NELSON R. CABEJ :: Epigenetic Principles of Evolution

The evolution of life on Earth is a fact that by consensus is accepted in modern biology. However, the biological community is polarized in regard to the mechanisms of biological evolution. On the one hand, is the prevalent view that evolution of the living world is determined by changes in genes and gene frequencies, and on the other, a new, less powerful, but already significant and rapidly crystallizing concept, holding that nongenetic, epigenetic factors and mechanisms, also play an important role in the evolution of life.

The eclectic integration of the Darwinian doctrine into gene theory by the 30-50es of the 20^th century led to the Modern Synthesis (modern evolutionary synthesis, neoDarwinism, evolutionary synthesis, etc.). For simplicity’s sake and for avoiding the confusion arising from the use of almost synonymous terms essentially naming that same theory, I will consider all of them under the common designation of the neoDarwinian paradigm.

The paradigm, which represents the mainstream theory, posits that evolution is the result of changes in allele frequencies with gene mutations, genetic recombinations, and gene drift being the source of genetic variability necessary for the action of natural selection. At its extreme form, the theory sees the life and evolution of living forms as a way of propagation and perfection of genes, while the carriers of genes, the organisms themselves, serve as machines or vehicles for survival and reproduction of genes.

Scientific candor requires us to plainly admit that despite the tremendous amount of effort, biology has never succeeded in showing how a change in gene(s) during evolution led to an evolutionary change in morphology.

In recent decades, a number of new alternative ideas, perspectives, hypotheses, and theories (Eldredge, Gould, West-Eberhard, Piggliucci, Schlichting, Newman, Müller, Cabej, and others) have been propounded to explain the biological evolution or particular aspects of it. Rather than an unexpected or accidental phenomenon, the development of these hypotheses and theories is the logical result and manifestation of the failure of the existing paradigm to cope with an ever-increasing body of empirical evidence. At the turn of the 20^th century evolutionary theory was steered into an explanatory crisis.

A general idea about the gravity and proportions of the crisis of the neoDarwinian explanans of evolution may even be obtained through a glimpse on the following incomplete list of crucial biological phenomena that it cannot account for (all of them will be considered in some details in respective chapters of this work):

1. Sudden evolutionary events, particularly the burst of body plans and emergence of almost 100 phyla within an evolutionarily narrow window of 5-15 million years during the Cambrian (~450 million years ago), whereas almost no new phyla have appeared in the following 430-445 million years. This, unambiguously, contradicts the basic neoDarwinian tenet of the gradualism of the evolutionary change.

2. Rapid speciation and morphological changes observed in nature, such as formation of new cichlid species in East African Lakes in a matter of several to hundred thousands of years, evolution of the Drosophila species in the Hawaii Islands, etc., including the rapid evolution and huge phenotypical (morphological, physiological, behavioral and cognitive) divergence of humans and chimpanzees during the evolutionarily brief period of several million years.

3. Reproductive isolation and sympatric speciation in the absence of geographic isolation, involving no gene mutations, gene drift, or genetic recombination.

4. Frequent appearance of evolutionary reversions, return of lost ancestral traits even after many millions of years, clearly refuting the neoDarwinian principle of the irreversibility of evolution.

6. Sudden and systematic appearance in the offspring (transgenerational developmental plasticity under the influence of environmental stimuli experienced by parents) of inherited changes in morphology, physiology, life history, and behavior, involving no genetic factors or mechaniosms.

7. Intragenerational developmental plasticity - discrete changes in morphology in response to environmental stimuli.

8. Developmental polymorphisms, i.e. systematic production of different morphs in the offspring of the same brood and the same genotype, sometimes in adaptive responses to specific environmental stimuli.

9. Rapid and reproducible experimental reversion of the lost ancestral, physiology, behavior and life histories of Drosophila melanogaster, within as little as 5 to 20 generations.

10. Generation of the huge amount of quadrillions of bits of the epigenetic information (exceeding millions of times the amount of the genetic information contained in the human genome) necessary for experience-indepenent establishment of specific neuronal connections during the embryonic development of the central nervous system in higher vertebrates.

With all the above in view, the reader is asked to decide whether these counterinstances represent “exceptions to the rule”, “exceptions that prove the rule”, or whether the paradigm, at its present status, is “ruled by exceptions”.

Not only does the neoDarwinian paradigm fail to account for the above and many other phenomena, but empirical evidence is at odds with some of the basic neoDarwinian tenets, as it will be argued in respective chapters and subsections of this work. The failure is the unavoidable result of the doctrinaire attitude, disregard of the challenging developments in various fields of biology, especially the developmental biology and paleontology, dismissal of the ever-increasing body of evidence on the epigenetic factors involved in the individual development and heredity.

The NeoDarwinian Paradigm and Darwin’s Heritage: Darwin in Procruste’s Bed

Since it was presented for the first time about one and a half century ago, Darwinian theory was used as a shield for protecting and fending off criticisms by the most diverse biological and even social theories and doctrines from the amorphous Lysenkoist doctrine of inheritance of acquired characters on the extreme left to Herbert Spencer’s social-Darwinism on the right. Theoretical constructions in the 20^th century could not afford to opt out of using Darwin’s imposing scientific reputation even when particular Darwinian ideas contradicted some of their basic tenets.

While claiming loyalty to Darwinian theory, neoDarwinians in fact dwarfed Darwin’s heritage and excluded from their theory some of his basic ideas, such as the role of changes in the environment and the use/disuse of organs in evolution, evolutionary reversion to ancestral traits, role of behavior and learning in modifying instincts, sympatric speciation, etc.

First, in relation to the central issue of natural selection, neoDarwinians, implicitly on Darwin’s behalf, excluded from the theory any non-selectionist mechanism of evolutionary change. According to the neoDarwinian paradigm, the only real attribute of the living organism, the evolving entity, is to be subject to random changes in its genes, while the environment via natural selection (seen as a process) brings order to the random variability. Accordingly, living organisms produce random variability or, in a figure of speech, only “letters” and “words”. It is the environment, which via the natural selection, uses these letters and words in writing the text of the evolution.

The neoDarwinian paradigm has already paid a high price for stubbornly holding fast to the strange idea that the driving force of the evolution of living systems is to be found outside the living systems themselves, in the environment, in a natural selection that designs from the random changes occurring in living systems. The cult of chance as the ultimate source of variability and evolution via natural selection was proclaimed to be continuation and advancement of Darwinian legacy. Is this true?

In fact, from the first publication of the “Origin”, and repeatedly in the later editions, Darwin pointed out in a visible part of the Introduction:

I am convinced that Natural Selection has been the main but not exclusive means of modification. (Darwin, 1859a1)

Darwin made clear his belief that evolution may occur even without natural selection being involved:

It should not, however, be overlooked that certain rather strongly marked variations, which no one would rank as mere individual differences, frequently recur owing to a similar organisation being similarly acted on—of which fact numerous instances could be given with our domestic productions. In such cases, if the varying individual did not actually transmit to its offspring its newly acquired character, it would undoubtedly transmit to them, as long as the existing conditions remained the same, a still stronger tendency to vary in the same manner. There can also be little doubt that the tendency to vary in the same manner has often been so strong that all the individuals of the same species have been similarly modified without the aid of any form of selection. (Darwin, 1872a1)

implying that convergence, this universal phenomenon in the evolution of the living world, is an intrinsically determined adaptive process that needs neither random inherited changes (genetic variability or gene mutations) nor selection to occur.

Contrary to the neoDarwinian idea that the loss and vestigialization of organs results from the accumulation of mutations under the action of natural selection, Darwin denied any role of natural selection (and implicitly of the genetic variability) in the process of evolutionary vestigialization and ultimately in the loss of organs:

Rudimentary organs, from being useless, are not regulated by natural selection. (Darwin, 1872c)

The neoDarwinian temptation to dismiss from the Darwinian doctrine all but the principle of natural selection and indefinite changes is not unprecedented. It is as old as the Darwinian theory itself. The genius had to deal with the same misrepresentation problem during his lifetime:

But as my conclusions have lately been much misrepresented, and it has been stated that I attribute the modification of species exclusively to natural selection, I may be permitted to remark that in the first edition of this work, and subsequently, I placed in a most conspicuous position - namely, at the close of the Introduction - the following words: “I am convinced that natural selection has been the main but not the exclusive means of modification”. This has been of no avail. Great is the power of steady misrepresentation; but the history of science shows that fortunately this power does not long endure. (Darwin, 1872d)

Not only did Darwin not exclude the role of non-selectionist factors in evolution but he even elaborated on some of these factors.

The neoDarwinian theory neglects, if it considers at all, the role of use and disuse of organs in evolution of the living world. To the contrary, Darwin pointed out:

Disuse, aided sometimes by natural selection, will often tend to reduce an organ, when it has become useless by changed habits or under changed conditions of life. (Darwin, 1859k)

The animal structure may change by mechanisms different from random changes in genes, in the modern biological meaning. Darwin believed that disuse may lead to reduction and vestigialization of organs or parts, biological phenomena that “are extremely common throughout nature” (Darwin, 1859i) and which result from the use and disuse:

There can be little doubt that use in our domestic animals strengthens and enlarges certain parts, and disuse diminishes them; and that such modifications are inherited. (Darwin, 1859e)

I believe that disuse has been the main agency; that it has led in successive generations to the gradual reduction of various organs, until they have become rudimentary,—as in the case of the eyes of animals inhabiting dark caverns, and of the wings of birds inhabiting oceanic islands, which have seldom been forced to take flight, and have ultimately lost the power of flying. (Darwin, 1859j)

Based on the idea that spontaneous random changes in the hereditary material, i.e. gene mutations, are the only source of inherited variability, neoDarwinians excluded the possibility of environmental agents acting as stimuli inducing inherited changes in the structure and function of organisms. To the contrary, Darwin accepted, and modern biology has substantiated, the idea that environmental stimuli can induce inherited adaptive changes in living organisms:

Changed conditions generally induce mere fluctuating variability, but sometimes they cause direct and definite effects. (Darwin, 1872c)

Translated into modern biological parlance, these “direct and definite effects”, are nonrandom, nongenetic and therefore epigenetic changes. Indeed, firmly established observational facts on transgenerational developmental plasticity have shown that Darwin was right, neoDarwinians are not (see chapter 12).

In line with their idea on gene mutations as the exclusive source of inherited variability, neoDarwinians believe that evolution is irreversible. They still are denying the possibility of evolutionary reversion of lost ancestral structures, as formalized in Dollo’s law. To the contrary, Darwin believed that evolutionary reversions are possible and hypothesized about the underlying cause of the phenomenon:

When a character which has been lost in a breed, reappears after a great number of generations, the most probable hypothesis is, not that the offspring suddenly takes after an ancestor some hundred generations distant, but that in each successive generation there has been a tendency to reproduce the character in question, which at last, under unknown favourable conditions, gains an ascendancy. (Darwin, 1859f)

Then he iterates that “there is a tendency in the young of each successive generation to produce the long-lost character, and that this tendency, from unknown causes, sometimes prevails” (Darwin, 1859g). More than adequate evidence on evolutionary reversions shows that Darwin was right, neoDarwinians are not (see chapter 16, Evolution by Reverting to Ancestral Characters).

Exclusion of all the above Darwinian factors from the neoDarwinian theory of evolution was a timid criticism of Darwin’s concept on organic evolution. It is somewhat ironical that by proclaiming Darwinism, the neoDarwinian approach to the problem of evolution is more Wallaceian than Darwinian. R. A. Wallace, the coauthor of the theory of natural selection, has also criticized Darwin’s acceptance of non-selectionist factors as important players in the process of living world:

Now Mr. Darwin has himself admitted that there are these unknown causes at work, and that ‘natural selection is the most important but not the exclusive means of modification.’ There may be some question as to the term ‘most important’, if, as is not improbable, the most radical differences in animals and their most important organs could not have been produced by it alone in the same way as the specific modifications of a genus or family may be produced. (Wallace, 1880)

Elimination of Darwin’s nonselectionist heritage from neoDarwinian explanans was a necessity rather than an accident. Any attempt to apply the new knowledge on genes as material carriers of heredity to nonselective factors of Darwinian evolution (use and disuse of organs, direct effects of changed conditions of living, loss of organs as a result of disuse, evolutionary reversions) is confronted with an insuperable difficulty: changes in genes, gene mutations are random events, while the nonselective Darwinian factors implied directed change in evolution. Arbitrary exclusion of all these Darwinian factors was found to be a convenient “solution” to the problem of introducing genes into the theory of evolution, for adapting the Darwinian theory to the needs of the “evolutionary synthesis”.

Now, more than one century after Darwin, his assumptions on the direct influence of the environment on heredity, evolutionary reversion of ancestral phenotypes, and the loss of organs or traits that were excluded from the neoDarwinian explanans of evolution, are unambiguously validated by empirical evidence, respectively in the fields of transgenerational developmental plasticity, paleontological record, speciation and experimental evidence on evolutionary changes, all to be discussed in separate chapters and subsections of this work.

At the foundation of the neoDarwinian paradigm is the idea that evolution results from changes in gene frequencies in natural populations and the source of these changes are basically three genetic phenomena: gene mutations, gene drift, and genetic recombination. Natural selection creates novelty by acting on the genetic variability.

For more than half a century, a steadily growing body of evidence contradicting the neoDarwinian view has been considered to represent only puzzles and anomalies and attempts to explain or reconcile these phenomena with the neoDarwinian paradigm have generally failed. Rather than trying to confront and resolve these “puzzles”, abandoning the ostrich attitude and dealing objectively with the disproving “counterinstances”, neoDarwinians choose to ignore contravening facts. Remember:

Einstein saw as counterinstances what Lorentz, Fitzgerald, and others had seen as puzzles in the articulation of Newton’s and Maxwell’s theories. (Kuhn, 1996)

Genes and Phenotypic Characters in Metazoans. In our time, the central role of genes in the evolution of unicellulars is proven. So is the role of genes in the process of biochemical evolution of multicellulars that to a great extent results from gene mutations accumulating via natural selection during long evolutionary periods of time.

An enormous amount of energy and intellectual resources have been, and continue to be, devoted to finding and identifying the gene(s) responsible for various morphological characters in metazoans. In thousands of experiments it has been demonstrated that spontaneous and induced mutations lead to anomalies in morphology, physiology, and behavior. We know of numerous genes in various species of invertebrates and vertebrates that are clearly related to specific characters. No one can deny that mutations, deletions, or generally nonfunctioning and malfunctioning genes lead to specific abnormal morphologies. Such experimental facts, clearly show that functionally normal genes are necessary for the development of particular normal morphologies. But not more than that. In other words, it is correct to say that in metazoans the normal gene is a necessary condition for the development of a specific normal character, but it would be logically erroneous to grant the “necessary conditions” attributes of the cause when these conditions are not sufficient for the development of normal morphology. Many biologists believe that by demonstrating that the gene is also sufficient for the development of the phenotype, it suffices to demonstrate that it can induce the ectopic expression of that phenotype (Baker et al., 2001). But even this “sufficiency test” is methodologically wrong and misleading. For ectopic expression of the phenotype in experiments does not exclude participation of other nongenetic and genetic factors in the ectopic development of the phenotype; the gene in this case as well is not “all what is needed” for the development of that phenotype.

Development of phenotypic characters in metazoans is function of signal cascades and gene regulatory networks with each network comprising from several to hundreds of genes. The presence of each of these genes is a necessary condition for the normal development of the specific character, but none of these genes are the cause of that character. Moreover, even these several to hundreds of genes in their entirety, do not rise to the level of a cause. For contemporary biological knowledge says that the gene regulatory networks generally represent downstream entities of signal cascades that are activated by neurohormonal signals and the primary source of the information for starting these signal cascades is a chemical output released as a result of processing of electrical signals (into which all external and internal stimuli are converted in the nervous system) in neural circuits. In a chain of events such as signal cascades the ultimate cause of the phenotypic result is at the very beginning of the causal chain.

Any malfunction of an upstream element of the cascade could lead to defects of the character determined by the gene regulatory network. The higher the position of the affected element in the cascade, the greater the effect of the change could be. So the first conclusion to be drawn is that no single gene is responsible for the formation of the affected character. To single out a particular gene as the cause of the phenotypic character in such cases is to attribute to the part the functions of the whole.

There are no known genes that individually encode large amounts of information specifying the structure or patterns of development of an organism. Although we may simply not know how to appreciate or find such genes, I assume they do not exist. (Britten , 2003)

But, above all, the fact that the signal cascades that activate gene regulatory networks start with electrical/chemical outputs of the processing of internal/external signals in neural circuits suggests that the activation/inactivation of gene regulatory networks is determined by nongenetic factors, by the computational activity of specific neural circuits, which ultimately determine when and whether to turn on/off gene regulatory networks (see Epigenetic or Genetic? On the Nature of Information for Signal Cascades, in chapter 2). Thus, in metazoan development genes are tools which need epigenetic instructions on whether, when, and where they should be expressed.

Newman and Müller (2000) also have argued, the relationship between genes and morphological characters may not be a causal relation but a product of evolution (Newman and Müller, 2000).

Gene mutations vs. Darwinian variability. The neoDarwinian identification of spontaneous mutations with Darwin’s gradual individual variations or differences caused by the principle of divergence is questionable. Despite the lack of knowledge on the nature of these variations at the time, intuitively Darwin denied the possibility that these variations were random and spontaneous occurrences. According to Darwin, modification of species:

has been effected chiefly through the natural selection of numerous successive, slight, favourable variations; aided in an important manner by the inherited effects of the use and disuse of parts; and in an unimportant manner, that is in relation to adaptive structures, whether past or present, by the direct action of external conditions, and by variations which seem to us in our ignorance to arise spontaneously (my emphasis - N.C.) It appears that I formerly underrated the frequency and value of these latter forms of variation, as leading to permanent modifications of structure independently of natural selection. (Darwin, 1872d)

Note, Darwin believed that the apparent spontaneous inherited variations (presumably not related to external stimuli) are not genuine random events but products of our ignorance. He felt that even if random changes would occur, they could not lead to the degree of variations observed between species:

Mere chance, as we may call it, might cause one variety to differ in some character from its parents, and the offspring of this variety again to differ from its parent in the very same character and in a greater degree; but this alone would never account for so habitual and large a degree of difference as that between the species. (Darwin, 1872b)

Translated into the modern biological language, Darwin believed that what we call spontaneous variability is neither spontaneous nor random because random events such as gene mutations “would never account for so habitual and large a degree of difference as that between the species of the same genus”. This unequivocally contradicts the neoDarwinian tenet on gene mutations as the source of evolutionary change and speciation.

The neoDarwinian synthesis has been extremely successful in explaining the evolution of unicellular life and the tremendous biochemical evolution in both unicellulars and multicellulars, but it has failed to bring any understanding of the evolution of multicellulars at the supracellular level, especially the evolution of animal morphology, the most visible aspect of metazoan evolution. One century-long research in the fields of evolutionary biology, and induced experimental mutagenesis, etc. did not provide any proof that a particular mutation can lead to an adaptive morphological change in metazoans.

What is the reason for the discrepancy between the success and the failure of the theory in dealing with two aspects of a single process, the evolution of the living world?

The unity of the living world, from unicellulars to multicellulars, like the unity of the material world in general, does not imply that the principles of organization at all the levels of organization of living systems are the same or that no new principles and rules may emerge at higher levels of organization of these systems. By extrapolating the role of genes in the structure, function and evolution of unicellulars for understanding and explaining the structure, function, and evolution of multicellulars, neoDarwinians committed a serious methodological error, with heuristic consequences that can hardly be overestimated. Extrapolation of the role of genes as carriers of information for protein biosynthesis for explaining a totally different process, the spatial arrangement of cells of various types from which the metazoan morphology arises, represents of rare case of resorting to Deus ex machina for resolving problems in science.

Exaggeration of the importance of the knowledge of the time, and extension of that knowledge beyond the scientifically justified limits, has always been a flaw of human wisdom. Genes became a biological jack of all trades and were used for explaining anything related to the living, from protein biosynthesis to the nature of human behavior and intelligence and even the evolution and functioning of human societies. Almost half a century ago, at the zenith of the progress in the fields of molecular genetics, after the discovery of the material basis of the gene and genetic code, Erwin Chargaff, one of the main contributors to the discovery of DNA structure predicted (and warned against) the rise of what he called “molecular mythology”. The science of biology, under the influence of the Zeitgeist, for half a century would focus on the study of genes as separate and almost independent entities, underestimating the dynamics of their interactions with other cellular and extracellular components and by ignoring the wider epigenetic context that determines very expression of genes in metazoans.

What is the status of the neoDarwinian theory now, 70 years after its formulation, on strictly scientific terms? Does the neoDarwinian paradigm, in its slightly varying forms, provide a verified and verifiable genetic mechanism of evolution?

From the neoDarwinian view, evolution is a statistical process of accumulation of favorable genetic variability under the action of natural selection and the source of that variability are gene mutations, gene drift, and genetic recombination. Gradual accumulation of changes in allele frequencies in populations that are geographically isolated, over time, leads to reproductive (post-zygotic and less frequently, if ever, prezygotic) isolation of the geographically isolated populations and formation of species and higher taxa. While it is theoretically argued and empirically demonstrated that changes in allele frequencies do occur, in no single case has it been possible to show that one or a number of changes in genes has lead to an adaptive change in a morphological trait in metazoans.

Validating neoDrawinian predictions. Verification of scientific theories is based on empirical evidence directly supporting the theory and on the substantiation of its basic predictions. Have the experimental evidence and observations from nature lent weight to the basic predictions of the theory?

The neoDarwinian paradigm would predict that the tempo of evolution would be steady with no periods of evolutionary stasis. This prediction has been refuted by the large body of paleaontological evidence. In early seventies N. Eldredge and S.J. Gould presented paleontological evidence demonstrating that evolution is characterized by short periods of rapid change and longer periods of morphological stability, and formulated the theory of punctuated equilibria (Eldredge and Gould, 1972). Schindewolf also believed that evolutionary development is episodic - it proceeds in phases, or in quantum leaps; it exhibits an unmistakable periodicity. The unfolding of lineages is divided into evolutionary periods or cycles…At the onset of a cycle, there is a brief period of abrupt development of forms…We call this first phase the origin of types or typogenesis. This is followed by a second phase, one of type constancy, or typostasis. (Schindewolf, 1993)

The NeoDarwinian paradigm would predict that, with mutation rates comparable in various organisms and with other factors equal, the tempo of evolution will be faster in organisms that have higher rates of reproduction. This prediction is also refuted empirically: unicellular organisms that have shorter life cycles have exceptionally slow evolutionary rates and the class of mammals, which has longer generation times, has evolved faster than any class of vertebrates that have shorter life cycles.

The neoDarwinian prediction that the same genotype under the same environmental conditons will produce the same phenotype is no longer valid. Vast evidence shows that in species, populations or individuals of the same/identical genotype reared under the same conditions may exhibit very different phenotypes, as is observed in numerous cases of developmental polymorphisms, predator-induced defenses, phase transition in locusts, etc. and even in cases of the penetrance. Confronted with this and two essential facts that

1. Gene mutations are very rare and deleterious; according to T. Dobzhansky, one of the leading neoDarwinists of the 20^th century, a vast majority of the mutants observed in any organism are detrimental to its welfare (Dobzhansky, 1971a) and

2. Gene mutations that are evolutionarily useful are even more rare to account for the sudden morphological changes observed in nature [Dobzhansky believed that finding a useful mutation in nature is as difficult as finding “a needle in a haystack” (Dobzhansky, 1971b)], by the middle of the 20^th century many evolutionists came to the conclusion that genetic recombinations, not gene mutations, are the main source of genetic variability on which natural selection acts. The idea is that since individuals of a species are in possession of different alleles, genetic recombination (in dioecious organisms, which represent the overwhelming majority of metazoan forms) may lead to reshuffling of alleles and thus create new genetic variability. It was assumed that natural selection determines the evolution of the living world by acting on this genetic variability (and the related phenotypic variability) provided by genetic recombinations. But, theoretically, it has been argued that even if recombination would produce new favorable genetic variability (which has not been demonstrated), the variability would hardly be maintained in further generations because of the extremely low probability of the recombinant to mate with another individual of the same recombinant genotype:

There is no guarantee that such an exceptional individual will engage in genetic recombination only with individuals having a similar adaptive genotype, it is inevitable that this exceptionally favorable genotype will eventually be destroyed by recombination during reproduction. (Mayr, 1964)

Furthermore, evolution of the parthenogenetic species, in which genetic recombination is excluded, is not slower than that of sexually reproducing organisms, suggesting that genetic recombination, may be neither involved in, nor necessary for, the evolution of metazoans.

If the evolution of metazoans would depend on, or be related to, the evolution of genes, it will be expected that a correlation will exist between the number of genes and the position of organisms in the evolutionary ladder (this is what was predicted before the gene sequencing era). While a clear correlation is observed to exist between the number of genes and the structural and functional complexity of unicellulars, no such correlation has been observed in metazoans; the number of genes in the human genome is comparable to that of the simple worm, Caenorhabditis elegans, but 4-5 times smaller than that of sponges, the simplest known metazoans. Even an evolutionist like J. Maynard Smith (Maynard Smith, 1986) would express his surprise that the biochemical difference between a bony fish, such as carp, and a jawless fish, as the lamprey, is about the same as that between human and lamprey (Wesson, 1991c).

According to the neoDarwinian view on the existence of a genetic program and on the relationship genotype-phenotype it would be predicted that evolution of similar morphologies (parallel evolution, convergent evolution, and homology) would be related to the evolution and presence of similar genes. This prediction has been rejected by observations on individual development. Long before, Gavin de Beer concluded that “Homologous structures need not be controlled by identical genes”, and that “the inheritance of homologous structures from a common ancestor ... cannot be ascribed to identity of genes” (de Beer, 1971b).

The reverse has also been observed. Complex gene regulatory networks for the development of parts or organs of animals are discovered, which are surprisingly conserved among phyla, subphyla and lower taxa, and still with the same genes, with the same genetic information, different organisms and even organisms of the same species are able to produce very different morphologies (in the case of metamorphosis, polyphenisms, and developmental plasticity).

All the above facts strongly suggest that a causal relationship between changes in genes and evolutionary events in metazoans may not exist, hence the almost one century old hypothesis on changes in genes as causes of evolution, is still waiting to be validated.

The Modern Synthesis and the Rise of the New Trend

The neoDarwinian paradigm focuses on the selection of genetic variability. Correctly, it predicts that a favorable inherited change will be positively selected, but this is the second and easy part of the question on the mechanics of evolution. In the beginning there is the change; selection trails it in the process of evolution. If there is a Gordian knot, a crucial problem to resolve in modern evolutionary biology, it is the generation of evolutionary change, identification of the source of new information for producing the heritable adaptive change, not the process of natural selection, the universally accepted and intelligible Darwinian concept.

Gene mutations, random changes in the nitrogen base sequences of nucleic acids, do not and cannot produce adaptive changes (while they can produce defects), in animal morphology that is in the specific spatial arrangement of cells of different types from which that morphology arises. Molding animal morphology is not genes’ expertise. I am not aware of any study that would, even in theory, show how a random change in the structure of a gene might produce an adaptive change in morphology. Such changes require new information for the emerging pattern of spatial arrangement of the cells from which adaptive morphology arises. By definition this information is not genetic.

There is evidence that the genetic information determines the position of amino acids in peptide chains but there is no indication that it might determine the spatial order of cells, the building blocks of metazoan structure. The Watson-Crick system of heredity is self-evidently incapable, unequipped to provide information for the spatial organization of the extremely great number of cells from which metazoan structure arises. It may be argued, however, that the lack of evidence is not evidence that the genetic information does not or cannot determine the spatial arrangement of cells in multicellulars. While this is true, the burden of proof, the obligation to prove that genes may code for the spatial arrangement of cells, is upon the supporters of that idea. Affirmative statements need to be substantiated.

For half a century after the discovery of the chemical nature of the gene, biologists attempted to fill gaps in our understanding of the processes of individual development in metazoans by applying the concept of genetic program, without showing what it consists of, but vaguely positing that the genome is programmed to regulate individual development. The idea of the genetic program has never been formalized into a hypothesis that would elaborate on where in the genome instructions for the spatio-temporal patterns of gene activation/inactivation are and how these patterns might translate into spatial order of cells of different types from which the animal morphology emerges.

To the contrary, we know that the entire early development is regulated not by the genome (otherwise, not gametes alone, but all the somatic cells that are in possession of the same genome would be able to start individual development and produce embryos) but by the epigenetic information deposited in gametes in the form of mRNAs, proteins, hormones, neurotransmitters, nutrients, etc. Thus, if there is a developmental program that directs the early embryonic development it is the epigenetic information that parents provide with gametes in the form of maternal cytoplasmic factors and imprinted genes.

For the sake of argument, however, let’s take it for granted that a developmental program is somehow set up in the genome. But this assumption would raise the formidable sphinxoid riddle: How could a genome of a few billion bits of information code for an edifice, whose erection requires an amount of information that is millions of times greater?

For a long time biologists had high expectations that the completion of the sequencing of genomes of various organisms, including the human genome, would provide deeper knowledge on the interaction between genes. Now the human genome, and the genome of a considerable number of metazoan species are sequenced but, to the great disappointment of the proponents of neoDarwinian paradigm, the first decade of the genome sequencing era suggests that the expectation was not justified. It has made more visible the fact that the concept of the “genetic program” is a theoretical fossil of the past “genomic” age.

One century of studies on mutations has not provided a single verified example of a gene mutation that led to an adaptive morphological change in metazoans. On the contrary, examples are described of evolutionary changes having suddenly occurred in whole populations without changes in allele frequencies (numerous cases of transgenerational predator-induced defenses in invertebrates, sympatric speciation in sibling species involving no changes in allele frequencies, evolutionary reversions, atavisms, experimental induction of reversion of ancestral traits in as little as 5 generations in Drosophila, etc.).

Having failed to prove any causal link between changes in genes and the evolution of animal phenotype, modern biology has instead succeeded in demonstrating that changes in developmental pathways, involving no changes in genes produce evolutionary changes. Still modern synthesis ignores the developmental aspect of evolutionary change.

Population genetics posits that evolution results from changes in the allele frequencies of populations due to gene mutations, gene drift, and gene recombination under action of natural selection. On this theoretical basis a whole mathematical edifice for explaining evolution by changes in allele frequencies has been erected. However, the basic tenet of neoDarwinian paradigm, that changes in genes are responsible for morphological evolution, on which this structure rises, is not substantiated, hence the empirical foundation of the structure is questionable, at best.

We should always bear in mind that evolutionary biology is a science of realized potentialities, a science of the actuality rather than theoretical possibilities. While these methods can determine whether, under certain conditions, an event can happen, the conditions are sometimes selected at discretion, so as to allow the model to function in theory without first determining whether these conditions exist in nature. Even in such cases, the theoretical probability of an event to occur is not a proof that the event has ever occurred. The theoretical probability of an evolutionary event calculated in mathematical models is one thing and the factual occurrence - another. Additionally, the resolving power of mathematical methods is not unlimited. The empiry of experimentation and observation is the ultimate benchmark for testing theoretical models. Science, biology included, has an Antean dimension: its tremendous cognitive power vanishes as soon as it loses contact with the empiry of observation. The gold standard for verification of hypotheses and theoretical constructions is their congruity with the available empirical evidence.

With these limitations in mind, Norbert Wiener cautioned mathematicians themselves:

One of the chief duties of a mathematician in acting as an advisor to scientists is to discourage them from expecting too much of mathematicians. ( O’Connor and Robertson, 2003)

By ignoring the ever-increasing evidence on the epigenetic inheritance accumulated in the second part of the 20^th century and especially during the last 2-3 decades, theoretical biology is out of step with the advances of experimental biology. An ever-increasing body of evidence from various fields of biological study shows that, although changes in genetic information (genes) and in gene frequencies do unavoidably occur, they are not necessarily related to the evolution of animal morphology, behavior, and life history. In M.J. West-Eberhard’s aphorism genes are followers not leaders in evolution (West-Eberhard, 2003b).

Why has the neoDarwinian paradigm been so unresponsive to the multitude of empirically established counterinstances? As with most phenomena in human enterprise, there is more than one single factor, but probably the most fundamental reason for ignoring the disproving evidence is a Kuhnian one:

To reject one paradigm without simultaneously substituting another is to reject itself. (Kuhn, 1996)

Recognition of the Role of Epigenetic Factors in Evolution. When Mendel discovered the factors of heredity, genes in a term coined by Bateson (1905), he had no idea of their nature. The concept on Mendelian factors in the early period of classical genetics was based on the results obtained mainly from experiments with the fruit fly, which suggested nothing about their chemical nature. Only by the middle of the 20^th century did biologists understand the material basis and chemical nature of genes.

In early 40-es of the last century, Conrad Waddington coined the term epigenetics (from Gr epi- upon, on, over but also after) for describing heritable changes in the expression of genes and the mechanisms that translate genotypes into phenotypes in the process of individual development. Due to lack of progress in the study of the nature of inherited changes in expression of genes, Waddington’s contribution to epigenetics is only mentioned as an episode in the history of experimental evolution and epigenetics.

By the early 60es it was demonstrated that even in unicellulars, where the genetic basis of the cell division and inheritance was definitely demonstrated, epigenetic information of some kind was responsible for certain phenotypic traits. By grafting pieces of DNA-free cortex from one individual of the ciliate protozoa Paramecium aurelia to another, Sonneborn and Beisson succeeded in obtaining protozoans with reverse polarity of fibers and with a different cortical organization, which was transmitted to the offspring for more than 700 generations (Sonneborn, 1964; Beisson and Sonneborn, 1965).

This is perhaps enough to show the extreme stability and determinism of a merely structural intracellular rearrangement in the absence of differences in genes or gene action. (Beisson and Sonneborn, 1965)

By early 80es biologists discovered another epigenetic mechanism of heredity, that is known as gene imprinting, a phenomenon of the parental determination of expression of alleles in the zygote and embryo. Gradually, the concept of epigenetics was restricted and presently is basically reduced to gene imprinting (DNA methylation) and chromatin remodeling., i.e. to changes in the structure of chromosomes and nucleosomes as a result of histone acetylation and deacetylation.

As it is used in this work, epigenetics encompasses a full range of non-genetic processes, ranging from nongenetic mechanisms of gene expression to deposition of cytoplasmic factors in gametes, developmental plasticity, transgenerational plasticity and various modes and mechanisms of evolution (including the speciation process), all of which involve no changes in genes or genetic information in general. It comprises generation of epigenetic information (parental cytoplasmic factors) used in gametogenesis, gene imprinting, the crucial role of parental cytoplasmic factors in activating the expression of zygotic genes, determining the early individual development, cell differentiation in the processes of organogenesis and morphogenesis in general, and the extracellular control (activation/inactivation) of nonhousekeeping genes in the process of individual development and in the maintenance of homeostasis. To put it more explicitly, epigenetic processes direct (control and regulate) individual development, which is another way of saying that epigenetic processes determine the inheritance at the supracellular level that is manifested in the visible metazoan phenotype (morphology, behavior and life history). This statement implies the existence of an epigenetic system of heredity, predicted by J. Maynard Smith, and to be dealt with in the first part of this work.

Although more than adequate evidence shows that epigenetic information is involved in the evolution of metazoans, even in the most recent standard works on evolution (Barton et al., 2007) epigenetic inheritance (parental cytoplasmic factors, changes in the expression pattern of genes or gene regulatory networks, etc.) is reduced to the phenomenon of gene imprinting in contexts that are not related to the generation of evolutionary novelties.

By neglecting all the experimental evidence on the role of epigenetic factors in inheritance and evolution, neoDarwinians inaccurately have expanded the meaning of the adjective “genetic” to such an extent that it is used synonymously with “hereditary” and “inherited”, wiping out any semantic distinction between them. Many biologists still continue to take it for granted that any Mendelian ratios of the inheritance of characters is related to the presence of genes or genetic factors alone. No rationale has been presented for the assumption that epigenetic factors, which are also transmitted to the offspring via gametes, could not be inherited in a Mendelian mode.

Toward a New Paradigm of Evolution

On the source of information for metazoan structure. Transition from unicellular life to multicellularity required the solution of a difficult problem, unique to multicellular organisms. In clear distinction from unicellulars, whose building blocs are proteins, the products of their activity and macromolecular structures, multicellular organisms represent complex material structures with cells as building blocks. Erection of multicellular structures needs something that unicellulars do not: huge amounts of information for astrictly determined spatial arrangement of a myriad of cells of different types and a mechanism for transmitting that information to the offspring.

The genetic information, encoded in the form of specific sequences of nitrogen bases in nucleic acids, determines the spatial order of amino acids in peptide chains, but there is no indication, let alone proof, that it can also determine the specific spatial arrangement of billions/trillions of cells of various types in the animal body. Even if, for the sake of argument, one would assume that genetic information could determine the spatial order of cells in metazoans, the amount of information contained not only in genes but in the whole metazoan genome, including the “junk” DNA, quantitatively represents only a negligible fraction of the information necessary for molding a metazoan structure. A human brain alone has one trillion nerve cells (Kandel, 2001). Before birth, that is experience-independently, each neuron establishes an average of 10,000 specific connections with specific neurons, implying that information for establishing these connections alone is of the order of quadrillions of bits, millions of times greater than the total amount of information contained in the genomic DNA. An even greater amount of information would be needed to erect the whole human body in the process of individual development. Qualitative unsuitability and quantitative negligibility of genetic information exclude the possibility that it may be responsible to mold the metazoan structure.

This informational constraint represented an insuperable barrier for the evolution of multicellularity. The evolution of an appropriate type of information capable of coding multicellular structures was a sine qua non for the evolution of multicellularity from unicellular organisms. The solution to the problem in the kingdom Animalia came in the form of the evolution of complex computational structures that were capable of generating information based on their ability to process external and internal stimuli. Hence, from an informational point of view, the evolution of multicellularity was the result of a radical informational revolution.

Where does that huge amount of information come from?

The control system and the epigenetic system of heredity in metazoans. One of the greatest enigmas of modern biology is how an organism, whose structure at the molecular, cellular, and supracellular levels is continually disintegrating, succeeds in maintaining that complex structure and function during its lifetime. The fact that metazoans succeed in doing so unambiguously proves that they

- Continually monitor the state of the system,

- Figure out structural losses, based on the presence of information about the normal structure,

- Figure out restitutive necessities, and

- Start signal cascades and activate gene regulatory network for replacing the lost structures at the right time and place.

The above functions performed by metazoans are typical functions of control systems, in principle similar to the control systems used in engineering.

Even logically it may be concluded that the maintenance of a metazoan structure is the function of a control system. No metazoan would exist as such in absence of a control system. The presence of a control system is one of the fundamental features of living-, as opposed to anorganic systems. That control system makes possible the development and maintenance of the metazoan system, a thermodynamically improbable structure. The presence of a control system is at the basis of the puzzle of the ability of living systems to defy the second law of thermodynamics.

In unicellulars the genetic system of heredity, that is the genome and the molecular mechanisms of gene expression represent at the same time the system control that maintains the cell structure at a steady state. By analogy, the question arises: is it possible that in multicellulars as well, the controls system acts as a system of heredity? Indeed, the maintenance of eroding metazoan structure implies possession by the control system of information on the normal structure. There is no visible reason why that information could not be used in the process of metazoan reproduction.

Transition from unicellularity to multicellular life required a post-genetic control system that would maintain the unavoidably degrading multicellular

structure. The metazoan control system, as we know it in extant animals, evolved some 550 million years ago during the Cambrian explosion with the differentiation of the neuron and the development of the neural net that rapidly evolved into the central nervous system (CNS). In metazoans this is an integrated control system (ICS)(Cabej, 2004b) with the CNS as its controller. During reproduction the ICS serves as the epigenetic system of heredity, which controls individual development. In the first part of this work (chapters 1-7) , I present extensive evidence on the elements of the system and their function in the process of biological reproduction.

The epigenetic system of heredity in metazoans implies the parallel presence of the genetic system of heredity at the cellular level. Although both systems are indispensable and represent fundamental aspects of metazoan biology, the evolution of the epigenetic system came as a solution to the problem of the organization of cells in the supracellular metazoan structures, parts, organs and the morphology in general. In the mutual relationship and interaction between the epigenetic and genetic systems, the latter is subordinate to the epigenetic system of heredity.

In an succinct description, the integrated control system (ICS), which also serves as an epigenetic system of heredity in the process of reproduction is a hierarchical system that in vertebrates looks as follows:

Genes interact and influence the function of each other via their products at a genetic level of control on two (transcriptional and translational) sublevels. Most of the nonhousekeeping genes in metazoans are activated/inactivated by extracellular signals (hormones, growth factors, secreted proteins, etc.), which act by binding specific membrane receptors or, in the case of small molecule hormones, by binding their nuclear receptors. This is the control at the hormonal (including growth factors, neuropeptides, neurotransmitters) level. Most of the hormones secreted by the peripheral endocrine glands are under the control of specific pituitary hormones representing the second level of hormonal control. Almost all the pituitary hormones are induced by the hypothalamic hormones, representing the third level of neuro-hormonal control. Still higher is another, fourth cerebral level of control, sending neural signals for the synthesis of most of hypothalamic neurohormones.

As pointed out earlier, in the process of metazoan reproduction, the integrated control system (ICS) functions as the epigenetic system of heredity. The individual development from the egg/zygote to adulthood is a bigenerational process in which early development from the unicellular stage to the phylotypic stage takes place based on the epigenetic information provided parentally to the gametes. In the second, the post-phylotypic stage, the embryo is in possession of an operational CNS, which generates and provides information for morphogenesis via the signal cascades that activate specific gene regulatory networks.

Adequate evidence allows us to inductively conclude that electrical signals resulting from the processing of external/internal stimuli in neural circuits in the CNS (neural net in lower invertebrates) determine the activation of specific signal cascades leading to the development of specific morphological traits. The epigenetic information for metazoan morphology is computationally generated in the CNS by processing the input of internal/external stimuli.

In principle, the processing of internal/external stimuli in neural circuits transforms the stimuli into inducers of gene expression by establishing causal relationships between stimuli and genes that otherwise would not be causally related. Thus, the gene expression in the CNS is manipulative.

Role of the nervous system in the epigenetic inheritance

Development of the metazoan structure requires considerable investment of mater, free energy, and information. With matter and free energy taken from the environment in the form of food, where the information for the individual development and restitution of the disintegrating metazoan supracellular structure comes from? This is one of the fundamental questions to be dealt with in this work.

A great enigma that puzled biologists of the 20 century has been the source of the information necessary for the prenatal, i.e. experience-independent, establishment of trillions of specific connections between neurons. Now, many biologists believe that this information is generated in the nervous system by processing the input of stimuli coming from the developing embryonic structures and its environment, based on the self-organizing properties and the “best guess” (Katz and Shatz, 1996) of the nervous system.

The possibility of an involvement of the CNS in the development of animal morphology, at least tacitly, has been rejected, if not considered taboo. But now such a view is hardly defensible. Vast empirical evidence presented in this work shows that the development of various organs during embryogenesis is induced from signals and signal cascades originating in the CNS. The CNS also determines and regulates the development of postnatal development, including the onset of secondary sexual traits.

Despite the fact that no investigations specially aimed at discovering the possible role of the nervous system in individual development have ever been conducted (and “you are not able to find what you are not looking for”), coincidental evidence on the control of the central nervous system in the post-phylotypic development is not simply adequate but surprisingly comprehensive.

As an intellectual remnant of the “one gene-one trait” concept of classical genetics, many biologists are still speaking of particular genes being responsible for particular traits. The tremendous progress made in identifying the complex gene regulatory networks (GRNs) has recently shifted attention from genes to the study of GRNs as determinants of phenotypic traits. Their study is considered to be sufficient for understanding the mechanism of the development of phenotypic traits. This concept ignores the source of information for the spatio-temporally strictly determined activation of GRNs, as well as the fact that the GRNs as well are downstream entities of signal cascades originating in the CNS.

Besides the evolution of an information-generating contrivance, the evolution of a mechanism that would transmit the huge amount of epigenetic information from parents to the offspring has been crucial. This has been an extremely difficult problem to resolve as it may be inferred from the fact that it took more than ¾ of the time of the existence of life on Earth to evolve, occurring only about half a billion years ago, during the Cambrian explosion, with the emergence of the nerve cells and their organization into nerve nets and nervous systems.

The fact that only gametes are uniquely capable of developing into adult organisms, while somatic cells of the same genotype cannot, unambiguously suggests that some form of epigenetic information is transmitted from parents to the offspring via gametes. But gametes as well are not capable of carrying all the information necessary for developing the metazoan structure. Hence, the evolutionary solution to the informational problem of individual development in metazoans was one of compromise; parent(s) would provide gamete(s) with a limited amount of epigenetic information in the form of parental cytoplasmic factors (there is some evidence that deposition of these factors in gametes is function of the nervous system) required for early development up to the phylotypic stage.

At the phylotypic stage, the embryonic CNS is operational and takes over the post-phylotypic development until adulthood, by generating the epigenetic information necessary for the later stages of individual development.

Indeed, a careful examination of the inductive signals for the development of tissues and organs during individual development shows that in almost all studied cases these signals originate in the CNS. During the adult life, as well, signal cascades for the maintenance of animal morphology come from the CNS, via neuroendocrine cascades, often with essential participation of the local innnervation.

In this work I will present more than adequate empirical evidence on the CNS control of the development and evolution of the metazoan phenotypic characters. Could all this extensive evidence be irrelevant or accidental? Take a look at numerous signal cascades regulating patterns of expression of genes and gene regulatory networks. Generally they are under hormonal control. One might admit that it may be a coincidence that the secretion of hormones by terminal endocrine glands is regulated by the secretion of pituitary hormones. I would admit that it may be another coincidence that the secretion of pituitary hormones is induced by the secretion of the hypothalamic releasing hormones. After all, signals have to come from somewhere and the hypothalamus happens to be a part of the brain. For the sake of argument, I would admit that the secretion of hypothalamic neurohormones in response to the input from other brain regions and not by any other part of the body might be a mere coincidence. But could anyone believe that the fact that all the fully known signal cascades ultimately start in the brain, and not in any other part of the body, represents nothing more than a coincidence? Why must the stroke of luck always fall on the CNS rather than on the other parts of the body? I believe that this “coincidence obsessed” approach defies common sense and could lead to absurdity. For, by the same token, one might proclaim that the fact that genetic information flows from DNA down to RNA and proteins and not the other way around might also be a coincidence. Hence, DNA may not be the source of genetic information (!!)

It would contradict any statistic and common sense to believe that mere coincidences could determine:

- The cerebral origin of morphogenetic information in numerous cases of developmental plasticity, including predator-induced defenses that start with signals from the CNS;

- The cerebral determination of several described cases of transgenerational developmental plasticity;

- The cerebral origin of signal cascades for numerous described cases metamorphosis in both invertebrates and vertebrates;

- The central nervous origin of signals inducing development of organs during the individual development in numerous experimentally verified cases;

- The neuro-cognitive determination of reproductive isolation in numerous described cases of incipient species that manifests itself in changed mating preferences without changes in genes.

When considered in their entirety, all these examples of neurally controlled cases of developmental, circumevolutionary, and evolutionary phenomena, logically lead to the conclusion that the morphogenetic information, the epigenetic information necessary for the development of metazoan structures originates in the brain.

The Epigenetic Mode of Evolution

There is sound experimental and observational evidence, an essential part of which will be presented in this work, that the animal phenotype (behavior, morphology, physiology and life history) evolves without changes in genes. There is also sound evidence that speciation can proceed without changes in genes. While neoDarwinism has blatantly failed to account for the facts that contradict its basic tenets, what would be the alternative epigenetic explanation of evolutionary change?

As a general trend, metazoans have evolved from simple to more complex organisms. They evolved increasingly complex structures because they have to accomplish more complex functions in the “struggle for life”. Complex structures arise to perform complex functions; the function is the raison d’être of the structure.

Evolutionary changes in morphology result from specific changes in developmental pathways, which represent the proximate causes determining individual development. Adaptive changes in developmental pathways do not arise randomly and specific epigenetic information is required for such changes to take place. As I have shown in Neural Control of Development (2004), this information is generated in the neural circuits.

Neurobiological component of the evolutionary change. Adaptation to new conditions of life requires modifications of functions, as well as modifications of morphology and behavior. Conditions of living in the environment sometimes may change so suddenly and drastically that species or populations may go extinct before having a chance to evolve adaptive modifications in their morphology .

In the course of evolution metazoans have evolved and perfected a complex system for dealing with the antihomeostatic effects of the adversely changing environment. The stress response is expressed in full and complex form in higher vertebrates, but its evolution can be traced back to invertebrates, is function of the neuroendocrine system and is characterized by the increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. The neurobiological nature of the stress response is illustrated by the fact that the stress response arises not only as a response to real but also to perceived changes (Greenberg et al., 2002) in the environment.

Besides changes in the activity of the HPA axis intended to restore the impaired homeostasis, the stress response is characterized by a series of adaptive behavioral changes. Metazoans have a unique ability to instantly adapt to the changed environment by appropriately changing their behavior, e.g. by fleeing the hostile environment and predators, by using alternative food sources, etc. Behavioral changes in metazoans are related to learning, including perception, conditioning and memory. In the process of learning and behavioral change, animals use existing neural circuits and FAPs (fixed action patterns). The behavioral adaptation by learning may be a quick remedy but is not a long-term solution to the problems related with the adversely changed conditions of living. However, theoretically at least, it may enable metazoans to “buy time” until inherited physiological and morphological adaptations can evolve. There is also a possibility that the behavioral adaptations, acquired by learning, may evolve into an innate behavior.

Evolution of heritable adaptations that may arise over time imply the generation and investment of new information for evolving morphological and physiological novelties. We know that the information for changed behavior is a product of neurocognitive processes taking place in the CNS. The question now arises: Where is the new information for adaptive evolutionary changes in morphology generated?

Although we cannot hope to find direct evidence on the source of information for inherited changes that occurred in the past, we can use other related empirical evidence for drawing relevant scientific inferences.

Firstly, the fact that metazoan morphology is determined by developmental pathways during ontogeny suggests that adaptive evolutionary changes in morphology will also be determined during ontogeny. And the fact that during ontogeny many developmental pathways for animal structures are activated by signals that ultimately start in the CNS (see chapter 6) suggests that the information necessary for the evolution of these structures may also originate in the CNS.

Secondly, developmental pathways that determine dramatic morphological transformations in metamorphosizing organisms (see Neural Control of Metamorphosis in Invertebrates and Neural Control of Metamorphosis in Vertebrates in chapter 6) are, ultimately, activated by CNS signals.

Thirdly, many discrete changes in metazoan morphology that are observed in numerous cases of phenotypic plasticity, are induced by signal cascades starting in the CNS (see chapter 11).

Fourthly, the biological phenomenon of transgenerational plasticity, that is the appearance in the offspring of inherited morphological (usually adaptive) modifications in response to environmental stimuli that have affected their parent(s). In a number of described cases it has been demonstrated that the information for these inherited changes in the offspring morphology and behavior comes in the form of brain signals (see chapter 12).

“Inherited changes in morphology” are determined by brain signals! But, evolutionary changes in morphology are nothing more than “inherited changes in morphology”. Hence, logically it may be inferred that the mechanism of the induction of evolutionary change may be a neural mechanism. Indeed, it would be against the logic of evolution to believe that metazoans would have evolved two different mechanisms for attaining the same result, which is the inherited change in morphology. Evolution is inherently parsimonious.

The new information necessary for inducing specific inherited changes in cases of transgenerational developmental plasticity is provided by the CNS. That information results from the processing in specific neural circuits of internal/external stimuli and, in the form of a chemical output (neurotransmitter/ neuromodulator) is provided to a particular type of neuron for activating a signal cascade that results in a specific change in the epigenetic information (parental cytoplasmic factor, imprinted gene, etc.) deposited in the gamete. The information leads to the modification of a specific developmental pathway in the embryo in order to produce a specific inherited phenotypic change.

Mechanisms of the neural computation in the neural circuits that lead to generation of the new information necessary for changes in developmental pathways represent a blackbox. We know what these neural circuits do but we do not know how. We have some good evidence on electrical and chemical events related to the transformation of internal/external stimuli at the entrance of the black box and, on the other end we see electrical and chemical outputs that activate specific signal cascades in the offspring.

Although in metazoans the evolution of genes is decoupled from the morphological and behavioral evolution, the epigenetic mechanism of evolution makes use of favorable changes in genes in the course of evolution and of the genetic mechanism of heredity with the genome as its central machinery. In their mutual interaction, the genetic mechanism of inheritance is subordinate to the epigenetic mechanism. Evolution of metazoans at the organismic level, evolution of metazoan morphology, behavior, and life history, contrary to the evolution of unicellulars, does not depend on changes in genes (a sponge, the simplest of metazoan organisms, has more genes than a human).

Adaptive evolutionary changes in the phenotype (behavior, morphology, physiology, and life history) in metazoans start with complex neurobiological processes of reception, informational conversion, integration and processing of external/internal stimuli in the neural system, the CNS or neural net and investment in gametes of new epigenetic information for inducing specific changes in the developmental pathways in the process of individual development of the offspring. It is encouraging that modern biology, slowly, but steadily is coming to recognize that

Irrespective of their different nature, most animal adaptation mechanisms share the involvement of the central nervous system and often include endocrine activity. (Kolk, et al. 2002)

On the principles and the method

The development of biological science, as well as science in general, is a continuous but not a linear process. Ideas, hypotheses, and theories of the past are not infallible. Change and continuity in science are two sides of the same coin: the continuity of scientific progress also implies discontinuities with the previous ideas and hypotheses, many of which have to expire in the long and laborious path to the truth. The same goes for the authorities. The only immutable and enduring bedrock in biology, the ultimate and incontrovertible authority, is the scientific fact as acquired by observation and experiment, not its interpretation or inferences which are liable to the flaws of human judgment.

My attempt to reconstruct and visualize the developmental mechanisms of evolutionary changes in metazoans is chiefly based on empirical evidence. Biological facts have been the starting point of the inquiry that logically and unavoidably led me to the theory I present in this work and empirical evidence is the foundation on which my theory arises. I have not built on previous theoretical structures that are still waiting to be validated. Even in those cases when other hypotheses have been used for supporting the epigenetic theory of evolution presented herein, I have factored in that they rank lower than empirically established facts but in no case, unproven hypotheses or theoretical constructions have been used to draw conclusions.

Any phenotypic change, before being fixed as an evolutionary change, goes through two stages. First, it is generated and then it has to undergo a process of selection, in which useful changes, those that improve the fitness of the organism to the environment, or at least do not reduce it, will be conserved and propagated to the progeny. This process in which the evolutionary “chaff is separated from the grain” is natural selection. Modern evolutionary biology deals predominantly with the second stage, with the process of selection of the change under particular environmental conditions. With a tolerable risk of exaggeration, I would say that by focusing on the process of selection, it has payed little attention to the crucial event in the process: the mechanism of generation of the change that is to be selected.

Given that Darwin and generations of biologists after him have exhaustively discussed and elaborated on the role of natural selection in determining the spread and elimination of evolutionary changes, my focus in this work will be on the mechanisms of the generation of the evolutionary innovations rather than on their selection. To build on the metaphor on natural selection as editor, in this work I focus on the process of “writing” rather than on the “editing” of the evolutionary changes.

Evolutionary changes in morphology, resulting from changes in developmental pathways have to be generated/produced sometime during the ontogeny, in the process of the individual development, from the zygote stage to adulthood. Hence, causally, the evolutionary change in morphology is the result of a specific change in a developmental pathway. This is the reason why key evolutionary events, the appearance of evolutionary novelties, in Part Four of this work (chapters 14, 15, 16, and 17) will be considered at a developmental level and to the extent that the molecular mechanisms, cascades and gene regulatory mechanisms are known, signal pathways and sources of information for evolved structures, functions, and behaviors will be examined.

In modern treatises on evolution, the observational evidence is in the function of validating the standard set of established hypotheses and theories, i.e. the theory is given preponderance and the function of empirical evidence is to illustrate the theory.

My work on the epigenetic basis of metazoan evolution is not an established or accepted theory; it is a product of the analysis and synthesis of the available experimental evidence on metazoan evolution. As the intention of this book is not to illustrate an established theory but rather to present the available evidence on which I have erected my theory, the empirical evidence gets the lion’s share in this book. Presenting a theory that needs to be substantiated, in this work I naturally focus on the evidence substantiating my theory, but evidence that seems to contradict my theory is not ignored.

In cases when I have felt that the interpretation of results of experiments or observations may be contentious, and this has not rarely been the case, accounts and conclusions drawn from leading investigators are quoted in appropriate contexts. This has imposed a relative abundance of quotations in this book.

In a number of cases competing hypotheses are not discussed in length or even considered at all. In any case this is related to one or more of the following reasons:

1. Failure of the hypotheses to find experimental and observational support for a long time since first presented,

2. Insufficient relevance to the discussed topic, or

3. Author’s unawareness of the hypotheses.

Given that the neoDarwinian theory still represents the most widely accepted explanans of organic evolution, description of almost all the evolutionary and developmental phenomena is followed by a comparative presentation of the neoDarwinian view and my epigenetic explanation, in order to enable the reader to assess the relative explanatory power of both the genetic and epigenetic approaches to the mechanism of metazoan evolution.

In order to avoid any misinterpretation, whenever possible, the neoDarwinian explanation is presented as rationalized by neoDarwinian authors. However, if in some cases the reader will find my neoDarwinian interpretation as misleading or incorrect, the reason will be anything but the intention of creating a neoDarwinian straw man.

The material included in the work for supporting the theory comprises evidence from widely different fields of biological research, which may sometimes make the reading difficult. To help the reader in overcoming these difficulties, figures are extensively used as a part of the explanatory apparatus. Whenever it has been possible, figures are reproduced without modifications.

I am aware that the literature used may not be in every case the most representative and studies more important than the ones cited in this work often may be missing. Sometimes, abstracts have been used instead of full papers which have been out of my reach.

The structure of the book

This book consists of five parts. In the first part of the book, Epigenetic Basis of Metazoan Heredity (chapters 1-7) the general features of the control system and its function as the epigenetic system of heredity in the process of metazoan reproduction and individual development are described and substantiated with empirical evidence from invertebrates and vertebrates.

In the Part 2, Neural-developmental Premises of Evolutionary Adaptation, I discuss interactions organism-environment as exemplified in neural, neuroendocrine, and behavioral responses to changed conditions of living as well as ontogenetic mechanisms of developmental stability and instability (chapters 8-10).

Discrete intragenerational changes in the phenotype, involving no changes in genes, in response to the changed conditions in the environment or in response to specific stimuli are discussed in Part 3, Circumevolutionary Phenomena and the Mechanism of Evolutionary Change. These phenotypic changes, in distinction from evolutionary changes, in most cases are not inherited, but like them, result from changes in developmental pathways leading to developmental plasticity, adaptive coloration, mimicry, polyphenisms, etc. A separate chapter is devoted to transgenerational developmental plasticity, a phenomenon which at the same time is an evolutionary phenomenon in the meaning that the morphological changes are transmitted to the offspring.

In the Part 4, Epigenetics of Metazoan Evolution, I deal with factual evidence on four different modes of divergent and convergent modes of metazoan evolution. In this part I review concrete evolutionary events focusing on the developmental mechanisms of the change. Special emphasis is placed on the comparative presentation of the neoDarwinian and epigenetic explanations of evolutionary changes.

The process of speciation and the epigenetic mechanisms of sympatric speciation are discussed in the fifth part, Epigenetics of Speciation in Metazoans (chapters 19 and 20).