Mathematical modelling to understand homeostasis and bacterial infection in human gastric glands

The human stomach is organized into millions of deep invaginations, called gastric glands, which have a well-defined architecture and are covered by a monolayer of epithelial cells. Each gland contains two distinct pools of stem cells: slow-cycling stem cells maintain the epithelium in the lower regions; actively cycling stem cells maintain the upper regions where cell turnover is rapid. Parietal cells secrete gastric acid and are crucial to the normal function of the stomach. They have also been shown to act as a barrier to adjacent cell proliferation, and so regulate gland regeneration. The mechanisms by which gastric glands are maintained under normal conditions, and the processes driving regeneration following injury, remain to be fully understood. To improve our understanding of normal and pathological gland physiology, I have developed a multicellular stochastic model of gastric gland cellular dynamics, focusing on stem cell proliferation, regeneration, and cell fate specification. During my PhD, I aim to extend this model to a larger scale, spatially resolved two- or three-dimensional model that captures more complex dynamics of gastric glands. These models will incorporate morphogen gradients (such as BMP, EGF and Noggin), mutation, and axial proliferation and movement of cells along the glands. As parallel work, I plan to analyse and model cellular pattern formation of two-dimensional mucosoids. These mucosoids can simulate different sections of the gland when fed different combinations of signalling proteins, and so can aid in designing accurate models of the full gland with different cell types at appropriate frequencies throughout. Through this modelling, I hope to understand how homeostasis is maintained in human gastric glands and how this homeostasis can be disrupted by bacterial infection. I aim to explore how infection by helicobacter pylori can lead to gastric cancer and the morphological changes the glands undergo in the progression towards carcinogenesis. The stomach is a model organ for such investigations, and this work will aid understanding in the study of the causes of other cancers. This project falls within the EPSRC mathematical biology and physical sciences research areas. I will undertake this research under supervision of Prof. Helen Byrne and Prof. Ruth Baker at the mathematical institute in collaboration with Dr Francesco Boccellato at the Ludwig Institute for Cancer Research. The Boccellato group will undertake experiments in parallel with our modelling work, which will allow accurate parameterisation of models and provide a biological basis for comparison with the simulated results.

The main impact of the SABS CDT will be the difference made by the scientists trained within it, both during their DPhils and throughout their future careers.

The impact of the students during their DPhil should be measured by the culture change that the centre engenders in graduate training, in working at the interface between mathematical/physical sciences and the biomedical sciences, and in cross sector industry/academia working practices.

Current SABS projects are already changing the mechanisms of industry academic collaboration, for example as described by one of our Industrial Partners

"UCB and Roche are currently supervising a joint DPhil project and have put in two more joint proposals, which would have not been possible without the connections and the operational freedom offered by SABS-IDC and its open innovation culture, a one-of-the-kind in UK's CDTs."

New collaborations are also being generated: over 25% of current research projects are entirely new partnerships brokered by the Centre. The renewal of SABS will allow it to continue to strengthen and broaden this effect, building new bridges and starting new collaborations, and changing the culture of academic industrial partnerships. It will also continue to ensure that all of its research is made publically available through its Open Innovation structure, and help to create other centres with similar aims.

For all of our partners however, the students themselves are considered to be the ultimate output: as one our partners describes it,

"I believe the current SABS-IDC has met our original goals of developing young research scientists in a multidisciplinary environment with direct industrial experience and application. As a result, the graduating students have training and research experience that is directly applicable to the needs of modern lifescience R&D, in areas such as pharmaceuticals and biotechnology."

However, it is not only within the industrial realm that students have impact; in the later years of their DPhils, over 40% of SABS students, facilitated by the Centre, have undertaken various forms of public engagement. This includes visiting schools, working alongside Zooniverse to develop citizen science projects, and to produce educational resources in the area of crystal images. In the new Centre all students will be required to undertake outreach activities in order to increase engagement with the public.

The impact of the students after they have finished should be measured by how they carry on this novel approach to research, be it in the sector or outside it. As our industrial letters of support make clear, though no SABS students have yet completed their DPhils, there is a clear expectation that they will play a significant role in shaping the UK economy in the future. For example, as one of our partners comments about our students

"UCB has been in constant search for such talents, who would thrive in pharmaceutical research, but they are rare to find in conventional postgraduate programmes. Personally I am interested in recruiting SABS-IDC students to my group once they are ready for the job market."

To demonstrate the type of impact that SABS alumni will have, we consider the impact being made by the alumni of the i-DTC programmes from which this proposal has grown. Examples include two start-up companies, both of which already have investment in the millions. Several students also now hold senior positions in industry and in research facilities and institutes. They have also been named on 30 granted or pending patents, 15 of these arising directly from their DPhil work.

The examples of past success given above indicate the types of impact we expect the graduates from SABS to achieve, and offer clear evidence that SABS students will become future research leaders, driving innovation and changing research culture.