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Modelling stem cell fate and alterations due to mutations

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About the Research

The group uses a combination of deep learning, stochastic models and Bayesian modelling to study questions relating to stem cell fate dynamics and how mutations in stem cells alter their normal behaviour, become fixed and accumulate in the tissue eventually leading to cancer. The group is made up of members with quantitative backgrounds (Theoretical Physics, Maths and Engineering) and would particularly welcome somebody with a similar type of background, for instance in Physics, Mathematics, Engineering, Statistics or Computer Science.

Currently we work on two main systems, the intestinal crypt and the haematopoietic system, both of which are fuelled by adult stem cells. The kind of questions we work on relate to understanding how stem cells make fate choices and how these choices lead to homoeostatic balance dynamics [Kozar et al 2013, Vermeulen et al 2013]. Also we study how these homoeostatic balances are disrupted by mutations and how the mutations spread through the tissue [Vermeulen et al 2013, Nicholson et al 2018].

We work in close collaboration with experimental scientists, in the WIMM and elsewhere (Cambridge, Cardiff, Canda), working with both cellular and molecular data. We develop modelling and statistical machine learning approaches to study and understand these systems. Some possible PhD areas to work on are blood cell mutation propagation in collaboration with experimental scientists at the WIMM, the relation between cell division properties and fate or stochastic modelling of single cell data in relation to tissue homeostasis.

Training Opportunities

The mathematical and statistical techniques that will be used cover a broad range of topics and will include deep learning, stochastic modelling, diffusion models and Bayesian Inference. Training and mentoring will be provided, so prior knowledge of these techniques is not necessary.

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

 

PuBLICATIONS

Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium. Nicholson AM, Olpe C, Hoyle A, Thorsen AS, Rus T, Colombé M, Brunton-Sim R, Kemp R, Marks K, Quirke P, Malhotra S, Ten Hoopen R, Ibrahim A, Lindskog C, Myers MB, Parsons B, Tavaré S, Wilkinson M, Morrissey E, Winton DJ. Cell Stem Cell. 2018 Jun 1;22(6):909-918.e8.
    
Defining stem cell dynamics in models of intestinal tumor initiation. Vermeulen L, Morrissey E, van der Heijden M, Nicholson AM, Sottoriva A, Buczacki S, Kemp R, Tavaré S, Winton DJ. Science. 2013 Nov 22;342(6161):995-8.
    
Continuous clonal labeling reveals small numbers of functional stem cells in intestinal crypts and adenomas. Kozar S, Morrissey E, Nicholson AM, van der Heijden M, Zecchini HI, Kemp R, Tavaré S, Vermeulen L, Winton DJ. Cell Stem Cell. 2013 Nov 7;13(5):626-33.

Supervisors

MRC WIMM Centre for Computational Biology© Martin Phelps

Part of the Centre for Computational Biology

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