Lung evolution as a cipher for physiology
ABSTRACT In the postgenomic era, we need an algorithm to readily translate genes into physiologic principles. The failure to advance biomedicine is due to the false hope raised in the wake of the Human Genome Project (HGP) by the promise of systems biology as a ready means of reconstructing physiology from genes. like the atom in physics, the cell, not the gene, is the smallest completely functional unit of biology. Trying to reassemble gene regulatory networks without accounting for this fundamental feature of evolution will result in a genomic atlas, but not an algorithm for functional genomics. For example, the evolution of the lung can be "deconvoluted" by applying cell-cell communication mechanisms to all aspects of lung biology development, homeostasis, and regeneration/repair. Gene regulatory networks common to these processes predict ontogeny, phylogeny, and the disease-related consequences of failed signaling. This algorithm elucidates characteristics of vertebrate physiology as a cascade of emergent and contingent cellular adaptational responses. By reducing complex physiological traits to gene regulatory networks and arranging them hierarchically in a self-organizing map, like the periodic table of elements in physics, the first principles of physiology will emerge.
- SourceAvailable from: John S TordayAJP Cell Physiology 07/2013; 305(7). DOI:10.1152/ajpcell.00197.2013 · 3.71 Impact Factor
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ABSTRACT: Significance: Oxygen, the main mode of support for premature infants with immature lungs, can cause toxicity by producing Radical Oxygen Species (ROS) that disrupt homeostasis, yet these same molecules were entrained to promote vertebrate lung phylogeny. By providing deeper understanding of this paradox, we propose physiologically rationale strategies to prevent chronic lung disease of prematurity. Recent Advances: To prevent neonatal hyperoxic lung damage biologically, we have exploited the alveolar defense mechanism (s) that evolutionarily evolved to combat increased atmospheric oxygen during mammalian water to land transition. Critical Issues: Over the course of vertebrate lung evolution, ROS promoted the formation of lipofibroblasts, specialized adepithelial cells, which protect the alveoli against oxidant injury; PPARγ, the 'master switch' for lipofibroblast differentiation, prevents such oxidant lung injury, both by directly promoting mesodermal differentiation and its anti-oxidant defenses, and indirectly by stimulating the developmental epithelial-mesenchymal paracrine interactions that have physiologically determined lung surfactant production in accord with lung's phylogenetic adaptation to atmospheric oxygen, preventing Respiratory Distress Syndrome at birth. Future Directions: The molecular strategy (PPARγ agonists) to prevent chronic lung disease of prematurity, proposed by us, though seems to be robust, effective, and safe under experimental conditions, it awaits detailed pharmacokinetic and pharmacodynamic studies for its safe and effective clinical translation to human infants.Antioxidants & Redox Signaling 01/2014; DOI:10.1089/ars.2013.5793 · 8.20 Impact Factor
Article: Evolutionary biology redux.[Show abstract] [Hide abstract]
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