Reverse engineering morphogenesis

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How does the shape and structure of a tissue arise during the development of an organism? This process, which is termed morphogenesis, involves the cells within a forming tissue moving and reconfiguring themselves in a coordinated manner. This choreography is self-organised. There is no central conductor. Instead, the morphogenesis depends on interactions and communication between the individual cells in the tissue. Understanding how this works remains one of the great challenges of science. How do complex tissue shapes arise just from interactions between individual cells? What explains the reliability of morphogenesis? How do mechanics and changes in gene activity interact with one another?Self-organisation necessitates an initial event that causes changes in the activity of specific genes in a subpopulation of the cells as they become a new cell type (they differentiate). This results in changes in the mechanics of these cells and precipitates a change in the shape of the tissue. The process then iterates. As new contacts form between cells of different type, as some cells lose contact with each other, and as new signals and mechanical interactions are produced, further rounds of organisation take place. Thus, understanding shape acquisition lies at the interface between physics and biology as it involves cycles of changes in mechanics and gene expression that feed back across multiple length and time scales.The challenges are: i) we do not know where and when changes in mechanics and gene expression occur; ii) we do not know how changes in the mechanics of individual cells add up to change the shape of the tissue; and iii) in turn, we do not know how changes in cell mechanics and shape influence gene expression to set up the next round of shape change. Our vision is to integrate physics and biological perspectives to develop an understanding of how cycles of gene expression and mechanical changes give rise to complex shape in tissues and organs over a duration of several days. We propose to determine how cell differentiation and cellular-scale mechanical changes interplay to control the acquisition of shape in an experimental model of tissue development, known as organoids. These are generated in vitro from embryonic stem cells grown in Petri dishes in defined conditions. This is an attractive system as organoids reproducibly produce defined cell types and undergo characteristic morphogenesis but remain sufficiently simple to explore cell morphology, mechanics, differentiation and gene expression with high spatial and temporal accuracy. In this project, we will use a combination of experimental assays to characterise tissue shape, cell morphology, cell differentiation, and gene expression in organoids and determine how mechanics, cell adhesion, and gene expression feed back onto one another. Using these data will determine rules linking differentiation to mechanics and mechanics to cell type. From this, we will develop computer models based on the experimental observations. We will use the models to identify underlying principles of tissue morphogenesis. And with these models, we will make predictions of organoid shape evolution in response to specific interventions and test these experimentally. Our team is ideally placed to answer these questions because of our combined expertise in spinal cord organoids and developmental biology (James Briscoe), cell and tissue mechanics (Guillaume Charras), and quantitative imaging, modelling, and theory (Tim Saunders). Beyond fundamental science, developing multi-scale simulations of tissue shape acquisition in a simplified model system will provide a foundation for understanding complex tissues comprising multiple and evolving cell types. This will have applications in disease modelling, regenerative medicine, synthetic biology and tissue engineering.