Abstract
Physiology integrates biology with the environment through cell-cell interactions at multiple levels. The evolution of the respiratory system has been "deconvoluted" (Torday and Rehan in Am J Respir Cell Mol Biol 31:8-12, 2004) through Gene Regulatory Networks (GRNs) applied to cell-cell communication for all aspects of lung biology development, homeostasis, regeneration, and aging. Using this approach, we have predicted the phenotypic consequences of failed signaling for lung development, homeostasis, and regeneration based on evolutionary principles. This cell-cell communication model predicts other aspects of vertebrate physiology as adaptational responses. For example, the oxygen-induced differentiation of alveolar myocytes into alveolar adipocytes was critical for the evolution of the lung in land dwelling animals adapting to fluctuating Phanarezoic oxygen levels over the past 500 million years. Adipocytes prevent lung injury due to oxygen radicals and facilitate the rise of endothermy. In addition, they produce the class I cytokine leptin, which augments pulmonary surfactant activity and alveolar surface area, increasing selection pressure for both respiratory oxygenation and metabolic demand initially constrained by high-systemic vascular pressure, but subsequently compensated by the evolution of the adrenomedullary beta-adrenergic receptor mechanism. Conserted positive selection for the lung and adrenals created further selection pressure for the heart, which becomes progressively more complex phylogenetically in tandem with the lung. Developmentally, increasing heart complexity and size impinges precociously on the gut mesoderm to induce the liver. That evolutionary-developmental interaction is significant because the liver provides regulated sources of glucose and glycogen to the evolving physiologic system, which is necessary for the evolution of the neocortex. Evolution of neocortical control furthers integration of physiologic systems. Such an evolutionary vertical integration of cell-to-tissue-to-organ-to-physiology of intrinsic cell-cell signaling and extrinsic factors is the reverse of the "top-down" conventional way in which physiologic systems are usually regarded. This novel mechanistic approach, incorporating a "middle-out" cell-cell signaling component, will lead to a readily available algorithm for integrating genes and phenotypes. This symposium surveyed the phylogenetic origins of such vertically integrated mechanisms for the evolution of cell-cell communication as the basis for complex physiologic traits, from sponges to man.