Understanding size-robust self-organization of morphogen gradients

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BACKGROUNDThere is an incredible diversity of biological structures throughout the natural world. These structures are complex yet precise e.g. a human hand must be the correct size and shape, as well as containing cell types (e.g. nerves, muscle, bone) in the right place and the right amounts. Unlike man-made structures, biological structures are not created fully-formed; we all began life as a single cell. Instead, growth, patterning and shape-changes transform a tiny embryo into a complex animal, a process known as development.OVERALL QUESTIONAs an animal or organ develops, it is essential that cells know where they are within it to become the correct cell type and activate the right genes. It has long been known that cells use molecules to measure their location, akin to a molecular GPS. The general idea is that a molecular signal is made in a specialized zone outside the organ (a signalling centre), which then gradually seeps in, forming a concentration gradient. If a cell senses a high concentration, then it knows that it is close to the signalling centre and activates the appropriate genes, and vice versa. However, our understanding of this process has changed dramatically in recent years. Whilst cells do measure their position using molecular gradients, we are finding that these gradients still form if signalling centres, originally thought to be essential, are removed. In other words, cells are not just passively responding to the gradient, they are actively involved in making it, a process that we do not yet fully understand. This would be like a bathtub full of water forming waves without you ever touching it. SPECIFIC QUESTIONHow do the molecular gradients that control development form without external signalling centres?WHY IS IT IMPORTANT?All animals use molecular gradients repeatedly throughout their development; understanding how they form is therefore a question of fundamental importance. This question also has real practical significance. Recently discovered organoids - organs that can be grown outside of the body from human stem cells - show great promise, since they can be used to mimic human disease and pave the way for organ replacement therapies. However current organoids are highly error-prone and often fail to form the molecular gradients necessary for organ development. Our work will identify strategies to reduce these errors and improve the usefulness of organoids to biomedicine. OUR APPROACHWe will combine mathematics and experiments to build quantitative models of molecular gradients and use these models to predict how organoids can be made less error-prone. Just as we need a precise understanding of materials physics to engineer reliable bridges and buildings, we need a quantitative understanding of developmental biology to bio-engineer reliable organs and organoids. OUR PLANSWe will take two complementary approaches. First, we will study in detail an organoid system which already forms gradients reliably. This is one of the earliest gradients to form in animal species, including humans, controlled by a signal called Nodal. We choose to study this in zebrafish embryo organoids (known as pescoids), ideal for quantitative approaches since we can watch the gradients forming in real-time as well as being able to precisely manipulate them, whilst the genes involved are very similar to those in humans. After building an accurate mathematical model of the Nodal gradient, we will use this model to understand why pescoids make gradients so reliably; we expect that the answer lies in how much individual cells are moving around. In parallel, we will study other molecular gradients known to self-organize in a variety of organs/organoids. By building models of many different molecular signals we will ask whether the principles behind robust Nodal gradients also apply to other systems, and therefore identify general engineering principles to reliably make organs outside the body.