NIH P50

Center for Biological Systems Architecture (CBSA)

Christina D. Smolke (PI)
Anand Asthagiri      David Baltimore      John Doyle      Michael Elowitz
Grant Jensen      Richard Murray      Dianne Newman      Rob Phillips

Goals To develop a complete and predictive understanding of the control systems that are responsible for core processes of metabolism, polymerization, assembly and signal transduction in microorganisms To apply the techniques developed through the study of individual cells to the complementary problems of communication modes and probabilistic decision processes in multi-cellular systems To develop a complete and predictive understanding of the control systems that are responsible for regulating the processes directing how mammalian cells interact with their environment. Objectives CDS: A modular platform for detecting activation through signalling pathways using FRED-basted molecular sensors applied to mapK signalling pathways.

Timeline 24 Oct, 3 pm: objectives + writing assignments (charts) 30 Oct-2 Nov: work on individual sections 3 Nov (Fri): first cut at individual sections due 5 Nov (Sun): first draft of full proposal out 6-10 Nov: updates to individual sections 13 Nov (Mon): second cut at individual sections due 14-15 Nov: CDS writing 16-19 Nov: Grants.gov massaging 20-21 Nov: polishing

Proposal Outline

Program summary (2 pages)

• Statement of goals and objectives (milestones)
• Build off of vision statement
• What makes us unique? Bringing together three essential elements
  • Computational and theoretical infrastucture for pursuing regulatory architectures
  • Unique experimental platforms
  • Unique combination of driving biological problems
• Move from small scale static to large scale, dynamic
  • Look across a class of biological applications
  • Make use of theory and computational tools to guide experiments
  • Spatial structure and stochastics become important (primarily affect the dynamics of regulation)

Organizational structure/decision making plan (2 pages)

Christina Smolke (PI)
Thrust I: Theory and computation JD? Model-checking and SOS methods for analysis of regulatory networks (John) Stochastic simulation/SBML with spatial structure (John, CACR) Feedback design of synthetic regulatory structures (Richard, John)	Thrust II: Experimental Platforms RP? FRET-based molecular sensors (Christina) Cryo-EM (Grant) Single-cell measurements (Rob, Michael, Christina)	Thrust III: Driving Biological Problems DB? NFkB, G-protein, MAPK signal transduction [& inflammation?] (David, Anand) Multi-component phosphorelays in bacterial fate choice and development (Michael) Regulatory architectures in biofilms (Dianne) Regulatory architectures in bacterial envelopes and structures (Grant, Rob, ???) Re-engineering core microbial processes/metabolic engineering (Christina)
Postdoc program Seed funding? Visitors Workshops?

Center development and outreach plans (5 pages)

• Postdocs - what we were thinking here was something like the BI fellows program, which is nicely described on the web at

http://www.its.caltech.edu/~bi/fellows.html

(basically: $50K/year stipend, $25K/year research fund. BI fellows work either with a group (or groups) in the BI or with some other group at Caltech).

• Workshops - for some of the theory tools, we could imagine running some 1-3 day workshops that provide an introduction to the use of those tools. What I'm imagining here is graduate students coming together and spending 6-8 hrs/day for a few days learning things like SBML, modeling and analysis tools, etc. We could run these for people inside and outside Caltech.

• Boot camp (?) - Rob: what do you think about the idea of incorporating the physical biology boot camp into the proposal. I think we could do this by essentially doing exactly what you are already planning - once per year for students in the BE and/or incoming students associated with CBSA plus a few times a year for outside people. The only change would be that we could use CBSA resources to help cover costs, purchase equipment, etc. All: more info on the boot camp at

http://www.rpgroup.caltech.edu/courses/PBL/bootcamp0206.htm

• Summer school (?) - within IST, we have run a "computing beyond silicon" summer school that ran for 4 weeks and brought in students and lecturers from around the country. We had lectures on various aspects of information science and technology (ranging from fundamental limits of computing to molecular electronics to information theory) and students did a small research project. We could do something similar in systems biology (but perhaps this is already covered by MBL and/or CSHL)?

• SURF support
• Visiting scientists

Research projects and preliminary studies (30 pages)

RMM: Design of feedback systems in engineered biological circuits

• Focus on developing appropriate mathematical abstractions for design of feedback circuits
• Possible thrusts:
  • Developing components of feedback systems: amplifiers (ongoing work with Erik Winfree), sensing and actuation systems (joint with Christina). Example might be a bio-PID circuit.
  • Different mechanisms for feedback in biology. This is a topic that Christina, John and I have discussed. Starting a reading group with Eric Kelsic plus some of my students to look into this.

Timeline (2 pages)

• List of milestones for years 1, 2, 3 and 4-5