“From using stem cell models to unpick cardiovascular disease to shaping the future of heath biotechnology in the Biodiscovery Institute”

Host: Mike Ferguson 

Venue: Small Lecture Theatre, MSI

Abstract: 

This hybrid seminar will comprise two parts. First, we will provide a snapshot of my lab’s research. We use cardiovascular lineages derived from human pluripotent stem cells (hPSC-CMs) to provide a powerful tool for modelling impact of disease and drugs on heart structure and function, or for trialling cell therapies for the failing heart. We use isogenic models – engineered to carry or not carry mutations that impact heart function – to explore new mechanisms and pathways that may contribute to disease phenotype. We have implicated small nucleolar RNAs (snoRNAs), long noncoding RNAs (lncRNAs) and the mitochondrial genome in cardiomyopathies. Using this technology platform and iterations thereof, we are exploring gene-drug-phenotype relationships, with the aim of providing new therapeutics or stratification approaches to manage the impact of heart disease.

This will segway into the second part of the seminar, which will consider my role as Director of the Biodiscovery Institute (BDI). The BDI is a £100m interconnected building complex, representing the largest interdisciplinary research facility at the University of Nottingham and housing 850 researchers and support staff, including 90 academics from 5 Schools and 3 Faculties. Focus will be on how, at the start of my Directorship tenure in 2018, I coined the phrase that, “metrics are gold but people are diamonds”, to create a team ethos and an exemplary research culture. This foundation has provided an environment permissive for everyone from all career stages and job families to succeed. Across our 6 Research Themes of global importance, this is evidenced by the ‘BDI family’ leveraging £150m of new grant funding and supporting 10 new start-up companies in the last 2 years alone, towards the goal of achieving the BDI’s strapline of ‘shaping the future of health and biotechnology’.

Biography:  

Chris Denning is Professor of Stem Cell Biology and Director of the Biodiscovery Institute (BDI). The £100m Institute is the largest research facility at the University of Nottingham and houses 850 researchers, clinicians and support staff. Research is across 6 themes of global importance, encompassing Cancer, Engineering Biology, Pioneering Therapeutics, Regenerating & Modelling Tissues, Taming Microbes, and Demystifying Biomolecular Complexity.

Spanning several of BDI’s themes, Chris’ interests are in cardiovascular differentiation of human pluripotent stem cells (hPSCs: human embryonic stem cells [hESCs] and human induced pluripotent stem cells [hiPSCs]) for use in drug screening and in production of new in vitro models of genetic-based cardiovascular disease. Broadly, the main areas are:

1) Disease mechanisms. Enabled via hPSCs with or without additional targeted genetic manipulation, the lab explores how in vitro models can shed light on hitherto unknown pathways that may regulate severity and penetration of cardiovascular disease. Present and past disease examples of models investigated include defects in electrophysiology (e.g. long QT syndrome, CPVT, myotonic dystrophy), structure (e.g. myosin heavy chains, alpha-actin), survival (e.g. DMD) and signalling (e.g. beta-adrenoceptors, GRK5). This has led to the unveiling of putative modifier pathways that involve the mitochondrial genome, exosomes, long noncoding RNAs and small nucleolar RNAs in conditions such as hypertrophic cardiomyopathy. Such findings may account for the variation in clinical outcomes from patients who harbour the same primary pathogenic variant.

2) Gene-drug-phenotype relationships. Relying on healthy or diseased hPSC derivatives, particularly those carrying pathogenic variants associated with hypertrophic or dilated cardiomyopathy, Chris’ lab uses mono- or mixed-cultures of cardiomyocytes, cardiac fibroblasts and/or cardiac endothelial cells to explore gene-drug-phenotype relationships. The aim is to understand why and how different individuals respond so divergently to the same classes of drug, hence provide routes for safer drugs and personalised medicine.

3) Public outreach. Chris has spearheaded numerous initiatives to take science into the community, especially in socially deprived areas. Emphasis is on hands-on interactive workshops in the community or in the Biodiscovery Institute that typically use creative and artistic approaches to break down the barriers, which prevent non-scientists from being excited by the wonder of nature, medicine and biotechnology.