NY Times 111607

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NY Times 11-16-07
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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

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CQGF Mission

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

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Examples

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

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How do cells to environmental stimulus

• Stimulus perceived (receptor)
• Signal propagation
• Physiological response (output)

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Yeast mating response signaling pathway

• Use as a model system for obtaining a
  quantitative understanding of signaling systems

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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

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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.

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Cell morphology
Cell cycle arrest
Gene expression
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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

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Models and Simulations

• Aid our understanding, intuition and reasoning
  about complex systems
• Allow us to conduct virtual experiments before
  going into the lab

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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)

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Measuring system output
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• 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)