Wellcome Trust Intermediate Clinical Fellow
- Consultant Physician
Inherited heart disease is neither rare nor benign. It is a leading cause of death and premature heart failure in apparently healthy young adults. Patients in this cohort account for half the UK heart transplant population. In the past decade the genetic basis for the condition has been defined but progress establishing exactly how and why particular mutations cause particular conditions has been difficult and slow.
There are two reasons for this. Firstly the biochemical events driving the cardiomyopathy process occur rapidly and reversibly within a beating cell making them difficult to isolate. Secondly heart cells (cardiomyocytes) are difficult to work with outside the body, and last only hours in a lab environment. We are trying to overcome these difficulties, to improve understanding of disease mechanism, with a combination of light and magic.
LIGHT: In a beating cell we need to resolve biochemical events with millisecond speed and micrometer precision. We can do that with light emitting reporters that change their brightness in the presence, or absence, of a chemical of interest, eg calcium. In collaboration with Takeharu Nagai (Royal Society International Joint Project Grant) we are adapting and evolving current reporters to provide a real time, multicolour image of the internal workings of a living heart cell.
MAGIC: By the forced expression of only four genes we can now make cells that behave like the cells of the early embryo from any tissue. These cells are called induced pluripotent stem cells, and have two important properties. Firstly they can self renew indefinitely. Secondly they can be told to become any cell type in the body. When we make these cells from the skin cells of patients seen in the Inherited Heart Disease Clinic they carry the same genetic spelling mistake allowing us to model the patients disease in the lab. Fortunately heart cells that have only ever known life in a dish are much more robust and live for months rather than hours.
Putting these two technologies together provides a unique basis for understanding the process of how mutation causes disease. We hope this knowledge will enable us to search for new treatments. If you would like to know more about our work, and think you could contribute, either as a colleague or a sample donor please get in touch via the details above.
Fluorescent, Bioluminescent, and Optogenetic Approaches to Study Excitable Physiology in the Single Cardiomyocyte.
Broyles CN. et al, (2018), Cells, 7
Genetically encoded bioluminescent voltage indicator for multi-purpose use in wide range of bioimaging.
Inagaki S. et al, (2017), Sci Rep, 7
Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations.
Liao C. et al, (2017), Neurology, 88, 131 - 142
Non-invasive phenotyping and drug testing in single cardiomyocytes or beta-cells by calcium imaging and optogenetics.
Chang Y-F. et al, (2017), PLoS One, 12
Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma.
Falletta P. et al, (2017), Genes Dev, 31, 18 - 33