Professor Massachusetts Institute of Technology, United States
The liver performs a dizzying array of functions, from metabolic homeostasis to regulation of immunity and tolerance, along with production of a vast number of serum proteins involved in wound healing, endocrine function, and many other processes. Portal blood from the gastrointestinal tract is the main blood supply, bringing with it not only all the nutrients adsorbed from the intestinal tract but many hormonal and immune regulatory molecules, and any orally-consumed drugs. This talk will provide perspective on how in vitro liver models are being developed and deployed across a spectrum of applications in drug discovery and development, from specialized “fit for purpose” assays important in prediction of human ADME-Tox (Adsorption, Distribution, Metabolism, Clearance and Toxicology) to models of complex systemic diseases such as Type 2 diabetes. A question we pose and consider is how well relatively simple fit for purpose assays capture the most important preclinical features in predicting human response, given the rising rates of metabolic liver disease in the general population. We speculate that pre-clinical ADME-Tox models may need to incorporate features of disease models, and features of the local “neighborhood” which includes intimate connection to the upstream sources of nutrients and regulatory molecules in portal blood, from the gut and pancreas. How to build such models and interpret data from them requires conceptualization of the important phenomena along with advances in hardware (microfluidic platform) and tissue engineering approaches.
