Lung evolution as a cipher for physiology

Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
Physiological Genomics (Impact Factor: 2.37). 05/2009; 38(1):1-6. DOI: 10.1152/physiolgenomics.90411.2008
Source: PubMed


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.

3 Reads
  • Source
    • "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]. Therefore, by identifying those mechanisms that have evolved under selection pressure for optimal gas exchange [5], we have theorized that we can effectively reverse the deleterious effects of CLD by promoting the evolutionarily adaptive mechanism [6], rather than by just treating the symptoms [7]. "
    [Show abstract] [Hide abstract]
    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(4, part 1):289867. DOI:10.1155/2012/289867 · 1.64 Impact Factor
  • Source
    • "For example, the epithelial lining cells of the fish swim bladder express surfactant protein and phospholipid in an unregulated housekeeping fashion. In contrast to this, the amphibian lung epithelium expression of surfactant is regulated by leptin produced by lipofibroblasts (Torday et al. 2009), which are the key to mammalian lung evolution—the cellular paracrine interactions between cells that mediated lung evolution (depicted in fig. 3A, 1–4) are underpinned by the evolution of cell–cell signaling through leptin and PTHrP, soluble factors that bind to their cell surface receptors, triggering a downstream cascade of cis regulatory mechanisms (fig. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In contrast to the conventional use of genes to determine the evolution of phenotypes, we have functionally integrated epithelial-mesenchymal interactions that have facilitated lung phylogeny and ontogeny in response to major geologic epochs. As such, this model reveals the underlying principles of lung physiology based on the evolutionary interactions between internal and external selection pressures, providing a novel understanding of lung biology. As a result, it predicts how cell-molecular changes in this process can cause disease and offers counterintuitive insights to diagnosis and treatment based on evolutionary principles.
    Molecular Biology and Evolution 05/2011; 28(11):2973-81. DOI:10.1093/molbev/msr134 · 9.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In the post-genomic era the complex problem of evolutionary biology can be tackled from the top-down, the bottom-up, or from the middle-out. Given the emergent and contingent nature of this process, we have chosen to take the latter approach, both as a mechanistic link to developmental biology and as a rational means of identifying signaling mechanisms based on their functional genomic significance. Using this approach, we have been able to configure a working model for lung evolution by reverse-engineering lung surfactant from the mammalian lung to the swim bladder of fish. Based on this archetypal cell-molecular model, we have reduced evolutionary biology to cell communication, starting with unicellular organisms communicating with the environment, followed by cell-cell communication to generate metazoa, culminating in the communication of genetic information between generations, i.e. reproduction. This model predicts the evolution of physiologic systems-including development, homeostasis, disease, regeneration/repair, and aging- as a logical consequence of biology reducing entropy. This approach provides a novel and robust way of formulating refutable, testable hypotheses to determine the ultimate origins and first principles of physiology, providing candidate genes for phenotypes hypothesized to have mediated evolutionary changes in structure and/or function. Ultimately, it will form the basis for predictive medicine and molecular bioethics, rather than merely showing associations between genes and pathology, which is an unequivocal Just So Story. In this new age of genomics, our reach must exceed our grasp.
    Cell Communication Insights 09/2009; 2:17-25.
Show more