Leap in modelling cardiovascular disease

American scientists have made a huge leap forward in genetic modelling after growing functioning human heart tissue carrying an inherited cardiovascular disease for the first time. The Harvard team combined “organ-on-a-chip” and stem cell technologies to show that a chunk of tissue containing a patient’s specific genome can be replicated in the laboratory. “You don’t really understand the meaning of a single cell’s genetic mutation until you build a huge chunk of organ and see how it functions or doesn’t function,” said Kevin Kit Parker, who has spent more than a decade working on organ-on-a-chip technology. Researchers took skin cells from two Barth patients – a rare X-linked cardiac disorder caused by a mutation in a single gene called Tafazzin or TAZ – and manipulated the cells to become stem cells that carried the patients’ TAZ mutations. The cells were grown on chips lined with human extracellular matrix proteins that mimicked their natural environment, tricking the cells into joining up as if they were forming a diseased human heart. The engineered tissue contracted very weakly, as would the heart muscle of a Barth syndrome patient. The researchers then used genome editing to mutate TAZ in normal cells, confirming that the mutation is enough to cause this weak contraction. Delivering the TAZ gene product to diseased tissue in the lab corrected the contractile deficit, creating the first tissue-based model of correction of a genetic heart disease. “In the case of the cells grown out of patients with Barth syndrome, we saw much weaker contractions and irregular tissue assembly,” said Parker. “Being able to model the disease from a single cell all the way up to heart tissue, I think that’s a big advance.” The scientists discovered the TAZ mutation disrupts the normal activity of mitochondria by producing an excess amount of reactive oxygen species, but didn’t seem to affect the overall energy supply of the cell. The researchers could have identified a new function for the organelle, describing a direct link between mitochondrial function and the heart’s ability to build itself in a way that allows it to contract.” The research team are now trying to translate this finding by doing reactive oxygen species and gene-replacement therapy in animals of Barth syndrome to see how it might help human patients. They are also using their heart disease-on-a-chip as a testing platform for drug under trial or already approved that might be useful to treat the disorder. The work has been published in Nature Medicine.