Developing quantitative models of tissue morphogenesis using vertex models with boundary constraints

The context of the research
Many human diseases can be traced to defects during embryogenesis. for example, upwards of 50% of human heart disease can be traced to tissues during development. Yet, understanding the fundamental mechanisms driving organ formation remain porrly understood. This is due to lack of accessibility to the organs during their formation. Recently, organoid systems have been developed, which enable organ-like structures to be grown in the lab from stem cells. These organoids can self-organise into morphologies that resemble the real organs. Using these organoid systems, we cna imagine their formation and use these to develop quantitative models for organ formation. Until recently, organoids have not been physicallt contstrianed during their growth: yet in vivo, organs do not grow independant from the surrounding space. Here, we plan to explore how boundary constraints and tissue-tissue interactions drive the emergence of complex organ morphology.
The aims and objectives of the research
The overarching aim is to develop a three-dimensional model for the initial formation of the human nervous system. Specifically:
Aim 1: Advance vertex models to develop three-dimesional cell morphologies with multiple tissue types (year 1)
Aim 2: Develop a framework to implement a variety of boundary constraints and tissue-tissue interactions (year 1-3)
Aim 3: Generate quantitative predictions that can be tested in the partner laboratory (year 2-3)
The novelty of the research methodology
Vertex models have been extensively used over the past 15 years. However, they have typically been either in two- dimensions or not constrained aggregates in three-dimensions. Yet, in vivo, tissues form layered tissues in three-dimensions within constrained environments. We will develop novel approaches to tackle more realistic tissue formation that have broad potential for impact. This will provide new insights into the theory of active matter, as well as developing important computational tools that will have broad applicabilty. In particular, the role of boundaries in determining active tissue behaviour is currently poorly understood.
The potential impact, applicaitons and benefits
The study of tissue morphogenesis answers fundamental questions in developmental biology. The development of constrained three-dimensional models of organ fomraiton has wide potential impact and application. At a fundamental level, this framework will enable exploration and testing of active models of living systems, or even deduce which local proliferation and reorganisation patterns are necessary for achieving organ shaping. The model can also be applied to make specific predictions regarding how complex organ shape emerges. This has potential to provide importnat insights into health and medicine.
How the research relates to the remit
EPSRC is fully supportive of interdisciplinary science that applies the strengths of physics and mathematical approaches to biologically relevant problems. This is exemplified by the EPSRC-funded Physics of life grant held between the Saunders, Charras and Briscoe laboratories. The research will generate new models and approaches that will have clear interest to physicists and mathematicians yet will also provide strong insights into fundamental biological questions. This project falls in Healthcare technologies, Mathematical Sciences and Physical Sciences research areas.
External Partner - Crick Institute - This work is part of a Physics of Life grant awarded to Assoc. Prof Sunders and Dr James Briscoe. James Briscoe and his lab will provide high quality experimental imaging data that is an essential input into the model. This will involve live movies fo organoids as they form,a s well as imaging data from fixed tissue samples. Importantly, they will also perform perturbation experiments to test model predictions. This back-and-forth is an exciting part of modern quantitative biological approaches.

In the 2018 Government Office for Science report, 'Computational Modelling: Technological Futures', Greg Clarke, the Secretary of State for Business Energy and Industrial Strategy, wrote "Computational modelling is essential to our future productivity and competitiveness, for businesses of all sizes and across all sectors of the economy". With its focus on computational models, the mathematics that underpin them, and their integration with complex data, the MathSys II CDT will generate diverse impacts beyond academia. This includes impacts on skills, on the economy, on policy and on society.

Impacts on skills.
MathSys II will produce a minimum of 50 PhD graduates to support the growing national demand for advanced mathematical modelling and data analysis skills. The CDT will provide each of them with broad core skills in the MSc, a deep knowledge of their chosen research specialisation in the PhD and a complementary qualification in transferable skills integrated throughout. Graduates will thus acquire the profiles needed to form the next generation of leaders in business, government and academia. They will be supported by an integrated pastoral support framework, including a diverse group of accessible leadership role models. The cohort based environment of the CDT provides a multiplier effect by encouraging cohorts to forge long-lasting professional networks whose value and influence will long outlast the CDT itself. MathSys II will seek to maximise the influence of these networks by providing topical training in Responsible Research and Innovation, by maintaining a robust Equality, Diversity & Inclusion policy, and by integration with Warwick's global network of international partnerships.

Economic impacts.
The research outputs from many MathSys II PhD projects will be of direct economic value to commercial, public sector and charitable external partners. Engagement with CDT partners will facilitate these impacts. This includes co-supervision of PhD and MSc projects, co-creation of Research Study Groups, and a strong commitment to provide placements/internships for CDT students. When commercial innovations or IP are generated, we will work with Warwick Ventures, the commercial arm of the University of Warwick, to commercialise/license IP where appropriate. Economic impact may also come from the creation of new companies by CDT graduates. MathSys II will present entrepreneurship as a viable career option to students. One external partner, Spectra Analytics, was founded by graduates of the preceding Complexity Science CDT, thus providing accessible role models. We will also provide in-house entrepreneurship training via Warwick Ventures and host events by external start-up accelerator Entrepreneur First.

Impacts on policy.
The CDT will influence policy at the national and international level by working with external partners operating in policy. UK examples include Department of Health, Public Health England and DEFRA. International examples include World Health Organisation (WHO) and the European Commission for the Control of Foot-and-mouth Disease (EuFMD). MathSys students will also utilise the recently announced UKRI policy internships scheme.

Impacts on society.
Public engagement will allow CDT students to promote the value of their research to society at large. Aside from social media, suitable local events include DataBeers, Cafe Scientifique, and the Big Bang Fair. MathSys will also promote a socially-oriented ethos of technology for the common good. Concretely, this includes the creation of open-source software, integration of software and data carpentry into our computational and data driven research training and championing open-access to research. We will also contribute to the 'innovation culture and science' strand of Coventry's 2021 City of Culture programme.