Author Archives: admin

Part 4: Epigenetics and Chromatin – Epigenetic Changes


Epigenetics and Chromatin

Chromatin represents the combination of both the DNA and proteins in a cell nucleus. This combined material can assume specific configurations. This chromatin architecture is currently viewed as having a critical role in controlling gene expression and DNA replication. The primary protein elements of chromatin, or histones, compact DNA and assist in mitosis. Epigenetic changes occur by complex interactions between environmental influences and the underlying protein structure and DNA of a genome, which can alter the configuration of chromatin or change how segments interact in their three-dimensional environment. Examples include DNA methylation and alternations to chromatin architecture through histone modification. It is believed that most epigenetic modifications to underlying DNA sequences, either through promotion of genetic expression or silencing of genetic sequences proceeds through alterations in chromatin architecture.

In general, it is currently considered that epigenetic changes to a genome are less stably heritable than base genetic heritability. That is, if a genetic change occurs to the underlying genetic code it is more likely to be stably transmitted to future generations than epigenetic changes, termed epialleles. These latter modifications are thought to be generally unstable. In addition, the fidelity of transfer if it occurs may not lead to exactly the same degree of genetic expression in a further population, termed variable penetrance. So the genetic expression potentiated by the epigenetic change may still persist, but be lessened or the new trait may entirely disappear in future generations. The process that appears to account for this is that most epigenetic changes are believed to act by modification of underlying chromatin architecture rather than the intrinsic DNA base sequences within that complex assembly. It has even been postulated that the protein histone elements of chromatin may even constitute its own form of code that offer cues and instructions for gene regulation and could then account for differing states of genetic expression and activity.

Yet, according to William Kelly at Emery University in a recent article on transgenerational epigenetics, some things are clear. Complex and overlapping epigenetic mechanisms build changes in chromatin architecture that are heritable. These changes can guide genetic expression in germline cells, and then guide chromatin architecture in the zygote. There is an “initiating event” that triggers these epigenetic processes. Some further maintenance mechanism assures that this altered genetic expression and activity is maintained through successive rounds of replication and reproduction. Further, there appears to be some ability to discriminate at the germline as to which epigenetic processes persist and which are expunged. All of these mechanisms are fully compatible with hologenomic evolution theory, as explored in The Microcosm Within. Importantly, such new scientific findings critically undermine the simplified paradigms of conventional of the Modern Synthesis and its unfaltering allegiance to unfettered natural selection and random genetic mutation.

Part 3: Epigenetics and Cancer | Epigenetic Modification

Epigenetics and Cancer

Epigenetics and Cancer

New research is demonstrating that the etiology of cancer is complex. Epigenetic modifications of the genomes of cancer cells appear to be quite important. These are changes that do not necessarily reflect the exact DNA sequences within a cell, but alter, by various means, the expression of the underlying code. It is increasingly apparent that epigenetic modification may be as important as genetic mutation in the transformation of a normal cell to a cancer cell. This does not change the fact that many cancers are induced by infectious disease which itself can be considered an epigenetic variable. 

Such epigenetic mechanisms are being successfully defined. These include DNA methylation, arguably the most researched marker, by which the methylation profile can be linked to tumorigenesis as promoters of unlicensed cell reproduction. Alternatively, hypermethylated DNA zones can result in consequential gene silencing, which is considered itself to be a form of carcinogenic epigenetic mutation. It is also theorized that hypomethylation in parts of a genome can lead to chromosomal instability and the activation of transposable elements which can increase cancer risk or directly induce it. 

Recent studies have implicated an epigenetic signature that can predict whether a woman may develop breast cancer, even without those BRCA gene mutations that are typically considered a prime risk factor. An epigenetic signature in women with a mutated BRCA-1 gene has been linked to increased cancer risk and lower survival rates in a study conducted at the University College of London. 

Interestingly, a new epigenetic therapy designed to treat cancer by regulating gene expression has been cleared for Phase I trials. A recent clinical trial of a small molecule inhibitor drug of a particular class of proteins helps to control gene expression. This epigenetic control mechanism has shown initial promise in the treatment of refractory carcinomas. As the researchers note, the success of this initial trial, albeit limited, points the way for other investigational epigenetic cancer therapies. Thus, our emerging understanding of epigenetics if offering profound clues to both the causes of cancer and its cure. 

Part 2: Epigenetics and Evolution – Transgenerational Epigenetic Inheritance


Transgenerational Inheritance

New scientific findings involving epigenetics are having a profound impact on our understanding of evolutionary mechanisms. It is becoming increasingly apparent that epigenetic modifications play a critical role in the regulation of gene expression. In so doing, they produce phenotypic changes. It is becoming abundantly clear that these influences are an important factor in our own human experiences, influencing life span, mood disorders, immunological status, obesity or tendencies towards the variety of chronic illnesses that have afflicted our human experience. Although it has until recently been assumed that these epigenetic marks are cleared in each generation and then re-established by reiteration of similar environmental influences, it is now manifest that this is not always the case. The term ‘transgenerational epigenetic inheritance’ has been applied to this phenomenon.

Epigenetics is now an established discipline. Examples abound. For example, one of the first fully documented instances was the transgenerational epigenetic inheritance of flower symmetry from bilateral to radial in Linaria vulgari. This results from a change in DNA status, a process of methylation, rather from any change in the underlying DNA sequence. In essence, a different form of gene expression and its phenotypic trait correlates to either an active or silent state of underlying genetic code based on environmental experiences. This has been shown to be heritable over multiple generations and might be permanent. Obviously, there remain difficulties in ascertaining with certainty what might be an ‘epigenetic’ change and what could be an underlying genetic mutation, yet the concept seems robust. There is a means for the experiences of an organism within its environment to affect its genetic expression and that change can be either meiotically transferred to the next generation or through RNA transcripts in germ line cytoplasm to progeny. Importantly, in hologenomic evolutionary theory, the targets of these kinds of transfers and their influences are extensively available to organisms that are pictured as vast inter-related ecologies of innate and microbial cellular life… a microcosm within. We, and all hologenomes are subject to a vast array of both internal and external environmental influences in an exquisite, complicated and co-dependent interplay.


Part 1: Definition of Epigenetics and Acquired Characteristics

What is epigenetics?

Jean-Baptiste Lamarck

This is the first of a five part series discussing epigenetics.

In science, what is old can once again become the new. To better understand the definition of epigenetics, we must look back at the time before Darwin. Charles Darwin proposed his version of natural selection and heritable descent by gradual modification in 1859, but before that, many theories had been considered before creationism. One leading evolutionary proponent was Jean-Baptiste Chevalier do Lamarck. He was the protégé of the Comte de Buffon who had believed that living organisms can vary over time and their experiences in the environment may affect them and their progeny. Lamarck proposed the concept of the inheritance of acquired characteristics as just this sort of mechanism. He believed that evolution can be effected by the manner in which a body part is used or altered during the lifetime of an organism and that this acquired character was then heritable. For example, a blacksmith using upper body strength for work would be more likely to produce children with greater upper body strength. Although carrying considerable weight as a scientific theory in its era, scientists were rather easily able to point out the many apparent contradictions to it. Ultimately, it was eclipsed and discredited. Indeed, Lamarckism has often been used as a specific example of fallibility of belief systems in scientific progress.

However, it seems that Lamarck was not entirely incorrect. Prior to our genetic era, C.H. Waddington developed the term epigenetics as a means of naming a process in which heritable factors might interact with the environment to produce the phenotypes and forms that we can observe. Although it was firmly believed until relatively recently that genes are fixed in an individual and that only random mutation can affect them, current scientific information has revealed that genes and genetic expression can be affected in a variety of consequential ways by environmental factors. Currently, epigenetics is established to mean the heritable phenotypic changes that an organism can express without specific alteration to the relevant underlying DNA sequences. It is becoming increasingly apparent that this type of inheritance is consequential and multi-generational, and may be permanent in particular instances. So, Lamarck’s derided notions have been unexpectedly revived as our understanding of the fuller complexity of genetic variation has deepened.

Metagenomic Assembly

Metagenomic evaluation of any environment, ecology or tissue sample requires extensive computational power in order to properly assess large volumes of sequence data. This is required to mobilize an accurate representation of genetic diversity in a sample. New techniques in de novo metagenomic assembly effectively filter the total amount of data to be analyzed; yet, vast amounts of computer power are still required. New approaches to that analysis and changes in
the filtering methods have enabled improved methods of metagenome assembly of a more accurate characterization of the full range of microbial life in a sample. Complex software is necessary since in conventional genome analysis, only one species is being analyzed. However, metagenomic sample analysis, the required metagenome assemblers use algorithms to additionally separate species and to also attempt to assess their relative abundance. Different assemblers, utilizing differing techniques, can skew results based on scalability of the software and variability in data reconstruction filtering techniques. Recent studies have attempted to demonstrate that filtering shortcuts can still permit accurate analysis of any sample.

For example, the exact composition of the microbial life in any given sample surely contains mixed populations, but the exact species and the relative abundance of them are unknown. When standard metagenomic analysis is applied (shotgun sequencing), there is disruption of the sequencing data and grouping by species can be very difficult. Newer techniques are permitting more accurate analysis through chromatin level probability maps so that the individual genomes of microbial species can be accurately reconstructed within a mixed sample. 

The validity of some of the short cut techniques employed by metagenomic assemblers is typically assessed against published references of current metagenomic data. One problem is that the full complement of microbial life for any sample, for example, the human gut is still not fully understood. Metagenomics is only in its initial phases and surprises are revealed routinely in the analysis of tissue and environmental samples. 

For example, very recent evaluation of the human gut metagenome revealed a previously unknown gut virus, which has been linked to human chronic disease. Researchers indicate that this virus, called Assphage, lives in the gut of more than half of the world’s population and infects a common gut bacteria, Bacteroidetes. This particular virus was identified through a computer program and had not been previously identified. Yet it is ubiquitous and is currently believed to have a major role in diabetes and obesity. So at this moment, exciting new technologies are deepening our understanding of ourselves as the complex linkages of co-dependent ecologies outlined in The Microcosm Within. Metagenomic assembly is one tool to assess that partnership. Yet, there will be many surprises along the path to our fuller understanding of the power of those associations. 

Books on Evolution

It is surprising how few people have actually ever read Darwin’s On the Origin of Species by the Means of Natural Selection (1859) since it is referenced abundantly and considered a foundational event in evolutionary biology.
It is not surprising then that it is generally unappreciated that Darwin did not actually answer the specific question of exactly how species arise. Instead, he proposed that evolutionary development proceeds through differential reproductive success, through competitive natural selection and also championed the concept of descent by gradual modification. But, there is a long list of scientists that have offered credible and thought provoking books to further explain evolutionary development and speciation and many of these were critical to the construction of the ideas underlying of The Microcosm Within.

Which sources might an interested person read in order to get a general background in the history of evolutionary thought? Certainly, skipping towards the present day makes the most sense. Interested individuals should consider becoming familiar with some of the works by Stephen Jay Gould. For example, his Wonderful Life: The Burgess Shale and the Nature of History (1989) is beautifully written and examines the critical Cambrian explosion and other discontinuities in evolutionary development. The works of Richard Dawkins [e.g. The Selfish Gene (1976)] are thought provoking and are useful in an historical sense. Much of what is currently written is a reaction to his critical thinking.

Acquiring Genomes: A Theory of the Origins of Species (2002) by Lynn Margulis and Dorion Sagan represented a radical rethinking of evolutionary biology with their championing of symbiogenesis. This courageous departure from mainstream thought remains a powerful influence in evolutionary biology.

Sean Carroll in Endless Forms Most Beautiful (2005) lucidly explains the newer concepts of evo-devo, particularly how HOX genes serve conservation of forms.

For those interested in an informative critique of Neo-Darwinism, What Darwin Got Wrong (2010) by Fodor and Piattelli-Palmarini offers a trenchant review of its inadequacies. Speciation (2004) by Coyne and Orr gives an excellent capsule background into modern concepts in speciation. Fox and Wolf, in Evolutionary Genetics (2006) do the same for gaining an initial grounding in genetics. In The Plausibility of Life (2005), Gerhart and Kirschner offer an elegant attempt to find some means for accounting for the failures of the Modern Synthesis through concepts of facilitated variation. Their struggle to offer satisfactory answers, just like Dawkins, is pertinent to our ongoing debate.

Arguably, the best of the current works is the thin volume by James Shapiro, Evolution: A View from the 21st Century (2011). His concepts of natural genetic engineering, which are wholly part of hologenomic evolution theory, are explained in careful and rich detail.

All of these sources have been critical to the formulation of hologenomic evolutionary theory and I consider myself indebted to all of them. Each has contributed brilliantly to a field in which there is never final truth.

Microbiomes and Their Role in Evolution Biology

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 innate cells by a factor of 10 to 1 or more. We cannot do without many of them for proper function of our brains, gut, central nervous and immune systems.They cannot exist as they want without us.

Some researchers have begun to view organisms as multi-species units but remain constrained by retaining an outmoded model of ‘host’ and ‘guest’ with respect to those interacting species. However, instead of viewing organisms as inherent singularities or even as a group of linked singularities, it is more accurate to regard organisms as united vast collaborative enterprises. These consist of a co-linked, cooperative, co-dependent and competitive ecological community of microbiomes merged together so seamlessly that they seem, at least to the consciousness of any particular organism, as one discrete entity. In this model, there is no simple or absolute ‘host’ and ‘guest’ as all function reciprocally to make the effective whole. In this conception, it is the specific collection of such linked ecological communities that makes each species unique. Any complex organism itself represents an entire ecology reiteratively constructed from all of the relevant smaller ecologies that make it so. That larger coalesced ecological unit then has its own exquisite place within the larger external environmental ecologies. Each ecology and all the linked ecologies remain together and function with purpose to sustain the individual constituent cells that make up each ecology. So at every time, the linked ecologies that make an organism such as ourselves are working to maintain the preferred status of their constituents’ cells. To serve those needs, they remain separably discriminative in their range of responses. Those specialized responses serve the whole. Yet, they are so harmoniously associated together as to seem to the organism itself as though they are one.

There would be no requirement that all of the exact constituents of the conjoined ecologies that make an organism stay static. Indeed, we know that they do not. However they do need to stay within biological boundaries or that exact species forfeits its place in a competitive landscape in which any organism is under continuous assault by a very aggressive external genetic milieu. This is the exact interface between health and disease for all complex creatures. 

If this seems a bit daunting, it is so only at first blush. Nature certainly does not see us as singularities as the Darwinist have long believed. Instead, we are holobionts. There is no pore, orifice or hidden compartment within us that is ‘sterile’. That concept is now defunct. Importantly though, it is not that just some complex organisms are hologenomic beings. All complex organisms are, and there are no exceptions on this planet. So any coherent theory of evolutionary development must endorse that endpoint as its narrative. 

Neo-Darwinism and Modern Evolutionary Synthesis

It is not well recognized that Darwin in his book On the Origin of Species did not specifically explain how a species originates but discussed how an organism became fitter and better adapted gradually over time. Even during his lifetime, others pointed out the problem of dilution of favorable traits by blending within the reproductive population. George Romanes, one of Darwin’s academic friends, emphasized variation in reproductive ability as a source of new species and coined the term Neo-Darwinism. From that time forward and through successive iterations, the core concept of Neo-Darwinism has remained rooted in variation. Natural selection drives evolution based on that variation. In a modern context, that variation is produced by genetic mutation and genetic recombination.
Despite vigorous discussion, Darwin’s theories did not really gain widespread acceptance until the 1930s and 1940s with the formulation of the Modern Evolutionary Synthesis (Neo-Darwinism). This was the unification of Darwin’s ideas with those of Mendelian genetics. This widely accepted theory holds that genetic variation arises by chance through random genetic mutation with evolution consisting primarily of changes in the frequency of alleles (any one of a number of alternative forms of the same gene) between one generation and another. The consistent attempt to reconcile Mendelian genetics with the introduction of new species has been an important feature of the debate.

Hologenomics: A Modern Theory of Genetic Evolution

Hologenomic Evolutionary Theory is a modern theory of evolution that is entirely centered within the context of all organisms as hologenomic beings. In viewing the cell as the basic agency of evolutionary change and viewing natural selection as a filter instead of a driving force, it stands apart from Neo-Darwinism.  What are the major tenets?

Evolutionary development must start from a new biologic base compared to the Modern Synthesis. All cells are cognitive. There is a base level of awareness at the cellular level that permits limited discriminative preference as to cell status.

All cells seek to maintain themselves within a narrow functional boundary. This is termed homeostasis and is a fundamental property of cells. Importantly, each cell can cooperate and collaborate as well as compete towards its goal of sustaining its best homeostatic moment.

From this, evolution proceeds by a dramatically different dynamic than by simple natural selection – genetic transfer, cellular intentionality and natural genetic engineering empower its course. Natural genetic or cellular engineering is the process by which cells constructively cooperate, collaborate and compete to sustain their preferred homeostatic level. In successive layers of interactive cooperation and competition, phenotypic novelty is built. Importantly, it is always an expression of the efforts of the conjoined cellular constituents to successfully maintain themselves. In this way, it is not really conceptually different from how we humans build cites. We each collaborate and cooperate and mutually compete to enact a city with all its forms and intricacies that in no manner resembles any individual human. We do this with the tools that we can employ in both the inorganic and organic realms based on our own privileged and still limited capacities. Cells do similarly but strictly according to their own limitations. They use what they can, which in their circumstances, are biological substrates. In an important sense then, we humans demonstrate capacities that are themselves direct iterations of base cellular faculties. We express them too, through our means, in a manner unique to our human species.

Critically then, the wondrous forms and biologic processes that we readily assess emanate from a process of cellular creativity. That creativity is enacted at all times to best maintain all of the cellular constituents within any localized ecology, and reiterating onward and outward towards the forms and functions that we can easily apprehend. This process is not merely random. It has the directional component of the self-awareness within cells, which can be termed ‘cellular ipseity.’ Random events still manifest. However, they are utilized as they can be or simply accepted if resistance is futile. That output however must be ‘fit enough to survive.’ It is here that natural selection operates. 
In the cellular realm, this engineering process is effected by genetic transfer mechanisms that are not haphazard but proceed along the lines of biologic interactions that have previously and casually been recognized as infectious disease dynamics, a new principle in biology and evolution.

Importantly though, the guidelines governing this process are immunological in nature. All cell-to-cell interactions are immunologically governed. In evolution, immunology rules. 

Its yield then is just the end point that modern science informs us is our natural reality. All complex creatures are hologenomes. Not as exceptions, but as the only complex organisms on this planet. Any new theory must completely explain this biologic endpoint. How is this best explained by Hologenomic Evolutionary Theory?  It alone is a theory rooted in cellular collaboration, cooperation, and co-dependence just as much as competition. It is a theory of connections, enacted cell-to-cell, layer-by-layer, and ecology-to-ecology. Evolutionary development is a building process through collaborative cellular dynamics and not merely a whittling process through natural selection. In Hologenomic Evolution Theory, connections are built upon the discrete and omnipresent primordial awareness of cells and genetic aggregates. Every biologic process that can be witnessed is its current expression.

For all its varied contortions, Darwinism is deeply rooted in Victorian sensibilities … competition through natural selection… ‘Survival of the Fittest.’ In contrast, Hologenomic Evolution Theory asserts that complexity and novelty are acts of cellular creativity to serve the limited and discrete needs of constituent cells in an endless series. Genes are a form of communication as well as reproduction and act to sustain the varied environments and collected ecologies that comprise any complex organism. In this manner, genes primarily exist to ‘serve’, another important difference from Darwinism. Despite our prolonged Darwinian detour, fresh scientific findings are confirming that our evolutionary narrative has been affected through the demonstrable capacities of cells and the immunological reactions that govern their world.

Mass Extinction Events Diffrentiate Patrick Mathews’ Work from Darwin Evolution Theory

The publication of Charles Darwin evolution theory found in Origin of Species in 1859 and the Descent of Man in 1871 initiated a clamorous public and scientific debate that remains unabated today. His insightful analysis of the means of evolution by natural selection and descent by gradual modification has undergirded the discussion and investigation ever since.

Interestingly, Darwin was not the first to propose evolution by natural selection. New York University geologist Michael Rampino argues that there was an earlier theory of selection and gradual evolution advanced by Scottish horti-culturalist Patrick Matthew in the 1831 book,  Naval Timber and Arboriculture, prior to the publication of Darwin’s work.

Matthew further elaborated on this speculation in 1860. In those works, Matthew clearly stated the idea of natural selection as fundamental to the origin of species, but also emphasized that he believed that there are long periods of evolutionary stability disrupted by catastrophic mass extinction events. Even though both Darwin and his colleague, Alfred Russel Wallace, acknowledged that Matthew was the first to put forth the theory of natural selection, he has not been typically credited. Darwin’s notebooks show that he first promulgated his idea in 1838, and he composed an essay on natural selection as early as 1842 – years after Matthew’s work appeared. Matthew described the theory of natural selection in a way that Darwin later echoed: “There is a natural law universal in nature, tending to render every reproductive being the best possibly suited to its condition… As the field of existence is limited and pre-occupied, it is only the hardier, more robust, better suited to circumstance individuals, who are able to struggle forward to maturity…”

As opposed to Darwin, Matthew saw catastrophic events as a prime factor, maintaining that mass extinctions were crucial to the process of evolution: “…all living things must have reduced existence so much, that an unoccupied field would be formed for new diverging ramifications of life… these remnants, in the course of time moulding (sic) and accommodating … to the change in circumstances.” This insight was remarkably prescient as it is generally believed that evolution is indeed best understood by long periods of stability interrupted by major ecological changes that can occur both episodically and rapidly as opposed to only continuous and gradual modulation.

In On the Origin of Species, Charles Darwin skillfully advanced the concept that evolution proceeded by a process of gradual modification and that natural selection was its primary mechanism.

Even if not the first to consider these factors, he did contribute enormously. He put these concepts into a coherent evolutionary frame and defended it vigorously and well.

With new scientific discoveries, Darwin’s theories have been modified in an attempt to be concordant with new evidence. This has yielded substantial alterations of the purported mechanisms of evolution on a nearly continuous basis. Many of these same debates are in fact continuing. Aspects considered as conclusively settled at one time by some are reopened for discussion in the face of new discoveries. Consequently, issues involving the most basic processes in evolution that were nettlesome to Darwin such as blending or discontinuous inheritance, continuous evolution by gradual modification or by gaps, and differing viewpoints on the origin of organic complexity are still a part of our continued debate. However, Darwin’s looming presence has been a critical factor at every step.