Twigg Group: Building the skull – normal and abnormal development

Supervisor: Stephen Twigg

About the Research 

Using a combination of patient samples and mouse models, we study the causes and developmental origins of craniofacial malformations, particularly those affecting the skull. The work ranges from screening human DNA for new mutations, to the use of genome editing and single cell transcriptomics to model and analyse the developmental causes of these malformations in mice. Projects on offer would particularly appeal to students interested in genetics, genomics and developmental mechanisms and for whom clinical application is a key motivator. There will be particular opportunities to learn core bioinformatics skills, perform single cell analysis, work with iPS cells, and use genome editing to generate and characterise mouse models to understand disease mechanisms.

Our work is focused on the causes of skull malformations, particularly craniosynostosis, the premature fusion of one or more sutures separating the bones of the skull vault. A complex network of developmental mechanisms is involved in patterning and maintaining this complex system of bones, and a variety of genetic mutations can affect these processes to cause serious skull malformations. Oxford is a leading national referral centre in the surgical treatment of these malformations, enabling us to study the entire process by which these arise from patient to mutation, and from mouse model to molecular pathogenesis.

For the study of clinical samples, massively parallel genome sequencing has revolutionised the identification of Mendelian disease genes. Our group has identified many new human disease genes using this approach and the UK’s Genomics England 100,000 Genomes project (https://www.genomicsengland.co.uk/), NHS Genomic Testing and our own genome analysis programme will provide further opportunities for discovery during the course of the studentship. To investigate pathophysiology, we model carefully selected mutations in mice. We still know very little about what happens biologically in the cranial sutures themselves: these structures must achieve a delicate balancing act of enabling growth of new bone at the margins of the suture, whilst also ensuring that the mid-part of the suture remains open along its entire length. We explore how the suture works by mapping out the cellular hierarchy of activities from undifferentiated stem cell to fully formed osteoblast, comparing results between normal sutures and those from mice with targeted mutations. In addition, we are very interested in the mechanical processes that drive skull expansion, and some of the work of the group is devoted to understanding mechanotransduction in the suture, and how this could potentially help children who have cranial surgery.

This project is not suitable for part-time research. 

Training Opportunities 

You will learn how to use a wide range of web resources to interpret genomic information from human, mouse and other species. For experimental work, you will be exposed to a wide variety of techniques, including cell culture, fluorescence-activated cell sorting (FACS), microscopy, single cell transcriptomics and next-generation sequencing, as well as basic molecular biology methodologies for analysing DNA, RNA and protein, all of which are essential for functional characterisation of mutations. If working on mice, you will obtain your own personal license and undergo training in husbandry and experimental analysis, with opportunities for further training through courses offered via the NMGN at the Mary Lyon Centre at Harwell.

Acquisition of bioinformatics skills is central to progress in biology, whether applied to genome sequence analysis, single cell transcriptomics, or epigenomics. Full support will be available through the WIMM Centre for Computational Biology and ongoing collaborations with bioinformatic groups. For clearly defined projects requiring advanced bioinformatics skills, there will be the opportunity for more intensive training through the in-house Computational Genomics: Analysis and Training (CGAT) programme.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine 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.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold 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.

Additional Supervisors

1. Andrew Wilkie

2. Jim Hughes 

Publications