The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

1
The DARPA BioSPICE ProjectClifford A.
ShafferDepartment of Computer ScienceVirginia
Tech
2
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

3
Comments on Collaboration
4
Comments on Collaboration

• Domain team routinely underestimates how
  difficult it is to create reliable and usable
  software.

5
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.

6
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.

7
Systems Biology Pathway Modeling
8
Systems Biology Pathway Modeling

• Focus on regulatory mechanisms for biochemical
  networks

9
Systems Biology Pathway Modeling

• Focus on regulatory mechanisms for biochemical
  networks
• Start with a wiring diagram

10
Budding
Sister chromatid separation
Cln2
SBF
Mass
Cdh1

Cln3
and
Bck2
SCF
Cdc20
MBF
Clb5
DNA synthesis
11
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

12
(No Transcript)
13
Simulation of the budding yeast cell cycle
mass
Sic1
Cln2
Clb2
Cdh1
Cdc20
Time (min)
14
Usage Scenario
Data Notebook
Wiring Diagram
Differential Equations
Parameter Values
Simulation
Analysis
Comparator
Data Notebook
15
The Cell (Modeler) Cycle

• Outer Loop
• Define Reaction Equations
• Inner Loop
• Adjust parameters, initial conditions

16
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

17
Our Mission Build Software to Help the Modelers
18
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

19
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

20
Another View

• Current models of simple organisms contain a few
  10s of equations.

21
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.

22
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.

23
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.

24
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

25
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)

26
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)

27
JigCell

• Model Builder
• Run Manager
• Comparator
• Plotter
• Parameter Estimation
• Database support

28
JigCell Model Builder
29
JigCell Run Manager
30
JigCell Comparator
31
Plotter