature are quite adequate to provide the energy and forces necessary to induce such scissions prior to the evolutionary development of enhanced molecular machinery specifically designed to carry out such gross modern cell membrane modifications as occurs in cell division (Figure 8a and 8b).

Figure 8a (top) and 8b (bottom).  Simple fluid cascades and waves breaking can provide the shearing forces to stretch and pinch off the membranes of larger vesicles and produce multiple copies of smaller versions of the parent version of vesicles without losing the original content compositions or internal chemistries.  It is argued here that these were the first forces available and involved in the earliest versions of protocell formation, division and even subsequent fusions of protocells initially possessing different internal constituents. (Unknown sources).

So with this rudimentary mechanism on early earth operating and which caused an increase in protocell numbers, this could be construed as a form of protocell division.  It is important to highlight at least one process that would have naturally occurred to show we have a likely physical process for protocell division.  Not only would it have been likely to occur anywhere in the world of early earth, it would have sped up the evolution of more successful versions of protocells.  Thus it would have increased their survival as well as rates of generation.

As long as nutrients are present and waste elimination is not limiting, each separated vesicle of a more successful composition would become another center of growth through mass accumulation.  This is a seminal feature of the application of both Chaos Theory and Complexity Theory.  This combination of advantages is all proposed to have occurred as a precursor to the development of a genetic code, genomic information recording and directed synthetic management  system (DNA, RNA and protein biosynthesis).  It provides a plausible mechanism for enhanced multiplying of the more successful combinations of protocellular compositions over those that were less successfully composed in a non-genetic manner through the Butterfly Effect.

Self-sealing, membrane-bounded vesicles can also fuse together, safely combining their protected internal contents into new admixtures.  This mechanism also provides a higher order potential of developing larger steps in the protocell design changes during the continuous march of trial-and-error experimentation that evolution rests upon.  Membrane fusion is also useful for the development of later capabilities of phagocytosis found in many kinds of modern day cells.  For instance, a cell engulfs a food particle and takes it into its cytoplasm where that membrane-bounded particle now fuses with lysosomes or other membrane-bounded organelles for further processing.  For protocellular survival, the ability to take in non-soluble structures, such as other protocell membrane fragments and less successful protocell versions, and reduce them to soluble nutrients would provide new sources of nutrition.  Without that property, insoluble protocell debris would continue to accumulate with no means to rapidly remove it from the niche.  This competition could quickly develop into a very early version of survival-of-the-fittest in a predator-prey relationship of protocell types.

Modern day cell membranes have many molecular “helpers” to accelerate various membrane-based mechanical movements and modifications.  But the intrinsic molecular properties of the phospholipid framework upon which it, as well as protocells, were built was already designed to allow such actions to occur given the right environmental conditions and an adequate, naturally-occurring energy source.  The later developments of pino-cytosis, endo-cytosis, exo-cytosis, phago-cytosis and syncytium formation all have highly developed machinery to aid and control these processes.

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Figure 9.  Dictyostelium slime mold amoeboid movements, chemotaxis-based association behavior and differing functional movements at both the individual cellular and multicellular organizational levels. (Produced by John Bonner, Princeton University.  Taken from public posting on YouTube at  Accessed 12/5/2015)

But none would have developed had not the phospholipid component of cell membranes already possessed, in a chemically built-in fashion, its very unique set of associative, disassociative, fusibility and localized variation of permeability properties.  And all attendant functions connected to those developments would also have suffered or been unsupportable and lost.  Such functions are paramount to the organization and operation in multi-cellular organisms and as such, may be necessary to attain before such larger collective and specialized multicellular organisms could evolve.

Animacy is a broad collection of evolutionarily useful potential mechanisms based upon the physicochemistry of protocell membrane lipids.  It is an almost incomprehensible testament to the persistence, protection, permanency and survival power of the membrane design that finally occurred in the first successful protocell.  That membrane, only two molecules in thickness, had to capture, retain and protect the living chemical processes operating within it in a continuous, never-ending sequence of growth, multiplication and interaction with the outside world for billions of years.  It had to have the plasticity to move through even the smallest of passages and instantly seal when any sharp physical insult threatened its integrity.  The complex chemistry leading up to the production of membrane-forming molecules is seemingly pre-destined to always form anywhere in our cosmos.  What a marvel!

Next:  Pre-Biotic Evolution.  Part IV.  The Development of Electrochemically-Generated Energy Linkage, Extraction and Storage in Protocells

* Scientific and Forensic Services, Inc., Delray Beach, FL. and Norfolk, VA


  1. Guth, J. H.  “Pre-Biotic Evolution:  I. From Stellar to Molecular Evolution”.  Society for the Advancement of Metadarwinism, Volume 1, November 19, 2014.   Accessible at
  2. Guth, J. H.  “Pre-Biotic Evolution:  II. Pre-Biotic Chemical Oscillations and Linked Reaction Sequences”.  Society for the Advancement of Metadarwinism, Volume 2, June 12, 2015.   Accessible at
  3. Taylor, D. L., J. S. Condeelis, P. L. Moore and R. D. Allen.  “The Contractile Basis of Amoeboid Movement, I. The Chemical Control of Motility in Isolated Cytoplasm”.  J. Cell Biol. 59:378-94 (1973)
  4. Norberg, B., U. Bandmann and L. Rydgren.  “Amoeboid movement in human leucocytes: basic mechanisms, cytobiological and clinical significance”.  J. Mechanochem. Cell Motil.  4:37-53 (1977)
  5. Dobereiner, H.-G., J. Kas, D. Noppl, I. Sprenger and E. Sackmann.  “Budding and Fission of Vesicles”.  Biophys. J. 65:1396-1403 (1993)
  6. Takakura, K. and T. Sugawara.  ” Membrane Dynamics of a Myelin-like Giant Multilamellar Vesicle Applicable to a Self-Reproducing System”.  Langmuir, 20:3832–3834 (2004)

© Copyrighted by Joseph H. Guth, 2015.  All rights reserved.