Courtesy of Michael Carroll
The evolution of complex biologic organisms began with the symbiotic relationship between pro- and eukaryotes (I). This relationship gave rise to mitochondria (II), and the resulting diversity of unicellular organisms (III) led to their metabolic cooperativity (IV) mediated by ligand-receptor interactions and cell-cell signaling. Natural selection generated an increasing complexity (V). Failed homeostatic signaling (VI) recapitulates hylogeny/ontogeny, offering pathology/repair as the inverse of phylogeny/ontogeny.
From the beginning of written history, humans have gathered information and imparted order, starting with Denis Diderot's Encyclopedia, to Carl Linnaeus' binomial nomenclature for the classification of animals and plants, to today's numerous genome annotations. Several physicists in the 19th century had attempted to order the known elements. Notably, Dmitri Mendeleev published his periodic table and law in 1869. Its most stunning feature: Holes within its hierarchical structure predict the existence and properties of additional elements – the ultimate validation...
COOPERATION IS KEY
The cooperativity that underlies endosymbiosis in the rise of eukaryotes has evolved from a metabolic form to a cellular form that has been recapitulated throughout the evolution of multicellular organisms as well as vertebrate phylogeny and ontogeny.
Take, for example, the epithelial-mesenchymal interactions that form the tissues and organs. Such interactions are necessary for both the formation of the liver, as well as its homeostatic control of lipids, which shuttle back and forth between stellate cells and hepatocytes. Cell-cell interactions that control development and regulation of endocrine tissues such as the adrenals, gonads, prostate, and mammary gland can be viewed similarly.
In the lung-development and homeostasis model we study, lipids maintain the structural integrity of alveoli. Surfactant, a lipid-protein complex, is produced by epithelial type II cells in the corners of alveoli. As lung volume changes from moment to moment, physical force (or stretch) on the alveoli regulates surfactant production and secretion. The connective tissue cells of the alveolar wall actively recruit lipids from the circulation and transfer them to the epithelial type II cells for surfactant phospholipid synthesis.
This process is mediated by adipocyte differentiation-related protein (ADRP), which is under the control of the parathyroid hormone-related protein (PTHrP) signaling pathway. This series of functionally interrelated proteins is expressed compartmentally: PTHrP, surfactant, and ADRP receptor in the epithelium; and PTHrP receptor and ADRP by fibroblasts in the alveolar wall.
Interrupting this cellular crosstalk causes epithelial and mesodermal cells to readapt in a process we recognize as disease. Similar chains of events occur in all structures that ascribe to such developmental cell-cell interactions. The recognition that ontogeny, phylogeny, physiology, and pathophysiology are a genetic continuum2 suggests that such motifs represent "rules" that could serve as construction guidelines for a biologic periodic table.
The genius of the periodic table of elements lies in its hierarchical organization with atomic weight as its first principle. A comparable approach to the creation of a biologic periodic table would need to be based on specific functional principles of homeostasis, linked mechanistically through the genes that determine such processes. My laboratory has taken a developmental approach to understanding the origins, homeostatic control, and pathophysiology of the lung, based on the vertically integrated effects of PTHrP.
During development, PTHrP signaling to its receptor is stimulated by fluid distension of the lung, and is amplified via cyclic AMP-dependent protein kinase (PKA) signaling through multiple pathways for differentiation of the connective tissue. Connective-tissue cells, in turn, produce factors that coordinate the growth and differentiation of the surrounding epithelial and vascular compartments, culminating in physiologic homeostasis. Disruption in the system causes changes through the same cellular crosstalk that mediates development, indicating a disease-development interrelationship.23
PTHrP AS ARCHETYPE
The recognition that development, phylogeny, homeostasis, and pathophysiology represent a continuum of interrelated genes, signaling through specific cellular pathways, affords the opportunity to consider how these cell and molecular motifs have been retained through convergent evolution. I have previously hypothesized that the progressive complexity of the gas exchange unit has resulted from the phylogenetic amplification of the PTHrP signaling pathway.1 PTHrP and its receptor are expressed as early in vertebrate phylogeny as the swim bladder of the fish, as is the expression of surfactant; the swim bladder functions for buoyancy, not to provide oxygen for metabolism. The swim bladder doesn't need surfactant to function, yet it expresses both PTHrP signaling and surfactant.
During lung evolution from the swim bladder, the structure-function interrelationship between alveolar surface area and surfactant production has amplified. I have hypothesized that both of these properties of the lung are mechanistically linked through stretch regulation of PTHrP signaling.1 Cyclic stretch enhances the expression of both PTHrP and its receptor on apposing epithelial type II cells and mesodermal fibroblasts.3
As the metabolic demand on vertebrates drove their evolution, the lung surfactant system became more efficient through the process of natural selection as follows: PTHrP amplification of surfactant, along with PTHrP inhibition of fibroblast growth, may have promoted the thinning of the alveolar septa and allowed the progressive phylogenetic and developmental decreases in alveolar size. The resultant progressive increase in surface tension (by the Law of Laplace) was apparently compensated for by the ramping-up of the surfactant mechanism.4
Gene knockouts yield evidence that a variety of tissues use such signaling between cells of different embryonic origins for varied functions. For example,
This pattern of physiologic effects mediated by ligands from one cell type stimulating neighboring cell types through a specific receptor-mediated recognition mechanism reflects the evolution of multicellularity through the nature of the cell-surface receptors. This variation in cell-surface markers identifies the signaling partners in a recapitulation of evolution that plays itself out repetitively through ontogeny and phylogeny, and reprises itself through injury-repair.
EVOLUTION AS SOLUTION
We are beginning to recognize the convergent expression of genes that have given rise to the complexity of physiologic processes. Lung evolution has been driven by the amplification of the PTHrP signaling pathway,1 which in turn has provided insights into the development,35 function,3 and dysfunction6 of the lung. Thus, the phylogeny, ontogeny, physiology, and pathophysiology of the lung may be viewed as a family of parallel lines, providing enough variables to solve for all these simultaneous equations.
The solution for this set of simultaneous equations is the process of evolution. The other PTHrP-dependent phenotypes, namely bone and skin, could be evaluated similarly, providing for a systematic approach to the integration of biologic knowledge. By using interactive algorithms such as self-organizing maps or neural nets to integrate the totality of biologic data, the periodic table for biology will emerge, based on first principles rather than on description. Mendeleev's periodic table gave chemists a framework to understand the behavior of the elements. If the biologic version is equally robust, it will provide novel ways in which to view life itself.
John S. Torday is a professor of pediatrics, and obstetrics and gynecology at the University of California, Los Angeles. His career-long focus has been on epigenetic determinants of fetal lung development, and their role in the etiology of lung disease in newborns and adults. He has published more than 100 papers on this subject.
He can be reached at