Epigenetics Beyond the Cell: Supracellular Organization of Fate and Form in Morphogenesis.

How biological systems obtain their shape and structure is a fundamental question with many practical implications. Like much of biology, over the last several decades, tissue and organ morphogenesis has focused on uncovering regulatory mechanisms at the cellular and subcellular scales. Such studies have either implicitly or explicitly reified the view that the creation of form is instructed or controlled by a combination of genetic and molecular processes. However, pioneering early twentieth century biological theorists such as Conrad Waddington cautioned against the total subsummation of biology by, for instance, biochemistry and molecular biology. Through the coining of terms such as "epigenotype," it was argued that processes at every scale between genotype and phenotype were necessary to organize morphogenesis. Thus, organizing processes exist that are not reducible merely to the sum of inputs from "genes" and "environment." Here, we argue that uncovering generative epigenetic processes beyond the cell yet within the organism requires a holistically oriented use of physical concepts involving mechanics and material phases. To uncover and clearly articulate such "supracellular" processes, we discuss how relations between mesenchymal cells and extracellular matrix (ECM) serve as a powerful model system. Based on the study of mesenchymal-ECM systems, we suggest that it may not be possible to understand the ultimate functional role of gene products such as signaling molecules without an appreciation of supracellular processes in their own right.