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.

 

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.

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.

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.

  and there were theories of evolution before his time. Among these was a one advanced by Jean-Baptiste Lamarck in the early nineteenth century. He proposed that individuals can gain or lose capacities based on their advantageous use or lack of use. Therefore, individuals can inherit features from their ancestors based on their pattern of use. Examples that are often presented include giraffes stretching their necks to reach leaves thus imparting slightly longer necks to their offspring. In this way, it was contended that changes in the environment can yield gradual changes in individual organisms based on that pattern of their respective use or disuse of capacities.

Another theory, Uniformitarianism, was propounded by Charles Lyell between 1830 and 1833. He asserted that the laws of nature are constant and immutable over time and space and that such laws could be identified and would account for evolution.

New theories abounded after Darwin, too. In 1893 William Haacke and the zoologist Theodor Eimer espoused Orthogenesis. They generally conceived of evolution as moving forward in a straight line and held to a regular course by non-random forces that are internal to the structure of organisms. These internal factors essentially propel an organism forward developmentally and selection is limited in scope.

The Vitalists in the early 20th Century proposed that evolution was driven by the fact that living organisms are fundamentally different from inanimate ones as they are imbued with an intrinsic ‘vital spark’ or energy. This was not a new idea and, in fact, it was an ancient doctrine that had been believed by many great scientists including Louis Pasteur. However, this concept was eclipsed by the rediscovery in 1900, by Hugo De Vries and Carl Correns, of the critical work previously done by Gregor Mendel, an Austrian friar and scientist who is considered the father of classical genetics. He had discovered by working with garden peas that the result of a cross between peas of different colors was not only a blend, but also yielded offspring of both separate colors in predictable ratios. He conceived of the concept of heredity units, which he called “factors” and were later called genes.

The rediscovery of Mendel’s work in genetics led to a variety of new proposals and theories and a division in perspective that this reverberates today. One school of theory favored viewing evolutionary development as primarily proceeding by large mutations or jumps, called Saltationism. Another opposing school, the Biometric school, advocated that variation was continuous and gradual in most organisms and favored a mathematical and statistical approach. Both were attempting to unite Darwinism with genetics and it is this latter approach that is embodied in what is termed the Modern Evolutionary Synthesis or current Neo-Darwinism.

The development of population genetics as the study of genetic variation and gene distribution in populations under the influence of natural selection was pioneered by Fisher, Haldane, and Wright. Their work was fundamental in establishing many of the underlying principles of Neo-Darwinism. The Williams Revolution of the mid 1960s shifted thinking from population genetics models to natural selection via kin selection. In this model, the gene is the fundamental unit of self-preservation either by acting to protect and preserve itself or closely related genes. This was expanded by Richard Dawkins who popularized the concept of the “selfish gene,” a gene centered view of evolution with selection acting on the genes themselves and not only on organisms or populations. In this view, we are just genetic vessels or carriers.
Contemporaneous to Dawkins, the concept of endosymbiosis was widely popularized by Lynn Margulis in the 1970s although it had been proposed decades earlier. The underlying theme of ‘endosymbiotic theory’ as formulated as early as the late 1960s was that the evolution of eukaryotic cells (cells with complex structures enclosed by membranes) over millions of years was enacted by the interdependence and cooperative existence of multiple prokaryotic organisms engulfing and incorporating one another. Although originally dismissed as a fringe concept, it is now recognized as the key method by which some organelles have arisen.

More recently, Eugene Rosenberg and Ilana Zilber-Rosenberg presented research advancing the concept that the object of natural selection on genomes is not solely on the individual and its central genome but on the combination of a ‘host’ organism and the entire symbiotic community with which it is associated. From this concept of the hologenome, originally conceived by Richard Jefferson, an entirely robust and alternative narrative of evolution can be offered, Hologenomic Evolution Theory. In this theory, evolutionary development builds upon cellular interactions governed by immunological rules. Natural selection remains an important factor but is displaced from its central role.

virulence of many microbial pathogens, no matter the underlying cause. This correlates with the rich complexity and diversity of all ecologies in which pathogens thrive. So shifts in the distribution of vegetation, the dispersal and range of animal predators or their prey, or distortions in the variety, concentration or specific strains of vectoring insects or other disease-carrying organisms can all influence the transmission of pathogens or their relative abundance.

Support
Many researchers believe that this effect can be currently observed. For example, malaria[1] spreading to the highlands in Africa and the northward spread of West Nile Virus[2] in the United States has been linked to the changing distribution of disease-carrying mosquitoes relating to climate change. So, too, have shifts in the spread of dengue fever[3] in endemic areas.

A wide range of diseases are zoonotic in etiology so a shifting climate may enhance the likelihood of that cross-transmission or its virulence. There is evidence for just this type of consequential shifting pattern. Ecological variation has been ongoing over earth’s history, and that of man’s time on earth. Humans have been both victims of pathogens and carriers. For example, the loss of the North American large mammals like the woolly mammoth and saber-toothed tiger has been correlated by some researchers to a phenomenon termed hyperdisease[4]. In that instance, humans as carriers or our traveling companions, such as hunting dogs or domesticated animals, are thought to have introduced new pathogens or more virulent ones to an unprepared environment.

Response
How then should this affect our global response to climate issues? It must begin with increasing awareness among climate scientists and physicians. However, there should also be a redirection of scant available resources from unproved expensive projects of carbon capture and sequestration to productive research studying the patterns of communicable disease. This might mean evaluating and implementing better means of mosquito, tic, and rat control; sharpening our tracking of current patterns of communicable diseases; and aggressive research into improved prevention or therapies. All would yield substantial benefits with certainty, whether a shifting climate is consequential now or in the future.
–Bill Miller, MD

References
1.    Bouma MJ, van der Kaay HJ. The El Niño Southern Oscillation and the historic malaria epidemics on the Indian subcontinent and Sri Lanka: An early warning system for future epidemics? Trop Med Int Health 1996;1:86-96.
2.    Morin CW, Comrie AC. Regional and seasonal response of a West Nile virus vector to climate change. Proc Natl Acad Sci USA 2013;110:15620-15625.
3.    Hales S, de Wet Neil, Maindonald J, et al. Potential effect of population and climate changes on global distribution of dengue fever: An empirical model. Lancet 2002;360:830-834.
4.    MacPhee RDE, Marx PA. Lightning strikes twice: Blitzkrieg, hyperdisease, and global explanations of the late quaternary catastrophic extinctions. American Museum of Natural History. Accessed 13 June 2014. www.amnh.org/science/biodiversity/extinction/Day1/bytes/MacPheePres.html.

 

Lee Hotz in the Wall Street Journal (Feb. 14, 2014) quotes Justin Werfel, a staff scientist at the Wyss Institute for Biologically Inspired Engineering at Harvard University, “Every robot acts independently, but together they will end up building what you want”.

The experiment demonstrated that the robot swarm can build a variety of shaped structures such as castles and pyramids out of foam bricks. Each individual robot can autonomously build staircases to reach the higher levels of these structures. Simple programming rules permit forward, backward, up and down motion. Each robot can also sense the individual bricks that it carries and also the presence of nearby robots. Relatively complex structures can be constructed since the robots are smarter as a group than they are individually, and can recognize and correct some mistakes.

Although the design of this experiment was inspired by termites, the scientists might just as well have done their modeling utilizing cellular dynamics. Individual cells, too, act independently yet collaborate by using their own sensory apparatuses. Cells are aware of their surroundings, their cellular neighbors and even cells at a distance via sophisticated sensing and communication mechanism. These robots were programmed to follow very limited rules that allowed them to “respond to conditions around them and to each other.” 

Cells are easily capable of the same range of responses. Indeed, the rules for cells, just as for real termites, are not exclusively straightforward nor as limited as in this experiment. Their awareness is much more sophisticated and extends beyond their immediate surroundings. However this experiment, even though limited, demonstrates that collaboration based only upon simple rules and basic sensory awareness can enable complex engineering of structures totally unrelated to the design of the originating individuals units. There need be no organizing principle beyond rudimentary rules of interaction. Therefore, it can be appreciated that in the biologic realm, complexity can be the yield of this sort of uncomplicated collaboration and it is reasonable to assume that natural systems would respond in the same manner. As Steven Johnson has said and this experiment elaborates, “ It is not the network itself that is smart; it’s that the individuals get smarter because they are connected to the network.” This is just as true for cells as it is for termites and humans. 

Indirectly then, the analogous power of natural genetic and cellular engineering by genetic aggregates and individual cells with limited awareness to create complex local environments is illustrated. That would be so even if cellular capacities were quite proscribed or comparable to the elementary rules devised by the researchers instead of the vastly broader and deeper capabilities that they possess. Constrained as these robots were, they were still able to build complex structures. Why would we doubt the correlative capacity of aware, linked and co-dependent cells to engineer biological results according to their own preferences, needs and limits? Nor should it be difficult to accept that all complex creatures have evolved and were elaborated by this same process, no different in kind than illustrated by this experiment. 

Collaboration, repeated at every level and at every scale, represents the fundamental process by which all the current biologic endpoints on this planet have been reached ………as hologenomic organisms. Every complex creature on this planet is one. There are no exceptions. Nor could there be if the fundamental pattern of evolutionary development is based on collaborative biological engineering across a broad spectrum of cells, each intent on serving its own aims but capable of working cooperatively to achieve those goals. Indirectly then, this experiment elegantly illuminates the inherent power of natural genetic and cellular engineering in biological processes. Our biological world is based on a system of collaboration and competition through cellular awareness, preference, and intentionality. Even limited as it must be solely to its microscopic scope and scale, its outputs are the wondrous creatures we see all around us.