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Molecular Sciences Institute Started in 1996 by Dr. Syndey Brenner (2002 Nobel Prize winner). Opened in Berkeley in 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 Center for Genomic Experimentation and Computation and the Alpha Project 2006-Became the Center for Quantitative Genome Function

How do cells recognize and respond to stimuli or perturbations to produce specific biological outcomes? CQGF Mission

Examples Cold, drought, growth and development in plants Inflammatory response Cell proliferation/differentiation Others…?

Stimulus perceived (receptor) Signal propagation Physiological response (output) How do cells to environmental stimulus

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  haploids and 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 cycle arrest Cell morphology 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

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) Measure system-wide parameters

Measuring system output

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)