Physics of Living Matter: From Molecule to Embryo

ABSTRACT Shape is critical for proper organ function. From genetic model animals, we have learned much about the principles of how morphogens setup body axes, and trigger a cascade of regulatory factors to setup a coordinate system of fate patterning the organism, and endowing each cell with a unique fate. Pioneering work demonstrated that the fate system controls shape. But how these processes control shape remains elusive. Mechanobiology demonstrated that shape emerges from physical interactions between cells. Therefore, morphogenesis is also a problem of physics, leading to the question: How does developmental biology control the physics of morphogenesis? From single cell studies in vitro, we have learned how cells utilize fundamentally dynamic processes that involve their cytoskeleton to generate forces. However, how forces are coordinated across tissues to reliably generate form remains elusive. Progress requires extending molecular analysis to investigation of cellular dynamics at the organ level, to study the interplay of forces and cell behaviors. The polymath D’Arcy Thompson already pointed out that quantitative analysis of morphogenesis promises new biological insights. His pioneering ideas came before the genetic revolution, that provided much of what we know about the molecular picture of morphogenesis. Since then, new tools such as fluorescence live imaging have emerged. In this proposal, we will lay the foundations for quantitative morphogenesis across length scales, connecting molecular level information with the dynamic processes that govern shape. Quantitative analysis of tissue dynamics at the organ scale, combined with emerging tools from physics will lead to the development of new, experimentally testable hypotheses for the dynamic rules of morphogenesis. We develop new quantitative tools to bring this interdisciplinary approach to fruition, and lead the way to the principles of morphogenesis. Multi view light sheet microscopy and emerging super resolution methods pave the way to interrogate the dynamics of molecular processes across entire embryos. Our biophysical image informatics approach extracts quantitative measurements of morphogenetic processes from microscopy data. These quantitative measurements are summarized in the powerful language of tensor morphogens, an emerging concept from physics. These concepts dovetail with theory development, and novel machine learning approaches – aimed to formulate a comprehensive framework that predicts how a genotype determines the outcome of morphogenesis. We begin with basic morphogenetic processes such as axis elongation, or folding. Both are wide spread strategies to shape the body across the animal kingdom. Our approach will open up new paths to a quantitative understanding of the physics of living matter, from the molecular level to the whole embryo.