Bioengineering shape, structure and function in primary and stem cell derived cardiomyocytes: in vitro and in-silico models of exitations contraction coupling

The pharmaceutical industry is facing a critical juncture: developing new compounds has become an extremely expensive process (~500M$/compound that makes it to clinical trials) with such a low efficiency (per single disease target, ~5/5000 compounds make it to the later stages) that will not be sustainable much longer. Return on investment in fact is threatened by the toxicity that a compound may have on on/off-targets organs or in patients with particular genetics, a fact that might be overlooked during traditional clinical trials due to limited sample size. Recently a new paradigm has been proposed named “Fail Fast, Fail Cheap” (FFFC): that is, if better predictive models can be designed for the pre-clinical trial phases a compound’s toxicity can be estimated when tests are cheaper, thus increasing the probability of the final ~5 compounds to be non-toxic. In this doctorate thesis the author investigates two strategies to achieve FFFC: i) a theoretical/computational approach to describe the biophysics of the biological systems of interest (in-silico) and male predictions regarding toxicity and efficacy and ii) an experimental approach with the use of primary and stem-cell derived cells (in-vitro). The work is focused on cardiac cells (cardiomyocytes) as cardiac toxicity has been introduced by regulatory agencies as one of the most important metric for drugs targeting any organ or disease.