Systems-Mechanobiology of Health and Disease

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.

The findings from the scientific work will have an immediate impact on basic biomedical research; this, by developing computational models to interpret existing data and drive forward future experiments through novel predictions. Then, by engaging with industrial partners (Astra Zeneca and MICA) and clinical advisors right from the start of this project, I will ensure that the basic understanding gained through this research will be translatable into the clinic. This research will therefore enable the pharmaceutical industry and clinical researchers to incorporate currently ignored mechanical information into precision medicine approaches, transforming diagnostics and opening up new avenues to therapies.

This work will initially be focused on cancer - a disease that is increasingly studied from a systems perspective, where it is appreciated that single perturbations of the system (e.g. through drugs) may have complex network effects that are hard to predict in in-vitro experiments. Yet, mechanical effects are not taken into account in systems approaches, despite the known effect of molecular, cell and tissue mechanics on disease progression. My modelling platform will be experimentally validated and then be made freely available to other researchers, clinicians and pharmaceutical companies spanning far beyond my project partners. The models will also help experimental groups to better understand how the drugs they apply will interfere with mechanochemical pathways and how different mechanical environments will affect therapy efficacy.

In solid tumours, increased matrix stiffness may reprogram cells to affect apoptosis in response to therapy. Such information will bring a new perspective to therapies that are characterised by direct mechanical effects (e.g. chemotherapies that target the microtubules (mechanical structures), and FAK, Src or integrin inhibitors that alter adhesive properties of cancer cells) or indirect mechanical effect (e.g. shrinking of the tumour will change the physical characteristics of the tumour microenvironment). Moreover, modern immunotherapies depend on the interaction of the immune system not only through cancer-immune signalling, but also through bidirectional interactions between immune system and stroma. Physical properties of the stroma may act as an impediment to immune activity (e.g. through forming physical barriers) or activate immune responses through mechanosensing pathways. By working with industrial partner AstraZeneca on the field of immuno-oncology, I will contribute to the field by delivering models that can predict the likely effect of physical characteristics of tumours on therapy success.

Moving beyond cancer, diverse diseases such as atherosclerosis, neurodegenerative diseases or liver cirrhosis are driven by mechanical alterations. Similarly, success of wound healing or regenerative medicine depends critically on mechanical properties of cells and tissues. My work will lay the foundation for systems-mechanobiology approaches that will be applied to these important health problems.

I will also contribute to the urgent need to educate the next generation of scientists that can cross the boundaries between the physical, mathematical and biomedical sciences. The PDRA and PhDs working with me will benefit from training in the latest mathematical models and methods and from cutting edge experimental biomedical research at the interface of systems and mechanobiology. The team will also work closely with leading experimental and industrial project partners to gain both the required specialist knowledge, while at the same time being immersed in a broad, transdisciplinary research environment. Moreover, outreach events and patient engagement will ensure that the general public is informed about the power of mathematical and physical sciences in transforming biology and medicine, ensuring a long-term support of the public for transdisciplinary research endeavours.