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

Dec 31, 2015

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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 - PowerPoint PPT Presentation
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Page 1: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

The DARPA BioSPICE Project

Clifford A. ShafferDepartment of Computer Science

Virginia Tech

Page 2: 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

Page 3: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

Comments on Collaboration

Page 4: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

Comments on Collaboration

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

Page 5: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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.

Page 6: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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.

Page 7: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

Systems Biology: Pathway Modeling

Page 8: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

Systems Biology: Pathway Modeling

• Focus on regulatory mechanisms for biochemical networks

Page 9: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

Systems Biology: Pathway Modeling

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

Page 10: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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

Page 11: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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

Page 12: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

'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

Page 13: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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

Page 14: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

Usage ScenarioUsage Scenario

Data NotebookData Notebook

Wiring DiagramWiring Diagram

Differential EquationsDifferential Equations Parameter ValuesParameter Values

AnalysisAnalysis SimulationSimulation

ComparatorComparator

Data NotebookData Notebook

ExperimentalExperimentalDatabasesDatabases

Page 15: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

The Cell (Modeler) Cycle

• Outer Loop:– Define Reaction Equations

• Inner Loop:– Adjust parameters, initial conditions

Page 16: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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

Page 17: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

Our Mission: Build Software to Help the Modelers

Page 18: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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

Page 19: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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

Page 20: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

Another View

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

Page 21: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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.

Page 22: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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.

Page 23: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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.

Page 24: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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

Page 25: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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)

Page 26: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

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)

Page 27: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

JigCell

• Model Builder

• Run Manager

• Comparator

• Plotter

• Parameter Estimation

• Database support

Page 28: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

JigCell Model Builder

Page 29: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

JigCell Run Manager

Page 30: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

JigCell Comparator

Page 31: The DARPA BioSPICE Project Clifford A. Shaffer Department of Computer Science Virginia Tech

Plotter