Molecular Sciences Institute • Started in 1996 by Dr. Syndey Brenner (2002 Nobel Prize winner). Opened in Berkeley in 1998. Roger Brent, President and Research Director. • Create a novel interdisciplinary research environment - new approach not previously envisioned • Bring together biologists, mathematicians, engineers, computer scientists, physicists, chemists to address fundamental biological problems • Designated an NHGRI Center of Excellence in Genomic Science in 2002- Center for Genomic Experimentation and Computation and the Alpha Project • 2006-Became the Center for Quantitative Genome Function
CQGF Mission • How do cells recognize and respond to stimuli or perturbations to produce specific biological outcomes?
Examples • Cold, drought, growth and development in plants • Inflammatory response • Cell proliferation/differentiation • Others…?
How do cells to environmental stimulus • Stimulus perceived (receptor) • Signal propagation • Physiological response (output)
Yeast mating response signaling pathway • Use as a model system for obtaining a quantitative understanding of signaling systems
Yeast (Saccharomyces cerevisiae) • Bakers/brewers yeast • Eukaryote • Complete genome sequenced ~6000 genes • Experimentally tractable • Available genetic and molecular toolkit • Lots of natural genetic variation to exploit
Yeast mating involves cellular responses to an external signal • Unicellular organism with three different cell types (a and a haploids and a/a diploids) • During mating haploid cells of opposite mating type must communicate with each other • The signaling system through which the presence of mating partner is perceived and propagated is conserved across eukaryotes.
Cell morphology Cell cycle arrest Gene expression
Systems approach • Systems biology as the study of the “behavior of complex biological organization and processes in terms of the molecular constituents” Kirschner Cell, 2005 • Interdisciplinary • Molecular genetics • Cell biology • Computational Biology • ‘Omics’ e.g. Proteomics, Transcriptomics, Comparative Genomics • Biochemistry • Modeling • Systems can be small or large with complex or simple networks and many or few interactions
Models and Simulations • Aid our understanding, intuition and reasoning about complex systems • Allow us to conduct virtual experiments before going into the lab
Measure system-wide parameters • Numbers of molecules and species • Reaction rates • Interactions among protein species (what binds and with what affinity) • Changes in protein modification (e.g. phosphorylation due to activity of kinases and phosphatases)
How does understanding yeast pheromone mating response pathway lead towards understanding of human health and disease? • By our own estimates ca. 15% of vertebrate coding capacity is devoted to receptors, signaling system components and downstream transcriptional regulatory proteins • Many diseases result from dysfunction in components of signaling systems • Many diseases are polygenic and quantitative in nature (e.g. metabolic syndrome/insulin resistance leading to type II diabetes) • Understanding system function may eventually lead to improved treatments (new drugs/therapies)