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  • Hugh Watkins

About the research

My group uses molecular genetic analysis of cardiovascular disease as a tool to define disease mechanisms and therapeutic targets. We work on rare/Mendelian genetic diseases, as well as common complex traits, and the interface between them – the influence of common variants on outcome in inherited disease. Recent work seeks to use gene silencing and gene editing techniques to create the first cures for genetic heart muscle diseases.

In inherited heart disease genetics, I have had a longstanding focus on heart muscle diseases, in particular hypertrophic cardiomyopathy, which is a common Mendelian condition which puts affected individuals at risk of sudden cardiac death and heart failure.  My group's work, using molecular biological, model organism and clinical research approaches, has defined underlying disease mechanisms and treatment targets.  Our work on genetic diagnosis of cardiomyopathy and other ‘sudden cardiac death’ syndromes has changed practice worldwide. 

Our current focus is on developing nucleic acid therapies that have the potential to cure inherited cardiomyopathies – through gene silencing, replacement or editing. To evaluate this we are modelling the effects of cardiomyopathy mutations in myofilament protein genes, and potential interventions (for example allele-specific silencing and base editing), in biochemical experiments, iPSC-derived cardiomyocytes and mouse models. I have longstanding collaborations with Professor Charles Redwood in this area and we often supervise jointly. The iPSC-cardiomyocyte work is led by Professor Chris Toepfer, a Henry Dale Fellow (Wellcome) who brings biophysical expertise to the wider group. 

This work is part of a larger international collaboration, CureHeart, winner of the British Heart Foundation’s ‘Big Beat Challenge”. This £30M programme, which I lead, brings together world leading laboratories in cardiomyopathy, gene editing and gene therapy and will provide access to cutting edge techniques and reagents, and potentially the opportunity to spend time in leading overseas laboratories. See https://www.bhf.org.uk/cureheart

Our genetic discovery efforts have included recent large scale GWAS in hypertrophic cardiomyopathy which have revealed surprisingly large influences of common variants on disease risk. We are now examining the utility of polygenic risk scores for risk prediction as well as the underlying biological implications of the many new loci.  We also have active projects using human genetic approaches to define novel disease genes (eg through the 100k genomes project), and downstream mechanisms, in families with unexplained familial cardiac syndromes. This continues to be a productive source of insights into fundamental cardiac biology and also often leads to direct improvements in patient care.

Additional supervision may be provided by Associate Professor Charles Redwood and Dr Chris Toepfer. 

 

Training Opportunities

Depending on the prior experience and interests of the successful candidate, projects in the group would provide training in computational and wet lab aspects of human genetic analysis, including gene discovery through whole genome sequencing, creation and analysis of mouse models and/or human iPSC-derived cardiomyocytes (both via genome-editing with CRISPR-cas9), cardiac phenotyping of mouse and cellular models, and exploration of gene silencing/gene editing (including use of allele-specific antisense oligonucleotides, Base editors and Prime editors) as potentially curative strategies for genetic diseases.

Students will be encouraged to attend 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.

 

publications

1

Watkins H, Ashrafian, Redwood C. Mechanisms of Disease: Inherited Cardiomyopathies.  New Engl J Med   2011; 364:1643-56.

2

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 Aug 17. doi: 10.1038/gim.2016.90.

3

Robinson P, Liu X, Sparrow A, Patel S, Zhang YH, Casadei B, Watkins H, Redwood C. Hypertrophic cardiomyopathy mutations increase myofilament Ca2+ buffering, alter intracellular Ca2+ handling, and stimulate Ca2+-dependent signaling. J Biol Chem. 2018;293:10487-10499.

4

Toepfer CN, Wakimoto H, Garfinkel A, McDonough B, Liao D, Jiang J, Tai AC, Gorham JM, Lunde IG, Lun M, Lynch TL 4th, McNamara JW, Sadayappan S, Redwood CS, Watkins H,  Seidman JG, Seidman CE. Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin. Sci Transl Med. 2019 Jan 23;11(476). pii: eaat1199. doi: 10.1126/scitranslmed.aat1199.

5

Harper AR, Goel A, Grace C, Thomson K, Petersen SE, Xu X, Waring A, Ormondroyd E, Kramer C, Neubauer S, Tadros R, Wars JS, Bezzina C, Farrall M, Watkins H.  Common genetic variants, and modifiable risk factors, underpin susceptibility and expressivity in hypertrophic cardiomyopathy. Nature Genetics 2021 Feb;53(2):135-142. doi: 10.1038/s41588-020-00764-0.