Flagship

Summary

Every person is unique and therefore we observe large differences between individuals in disease risk, treatment response and other human phenotypes. This diversity originates from an interplay between genetic and environmental variations. Optimal disease treatment or prevention for each individual requires a better understanding of the complex biology behind this interplay. Human disease modelling has been revolutionized by the arrival of induced pluripotent stem cells (iPSCs), which enables the generation of cellular and tissue models for each individual. Most iPSC studies have been conducted on a small number of donors (<10), but recent technical developments provide unique opportunities for large-scale applications (hundreds to thousands). Our Flagship “Convergence in a dish” proposes to build a novel platform to develop, test and apply large-scale Individualized CELLular models (iCELL) across the normal population, to capture and understand (genetic) diversity between individuals in complex diseases, such as neurodegenerative disease, osteoarthritis and cancer. We will use “village cultures”, where iPSCs from many individuals are co-cultured using homogeneous conditions across the village. This cost-effective design will be coupled to innovative cellular/molecular phenotyping: high-throughput spatio-temporal imaging in combination with image-guided optogenetic selection of single cells harboring specific phenotypes followed by single cell RNA/DNA sequencing and proteomics. We will further improve the iCELL models by mimicking the natural environment of cells and tissues, as well as including intrinsic (e.g., genetic) and extrinsic (e.g., environmental) factors relevant for the diseases interest. Although iCELL can be used to study all diseases, we will focus on two examples: DNA-repair and fibrosis. We will create computational models based on game theory and machine learning to analyze individual disease characteristics and predict their response to treatment. In addition, applications of iCELL technology will be guided in an interactive co-creation process, where ethics, cost-benefit and public awareness will be evaluated together with valorisation opportunities. 

Leads

1. Joyce van Meurs 

2. Joana Gonçalves 

3. Ken Redekop