Davis Group – Stem Cells & Genetics of Cardiac Diseases
It is currently estimated that inherited cardiac diseases such as channelopathies and cardiomyopathies affect between 1:500–1:3000 individuals in the general population. Also common are acquired cardiac arrhythmias, predominantly caused by an adverse response to medication, and are a major challenge to clinicians and pharmaceutical companies. These too have a significant heritable component. Although thousands of mutations have been associated with these diseases, two outstanding issues remain. Firstly, it is difficult to prove the identified mutation is causal, and secondly large differences in disease severity are seen even among patients with the same primary mutation (Figure 1). This variability in severity is related not only to the mutation type and position of the mutation within the gene but can also be influenced by variants in regulatory regions or in secondary modifier genes. It is likely that genomic loci identified in genome wide association studies (GWAS) contribute to this variable phenotype. However, an inherent limitation of GWAS is that it illuminates regions in the genome associated with a trait but does not identify the exact genetic variant and gene mediating that effect.
Figure 1. Examples of genetic contributors to variable disease expression. A) Variability in disease risk can be due to the location and/or type of mutation in the gene.
B) Variability in disease severity is also influenced by additional variants/SNPs in genetic modifiers. (van den Brink et al., Stem Cells, 2020).
Figure 2. hPSC-derived cardiomyocytes expressing genetic reporters for optically measuring the complete excitation-contraction coupling cascade.
Inherited cardiac diseases
The lab uses human pluripotent stem cells (hPSCs) to investigate how specific genetic variants/mutations contribute to these inherited cardiac diseases. We have demonstrated that hPSCs, namely embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) generated by reprogramming somatic cells, serve as suitable in vitro disease models. These cells can generate the major cardiomyocyte subtypes (atrial, ventricular and pacemaker cells), and as many cardiac diseases are autonomous to the cardiomyocyte, hPSCs are promising in vitro paradigms for understanding disease pathophysiology and for identifying pathways to target in ameliorating the conditions. However current methods for generating such models and then assessing the consequence of a genetic variant on the physiological properties of the cardiomyocyte are labour-intensive and time-consuming. Within the group we also look to develop strategies to make these procedures more scalable and higher throughput.
- Dr. Richard Davis (Group leader)
- Dr. Loukia Yiangou (Researcher)
- Karina Olivera Brandão (PhD student)
- Lettine van den Brink (PhD student)
- Tessa de Korte (PhD student)
- Albert Blanch Asensio (PhD student)
- Mervyn Mol (Research technician)