Grant: Foundation Grant

Complex networks of interacting genes and proteins control all aspects of human biology and are perturbed in genetic disorders, cancer, diabetes, infection, autoimmunity, neurological dysfunction and literally every other disease state. The overarching challenge in biomedical research is thus to understand how these interconnected networks govern cellular behaviour in both health and disease. This research program will exploit leading edge genome-scale technologies to systematically map biological networks in human cells. In particular, we will use genome-wide CRISPR/Cas9-based genetic screens and sensitive protein mass spectrometry techniques to probe the cellular networks that control the growth and division of normal and cancer cells. The complexity of these measurements will require the development of databases, software tools and computational models to track and predict network responses. To exploit this knowledge for therapeutic benefit, chemicals that alter cellular networks will be identified and combined to specifically control network outputs and thereby provide a more precise means of treating disease. In parallel, the effects of thousands of different drugs, toxins and industrial chemicals will be investigated using CRISPR/Cas9-based genetic screens to understand how these compounds act on human cells. To address a serious shortfall in the drug discovery pipeline, an innovative synthetic biology strategy will be used to create massive collections of natural product-like compounds that will be screened in ultra-high throughput and low-cost formats. These novel screening technologies will allow us to identify novel modulators of network activity and will be focused on targets in infectious disease and cancer. The combined systems biology, chemical biology and synthetic biology approaches we propose will help underpin a long-term framework that will transform our understanding and treatment of disease.