A Central Theory of Biology

AJP: Cell Physiology, 2013

esize that the First Principles of Physiology (FPPs) were co-opted during the vertebrate transition from water to land, beginning with the acquisition of cholesterol by eukaryotes, facilitating unicellular evolution over the course of the first 4.5 billion years of the Earth's history, in service to the reduction in intracellular entropy, far from equilibrium. That mechanism was perpetuated by the advent of cholesterol in the cell membrane of unicellular eukaryotes, ultimately giving rise to the metazoan homologs of the gut, lung, kidney, skin, bone, and brain. Parathyroid hormone-related protein (PTHrP), whose cognate receptor underwent a gene duplication during the transition from fish to amphibians, facilitated gas exchange for the water-to-land transition, since PTHrP is necessary for the formation of lung alveoli: deletion of the PTHrP gene in mice causes the offspring to die within a few minutes of birth due to the absence of alveoli. Moreover, PTHrP is central to the development and homeostasis of the kidney, skin, gut, bone, and brain. Therefore, duplication of the PTHrP receptor gene is predicted to have facilitated the molecular evolution of all the necessary traits for land habitation through a common cellular and molecular motif. Subsequent duplication of the ␤-adrenergic receptor gene permitted blood pressure control within the lung microvasculature, allowing further evolution of the lung by increasing its surface area. I propose that such gene duplications were the result of shear stress on the microvasculature, locally generating radical oxygen species that caused DNA mutations, giving rise to duplication of the PTHrP and ␤-adrenergic receptor genes. I propose that one can determine the FPPs by systematically tracing the molecular homologies between the lung, skin, kidney, gut, bone, and brain across development, phylogeny, and pathophysiology as a type of "reverse evolution." By tracing such relationships back to unicellular organisms, one can use the underlying principles to predict homeostatic failure as disease, thereby also potentially forming the basis for maneuvers that can treat or even prevent such failure. PTHrP receptor; ␤-adrenergic receptor; gene duplication; First Principles of Physiology "We dance round in a ring and suppose, But the Secret sits in the middle and knows."

The Scientific World JOURNAL, 2006

Today's biomedicine builds on the conviction that biochemistry can explain the creation of the body, its anatomy and physiology. Unfortunately there are still deep mysteries strangely “fighting back” when we try to define and understand the organism and its creation in the ontogenesis as emerging from biochemistry. In analysing this from a theoretical perspective using a mathematical model focusing on the noise in complex chemical systems we argue that evolving biological structure cannot in principle be a product of chemistry. In this paper we go through the chemical gradient model and argue that this is not able to explain the ontogenesis. We discuss the used gradients as information carriers in chemical self-organizing systems and argue that by use of the “Turing structures” we are only able to modelling the mostly simple biological systems. The bio-chemical model is only able to model simple organization but not to explain the complexity of biological phenomena. We conclude ...

Laboratory Investigation, 2006

History and Philosophy of The Life Sciences, 2023

Organismal death is foundational to the evolution of life, and many biological concepts such as natural selection and life history strategy are so fashioned only because individuals are mortal. Organisms, irrespective of their organization, are composed of basic functional units-cells-and it is our understanding of cell death that lies at the heart of most general explanatory frameworks for organismal mortality. Cell death can be exogenous, arising from transmissible diseases, predation, or other misfortunes, but there are also endogenous forms of death that are sometimes the result of adaptive evolution. These endogenous forms of death-often labeled programmed cell death, PCD-originated in the earliest cells and are maintained across the tree of life. Here, we consider two problematic issues related to PCD (and cell mortality generally). First, we trace the original discoveries of cell death from the nineteenth century and place current conceptions of PCD in their historical context. Revisions of our understanding of PCD demand a reassessment of its origin. Our second aim is thus to structure the proposed origin explanations of PCD into coherent arguments. In our analysis we argue for the evolutionary concept of PCD and the viral defense-immunity hypothesis for the origin of PCD. We suggest that this framework offers a plausible account of PCD early in the history of life, and also provides an epistemic basis for the future development of a general evolutionary account of mortality.

Physiology, 2015

The Quarterly Review of Biology, 1997

A cell's decision whether to undergo apoptosis (cell suicide) is examined herefrom an adaptationist perspective, rather than a mechanistic one. External and internal inputs to the cell's protein-based information processing network are used in making this decision, with the cell factoring in its replaceability. A system in which each cell takes primary responsibility for deciding its own fate has great adaptive value because it harnesses each cell's self-knowledge rather than waitingfor external cues to be recognized by other cells. Cell self-destruction can be an important selective mechanism, potentially leading to better performance of tissues over time. However, reliance on cells to monitor themselves has aflaw, since cells may incur selfish mutations that impair their apoptotic responsibility. The tight control exerted over somatic cells serves to check selfish genes involved in neoplasia and viral infections. Germ cells appear to be similarly monitored, both by other germ cells and by supportingfollicular or Sertoli cells, thus maintaining the advantages offered by an apoptotic system. The adaptationist approach views the limited replacement of neurons and cardiac myocytes as likely to have net survival value. The linkage of these cells into a network with their neighbors throughout a lifetime allows for a precisely functioning team of cells expected to compensateforgradual declines in individual cellfunctionality. Replacement of apoptotic cells with naive cells might decrease brain functionality and might risk upsetting the conduction of cardiac impulses. The evolutionary viewpoint lends itself to new hypotheses, but only the boldestspeculatorwould havepredicted a system in which cells aregiven primary responsibility for deciding whether to kill themselves when they deem it beneficial to the organism.

Journal of The Royal Society Interface, 2014

The sequencing of the human genome raises two intriguing questions: why has the prediction of the inheritance of common diseases from the presence of abnormal alleles proved so unrewarding in most cases and how can some 25 000 genes generate such a rich complexity evident in the human phenotype? It is proposed that light can be shed on these questions by viewing evolution and organisms as natural processes contingent on the second law of thermodynamics, equivalent to the principle of least action in its original form. Consequently, natural selection acts on variation in any mechanism that consumes energy from the environment rather than on genetic variation. According to this tenet cellular phenotype, represented by a minimum free energy attractor state comprising active gene products, has a causal role in giving rise, by a self-similar process of cell-to-cell interaction, to morphology and functionality in organisms, which, in turn, by a self-similar process entailing Darwin's proportional numbers are influencing their ecosystems. Thus, genes are merely a means of specifying polypeptides: those that serve free energy consumption in a given surroundings contribute to cellular phenotype as determined by the phenotype. In such natural processes, everything depends on everything else, and phenotypes are emergent properties of their systems.

Journal of clinical & experimental pathology, 2015

American Journal of Human Biology, 2004

2014

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