Understanding the mechanism of human disease is a critical step in developing novel therapeutics. However, small animal models fail to replicate human physiology and thus seldom translate to the clinic. Stem cell-derived organoids close this gap by emulating human physiology (Clevers Cell 2016). Our group integrates metabolic sensors in living human organoids to unravel complex biological processes over extended periods of time. Our research elucidated key mechanisms in nephrotoxicity, arrhythmia, and metabolic dysfunction, validating these findings in clinical studies.

 

 

Sensors allowed us to elucidate the idiosyncratic (‘unexplained’) toxicity of troglitazone, a drug withdrawn from the market due to liver damage (Bavli et al. PNAS 2016). In more recent studies we demonstrated that cisplatin-induced renal damage can be mitigated by co-administration of empagliflozin, a SGLT2 inhibitor, significantly improving therapeutic safety (Cohen et al., Science Transl. Med., 2021)​. Additionally, our work on cardiac organoids revealed that human mitochondrial fluxes oscillated at high frequency in tandem with the electrical activity of cardiomyocytes, providing insights into chemotherapy-induced arrhythmias and their partial reversal using metformin (Ghosheh et al., Nature Biomed., 2023)​.

 

This technology was integrated into the Dynamics® microphysiological flux analyzer developed with Tissue Dynamics. The technology offers a transformative approach for human-relevant drug discovery and mechanism-driven therapeutic development, marking a paradigm shift in biomedicine.