To apply, please send a CV and cover letter detailing your interest in the post and your relevant skills to [email protected]
Globally, cardiovascular disease is the leading cause of deaths and the related socioeconomic costs will soon exceed a trillion dollars. Unexpected cardiotoxicity arising from drugs is a contributor, both to this issue and to the problem of rising costs of drug development. Each new drug taken to market accumulates costs of up to $1.8bn. Even after launch, drugs that pose a risk to human health can be marked with adverse drug reaction or black box notifications, or even discontinued. Indeed, in recent decades, 462 (~1 in 7) drugs have been withdrawn from market.
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs), combined with addition Cas9/CRISPR gene editing approaches, are becoming a powerful tool in evaluating the impact of drugs and disease on heart function (e.g. see our references doi: 10.1093/eurheartj/ehy249; doi: 10.1016/j.stemcr.2018.10.006; doi: 10.1093/eurheartj/eht067; doi: 10.1016/j.bbamcr.2015.10.014). We have also recently completed a study in collaboration with GSK to assess the effect of 28 drugs on hiPSC-CM contractility when cultured in 2D monolayers or in 3D engineered heart tissues.
The aim of this PhD project is to extend the work further, with focus on three areas: 1) Improve the functionality of these cells. This will be approached by bioengineering different cell types (e.g. cardiomyocytes, endothelial cells and cardiac fibroblasts) into various configurations, potentially with additional stimuli such as electrical pacing. This will include use of cells that are considered healthy or diseased, which carrying Cas9/CRISPR engineered mutations in genes that cause conditions such as hypertrophic cardiomyopathy; 2) evaluate which of these configurations is most effective at determining whether drugs in a healthy or diseased cell background are likely to cause problems with heart function, hence assist in assigning risk warnings to drugs; 3) determine whether these approaches can be integrated into additional computer modelling to improve data output. Here, GSK will provide access to their dedicated computational biology and data science teams for expert advice in developing these methods.
It is expected that the student will spend time both in the academic labs in Nottingham and in the industrial labs at GSK in Stevenage. There will also be excellent opportunities to travel, for example to collaborator labs in Hamburg, Germany. This will create an exciting studentship of biomedical, industrial and international relevance.
Skills, Techniques and Training
The enthusiastic and talented will work in a truly interdisciplinary environment, within state of the art labs in Nottingham’s flagship Centre for Biomolecular Sciences. They should be prepared to work in labs in Nottingham, GSK and possibly Germany. The project will provide a broad skill base that includes culture and cardiac differentiation of hiPSCs, as well as integration of these cells into industrially-relevant automated robotic platforms for culture and differentiation (Tecan robot), cell imaging (Operetta confocal plate reader), metabolism (Seahorse) and electrophysiology / pharmacology (CellOPTIQ), as well as in 3D configurations within engineered heart tissues.
Additional molecular and cell assays will be used, such as gene expression, quantitative RT-PCR, immuno-staining, flow cytometry, RNAseq, and bioinformatics and computational approaches. Especially during the periods at GSK, the student will gain skills in pharmacological testing and development of therapeutics, including those that interact to exacerbate or rescue states of heart disease.
Due to the challenging but potentially highly rewarding nature of the project, it will be essential for the student to have the ability to work both independently and as part of a team, as required. The student will also be expected to present their work at multiple levels from lab meetings, national / international collaborator meetings and at conferences. The Graduate School in Nottingham offers a formal programme of transferrable skills development courses, which also form part of the development process for the student.