Systems-Mechanobiology of Health and Disease

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Systems biology underpins our success in integrating the wealth of quantitative biological data generated from basic research as well as from studying complex diseases, including the UK's major killers: cancer, cardiovascular and neurodegenerative diseases. Mathematical methodology is critical to achieve this integration, and to develop predictive models that can utilise patient specific data for precision medicine applications, improving diagnostics and optimising personalised treatments.Current systems-biology models focus on the integration of multi-omics data (e.g. genomic and proteomic data), but largely neglect signatures that recent research identified to be of critical importance in driving a large class of diseases: mechanical signatures. Mechanical signatures include stiffened and realigned extracellular matrix, alterations in intracellular forces and obstructions of blood flow. These occur in a broad range of conditions such as solid tumours, atherosclerosis, cardiac fibrosis or liver cirrhosis. Crucially, we now know that these mechanical signatures are sensed by cells and can activate intracellular pathways that may further drive disease development, progression and treatment responses.However, to date, mechanical information is neglected in systems biology. This is mainly due to the lack of mathematical methodologies: systems biology and mechanics are both based on mathematical formalism, yet they were historically developed in isolation by distinct scientific communities. Through this fellowship, I will develop the urgently needed mathematical methodology and then apply it to advance a new class of models that provide fundamental insights into the bi-directional interplay of mechanical and non-mechanical signatures of cells and tissues. To maximise the predictive capabilities of the models, I will form a transdisciplinary research group with modellers and experimentalists working together to develop data-driven models and novel experiments through a robust iterative process. This programme of work will then greatly advance experimental research at the interface of systems - and mechanobiology, the field studying mechanical signatures of biology.In the first four years, I will focus on developing mathematical methodology, models and in-vitro experiments to gain fundamental scientific insights into the interplay of mechanical and non-mechanical signatures of cells and tissues. The focus of this work will be on solid tumours; however, I will engage with experts, e.g. cardiovascular scientists, to test the applicability of my methods to other disease models. Moreover, I will also work closely with a team of experts from biomedical research and the pharmaceutical industry to maximise the translational potential of this work. I will perform specific translational work from year 5 of this project. This work, together with the tailored and comprehensive training programme, will enable me to establish myself as a leader in this newly formed field, systems-mechanobiology. This field will, for the first time, bring together modellers, biologists, clinicians and industry to tackle a wide range of biomedical problems - including cancer, cardiovascular and neurodegenerative diseases and regenerative medicine - through the new systems-mechanobiology approach.