Physics of Living Matter: From Molecule to Embryo

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ABSTRACT Organ form is vital for organisms to function properly. This is particularly evident for essential organs such as the human heart where shape defects result in congenital heart disease, a common birth defect. Despite major efforts, we still lack answers to this simple question: how does DNA encode shape? Developmental and molecular biology uncovered the principles of how maternal morphogens setup axes and trigger cascades of gene regulation to precisely determine cell fate patterns. Yet how the interplay of genetic information and mechanical activity orchestrates interaction of cells that shape organs remains elusive. In his seminal book “On growth and form” the polymath D'Arcy Thompson advocated for quantitative analysis of morphogenesis. His ideas where ahead of their time: they predate the genetic revolution, and many tools for quantitative analysis where missing. This proposal seeks to lay the foundations for quantitative morphogenesis, revisiting Thompson's agenda armed with the toolkit of the modern era. For a predictive understanding of morphogenesis, molecular investigation must be extended by quantitative analysis of tissue dynamics at the organ scale. At the organ scale concepts from physics of collective phenomena become relevant to study how thousands of cells streamline their `activity' to generate shape. Connecting developmental biology with physics harbors the promise to uncover new mechanisms at the organ scale. We know the transcription factors that determine fate, and cytoskeletal proteins that execute cell behaviors. Many of these players are conserved across a large portion of the tree of life. On the other hand, we learned shape of materials is determined by physical quantities such as force and mechanical stress. To unfold the full potential of an interdisciplinary approach, we need new tools bridging the gap between genetic players and physical quantitates. This approach will lead the way to the principles of morphogenesis. My team develops break through technology overcoming hurdles of whole organ quantitative analysis. Multi- view light sheet microscopy enables rapid in toto live imaging at subcellular resolution. Tissue cartography dives into the rest-frame of curved tissues and generates a panoramic overview, simplifying data handling and quantitative analysis. We pioneer biophysics-image-informatics to extract quantitative observables from fluorescence microscopy in the language of physics. Leveraging advanced understanding of the early embryo in the advanced genetic model system D. melanogaster, we aim for a comprehensive framework predicting how genotype determines tissue flows during axis elongation. Our approach will have a broad impact: by connecting development with physics we form the foundation of quantitative morphogenesis.