Abstract

Organoids: A Patient In the Lab

René Overmeer, Assay Development & Screening Manager, Hubrecht Organoid Technology (HUB)

Organoids such as IPSC derived brain organoids (Lancaster et al Nature 2013) or our adults epithelial stem cell derived organoids (Sato et al., Nature 2009, 2011) are proving to be a major breakthrough in preclinical models. The new patient like models are fundamental change in the way drug discovery and development can be performed. The development of the HUB Organoids started in the lab of Hans Clevers with the discovery of the identity of adult stem cells in human epithelial tissues such as intestine and liver (Barker et al., Nature 2007; Huch et al., Nature 2013). With the identification of these stem cells, we were able to develop a culture system that allowed for the virtually unlimited, genetically and phenotypically stable expansion of the epithelial cells from most, if not all, epithelial animal and human tissues, both from healthy and diseased tissue (Sato et al., Nature 2009, 2011; Gastroenterology 2011; Huch et al., Nature 2013, Cell 2015; Boj et al., Cell 2015). We have now generated HUB organoid models from most epithelial organs. Recently, we and others have demonstrated that the in vitro response of organoids correlates with the clinical outcome of the patient from which the organoid was derived (Dekkers et al., Sci Trans Med 2016; Sachs et al., Cell 2018; Vlachogiannis et al., Science 2018). In addition, we have developed a coculture system using HUB Organoids and the immune system to study this interaction and drugs that target the role of the immune system in cancer and other diseases. We have recently developed new models to study intestinal and lung barrier function and transport of the epithelium of these organs. These experiments show how organoids can be used to study mechanism that underly barrier function disruption in IBD or COPD. Furthermore, we have developed new models to study the interaction between immune system and epithelium. The combination of the new coculture models and assay development to study the epithelium allows us new insights into disease mechanisms and drug treatment strategies.