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Constructing and deconstructing biological models

Constructing and deconstructing biological models. John K Heath, Marta Z Kwiatkowska, Paolo Ballarini, Corrado Priami, Maria Luisa Guerriero. Dagstuhl 2009. Why would a biologist want to model?. Store and share knowledge Reason about the process Prioritise experiments

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Constructing and deconstructing biological models

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  1. Constructing and deconstructing biological models John K Heath, Marta Z Kwiatkowska, Paolo Ballarini, Corrado Priami, Maria Luisa Guerriero Dagstuhl 2009

  2. Why would a biologist want to model? • Store and share knowledge • Reason about the process • Prioritise experiments • Design better experiments • Identify flaws/errors/ignorance • Identify better interventions

  3. Components States Rates N2BB Executable or Algorithmic Biology Hypothesis Interpretation Evaluation Experiment Algorithm (instructions) BioSpi Ambient BB Model Checking (interrogation) PRISM The pathway is articulated as an executable programme • Fisher and Henzenger ‘07 • Priami ‘09 • Kwiatkowska and Heath ‘09

  4. Verifiable Biological Data Computational Formalism An equivalence relationship?

  5. 5 0 2 15 60 10 30 180 120 pY705 STAT3: STAT3: Time (mins) Locating and tracking State changes

  6. Spatial location and co-association Src-WT-GFP PY416 PY463 Src-WT-GFP + PY416 Src-WT-GFP + P463 All 3

  7. Dynamic movement between compartments

  8. Process calculus concepts and theirbiological counterparts

  9. A Biological Narrative language Can we formulate a signaling pathway in a biologically intuitive language which is based on experimental data and exploits the advantages of process calculi? • The compartments in which actions occur • The components comprising the system • The actions that occur (rates) • A “narrative” of temporal evolution • Assign confidence values to statements • Translate into an executable format (BB) • Biologically Intuitive yet logically precise

  10. Translating a signaling pathway • “Components”: • Gp130, LIFR, STAT • “Sites”: eg • Y653, Y654, Y55 • “States”: • phosphorylated, ubiquitinylated, exist • “Transitions”: • Bind, Phosphorylate, relocate, degrade, appear • “Compartments”: • Nucleus, plasma membrane, cytosol… • Merge, move, exclude

  11. Translated to Beta binders

  12. 0 2 5 60 10 15 30 180 120 pY705 STAT3: STAT3: Time (mins) Experiment vs model

  13. Parameter sensitivity: nuclear export

  14. Parameter sensitivity: nuclear dephosphorylation

  15. Parameter sensitivity: nuclear export vs dephosphorylation

  16. Directions • Decomposition of large (“real”) pathways • (Biological subroutines) • Automatic model building from data libraries • Synthetic biology • Articulating a specified biological device

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