Exploiting cellular-developmental evolution as the scientific basis for preventive medicine

Department of Pediatrics, David Geffen School of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Los Angeles, California 90502, United States.
Medical Hypotheses (Impact Factor: 1.07). 02/2009; 72(5):596-602. DOI: 10.1016/j.mehy.2008.09.057
Source: PubMed

ABSTRACT In the post-genomic era, we must make maximal use of this technological advancement to broaden our perspective on biology and medicine. Our understanding of the evolutionary process is undermined by looking at it retrospectively, perpetuating a descriptive rather than a mechanistic approach. The reintroduction of developmental biologic principles into evolutionary studies, or evo-devo, allows us to apply embryologic cell-molecular biologic principles to the mechanisms of phylogeny, obviating the artificial space and time barriers between ontogeny and phylogeny. This perspective allows us to consider the continuum between the proximate and ultimate causes of speciation, which was unthinkable when looked at from the descriptive perspective. Using a cell-cell interactive 'middle-out' approach, we have gained insight to the evolution of the lung from the swim bladder of fish based on gene regulatory networks that generate both lung ontogeny and phylogeny, i.e. decreased alveolar size, decreased alveolar wall thickness, and increased alveolar wall strength. Vertical integration of cell-cell interactions predicts the adaptivity and maladaptivity of the lung, leading to novel insights for chronic lung disease. Since we have employed principles involved in all of development, this approach is amenable to all biologic structures, functions, adaptations, maladaptations, and diseases, providing an operational basis for preventive medicine.

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    • "We have previously shown that viewing lung ontogeny and phylogeny from the common denominator of cell-cell interactive paracrine signaling reveals that they are one and the same mechanism of morphogenesis, suggesting that time is superfluous to understanding vertebrate evolution (Torday and Rehan 2009a, 2009b, 2009c). The time variable is an artifact of descriptive biology. "
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    ABSTRACT: This article offers a novel, enlightened concept for determining the mechanism of evolution. It is based on homeostasis, which distinguishes life from non-life and as such is the universal mechanism for the evolution of all living organisms. This view of evolution is logical, mechanistic, non-scalar, predictive, testable, and falsifiable, and it illuminates the epistemological relationships between physics and biology, ontogeny and phylogeny, development and aging, ultimate and proximate causation, health and disease. In addition to validating Haeckel's biogenetic law and Lamarckian epigenetics, reflecting the enabling value of the cellular approach, this perspective also expresses the evolutionary process at the cell-molecular level, since the mechanism of cell communication itself is universal in biology, in keeping with a Kuhnian paradigm shift. This approach may even elucidate the nature and evolution of consciousness as a manifestation of the cellular continuum from unicellular to multicellular life. We need such a functional genomic mechanism for the process of evolution if we are to make progress in biology and medicine. Like Copernican heliocentrism, a cellular approach to evolution may fundamentally change humankind's perceptions about our place in the universe.
    Perspectives in Biology and Medicine 01/2013; 56(4):455-84. DOI:10.1353/pbm.2013.0038 · 0.54 Impact Factor
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    • "Normal lung development is the result of a functionally interconnected series of cell-molecular steps. This sequence of biologic events has been positively selected for evolutionarily over biologic time and space [1], resulting in optimal gas exchange mediated by alveolar homeostasis [2]. Elsewhere we have suggested that chronic lung disease (CLD) causes simplification of the lung in a manner consistent with the reversal of the evolutionary process [3, 4]. "
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    ABSTRACT: Epithelial-mesenchymal interactions mediated by soluble growth factors determine the evolution of vertebrate lung physiology, including development, homeostasis, and repair. The final common pathway for all of these positively adaptive properties of the lung is the expression of epithelial parathyroid-hormone-related protein, and its binding to its receptor on the mesenchyme, inducing PPARγ expression by lipofibroblasts. Lipofibroblasts then produce leptin, which binds to alveolar type II cells, stimulating their production of surfactant, which is necessary for both evolutionary and physiologic adaptation to atmospheric oxygen from fish to man. A wide variety of molecular insults disrupt such highly evolved physiologic cell-cell interactions, ranging from overdistention to oxidants, infection, and nicotine, all of which predictably cause loss of mesenchymal peroxisome-proliferator-activated receptor gamma (PPARγ) expression and the transdifferentiation of lipofibroblasts to myofibroblasts, the signature cell type for lung fibrosis. By exploiting such deep cell-molecular functional homologies as targets for leveraging lung homeostasis, we have discovered that we can effectively prevent and/or reverse the deleterious effects of these pathogenic agents, demonstrating the utility of evolutionary biology for the prevention and treatment of chronic lung disease. By understanding mechanisms of health and disease as an evolutionary continuum rather than as dissociated processes, we can evolve predictive medicine.
    PPAR Research 06/2012; 2012:289867. DOI:10.1155/2012/289867 · 1.64 Impact Factor
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    ABSTRACT: Perhaps development is more than just morphogenesis. We now recognize that the conceptus expresses epigenetic marks that heritably affect it phenotypically, indicating that the offspring are to some degree genetically autonomous, and that ontogeny and phylogeny may coordinately determine the fate of such marks. This scenario mechanistically links ecology, ontogeny and phylogeny together as an integrated mechanism for evolution for the first time. As a functional example, the Parathyroid Hormone-related Protein (PTHrP) signaling duplicated during the Phanerozoic water-land transition. The PTHrP signaling pathway was critical for the evolution of the skeleton, skin barrier, and lung function, based on experimental evidence, inferring that physiologic stress can profoundly affect adaptation through internal selection, giving seminal insights to how and why vertebrates were able to evolve from water to land. By viewing evolution from its inception in unicellular organisms, driven by competition between pro- and eukaryotes, the emergence of complex biologic traits from the unicellular cell membrane offers a novel way of thinking about the process of evolution from its beginnings, rather than from its consequences as is traditionally done. And by focusing on the epistatic balancing mechanisms for calcium and lipid homeostasis, the evolution of unicellular organisms, driven by competition between pro- and eukaryotes, gave rise to the emergence of complex biologic traits derived from the unicellular plasma lemma, offering a unique way of thinking about the process of evolution. By exploiting the cellular-molecular mechanisms of lung evolution as ontogeny and phylogeny, the sequence of events for the evolution of the skin, kidney and skeleton become more transparent. This novel approach to the evolution question offers equally novel insights to the primacy of the unicellular state, hologenomics and even a priori bioethical decisions.
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