The DARPA BioSPICE Project

Clifford A. ShafferDepartment 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

Cln3

Mass

Budding

Cln2SBF

Bck2

and

Clb5MBF

DNA synthesisClb?

SCFP Sic1

Cln2

Sic1

Sic1 Clb5

Swi5

Sister chromatid separation

Unaligned Xsomes

Cdc20 Cdc20Clb5Clb2

Cdh1

Cdh1

Clb2Cdc20

Cdc20

Sic1 Clb2

Clb2Mcm1

Mitosis

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

'1 1 2

d[Cln2][SBF] [Cln2]

dk k k

t

' '3 3 4 4 5

d[Clb2][Mcm1] [Cdh1] [Clb2] [Sic1][Clb2]

dk k k k k

t

' '6 6 T 7 7

6 T 7

[Cdc20] [Cdh1] [Cdh1] [Clb5] [Cdh1]d[Cdh1]

d [Cdh1] [Cdh1] [Cdh1]

k k k k

t J J

synthesis degradation

synthesis degradation binding

activation inactivation

0 50 100 150

0.0

0.5

1.0

1.5

0.0

0.5

0.0

0.5

1.0

1

2

Time (min)

Sic1

mass

Clb2

Cln2

Cdh1

Simulation of the budding yeast cell cycle

G1 S/M

Cdc20

Usage ScenarioUsage Scenario

Data NotebookData Notebook

Wiring DiagramWiring Diagram

Differential EquationsDifferential Equations Parameter ValuesParameter Values

AnalysisAnalysis SimulationSimulation

ComparatorComparator

Data NotebookData Notebook

ExperimentalExperimentalDatabasesDatabases

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