Cilia—tiny, hair-like structures on the surface of most human cells—can be built in hundreds of different ways, and scientists do not yet understand how this diversity is controlled. This matters because when cilia go wrong, the consequences are severe. Mutations in over 200 genes cause more than 40 different ciliopathy syndromes, affecting how people see, hear, breathe, and reproduce. Yet patients with the same genetic mutation can have wildly different symptoms, and doctors cannot predict who will be mildly or severely affected. The root cause is that no one has mapped the full range of cilia types across the body or worked out why some are more vulnerable to damage than others. This project is fundamental science—it aims to uncover the genetic rules that build different cilia and how cells adapt these structures for specific jobs. If successful, it could explain why certain tissues are hit hardest in ciliopathies and point toward which cilia types might be correctable with genome editing. The team is already developing tools to track cilia assembly in living mice and to test “genome surgery” approaches. Similar fundamental work on cilia in the past revealed how they power sperm movement and clear mucus from lungs—breakthroughs that now underpin fertility treatments and cystic fibrosis therapies.
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Cilia are small, microtubule-based structures found on the surface of most mammalian cell types and that play important sensory and sometimes motile functions. Cilia are required for embryonic development and postnatally, for how we see, hear, smell, breathe, excrete and reproduce. Mutations in over 200 genes that affect cilia structure and/or function result in a growing list of over 40 syndromic conditions termed the ciliopathies. However, there is a growing discordance between patient genotype and associated phenotypes, with variable severity and expressivity characteristic of the ciliopathies as a group. This is in part because of the staggering structural and functional diversity of the mammalian cilia repertoire, with the underlying differences in dynamics of assembly and final molecular architecture still largely unexplored. These gaps in our understanding impact genetic diagnosis, clinical management and the development of therapeutics for the ciliopathies. We identify novel disease genes, build new disease models and uncover fundamental disease mechanisms. We engineer powerful in vivo biosensors and proximity-based proteomics reporters in mice to begin to profile differences in the mammalian cilia repertoire. We generate novel genome editing reporters to track in real time the differential ability to target primary cells and control editing outcomes in vivo, thereby enabling us to drive efforts towards 'genome surgery' so as to correct rare diseases like ciliopathies. We work with patient advisory groups nationally and internationally, drafted policy documents and acted as a hub for the international cilia and centrosome community throughout the pandemic. Here, we will harness the expertise and resources that we have developed to test exciting new hypotheses addressing how cilia diversity is hardwired at a genetic level, but also adaptively integrated at a spatial and temporal level to allow the cell to execute specialized functions via these cilia. We will explore the basis of the underlying susceptibility of different mammalian cilia types to dysfunction, and develop strategies to reverse these cellular and tissue level phenotypes with genome therapies.
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