Selected articles on the ‘Cellular-Molecular Evolutionary Basis to a Better Understanding of LIFE’ by John S. Torday and William B. Miller Jr. |


By: John S. Torday · Los Angeles, CA
455 Words

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What happens when we see ourselves as separate from or as a part of nature?

A great question. In my opinion, when we see ourselves as separate from nature, we divorce ourselves from our evolved selves, following an artificial, delusional trajectory that is destructive to ourselves and our surroundings. Whereas if we follow our evolved path as part of nature we act in a cooperative, constructive, cohesive, and integrated manner that is beneficial to animate and inanimate alike.

René Descartes sent us off on the trajectory of Man outside of Nature with his Mind/Body duality. Thoreau brought Mind and Body back together as Nature when he went to Walden Pond to live his life deliberately.

All of life began by entraining the negative free energy or entropy within the protocell, spontaneously formed from the lipids immersed in the snowball-like asteroids that formed the oceans on Earth. Combined with chemiosmosis, life was able to circumvent the Second Law of Thermodynamics, evading the consequences of dissipative energy. Homeostasis then enabled these First Principles of Physiology to perpetuate themselves, and change form and function when necessary as evolution. Each organism utilizes these principles in its own way, internalizing environmental factors that would otherwise have killed it. Instead, such environmental factors as gases, ions, and heavy metals are used for the organism’s physiologic benefit, which Claude Bernard called the “milieu interieur.”

This concept of life has become more dynamic by considering the influence of Niche Construction — the idea that organisms can form their own environments — on evolution. This is particularly true when one considers the likelihood that the cell was the first Niche Construction, offering the opportunity to scale up such relationships ecologically from unicellular to multicellular, from homes to villages, towns, cities, and nation states as Gaia, the notion that the Earth is an organic whole. The self-referential, self-organizational nature of life is reflected by the ways in which it has evolved.

Up until now it has been difficult to convey this argument for lack of a physical precedent for such behavior. But now there is empiric evidence for self-referential self-organization, referred to as “Time Crystals.” This term refers to the tendency for atoms to align themselves with one another spontaneously, forming a template for the organizational principles of animate life. It is only when we hominins consider this continuum from the inanimate to the animate that we can step out of the center of the biosphere and recognize all of life as a unified whole, interdependent upon one another.

Further Reading

Man Is Integral With Nature
From Minding Nature’s January 2015, Volume 8, Number 1 issue.

Torday JS and Rehan VK, Evolutionary Biology, Cell-Cell Communication and Complex Disease. Wiley, Hoboken, 2012.

Torday JS and Rehan VK, Evolution, the Logic of Biology. Wiley-Blackwell, London, 2017.


By: John Torday · Los Angeles, CA
259 Words

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I attended a meeting on evolutionary biology a while back, and the last presentation was by an emergency room physician from Seattle, Washington. His talk was on the rise in the crime rate in the United States, which he traced back to 1959. That marked the beginning of the Interstate Highway System, which fostered increased mobility in this country, but disrupted the relationship of people with their environments.

As a working scientist with an interest in human evolution, I find the intimate interrelationship between life and its environs of great interest. There are two emerging ideas in evolution and ecology, epigenetic inheritance and niche construction, respectively. The former deals with the direct inheritance of genetic information from the environment, the latter with how organisms fashion their own environments — worms modify the soil they live in, beavers build dams, humans build towns and cities. The merging of those two processes is a very powerful image of how life on this planet evolved from water to land, and then across the face of the Earth. My insight has been that the first cell was actually a niche construction (Torday, JS. The Cell as the First Niche Construction. Biology (Basel). 2016 Apr 28;5(2)), and that was what fostered all of the activities of life from that day to this.

So of course we must be good stewards of our environment, given that it is where we evolved from, and gained our existence from, past, present and future. Our current trajectory in forming the Anthropocene deviates from that path, but we must acknowledge it and ascribe to it or face extinction.


By: John S. Torday · Los Angeles, CA
400 Words

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As a biologist and working scientist for 50 years, I have finally come to the realization that reproductive success is not the driver for evolution…’s an epiphenomenon. Thankfully, Darwin’s contribution to humanity extricated us from “The Great Chain of Being.” The metaphors of his theory of evolution (‘survival of the fittest’ and ‘natural selection’) however, are not conducive to scientific testing and as a result, there is still no experimental evidence to support the reality of these evolutionary processes. I argue, that the process of evolution is instead based on epigenetic inheritance, which stems directly from the environment, and not just an arbitrary environment, but the niches we personally construct, like beavers building dams, worms conditioning the soil around them to accommodate their water-adapted kidneys, or humans building cities and cultural environments, referred to as Niche Construction Theory.

It is within those ecologic niches that environmental change is monitored over the course of the organism’s life cycle, incorporated into germ cells as epigenetic marks, either maintaining equipoise or ‘evolving’ accordingly due to sorting of the epigenetic marks during meiosis, embryogenesis, and over the course of the life cycle (The Cell as the First Niche Construction. Torday JS.Biology (Basel). 2016 Apr 28;5(2)). That process refers all the way back to the first eukaryotic cell, based on the First Principles of Physiology. The construction of that protocell, distinguishing external from internal (Claude Bernard) niche conferred both Free Will and Determinism on life as the origin of morality (Torday and Rehan. Evolutionary Biology, Cell-Cell Communication and Complex Disease. Wiley, 2012; Evolution, the Logic of Biology. Wiley-Blackwell, 2017).

In an earlier essay published in the Center’s Minding Nature journal, entitled “Man is Integral with Nature” (, William Miller and I made the case for the intimate relationship between physics and biology, annealed by the formation of the first cell from the lipids delivered by snowball-like asteroids during the early history of the planet. Briefly, lipids will spontaneously form primitive ‘cells’, or micelles, in water. Such semi-permeable membrane-bound spheres can generate bioenergy and reduce the entropy, or order, within them, referred to as negentropy (Schrodinger, What is Life?, 1944), controlled by homeostasis. That founding relationship, based on the First Principles of Physiology allows biology to circumvent the Second Law of Thermodynamics. That Faustian pact affords us the Free Will to test those constraints, but the aforementioned physiologic principles of life are determined. We live between those two boundary conditions, which we refer to as morality.


By: John S. Torday
1,610 Words

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“Wildness is the preservation of the world.”
— H.D. Thoreau

Reading Henry David Thoreau, I feel a moral and spiritual kinship with him and with all of life. Of course, that was his intent in sharing his experiences at Walden Pond, on the Concord and Merrimack Rivers, in the Maine Woods, and on Cape Cod. He was the first nature journalist to “mind nature.” He did all of that so he could live his life deliberately, transcending man’s law to discover natural law, encouraging us to do the same. He was also a mystic — for example, referring to a river in Maine being “peopled” with fish.

Thoreau’s intentions and aspirations are all noble ones that I support and uphold. However, as a working scientist for the last fifty years, I find it awkward to think in terms of metaphors instead of facts. Ironically, Thoreau was also a scientist of sorts, systematically measuring the height of the Concord River, counting annular rings on tree stumps, or doing seed dispersal surveys in order to fathom nature’s ways and determine her laws. He had a hypothesis, but he was not able to adequately test it scientifically, resorting to philosophy and speculation instead. He did not have the scientific knowledge needed to see the arc from the physical to the biological, a connection many have attempted but have failed to make — neither the Nobel Laureate Ilya Prigogine, in Order Out of Chaos, nor the polymath Michael Polanyi, in his essay “Life’s Irreducible Structure” in the journal Science, was able to show a direct relationship between physics and biology, concluding that the latter was too complicated. The essential data integrating biology and nature would not be available for another one hundred years, with the advent of molecular embryology. But we now have the scientific wherewithal to draw such conclusions.

I also tend to be philosophical, but prefer using the scientific method to support my epistemological claims about natural phenomena. I have spent decades trying to understand the principles behind human development as a basic scientist working in the field of neonatology, the clinical practice for taking care of pre-term newborns. My particular area of interest is in the development of the lung, because that is the “weakest link” in infant survival at birth. For example, in a case that received widespread public attention at the time, lung immaturity, originally known as hyaline membrane disease (now called respiratory distress syndrome), caused the death of the Kennedy baby, Patrick Bouvier Kennedy, in 1963. Just five years later, an observant obstetrician named G.C. Liggins was studying what triggers the birthing process; he thought that the hormone cortisol initiated labor, so he treated pregnant sheep with the hormone well before they would have given birth, discovering to his surprise that the resulting newborn lambs were able to breathe spontaneously despite being born prematurely. Liggins failed to determine how cortisol induced labor, but in the process he discovered that he could effectively accelerate fetal lung maturation. The use of cortisol to accelerate lung maturation in pre-term pregnancy marked a sea change in the practice of obstetrics and neonatology.

I have studied how cortisol affects lung development for my entire career because of the fundamental importance of such knowledge for both developmental biology and for human health. Finally, a decade ago, my colleagues and I had amassed enough information to formulate a working model of lung development down to its cellular-molecular components. It turns out that this process is determined by reciprocal leap-frogging interactions between cells from two different germlines, generating all forty cell types of the lung. When I stepped back and considered the biologic “histories” of these two cell types in forming the lung, I calculated the probability that this process occurred by chance — it would have taken longer than the existence of the universe, which was nonsensical. Alternatively, there was evidence that these cell–cell interactions had been caused by physical factors in the environment like gravity, oxygen, and ions that have also fashioned the lung and all of the other organs of the body.

That thought brought me back to Thoreau’s imaginings about his intimate, ancient relationship with the earth. His intent was to encourage us to reconnect mind and body, which had been philosophically separated by Descartes in the seventeenth century. Thoreau felt strongly that such dualistic thinking interfered with our ability to perceive ourselves as integral beings, at one with nature. So he went to Walden Pond to live his life “deliberately,” demonstrating by his actions that we humans have free will. We do not have to be condemned to “lives of quiet desperation” once we get in touch with our transcendent selves.

In a similar vein, my insights to human evolution stem from the work of others showing that life on earth began with snowball-like asteroids striking the earth in the absence of an oxidative atmosphere. Those snowballs formed the earth’s oceans, and contained lipids that coalesced as fat globules. Lipids immersed in water can form primitive cells, providing the origins of life, particularly when the moon started generating tides only 100 million years after the formation of the earth. It is well known that when lipids are wetted and dried they spontaneously form semi-permeable membrane spheres; imagine such lipids lying on the primordial shore, drying out at low tide and being wetted at high tide recurrently — life! It is thought that energy was eventually produced within such simple cells, in defiance of the second law of thermodynamics, by the process of chemiosmosis, which is sustained by homeostatic servo-regulation, the mechanistic basis for physiology. This unitary cell structure formed the basis for all of life on earth. The fact that it occurred spontaneously through self-referential, self-organizational principles is the biological origin and determinant of free will; the higher consciousness that characterizes intentional freewill is an epiphenomenon of this vertically integrated process. So, like Thoreau beseeching us to take personal responsibility for ourselves, I would argue that the possibility of freedom is in our DNA.

The main reason why I have been encouraged to amplify my cellular understanding of evolution is because it is predictive, which is the benchmark of science. The principles at work in the evolution of the cell and the cell membrane are the foundations of life that have been used recurrently in vertebrate evolution, most recently in the adaptation of fish to land, forced to do so because rising levels of carbon dioxide in the atmosphere caused a greenhouse effect, drying up the oceans. The weakest link in this chain of adaptive events was the lung, which evolved from the swim bladder of fish. But during this process there were periods when the evolving lung was inefficient, causing oxygen deficiency, or hypoxia, the most potent physiologic stressor known. This triggered the “fight-or-flight” mechanism by which the pituitary in the brain stimulates cortisol production by the adrenal gland, triggering adrenaline production. The adrenaline relieved the stress on the lung, and also stimulated metabolism by releasing fatty acids from fat cells, raising body temperature. The elevated body temperature on land was more efficient than being cold blooded, resulting in the evolution of warm-blooded mammals and birds. Importantly, hibernation has the opposite effect, reducing stress, cortisol, adrenaline, and body temperature, placing the organism in a trance-like meditative state.

In Walden, Thoreau describes his “morning work,” measuring the dispersal of seeds, the depth of Walden Pond, recording the first appearance of the local plant life, and the behaviors of animals and birds. But these activities are his entrée to the other-worldly, transcendent mysteries of his surroundings. He often finds himself in such a meditative state, allowing him to envision his place in nature and the universe. As a result, Thoreau’s experience at Walden Pond has a mystical quality to it:

Once, a few weeks after I came to the woods, for an hour I doubted whether the near neighborhood of man was not essential to a serene and healthy life. To be alone was somewhat unpleasant. But in the midst of a gentle rain, while these thoughts prevailed, I was suddenly sensible of such sweet and beneficent society in Nature, in the very pattering of the drops, and in every sight and sound around my house, an infinite and unaccountable friendliness all at once, like an atmosphere, sustaining me, as made the fancied advantages of human neighborhood insignificant, and I have never thought of them since. Every little pine-needle expanded and swelled with sympathy and befriended me. I was so distinctly made aware of the presence of something kindred to me, that I thought no place could ever be strange to me again.1

This spiritualism in nature raises the question as to whether there may be scientific evidence for such phenomena. In support of that notion, it has recently been found that the microbiome — the bacteria that inhabit our bodies — enters the soil and water when we are buried, forming the necrobiome. The necrobiome is predominantly composed of proteobacteria, which are present in plants, and animals, and in the gut, skin, lungs, and eyes of humans. In fact, the microbiome of the uterus is the source for the microbiome of the newborn, suggesting that there may be a path from one generation to the next via the bacteria that co-habit with us. How Zen. I think Thoreau would have liked the idea of going back to nature as a means of immortalization.


By: John S. Torday, William B. Miller, Jr.
4,922 Words

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“It is a country . . . with innumerable lakes and rapid streams, peopled with trout.”
— H.D. Thoreau, The Maine Woods

In the Beginning

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

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

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

Ouoroboros, an ancient symbol depicting a serpent eating its own tail. (Image by Abake, Wikimedia Commons).

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

The Advent of Multicellularity

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

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

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

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

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

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

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

Evolution, Cellular-Style

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

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

The Water-Land Transition and Vertebrate Evolution

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

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

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

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

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

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

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

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

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

The Cellular Approach to Evolution Is Predictive

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

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

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

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

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

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

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

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

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

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

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


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


By: John S. Torday, William B. Miller, Jr.
5,745 Words

Reproduced from:

We all know that Art is not truth. Art is a lie that makes us realize truth at least the truth that is given us to understand. The artist must know the manner whereby to convince others of the truthfulness of his lies.
—Pablo Picasso


Do you ever wonder why everything seems to be interconnected — humans, nature, planets, stars, the Cosmos? Life originated from unicellular organisms by circumventing the second law of thermodynamics using the first principles of physiology — namely, negentropy, chemiosmosis, and homeostatic regulation of calcium and lipids.2 The discovery of the first principles of physiology offers the opportunity to understand how and why we have evolved from the environment.3 By reducing developmental and phylogenetic processes to their cellular-molecular elements (which were ultimately driven by large-scale environmental changes), the causal relationships of “everything” can be more clearly envisioned, particularly when the mechanisms of homeostasis and dyshomeostasis (pathology) are superimposed. Viewing descriptive biology in the forward direction from unicellular to multicellular organisms, life’s physical and chemical processes can be understood logically rather than dogmatically. By understanding what makes us “tick” at this fundamental level, we can better realize how we fit in to the great scheme of things personally, societally, and as one species among other species.

Having made these observations regarding the integration of the animate and inanimate, why is human life full of deceptions, obfuscations, dualities, dialectics, cheating? There is no question that this is the case, as chronicled by Robert Trivers in his landmark book, The Folly of Fools.4 We would like to argue that deception is innate in the ultimate origins of humankind, so naturally it would pervade our existence.

In the Beginning

Life on Earth was spawned by the formation of the oceans and generated from frozen snowball-like asteroids striking the planet’s surface. The process is complex but chemically can be well understood. Those asteroids contained polycyclic hydrocarbons, which became suspended in these bodies of water. As the Sun warmed the waters during the day, these lipids liquefied, expressing their hysteretic property, which is a physical form of “memory.” The lipids deformed and reformed, ultimately generating protocells with semi-permeable membranes. Within these structures endomembranes partitioned positively and negatively charged ions, thereby creating bioenergetic flow. This electrical potential fostered negentropy, or the building of complexity, rather than the simplification of complexity within the cell in a process regulated by homeostasis. In the aggregate, this configuration of negentropy, chemiosmosis, and homeostasis constitutes the first principles of physiology, and the first niche construction.

Epigenetics and Niche Construction

As life thrived on Earth, it generated carbon dioxide, causing a greenhouse effect that warmed the atmosphere, causing waters to dry up, forcing some water-borne organisms to transition onto land, adapting to terrestrial life over eons. Two major characteristics that land life acquired — epigenetic inheritance and niche construction — were critically important for the successful adaptation to land. Epigenetic inheritance is the ability of the organism to acquire informational “marks” directly from the environment; niche construction is the organism’s ability to modify its immediate surrounding environment.5 When these two properties merge, this generates a dynamic capacity for the organism to interadapt to its environment, maximizing its likelihood of survival and ongoing evolution. And when niches impinge on one another and/or coalesce, they form networks for ever-expanding niches, ultimately covering the surface of the Earth. In the aggregate, this is the mechanism underlying the Gaia theory described by James Lovelock.

The Deception Proves the Rule

Robert Triver’s book The Folly of Fools shows that cheating seems to be pervasive in nature. Yet biology is founded on principles of cooperativity. How can these contradictory characteristics constitute life? This seeming paradox is a testament to the great prank that life has foisted on its physical environs, which behooves us to acknowledge this inherent sleight of hand in order to be true to ourselves.

There is an inherent fallacy engendered in our understanding the transition from the physical to the biologic. So many dualities, dialectics, paradoxes, and counterintuitive aspects encountered in human experience could be resolved by acknowledging this fallacy. The quantum physicist David Bohm in his book, Wholeness and the Explicate Order, wrote that we misperceive our physical reality because we experience our physical surroundings through our subjectively evolved senses. This leads us to think that living and non-living matter are ontologically different; we embrace the pervasive notion, for example, that we are machines. In fact, we are merely a mechanism for converting the physical into the animate, monitoring our ever-changing environment in order to be able to survive, thrive, and communicate knowledge from one generation to the next effectively.

Armed with this more informed perspective, many otherwise threatening and dogmatically understood aspects of our being could be comprehended instead as a continuum from our origins forward. In our previous works, we have redefined many terms in biology as mechanisms in service to biology — for example, natural selection, the cell, homeostasis, pleiotropy, heterochrony, and the life cycle. These insights enable us to see how and why we have evolved as an integrated whole, as an agent for collecting information from the environment, rather than as the result of random mutations, seemingly without rhyme or reason — no wonder people default to belief rather than science. Importantly, this holistic vision offers the opportunity to fully appreciate our ecology, ourselves, and all organisms as one grand scheme, as referred to in the opening paragraph of this article.

We could even formulate a periodic table of biology, integrating all of the natural sciences into one functionally predictive database. A similar realization that the Sun is the center of the solar system once fundamentally changed human thought and action. Likewise, a firm understanding of where we came from (ontology), and how (epistemology), would have equal if not greater impact on human thought. Prior to the recalibration of the Earth as one of the planets circling the Sun, autocrats and soothsayers had exercised power by striking fear in peoples’ hearts and minds through ignorance. But then came technological breakthroughs like the telescope and microscope, offering knowledge of our outsides and insides, respectively, that raised our sights and curiosity. And with the advent of the scientific method, we were enabled to “know what we do not know.”

Deception and Social Pathology

But the stigma of deception remains as a barrier to our fullest knowledge of who and what we are as a species. Deception arose from the very origins of life itself, “cheating” Mother Nature by circumventing the second law of thermodynamics, which states that free energy must disperse over time. By utilizing the first principles of physiology as a means of instituting self-organization and self-reference, life has been able to generate a mechanism distinctly different from the physical laws governing non-living matter and energy in the universe. In Wholeness and the Implicate Order, Bohm has stated that the end result has been two different realms: the explicate and the implicate. The explicate realm is the one we think of as reality, when in fact it is one of our own making, distorted by our subjective, evolved senses. The true reality, which Bohm refers to as the implicate realm, exists on another perceptual plane. This duality is what has led to the deceptions we are familiar with in the explicate realm, offering the opportunity to cope with the inherent paradoxes we encounter daily.

Our own physiology has equipped us with the ability to endure such duplicity, but the consequence of that is stressful — it stimulates the hypothalamic-pituitary-adrenal axis. In its optimal state, the stress reaction facilitates learning, offering the opportunity to dominate the circumstances and evolve novel structures and functions that mitigate and can even eliminate the source of the stress by evolving means of internalizing otherwise-toxic substances in the environment, metabolic cooperativity / multicellularity, endothermy / homeothermy — or what we think of as physiologic evolution. Ultimately, such adaptive strategies, in combination with niche construction and epigenetic inheritance, can lead to homeostatic balance, both physically and physiologically, at least for the moment. However, there are conditions that are not conducive to such harmonious outcomes. In human evolution, there are social constructs that are not conducive to homeostatic balance because they are predicated on false principles and produce social systems that are unable to integrate with their environmental surroundings, as Jared Diamond discusses in his book Collapse. Such conditions perpetuate stress, resulting in elevated levels of adrenocorticotrophic hormone (ACTH) and cortisol, causing physiologic wasting in the host and transgenerational depression in the offspring.

Conversely, if we were to be able to recognize the systematic problem in perpetuating societal deception, perhaps we could live in a more harmonious environment. Peter Whybrow addresses this in his book American Mania, seeing the pathology from the point of view of a social scientist. And this problem is becoming endemic and pervasive with the advent of computer technology because it feeds into narcissistic behavior that resulted from the deceptions in the first place. Dacher Keltner has pointed out that we humans are naturally cooperative in his book Born to be Good, which is based on experimental evidence.

Physiologic Stress

Before proceeding further, let us consider the evolutionary significance of stress in more detail. Hans Selye pioneered research on stress in his work on the physiology of the “fight or flight” mechanism.6 Stimulation of the hypothalamic-pituitary-adrenal (HPA) axis under duress is critical for survival, fostering learning under optimal conditions, but when over-stimulated it can also cause disease.

The evolution of this integrated mechanism is most apparent during vertebrate adaptation to land, when the adrenal cortex and medulla evolved into one structural-functional unit. Prior to that, these two elements of the adrenal gland were physically separate structures. The merging of these two components of the adrenal gland constituted more than just a physical change; it had a profound effect on physiologic adaptation since the microvasculature of the corticoid-producing cortex was continuous with that of the catecholamine-producing medulla. Under stress conditions, increased production of ACTH by the anterior pituitary stimulates corticosteroid production by the adrenal cortex; the corticoids produced by the cortex pass through the adrenal medulla, stimulating the rate-limiting step in catecholamine production, phenylethanolamine N-methyltransferase. Consequently, catecholamine production is increased, augmenting many tissues and organs necessary for adaptation to physiologic stress-vasodilation, increased lung function, and glycogenolysis / gluconeogenesis.

In a recent article, Torday attributed the evolution of endothermy/homeothermy in mammals and birds to this mechanism.7 Briefly, the lung evolved in a step-wise manner mediated by cell-cell interactions during the water-land transition in response to the increasing demand for metabolic drive. Periodically, the evolving lung would be inefficient for gas exchange, as evidenced by the fossil evidence for at least five independent attempts to breach land, suggesting a salutatory process of trial and error that would also have affected visceral organ development. That speculation is supported by research illustrating that when the parathyroid hormone-related protein (PTHrP) is deleted in the developing mouse embryo, it results in the failure to alveolarize the lung, calcify bone, and fully develop skin barrier function. The PTHrP-signaling mechanism was amplified during the water-land transition due to the duplication of the PTHrP type 1 receptor, likely due to the internal selection pressure for these specific tissues and organs generated by microvascular shear stress in adaptation to land.8

In parallel with their effect on the evolution of the lung, catecholamines would also have stimulated the secretion of fatty acids from fat cells in the periphery, increasing body temperature due to increased metabolism. This acute increase in body temperature would have been positively selected for since warm-blooded organisms require only one enzyme isomer per metabolic function, whereas cold-blooded organisms require several isozymes in order to accommodate their ambient environmental temperature efficiently. The former is much more energy efficient than the latter, favoring endothermy / homeothermy. This is consistent with the huge decrease in the genome of vertebrates in the post-Cambrian Burst era. We will return to endothermy again in another connection below.

Elsewhere, Torday has speculated that the evolution of endothermy in mammals and birds may have fostered bipedalism (both humans and birds are two-legged), since it takes more energy to walk on two legs than on four. The freeing of the forelimbs for specialized functions like flight and tool making would have offered positive selection for this cascade, putatively culminating in new and expanded behavioral and social possibilities for humans and birds.

Therefore, stress had a positive effect on vertebrate evolution. Yet too much of a good thing may lead to the law of unintended consequences. For example, we know that excessive myelination of neurons may lead to neurodegenerative diseases.9 And there may be long-term consequences of physiologic stress, causing transgenerational depression.

Ambiguities in Biology

We use the term “ambiguities” to denote the problems generated when biological science does not take sufficient account of the fundamental negentropic achievement of evolved life on Earth. For example, confusion arises if the cell is thought of merely as the smallest functional unit of life. It must be viewed in addition from the perspective of evolution, during which the achievement of the cell in biological organization constitutes the first principles of physiology. Like all matter and energy, life should have been constrained by the second law of thermodynamics, but the cell solved that problem — or worked around that constraint — by generating negentropy through chemiosmosis, regulated by homeostasis. It is those foundational principles that allowed for both sustaining and changing the phenotype when necessary.

A number of other ambiguities arise in biological knowledge that can be resolved through an evolutionary and thermodynamic perspective. These involve the concepts of homeostasis, aging, pleiotropy, life cycle, phenotype, and economy. In concluding the first part of this article, we will briefly review these in turn.

Homeostasis. Homeostasis is conventionally thought of merely as a synchronic (same time) servo-mechanism that maintains the status quo for organismal physiology. However, when seen from the perspective of developmental physiology, homeostasis is a robust, dynamic, intergenerational, diachronic (across-time) mechanism for the maintenance, perpetuation, and modification of physiologic structure and function. The integral relationships generated by cell–cell signaling for the mechanisms of embryogenesis, physiology, and repair provide the needed insight to appreciate the scale-free universality of the homeostatic principle. This offers a novel opportunity for a systems approach to biology. Starting with the inception of life itself, with the advent of reproduction during meiosis and mitosis, moving forward both ontogenetically and phylogenetically through the evolutionary steps involved in adaptation to an ever-changing environment, biology, and evolutionary theory need no longer default to teleology.

Aging. Organisms have survived because they have devised adaptive genomes that allow them to change in response to the ever-changing nature of Earth’s environments. This has come in the form of their reproductive strategy, which is optimized to generate the largest number of offspring suited for the environment into which they are born. This comes at a cost, however, because the energy of reproduction is selected to optimize the organism’s internal physiologic milieu. But that energy debt must somehow be repaid because the second law of thermodynamics cannot be violated — the first and second laws of thermodynamics state that the total energy content of the universe is constant, and that total entropy is continually increasing.

This assumes that there is a finite amount of energy during the life cycle. Leonard Hayflick has unequivocally stated that longevity is genetically determined, whereas aging is epigenetic. Therefore, by definition, there must be a finite amount of energy generated during the life cycle of any organism that is then distributed throughout the period between birth and death in response to selection pressure for reproductive success. As a result, the bioenergetics are optimized during the reproductive phase, followed by a progressive loss of energy during the post-reproductive phase of life, leading to the breakdown in cell–cell communication, aging, and ultimately death, as a result of the progressive increase in entropy. This mechanistic explanation for the process of aging is consistent with descriptive theories of aging such as the mutation theory, antagonistic pleiotropy, and the disposable soma.

Pleiotropy. Pleiotropy is usually defined as the random expression of a single gene that generates two or more distinct phenotypic traits. However, in contrast to this probabilistic conception of pleiotropy, it actually should be understood as a deterministic consequence of the evolution of complex physiology from the unicellular state. Pleiotropic novelties emerge through re-combinations and permutations of cell–cell signaling exercised during reproduction, based on both past and present physical and physiologic conditions, in service to the future needs of the organism for its continued survival. Functional homologies ranging from the lung to the kidney, skin, brain, thyroid, and pituitary exemplify the evolutionary mechanistic strategy of pleiotropy. The power of this perspective is exemplified by the resolution of evolutionary gradualism and punctuated equilibrium in much the same way that Niels Bohr resolved the paradoxical duality of light as complementarity.

Life cycle. Based upon observation, the life cycle describes the milestones of an organism through birth, infancy, childhood, adolescence, teenage years, adulthood, senescence, and death. Yet we know that there is a great deal of variability in these stages of life, both within and between species. Hominids have a protracted infancy and childhood, which is usually attributed to the amount of time required to form our oversized brains; neoteny is the process by which an organism retains its juvenile phenotype; longevity is highly variable, as exemplified by the Mayfly, which only lives for a day, and the giant sequoia, which lives for thousands of years. What should we make of this variability? Elsewhere we have laid claim to the idea that since the epigenetic marks acquired during the life cycle are not expunged during meiosis, their incorporation into the developing conceptus during embryogenesis is similarly a means of determining the “fit” of those epigenetic marks based on homeostatic principles. Based on that idea, why should we assume that the influence of epigenetic inheritance stops at the time of birth? Perhaps the phases of the life cycle are also a way of utilizing epigenetic inheritance.

Since the stages of the life cycle are determined by the endocrine system, that would be a place to look for the influence of epigenetics. As it turns out, epigenetics does affect the endocrine system, substantiating the fact that epigenetics affects the organism at all stages of the life cycle.

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

Resolution of the Ambiguities by Assimilating the Thermodynamic Deception

Thus far we have been examining the origin of the ambiguities in biology resulting from failing to acknowledge the deception of the second law of thermodynamics. Now we can move on to resolve many of the misunderstandings that have become dogma in biology.

The Cell as the First Niche Construction — Self-Organization Overcomes the Ambiguity
Niche construction nominally describes how organisms can form their own environments, increasing their capacity to adapt to their surroundings. It is hypothesized that the formation of the first cell as “internal” niche construction was the foundation for life, and that subsequent niche constructions were iterative exaptations of that event. (Exaptations are pre-existing characteristics that enhance the ability of a species to adapt to environmental change.) The first instantiation of niche construction has been faithfully adhered to by returning to the unicellular state, suggesting that the life cycle is zygote to zygote, not adult to adult as is commonly held. The consequent interactions between niche construction and epigenetic inheritance provide a highly robust, interactive, mechanistic way of thinking about evolution being determined by initial conditions rather than merely by chance mutation and selection. This novel perspective offers an opportunity to reappraise the processes involved in evolution mechanistically, allowing for scientifically testable hypotheses rather than relying on metaphors, dogmas, teleology, and tautology.

The Evolution of Endothermy; or, Self-Organization Overcomes Biologic Ambiguities. Only mammals and birds are warm blooded, or endothermic. How this trait evolved has never been explained based on an integrated physiologic mechanisms emanating from the ontogeny and phylogeny of visceral organs. A recent paper on the role of physiologic stress in the evolution of endothermy,10 based on the appearance of specific physiologic traits in birds and mammals, has provided such an explanation for the first time, as follows:

Conditional endothermy. It has been hypothesized that endothermy evolved as a direct consequence of intermittent hypoxia during the water-to-land transition. Briefly, based on fossilized skeletal evidence, vertebrates breached land several times thereby avoiding extinction in drying up bodies of water. Since our overarching hypothesis is that visceral organs evolved through cell–cell interactions, as the lung evolved from the swim bladder of fish there would have been stages at which the lung was inefficient, resulting in hypoxia; hypoxia is the most potent of all physiologic agonists, causing stress, stimulating the HPA. The net result would have been increased catecholamine production, which would have alleviated the constraint of the inefficient lung by stimulating surfactant production, increasing the distensibility of the alveoli and thus their surface area, increasing oxygenation acutely. Over time, this ad hoc response to hypoxia evolved into increased numbers of alveoli because stretching of the lung stimulates PTHrP, which promotes alveolarization of the lung. As evidence for this mechanism, PTHrP appears in the pituitary of mammals and birds, where it augments ACTH production. PTHrP also appears in the adrenal cortex of mammals and birds, where it augments the effect of ACTH on corticosteroid production. Corticosteroids produced in the adrenal cortex of mammals and birds stimulate phenylethanolamine-O-methyltransferase activity in the adrenal medulla, amplifying epinephrine production. As a note added in proof of the evolutionary amplification of the HPA by PTHrP, Richard Wurtman has shown that the microvasculature of the adrenal medulla is augmented in rats, increasing the surface area of the capillaries for corticosteroid amplification of the epinephrine production.

In tandem with the facilitating effect on air breathing, catecholamines also stimulate free fatty acid secretion by fat cells in the periphery, providing substrate for enhanced metabolism and increasing body temperature. Ultimately, the increase in endotherm body temperature would have been selected for since warm-blooded metabolism is much more efficient than cold-blooded. In order to metabolize efficiently, a cold-blooded organism requires several forms of the same enzyme to accommodate metabolism at different environmental temperatures, whereas endotherms / homeotherms only require one. This increased metabolic efficiency is evolutionarily advantageous in being much more functionally efficient.

The causal nature of the interrelationship among physiologic stress, catecholamines, and endothermy / homeothermy is validated by the reverse effects of hibernation or torpor on lung surfactant lipid composition and cell membrane fatty acid composition. Under such conditionally low stress conditions, decreased catecholamine production results in both increased surfactant cholesterol, rendering lung surfactant less surface active, and decreased unsaturated fatty acid content of cell membranes, adaptively reducing oxygen uptake. And there are commonalities among stress, endothermy / homeothermy, and hibernation and meditation, leading to thoughts about the role of these mechanisms in fostering higher consciousness (see below).

Constitutive endothermy. Ultimately, the endothermic phenotype became functionally integral to the organism. Recently, it was discovered that deletion of the oxytocin gene in mice inhibited their ability to thermoregulate, indicating that this hormone evolved to centrally regulate endothermy.

Stress-Induced Evolution of Endothermy
Stress-induced evolution of endothermy by step-wise changes in physiology predicts bipedalism, evolution of the avian and hominid forelimbs, and higher consciousness. It is noteworthy in the context of metabolic evolution that both birds and humans are bipedal, which may have been a consequence of their both being endotherms. Being upright is metabolically costly, but by increasing their body temperatures in adaptation to land, both birds and humans have become much more metabolically efficient; cold-blooded organisms require multiple isoforms of the same metabolic enzyme to survive at ambient temperatures, whereas endotherms usually have only one isoform. Bipedalism may have resulted, freeing the forelegs to evolve into wings and hands — the latter with prehensile thumbs — through common genetic motifs.

Allan Hobson and Karl J. Friston have hypothesized that the brain must actively dissipate heat in order to process information. This physiologic trait is functionally homologous with the first instantiation of life formed by lipids suspended in water forming micelles, allowing the reduction in entropy (heat dissipation). This circumvents the second law of thermodynamics, permitting the transfer of information between living entities — which enables them to perpetually glean information from the environment — that is considered by many to correspond to evolution per se. The next evolutionary milestone was the advent of cholesterol, embedded in the cell membranes of primordial eukaryotes, facilitating metabolism, oxygenation, and locomotion, the triadic basis for vertebrate evolution. Lipids were key to homeostatic regulation of calcium, forming calcium channels. Cell membrane cholesterol also fostered metazoan evolution by forming lipid rafts for receptor-mediated cell–cell signaling, the origin of the endocrine system. The eukaryotic cell membrane exapted to all complex physiologic traits, including the lung and brain, which are molecularly homologous through the function of neuregulin, mediating both lung development and myelinization of neurons. That cooption later exapted as endothermy during the water–land transition, perhaps being the functional homolog for brain heat dissipation and conscious / mindful information processing. The skin and brain similarly share molecular homologies through the “skin-brain” hypothesis, giving insight to the cellular-molecular “arc” of consciousness from its unicellular origins to integrated physiology. This perspective on the evolution of the central nervous system clarifies self-organization, reconciling thermodynamic and informational definitions of the underlying biophysical mechanisms, thereby elucidating relations between the predictive capabilities of the brain and self-organizational processes.

Cold Stress and DRD4-7, Out of Africa?
Peter Whybrow makes the case for the Dopamine Receptor DRD4-7 being the cause for primates migrating out of Africa, since it is associated with risk taking.11 At the time of the migration(s) out of Africa during the Pleistocene, the world was a lot colder than it is now and land masses were interconnected by ice bridges, facilitating human dispersal both north and east. Migratory behavior is of considerable biological importance because it leads to “gene dispersal” and reproductive advantage. “Out-migration,” or dispersion as the primatologists call it, is dangerous, but it opens up new opportunities. In most primate species some animals will ultimately leave the group of their birth and seek another habitat. Commonly it is the males, but for some — chimpanzees, gorillas, and spider monkeys, for example — it is the females. Most out-migration occurs in adolescence, when risk taking increases. It is important to understand that in most monkey groups the adolescents leave because they want to, not because they are driven out. There is a second factor that interacts with risk-taking predisposition of those who migrate, the competition for scarce resources. This is where social rank becomes important in determining which animals leave the troop. In bad times, when there is not enough food to go around, the high-ranking animals usually stay in place and the aggressive, lower-ranking animals are most likely to leave. Such dispersion does not happen regularly or in every generation, but when it does occur it has a major impact on future generations by weeding out the parent troop and potentially seeding new ones.

Numerous studies of migrant populations all over the world support Lynn Fairbanks’s conjectures that optimism, self-interest, curiosity (often described as restlessness or novelty seeking), and a vigorous ambition are the best predictors of emigres’ adjustment to their new environment. Studies show that ambition and optimism are more commonly expressed in the men than in the women who migrate.

During the Miocene 20 million years ago, a global cooling began, and it was under these challenging circumstances, as the food supply dwindled and competition for survival increased, that our direct forebears emerged from the Rift Valley in Ethiopia. We know from the fossil record and genetic studies that humans, gorillas, and chimpanzees all descended from common ancestors—small ape-like creatures, called hominids, that were distinguished by walking upright—who lived late in the Miocene period, some 5 to 7 million years ago.

Novelty seeking, curiosity, and impulsive behavior are interrelated. Fairbanks has found that the most impulsive, risk-taking males in her colony are those who have the lowest levels of the serotonin breakdown product 5-hydroxyindolacetic acid (5-HIAA) in their cerebrospinal fluid. (Serotonin modulates behavior, opposing the curiosity-provoking dopamine superhighway and the alerting drive of norepinephrine). In some individuals or subspecies serotonin only weakly opposes the dopamine drive, so they may not be genetically “programmed” for migratory behavior.

Jay Kaplan has found that those rhesus males who remain within a troop beyond puberty have higher levels of 5-HIAA in their CSF. In baboons in the Rift Valley, in whom dispersal occurs around puberty, there is an inverse relationship between serotonin levels and dispersal, again suggesting a strong role of dopamine drive in migratory behavior.

How Androgens Act to Reduce Ambiguities of Life
The sex ratio is defined as the number of males to females. At the time of conception the sex ratio is 4:1, whereas at birth it is 1:1 — which raises the question why three out of four males die in utero. There are two peaks of fetal demise during pregnancy, the first occurring at sixteen to eighteen weeks gestation, and the second during the peripartum period. The cause of excess male deaths during the peripartum period is largely due to the relative immaturity of the male lung, caused by the production of androgens in the male conceptus, delaying lung development. The earlier demise at sixteen to eighteen weeks is the much larger population of spontaneous abortions, which is also due to the production of androgens by the fetus, as follows. At this stage of development the maternal ovary produces progesterone that maintains the pregnancy. The progesterone, in turn, stimulates human chorionic gonadotropin (HCG), which is produced by the placenta and stimulates development of the fetal gonads. The fetal testis and ovary synthesize androgens in response to HCG, which pass from the fetus to the mother via the placenta. Androgens can inhibit progesterone synthesis if they are produced in too large an amount, causing the abortion of the fetus. This mechanism prevents the development of a fetus that produces large amounts of androgen, causing fetal overgrowth, which endangers the life of both the conceptus and the mother at birth because the fetus cannot pass through the birth canal. So we see here an example of how the sex steroids are being used as a failsafe mechanism for reproductive health. Androgens inhibit serotonin, thus increasing dopaminergic activity in the brain.

How Art Resolves the Deception of Life
When we view works of art, we often find solace or escape from reality in the content because it is evidence that there is logic, or truth, in nature. This is because the artist is providing a way of seeing reality in ways that are self-organizing and self-referential, much like our biologic origins. The artist who painted the first cave paintings in Lascaux, France, was probably telling a story about the hunt, providing a rationale for life. The use of techniques in painting that encourage the viewer’s eye to come full circle in appreciating the content of the work, for example, giving one the sense of an integral whole. So art encourages us to think that there is harmony in the universe, if only we could see it.

How Music Resolves the Deception of Life
Music similarly teaches us that there is harmony in the universe, like Gustav Holst’s “music of the spheres.” Again, we find refuge here but fail to find resolution outside of the musical construct. Instead, at least for us, it was encouragement to think that perhaps science could resolve this ambiguity. We realized biology is a deception, cheating nature by circumventing the second law of thermodynamics, which provided deep insight into the fundament of life as a pseudo-physical construct. Many physicists have tried to understand this interrelationship, but have failed. For instance, Ilya Prigogine’s assessment of life’s irreducible complexity concludes that biology is too complicated to define.12 In contrast to such attempts to understand biology by analyzing it in its present synchronic form, we have approached the question of the mechanism underlying evolution by starting from its cellular origins, moving forward in biologic time diachronically, factoring out time and space to reveal the absolute nature of the process. This is analogous to the physicists viewing the universe as having originated from the Big Bang, and understanding such phenomena as the patterned distribution of the elements and the cosmic microwave background, with the formation of black holes and supernovas as a result.


Understanding life as cognitive dissonance vs scientific principles. Most of hominid history has been dominated by myth making. It is only in the last five hundred years that we have begun to emancipate ourselves intellectually using the scientific method as a way of “knowing what we don’t know.” The use of science to leverage truth is a powerful weapon against the deception built into our DNA. The mere fact that creationism has held sway over evolution theory speaks to the fact that there is currently no scientific evidence for the latter, so the debacle comes down to one belief system versus another.

We must be able to address evolution theory using scientifically testable and refutable methods. We have proposed a cellular-molecular approach for scientifically determining the evolution of vertebrate physiology based on cell–cell communication. Thus far, we have used this approach to redefine a series of otherwise dogmatic concepts in biology — the cell, homeostasis, heterochrony (a change in the timing of development), pleiotropy, phenotype, and life cycle — successfully to show the value added in understanding these processes mechanistically rather than descriptively. Moreover, we have experimentally demonstrated the developmental and phylogenetic properties common to amphibian and mammalian lung, hypothesizing that leptin evolved as a cytoprotective mechanism against oxidant injury. Since evolution is a structurally and functionally linked series of exaptations, it was predicted that leptin would have the same effect on the amphibian lung as it does on the mammalian lung. Cell–cell communication will reveal the same evolutionary mechanisms for all of physiology, given that it can be traced back to the unicellular eukaryotic state using cholesterol-related traits as the common denominator to vertically integrate physiology.


By: William B. Miller, Jr., John S. Torday
5,791 Words

Reproduced from:

Whereat some one of the loquacious Lot—
I think a Sufi pipkin—waxing hot—
“All this of Pot and Potter—Tell me then,
Who is the Potter, pray, and who the Pot?”
—Omar Khyyam, Rubáiyát, LXXXVII


In a previous article in Minding Nature, “From ‘Egosystem’ to ‘Ecosystem’,” we discussed the origins of deception in biology from discrete physical conditions that are rooted within thermodynamics and cellular / molecular interactions.13 There is, however, another aspect of biological systems that must be explored to understand the origins of the pervasive deceptions in biology that are so much a part of our daily human behavior and relationships. This additional contingency is the problematic nature of the information upon which biology depends.14

All living organisms, including all cells and microbes, receive, communicate, and deploy information.15 However, as opposed to the inanimate realm of water or rocks, the living circumstance imposes some important restrictions on the ability of any organism to receive and assess any communicated information. In biological contexts, all information is inherently noisy and ambiguous.16 Any communicated information is subject to degradation by distance, time delay between delivery and receipt, and distortion by the medium of transmission through which it must travel as a signal of one kind or another. This obligatory limitation is the source of an ingrained dilemma within the living condition. Although life can be properly defined as the ability to actively use information directed toward communication and problem-solving, the reliability of information upon which it depends is always uncertain.17 When it comes to the use of biological information, ambiguity rules, and thus it is not surprising that deception is a prominent tool within a biologic system in which reality can never be assessed with precision.

There is also another pertinent aspect of this informational insecurity. As any living organism conducts its life, it is obliged to influence its environment. It necessarily leaves a trace of its impact on that environment through its own use of information.18 So all organisms, by their actions, alter their environmental information space, which represents the totality of the sources of information available to themselves or others. Any action or communication by a living thing changes the information value available to others within their contextual environmental space. Therefore, it is an essential reality that each organism is very definitely “of” the environment and not merely “in” it.19

However, the obligatory impact on the outward environment that is caused by any organism using information carries another codicil. Every living organism assesses information as a unique observer / participant within its own self-referential terms. So any time an organism passes information along it also communicates an interpretation of that information. Information is now filtered and changed. As a result, like a vast game of “telephone,” the quality of the communicated information sent and received is degraded by this subjective and idiosyncratic evaluation. Unavoidably, any living organism reciprocally communicates and casts informational cues into a shared environmental space. The result is that biological information is unalterably rooted in uncertainty from all sources. Since this is true for all living entities, humans must cope with a constant stream of ambiguous information. Our contention is that this conditional circumstance governs our human choices and social interactions, and so it underpins the origins of human culture.

The Grand Conceit

All organisms that can be seen with our eyes (multicellular eukaryotes) are collective organisms representing a vast collaborative partnership of microbial life and innate cells. These collective forms of life are termed hologenomes or holobionts.20 This is the case with the human microbiome as well, where the fraction of our total selves that is microbial in origin is currently estimated to be ten times greater than our innate “human” cells. Furthermore, the total amount of the genetic material within that microbial fraction is currently estimated to be at least one hundred times greater than our own eukaryotic cells. This microbial life is not merely appended. It is vital to our metabolism, our immune systems, and our survival.21 It has also recently been demonstrated that our microbial fraction significantly influences a range of behaviors and phenotypes that include our moods, appetite, circadian clock, satiety, and body weight. Therefore, our actual cellular makeup is best understood as a vast, interconnected system of collaborative, cooperating, co-dependent, and competitive mixed cellular ecologies. Although we feel ourselves to be a singular entity, we are decidedly not, and this is our greatest illusion.22 As Richard Schloss has so aptly put it, life on this planet is a “biotic arc of ‘we.’”23

The reason that the illusion of oneness can be sustained is that it is the nature of all the individual cells that form our cellular ecologies, such as our gut or respiratory system, to work together. It is the willing collaboration of each of these cellular / microbial ecologies that permits our body as a completely cellular entity to function as a seamless entirety. The organic glue upon which this is based is a few essential principles of cellular co-existence: cooperation, co-dependency, mutualism, reciprocation, and balancing competition. And importantly, all these mutual arrangements are driven by communication between and among cells.24 Therefore, it is not accidental that this collective form of life is the exclusive manner by which all visible organisms are formed. The reason is that ambiguous information from the environment is best assessed through collective cellular appraisal.25 Biological information is imprecise. This leads to stress, at all levels and scales. The collective form of cellular life that we represent is the best solution. Life is a unique type of information management system.26

Information and Our Cellular Selves

As ecological collections of cells control our physiology and cognitive capacities, our human perceptions of any stimulus must necessarily be based upon both physiological and cognitive systems through their inter-linked cellular actions. We and all other organisms use both our reason and our physiology to make the best of available information. Yet it seems as if we have an unconscious awareness that our sense of singularity is an illusion and that cellular communities underlie our living circumstance. We readily acknowledge that our rational thoughts are not necessarily reliable and can be misleading. It is not uncommon for our decisions to be guided by something other than our overt mental processes — for example, an instinct, an amorphous presentiment, or a “gut feeling.” Somehow, we know that our physiological mechanisms can intuit informational signals that our cognitive faculties have not quite discerned. As humans, all our faculties are used to assess information and attempt to overcome deceptive signals and background noise.

It is this dualistic approach to all sources of information, through both cognition and physiology, that energizes our exceptional human extension into collective information space. Our human expression of the exploration of that shared information is the visual arts, music, liturgy, and literature. The same impulses also govern economic practice and political interplay. Together, all these interpolate as our complex cultural fabric. In this way, humans use culture and its norms as one method of trying to impose a sense of predictable order to the analysis of complex sets of information in which meaning can be quite ambiguous. We use both our cognitive capacities and our physiological reactions to best assess our uncertainties. Research indicates that many species other than humans do the same.27

Up until now, the origin of culture has been assumed to operate within a Darwinian framework of natural selection from which social selection emerges as societal constraints.28 Instead, we suggest that the origin of the creative impulses that lead to culture and strongly influence human social behavior are grounded within the biological architecture of cellular being. By that obligatory architecture, we are forced to analyze information, the quality of which is always equivocal, in a distributed manner. The human expression of that predicament is to organize ourselves to try to make the best of our individual uncertainties through collective guideposts in our struggle to evade persistent stress. Social behaviors and many of our cultural proclivities are our best means of dealing with the uncertain information that reaches us from an agitating environment.

The Origins of Deception

The analysis we have offered is reinforced by the work of quantum physicist David Bohm. Since information is biology’s common currency and communication is its means, a root paradox arises. In his book, Wholeness and the Explicate Order, Bohm argued that it is our inherent nature to misperceive physical reality.29 Our experience of our physical surroundings is a subjective one in which our evolved senses offer a range of potential interpretations of information. He discussed this subjective phenomenon in terms of a series of superimposed “implicates” (directions an organism might take) as a range of unexpressed further potentials. Eventually, these must resolve into “explicates” as the actual expression of that prior range of possibilities becomes a particular action, function, or form. However, the crux of the paradox is that any implicate that yields explicate action also creates a new set of superimposed implicates. In such circumstances, any notion of fundamental reality is merely an illusion, and information is as likely to be deceptive as it is to be reliable. This produces a condition of stress, to which we will return below.

The problem further compounds when the intent is to transfer information between generations, as any parent might attest. Therefore, it is not paradoxical that deception is one of life’s conditions; deception is the inherent circumstance for all biological organisms. Deceptions, dualities, and cheating are a part of the panoply of uses to which information can be put and affect how it might be interpreted. In The Folly of Fools: The Logic of Deceit and Self-Deception in Human Life, Robert Trivers insists that deception is overwhelming in biology as a primal impulse toward self-deception.30 In his view, an organism first deceives itself to better deceive others. However, when life is properly regarded within its obligate circumstances as a living entity that must use information, we can push Trivers’s perspective one step further. Given the imperfect nature of information, no matter the intent of the user, an inherency of deceit is simply the conditional circumstance of life that depends on information.

Being Human: Stress, Ambiguity and Risk-Taking

All organisms use whatever information they have to the extent to which they are able. Many animals have a well-developed capacity to seek to relieve some stresses at the expense of imposing simultaneous fresh anxieties on others. This is more than mere impulsive behavior, however. Within Bohm’s construct of reality, which is composed of both superimposed implicates and realized explicates, a fundamental truth follows. There is no basis in biology in which any form of permanent relief from stress can be expected. Any range of implicates that can be settled into explicate action merely serves as the originating source of a differing set of renewed conflicting implicates with their own stresses. Any problem that is solved and dispatches one set of issues inevitably creates new opportunities or constraints. Either can be stressful. From the perspective of an information system, nothing is ever completely settled.

Therefore, it can be reasonably argued that this permanent reality underscores the impulse for the restless wandering of many species and which is particularly exemplified by humans. Since — in the terms of information management — one set of solutions simply yields a new set of uncertainties and stresses are met with both rational consideration and physiological set-points, it is natural to expect that there are inevitable biochemical responses to this situation. Indeed, it has been found that behaviors based on uncertain information leading to induced stress are physiologically mediated.

In most primate species, some animals will ultimately leave the group of their birth and seek another habitat. Commonly it is the males, but for some species such as chimpanzees, gorillas, or spider monkeys, it is the females. Most out-migration occurs in adolescence when risk taking increases. Robert Rose and colleagues noted that in most monkey groups, the adolescents leave volitionally, not because they are driven out.31 The initiating factors are ascribed to the risk-taking predisposition of those who migrate, competition for scarce resources, and social rank. In competitive circumstances, when environmental conditions deteriorate, the high-ranking animals usually stay in place and the aggressive, lower-ranking animals might leave. The migrating few explore new opportunities, incur new risks, and learn about their limits. Although such actions have complex causes, physiology has a dominating influence. When a new social group is formed in rhesus monkeys, the alpha dominant male shows a progressive increase in plasma testosterone.32 The newly subordinate males show a drop in testosterone that can be as much as 80 percent from baseline levels for the lowest ranking member. In rhesus monkeys, optimism, self-interest, restless curiosity, and ambition are the best predictors of emigres’ willingness to test the environment, explore their place within it, and deal with the insistent stress of ambiguities. Those that do leave are the subset willing to accept new information and its uncertainties in order to get away from the imposed cultural deceptions that nonetheless brought some limited order to their anxieties. However, these characteristics are specifically related to plasma testosterone levels that are, in part, attendant to status levels in hierarchical social groups. Exploration is a highly correlated response to uncertain status within a social network and its linked physiological consequences. In effect, uncertain information — such as from uncertain status and its anxieties — leads to behaviors that express as physiological changes. These changes can self-reinforce in ways that lead to new actions and differing anxieties. In short, the processing of information leads to a cycle of physiological augmentation that yields consequences well beyond the initiating behaviors.

Since all primates share most physiological pathways, we should expect that it is much the same for humans. Therefore, human cellular physiology not only permits us the opportunity to explore, but impels us to do so. Humans are a restless species with an exceptional capacity to adapt to a range of climates despite our otherwise limited physical gifts. We meet our own particular range of uncertainties in our own species-specific manner through an unusually flexible system of cultural adaptations to stress. Those faculties are used to explore the outward environment, but also to conduct an inquiry of our own inner terrain. Combined, these constitute our “information space.” Our explorations and inquiries are part of our constant search for an enhanced connection to our truer selves beyond any ambiguities that we confront. Our aggressions and impulsive risk-taking are tools for the exploration of the limited information that we can receive and assess in the furtherance of those deepest aspirations. Therefore, humans confront informational insecurity through cognitive capacity, which is deemed “reason,” and through our physiology, which is regarded as “animal instinct.” Indeed, both serve our predilection to explore our equivocal circumstances. But there is always an invariable and inevitable catch. Every new resolution of uncertainty in one sphere becomes its own new series of potential uncertainties and renewed anxieties in another. This represents our own obligate loop of perpetual recursive causality as an endless series of reciprocating causes and effects. One thing settled always leads to the next reaction. Any settled set of implicates becomes our evanescent “Truth.” But in most cases, we are only momentarily deceived, then disillusioned, and so we must begin again in a reciprocating cycle of recursive causality, which we see in the artistic mode of music. It is our permanent human condition.

Being Human: The Search for Unambiguous Truth

Humans are not the only creatures that deal with information in a skeptical frame. But, through our specialized discernment and skills, we have become a special case in its applications. Apart from the unique advancement of the scientific method, humans are separated from other species by our exploration of information space through the supplemental agencies of the visual arts, music, literature, liturgy, and economic and political systems. We shall discuss each of these briefly in turn.

The Search for Truth through Art’s Visual Deceptions

Unlike any other animal, humans view works of art with both cognitive associations and visceral feelings. It is common for us to proclaim our physiological reaction to one piece of art versus another. What might be an idealization of beauty or an imparted sense of inner completeness to one can be a source of agitation for another. For some individuals, a particular painting, sculpture, or photograph might enable a fleeting escape towards a new “reality.” For others, art conveys a sub-rosa evidence for logic or some ineffable truth in nature. Whatever the particular reaction, the universality of art across time and all cultures has ancient beginnings. These sensibilities were as true for the early human that created petroglyphs as for any modern abstract artist. Given this enduring expression of our humanity, it can be argued that this act of artistic creating and recording is one resonating format for addressing the ambiguities of being alive. This self-organizing and self-referential action becomes a connection to our deepest selves and thereby acts at all levels of the human emotional range. It does so by technical sleights-of-hand. For a painting, the viewer must imagine three dimensions when there are only two, and in so doing, the content of the work becomes an integrated artifice. Perhaps art’s universal appeal through this contrivance is that we are encouraged to suppose that there is harmony in the Universe if only we could see it. As the magician Marco Tempest put it, “Art is a deception that creates real emotions — a lie that creates a truth. And when you give yourself over to that deception, it becomes magic.”

Music and Universal Harmony

There may be no other art form that so explicitly exemplifies our exploration of information space as music. At first, we crave the familiar, the reliable. Soon, that becomes trite. Instead, we insist on new ambiguities with unfamiliar rhythms and cadences. This becomes our delight and then, in turn, even that becomes old, and the next musical form is required. It is an exact example of the phenomenon of recursive causality, in which dissatisfaction with one form of music leads to the next, inevitably resulting in an endless loop. Yet through the reiterating discourse of repeated harmonies, music beguiles us into a belief that there is larger harmony in the Universe despite our anxieties. Harmony in music whispers an unseen order amidst turbulent uncertainties and hints of humming hidden coherences. After all, any piece of music has a discrete beginning and always has an unambiguous end, and it may be that our satisfaction with music is that it is so unlike the uninterrupted stresses of our actual lives.

This does not imply that music does not have its own ambiguities. Through its differing meaning to each listener, music functions at both our rational level and through our emotions. G. F. Miller insisted that music is a universally distributed biological adaptation that must have been “too complex to have arisen except through direct selection for some survival or reproductive benefit.”33 The Darwinian frame is assumed. Even Darwin himself considered music an explicit example of mate choice shaping a behavioral trait.34 Yet it need not be so. Instead, one can argue that its universality is through its purchase on our instinctive selves as an echo of our eternal disquiet with our own equivocal form: singularities that are not, collaborative enterprises unsensed, and boundless ambivalences. The allure of music is that it transports us. In some transcendent manner, through music, we are permitted to explore our personal unknowns by imagining new places and fresh outcomes. Even so, the deceptions remain when the music stops. Yet, at least for some, there are joyful, ephemeral feelings of oneness with the outer Universe. Through the jubilance of music and its appealing endorsing structure, we simply feel our existence within a universal harmony in which we have been granted temporary, even if fanciful, resonance.

Sacred Rites, Rituals, and Our Uncertain Place

There is a central belief that Man originated in the Garden of Eden as an ideal world. The bite of the apple was Man’s introduction to knowledge. In an instant, he was immediately self-aware. The Bible asserts that it was through that pivotal, self-referential moment that man’s anxieties and doubts began. Yet it was not merely that Man became imperfect in that instant, but that the world was revealed to Man as itself imperfect, with entwining joys, sorrows, and impermanence. That complexity is reflected in Ecclesiastes (1:18): “For in much wisdom is much grief, and he that increaseth knowledge increaseth sorrow.” It is clear that the power of sacred rituals, observances, and rites rise from a universal desire for an unassailable connection to Oneness in the promise of an eventual release from uncertainty. Each of us is forced to confront our frailties and doubts and the deceptions of others while contending with inconsistent sources of information that are open to wide interpretation. For some, faith and its comforting practices are their answer to these stresses. For believers, it is their search for their vital center through secure knowledge. Yet devout believers or not, we all share in a binding enigma of doubt, vulnerability, and precarious awareness, and we arrive together at only one aspect of enlightenment: much is uncertain.

Literature and Deception: Truth and Untruth

Well, then, it is settled,” is a familiar phrase in literature and movies. Our human bias encourages our belief that a range of choices may be put to rest by choosing one course of action over another. The fallacy of that assumption is always apparent. Every action taken, any explicate enacted in Bohmian terms, becomes a fresh panoply of choice as renewed implicates and potential outcomes. There can be little doubt that through thousands of years of oral history and written literature, this has been a primary means by which we come to terms with those doubts. Stories are one of our powerful means of exploring information space without the actual risk of failure. In novels, plays, or movies, the protagonists wander for us or risk their lives, egos, and comforts. We are encouraged to follow and imagine ourselves within their unfamiliar circumstances. Clearly, any such journey is a conceit. But, quite willingly, we suspend our ordinary judgments and permit the deception. It may be that we all subliminally discern what Jane Austin observed in Emma: “Seldom, very seldom, does complete truth belong to any human disclosure; seldom can it happen that something is not a little disguised or a little mistaken.” We glean satisfaction in the creative, though safe, choice of ambiguity and all its potential variants toward discrete resolution. It serves its important purposes. It is a pleasurable cheat against the actuality of our condition, in which there is never any final resolution in our own lives. It provides a service as a trial exploration of our own doubts, limits, infirmities, and imagined strengths. For a time, we are transported beyond our uncertain existence. Through the deliberate artifice, somehow, we fathom what the physician and novelist Khaled Hosseini rightly remarked: “Writing fiction is the act of weaving a series of lies to arrive at a greater truth.”

Deception in Economics and Commerce

There is probably no human engagement (other than politics) that better exemplifies our anchoring roots in the cellular form or our ambiguous circumstances than our economic interrelationships. It is now known that bacteria lead complex social lives and display cognitive behaviors demonstrating memory, learning, and anticipation.35 Microbes exhibit an extensive array of cooperative behaviors, including group motility, layers of multicellular structures, and the consensual production of extracellular public-goods. These aggregated activities even include the active policing of non-cooperating defector cells. Each of these mechanisms reinforces cooperation. Its level of sophistication is such that it can be modelled in the same manner as trade between merchants.36 At their scale, microbes exhibit behaviors that have been closely likened to the economic principle of Structured Comparative Advantage. Many other organisms do also. It has been observed in plants, insects, fish, and mammals.37 Among microbes, these behavioral comparisons are exact enough that their trading patterns of essential resources are quite analogous to how countries exchange goods and services in modern economic markets. The similarity is so great that a biotic model of general equilibrium theory (GET) derived from human economics can be used to predict the population dynamics of trading microbial communities.38 Since it is known that microbial deception abounds, there can be no doubt that it is also represented in how trade is conducted through this universal model.39

In American Mania, Peter Whybrow notes that a dynamic tension always exists between innate desires and social learning, and it is clearly represented in human behavior.40 In turn, this complex interplay undergirds our social agreements, myths, and every aspect of culture. Whybrow asserts that this operates beyond our instincts for personal self-preservation and, instead, subordinates to “competitive collaboration” with others. A market economy can emerge from this dynamic in which trade flourishes through the give-and-take of social interaction and the internalization of conventions and customs. When examined in this frame, economics becomes an excellent example of basic cellular principles writ into commerce: order as self-organization, communication as an echo of cell–cell communication, protection from unpredictable outcomes as the principle of homeostasis, and self-interest as a manifestation of self-reference. These are together deployed to sustain any cell, but also as a means of forming a common barrier against deception. This actualizes in the multicellular form, such as ourselves, to liberate the common good at our scale. Even so, we are well aware that deceit is ever-present. In human commerce, there is a transparent impulse to diminish ambiguity through contracts, agreements, and formal understandings between participants.

Whom Do We Serve?

Each organism connects with information space and the outward environment through its own means. The individual judgment of any organism is always subjective, and the line between reality and dissimulation is not necessarily stark. Therefore, any attempt at discrimination between truth and fiction requires some general sensibility of where reality lies. Put differently, cheating and deceit require a baseline sensibility from which deception can skew. To be recognizable as deception, some things must be consistently reproducible to the extent that they can be a trusted pattern, even if not any absolute objective reality. Properly considered then, both fidelity to reality and duplicity masking reality are best understood as dual aspects of a shared information space. From this, it is plain that each must be considered useful aspects of our human societal requirements. If society had nothing to grip as social convention and individuals were absolutely overt in their opinions to everyone whom they met, society would promptly disintegrate. Therefore, biological deception serves abundantly. It is a part of our societal and personal toolkit that enables us to persist and collaborate. Therefore, deception is no unalloyed negative and is partially contributory to our happiness and survival.

Certainly, information has no intrinsic coloration on its own. Deception is simply one variational facet of a complex information space. What is duplicity to one entity can be truth revealed to the next. For example, the cheater at cards need not be duplicitous to all at the table. If one player recognizes the deception and becomes aware of the sham, then the potential arises that the cheater becomes his unintended tool. Therefore, deception is simply another form of context-dependent information. From this, it can be asserted that overt deception is not biology’s primary problem. The greater issue is the ambiguity that fostered it. Since information is pervasive, the substantive problem is this: what is noise, and what might be actionable input?

Many physicists have tried to understand this interrelationship. Ilya Prigogine, Michael Polanyi, L.L. Whyte, and others have tried. Prigogine and Isabelle Stenger’s assessment of life’s irreducible complexity in their book, Order Out of Chaos, concludes that biology is too complicated to define.41 However, a consonant biologic order can be identified if the conventional frame of reference is willingly changed. Biology must be analyzed from its unicellular origins42 and then, forward through time, as continuous responses to information governed by cellular processes.43 No matter our sensibilities, we emerged from unicellular roots and remain ever anchored within that cellular domain. That is the conditional deception in which we exist and with which we must always cope.

Throughout our human journey, there has always been one consistent existential question: What is our place? Clearly, this aspect of our condition has received obsessive attention in philosophy, art, and religion. Yet there is an equally compelling imperative that is less explored. Whom do we serve? Through contemporary scientific research, a direct answer is available. We serve our self-referential selves. However, to properly understand what that exactly means requires an understanding that the epicenter of this self-referential frame is not imbued within our personal notion of our singularity, our entirety. On the contrary, it is ever and always invested within the collective cellular whole that we represent. Through this perspective, our living circumstance condenses to cellular information sharing through cell–cell communication to resolve ambiguities at every scope and scale. Cells at their level certainly serve themselves, but do so within the constraining embrace of a co-dependent mutualism.

What, then, should we make of ourselves, our narcissism, or our gifts? Is it all egotism, or might there be purpose? For our present moment, there is no exact answer. However, art, music, politics, and commerce are our expressions of our directed search for exact information within our constitutive ambiguity. Each can be seen as both living touchstone and requisite attachment with our distant, but permanently connected, past. And by these means, we are privileged to direct our specialized gifts in a continual search for Truth as best as our condition permits.

Our attraction to art, music, literature, or liturgy therefore serves our condition. Each is an expression of our attempt to explore information space, and through that, to better comprehend the limits of our full range of possibilities. Through this process, our imaginings signal how potentials might fold into eventual actions. Each art form, as a creative endeavor, expands our wonder. It asks this: how might we deal with alternative stresses? Some might call this role playing, but it is a means of pre-sorting ambiguous information to allow for more certitude when those circumstances arise. Many organisms can predict, such as bacteria, amoebae, or plants.44 Anyone who owns a dog knows that a capacity to predict is distributed. Humans do this more. And we not only predict, but pretend to predict, in a further attempt to pre-categorize ambiguity. It has only been roughly two hundred thousand years since modern humans began, so it should not be surprising that humans are not necessarily good at this form of stress alleviation. Perhaps then, given this limited capacity, our human proclivity for psychoactive drugs can be understood. We share an impulse to expand our limited skills in meeting uncertainties and their stresses. It may even be true that this same impulse links us to our creativity. Perhaps this is why Coleridge is said to have used opium while creating his poetic masterwork, “Kubla Khan.45

When we knowingly accept artifice and permit ourselves to remain within its alluring grasp, it becomes its own form of self-referential guidance. Through it, we attempt to deduce our place in the Cosmos, to somehow grasp our connections with the outer Universe through the invisible threads of our evolutionary journey. We use art, music, literature, and liturgy in an attempt to understand the disquieting range of ambiguities that underscore our circumstances and that are, simultaneously, our anxieties. Our aim is to try to discern, at little risk, a personal set of potential actions toward the unknown through the creative agency of Art.

How then might we stand in apposition to the primal place of the inherency of deceit?

Bernulf Kanitsheder has speculated that the Cosmos is a universe of multiverses in which the concept of position may have no well-defined meaning.46 In any such array of multiverses, the concept of position collapses without any aligning spatial organization. What is our place if that is so? Instead of frustration or despair, our reaction should be to take instruction from our own cellular being as collaborative ecological architectures. We can look inwards toward those cellular principles under which we thrive. Cooperation, co-dependency, mutualism, reciprocation, and balancing competition must be our means. Our resolutions should always be toward reducing surprise (unpredictable outcomes) as much as possible without taking away our proclivity to continue exploring and taking risks. How might we achieve that difficult balance? We can follow the rules of our own cells through the maintenance of order (negentropic self-organization), abundant communication and information flow (chemiosmosis), a commitment to the protection of the environment (homeostasis), and the continuous reinforcement of life-centered individual identity against subordination by others (self-reference). These are the sustaining principles under which cells have flourished since life began. These are the rules by which we came to be. These should serve as societal guideposts and our guardians against hubris.


All living organisms depend on the assessment and deployment of self-referential information that must be received and transmitted through a variety of mediums and contexts, each with its own inherent time delay. Therefore, the fundamental aspect of information within the living condition is its imprecision. In consequence, the origin of biological deception is a direct facet of a biological information space that is inherently ambiguous. As this situates all organisms within the uncertainty of subjective and context-dependent circumstances, the living condition is one of continuous stress.

Evolutionary research has confirmed that all complex organisms emanate from cellular roots. Further, too, all reiterate through a single cell stage for reproduction. Despite outward appearances, every complex organism remains perpetually attached to an inherent cellular narrative as an intimate co-alignment of mixed cellular ecological units. We are cellular beings, and ever remain thus. Our range of unique human behaviors are therefore derivative, whether manifested as impulsive risk taking or artistic expression. All such human endeavors are our means of exploring a catalogue of necessary information within an obligatory circumstance in which the information upon which we must rely is always equivocal.

Yet, within this complexity, there is hidden unity. Our illusion of singularity depends on the transitory but inseparable conjoining cohesion of all our linked cellular ecologies. And from this emanates the largest Truth: we and the environment are entwined self-similarities. The environment that matters most is not without, it is embedded within our own natural being. And our only sure Truth is our own impermanent and ambiguous transit through this intimate and reciprocating dimension.

Why then is life full of deceptions? At all points in time and for every organism within the informational system that biology represents, the predominating driver is not just access to information, but an active assessment of its inherently equivocal context and quality. Biology’s continuous drama is the struggle to settle a range of unknowns into forms of information that are discretely recognizable as secure. Those actions that sustain us must always travel along that path. It is our simple plight that nothing need be as it seems and, in consequence, our survival is an unceasing battle to overcome inherent untruth.

Author, Physician

William B. Miller, Jr, MD is a physician, evolutionary biologist, and lecturer on the new science of the hologenome and the impact of the microbial sphere on evolutionary development.

Professor – David Geffen School of Medicine at UCLA

John S. Torday, MSc, PhD, is a Professor of Pediatrics and Obstetrics and Gynecology at the David Geffen School of Medicine at UCLA. He is the author of Evolutionary Biology: Cell–Cell Communication and Complex Disease (Wiley-Blackwell, 2012).


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