Wellcome Trust MRC Human Inducible Pluripotent Stem Cell Initiative

As it becomes cheaper and faster to sequence the DNA of individuals in the population we are faced with two challenges. One is to discover which aspects of the genetic variation between individuals are compatible with good health and which are linked to increased risk of specific diseases. The other is that it is not always obvious why a particular genetic mutation causes a particular disease; if we knew the answer we would be better placed to devise new ways to treat that disease. A technique that can help us meet these challenges is to make stem cells, known as induced pluripotent stem (iPS) cells, from small samples of the skin or blood of healthy and diseased individuals. By comparing the DNA of iPS cells with the way the cells behave when grown in the laboratory we can understand how variation in our DNA results in variation in cell behaviour and use this information to identify new disease mechanisms. The iPS cells and associated data that we generate will be freely available to researchers and doctors throughout the UK and will foster collaborations that will speed up the translation of research into improved diagnosis and treatment of disease.

We will exploit the opportunities of the UK National Health Service to generate a national resource of human iPS cells and associated data. We will generate and bank lines from 700 healthy and 800 disease-associated individuals, optimising techniques for iPS cell production and quality control. Cells will be subjected to extensive analysis of genome, epigenome, gene expression and proteome. For cells from healthy individuals, in-depth analysis of inter-individual variability will provide an open access platform for association studies of cellular function, and for distinguishing pathological from physiological variation. Patient collections will be selected via an open call, focusing initially on well-characterised conditions, where a single genetic lesion underlies a pleiotropic clinical phenotype. To characterise cellular phenotype we will construct high throughput artificial microenvironments. We will evaluate cell death, differentiation, morphology and division and specific signalling pathways. We will collaborate to produce protocols to differentiate iPS cells into disease-relevant cell types. These approaches will provide in vitro readouts of inter-individual variation and disease and a platform for gene correction and engineering specific mutations into different genetic backgrounds. Our proposal will give researchers in the UK and beyond access to iPS cells and technology linked to extensive genetic, cellular and clinical information.