Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech VT Team Biology: John Tyson, Jill Sible, Kathy Chen, Laurence Calzone, Emery Conrad, Andrea Ciliberto, Amit Dravid Computer Science: Cliff Shaffer, Layne Watson, Naren Ramakrishnan, Marc Vass, Nick Allen, Jason Zwolak, Dan Mosia, Sumit Shah, Mohsen Ghomi Comments on Collaboration Comments on Collaboration Domain team routinely underestimates how difficult it is to create reliable and usable software. Comments on Collaboration • Domain team routinely underestimates how difficult it is to create reliable and usable software. • CS team routinely underestimates how difficult it is to stay focussed on the needs of the domain team. Comments on Collaboration • Domain team routinely underestimates how difficult it is to create reliable and usable software. • CS team routinely underestimates how difficult it is to stay focussed on the needs of the domain team. • Partial solution: truly integrate. Systems Biology: Pathway Modeling Systems Biology: Pathway Modeling • Focus on regulatory mechanisms for biochemical networks Systems Biology: Pathway Modeling • Focus on regulatory mechanisms for biochemical networks – Start with a wiring diagram Sister chromatid separation Budding SBF Cln2 Unaligned Xsomes Cln3 and Cdh1 Clb2 Mitosis Sic1 Clb2 Bck2 Clb5 Clb2 Cdc20 Cdc20 Mcm1 Cdh1 Clb2 Cdc20 Swi5 P Sic1 Cln2 Sic1 Clb5 Cdc20 MBF Clb? Clb5 DNA synthesis Sic1 SCF Systems Biology: Pathway Modeling • Focus on regulatory mechanisms for biochemical networks – Start with a wiring diagram • Some example problems: – Cell Cycle (John Tyson) – Circadian Rhythms d[Cln2] k1 k1' [SBF] k2 [Cln2] dt synthesis degradation d[Clb2] k3 k3' [Mcm1] k4 k4' [Cdh1] [Clb2] k5 [Sic1][Clb2] dt synthesis d[Cdh1] k dt binding degradation ' k 6 6 [Cdc20] [Cdh1]T [Cdh1] J 6 [Cdh1]T [Cdh1] activation k ' k 7 7 [Clb5] [Cdh1] J 7 [Cdh1] inactivation Simulation of the budding yeast cell cycle 2 mass 1 1 . 0 Sic1 Cln2 0 . 5 0 . 0 G1 1 . 5 Cdh1 1 . 0 0 . 5 S/M Clb2 0 . 5 Cdc20 0 . 0 0 . 0 0 5 0 1 0 0 Time (min) 1 5 0 Usage Scenario Data Notebook Experimental Databases Wiring Diagram Differential Equations Analysis Parameter Values Simulation Comparator Data Notebook The Cell (Modeler) Cycle • Outer Loop: – Define Reaction Equations • Inner Loop: – Adjust parameters, initial conditions Fundamental Activities • Collect information – Search literature (databases), Lab notebooks • Define/modify models – A user interface problem • Run simulations – Equation solvers (ODEs, PDEs, deterministic, stochastic) • Compare simulation results to experimental data – Analysis Our Mission: Build Software to Help the Modelers Our Mission: Build Software to Help the Modelers • Now: Typical cycle time for changing the model is one month – – – – Collect data on paper lab notebooks Convert to differential equations by hand Calibrate the model by trial and error Inadequate analysis tools Our Mission: Build Software to Help the Modelers • Now: Typical cycle time for changing the model is one month – – – – Collect data on paper lab notebooks Convert to differential equations by hand Calibrate the model by trial and error Inadequate analysis tools • Goal: Change the model once per day. – Bottleneck should shift to the experimentalists Another View • Current models of simple organisms contain a few 10s of equations. Another View • Current models of simple organisms contain a few 10s of equations. • To model mammalian systems might require two orders of magnitude in additional complexity. Another View • Current models of simple organisms contain a few 10s of equations. • To model mammalian systems might require two orders of magnitude in additional complexity. • We hope our current vision for tools can supply one order of magnitude. Another View • Current models of simple organisms contain a few 10s of equations. • To model mammalian systems might require two orders of magnitude in additional complexity. • We hope our current vision for tools can supply one order of magnitude. • The other order of magnitude is an open problem. BioSPICE • DARPA project • Approximately 15 groups • Many (not all) of the systems biology modelers and software developers • An explicit integration team • Goal: Define mechanisms for interoperability of software tools, build an expandable problem solving environment for systems biology • Result: software tools contributed by the community to the community Tools • Specifications for defining models (markup languages) • “Electronic Lab Notebooks” and access to literature, experiments, etc. • User interface for specifying models, parameters, initial conditions • Simulators (equation solvers) Tools (cont.) • Automated parameter estimation (calibration) • Analysis tools for comparing simulation results and experimental results • Analysis tools for “higher order” analysis of models (bifurcation analysis) • Database support for simulations (data mining) JigCell • • • • • • Model Builder Run Manager Comparator Plotter Parameter Estimation Database support JigCell Model Builder JigCell Run Manager JigCell Comparator Plotter