Man is Integral to Nature

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

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

                                                                                    —H.D. Thoreau, The Maine Woods

In the Beginning

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

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

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

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

The Advent of Multicellularity

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

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

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

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

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

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

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

Evolution, Cellular-Style

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

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

The Water-Land Transition and Vertebrate Evolution

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

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

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

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

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

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

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

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

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

The Cellular Approach to Evolution Is Predictive

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

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

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

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

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

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

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

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

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

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

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


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

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