Using JigCell and other BioSPICE Tools to Understand the Regulation of Cell Growth and Division

1. Using JigCell and other BioSPICE Tools to Understand the Regulation of Cell Growth and Division John J. Tyson Virginia Polytechnic Institute and State University

2. The Virginia Tech Team: Kathy Chen & Jill Sible (Biology) Cliff Shaffer & Layne Watson (CS) Collaborators: Fred Cross (Rockefeller Univ) Bela Novak (Tech Univ Budapest)

3. Outline • The biological problem • BioSPICE tools, especially JigCell • Future needs

4. The fundamental goal of molecular cell biology

5. Hanahan & Weinberg (2000)

6. cell division mitosis (M phase) G1 G2 DNA replication (S phase) Kurt Kohn (1999)

7. Getting in Touch with Your Inner Yeast Kurt Kohn (1999)

8. Fission Yeast

9. Mutant Phenotypes wee1 - cdc25 - wild type 7 mm Long G1 Short G2 Size control at G1/S 14 mm Short G1 Long G2 Size control at G2/M Very long cells Stuck in G2 Never divide Lethal

11. Literature Experimental Databases Differential Equations Parameter Values Simulation Analysis Comparison Data Notebook The Modeling Cycle Data Notebook Wiring Diagram

12. Literature Experimental Databases Differential Equations Parameter Values Simulation Analysis Comparison Data Notebook The Modeling Cycle MONOD Warehouse Data Notebook Wiring Diagram

13. Literature Experimental Databases Differential Equations Parameter Values Simulation Analysis Comparison Data Notebook The Modeling Cycle Data Notebook JDesigner PathwayBuilder Wiring Diagram

14. Literature Experimental Databases Differential Equations Parameter Values Simulation Analysis Comparison Data Notebook The Modeling Cycle Data Notebook Wiring Diagram Jarnac ModelBuilder

15. Literature Experimental Databases Differential Equations Parameter Values Simulation Analysis Comparison Data Notebook The Modeling Cycle Data Notebook Wiring Diagram RunManager

16. Literature Experimental Databases Differential Equations Parameter Values Simulation Analysis Comparison Data Notebook The Modeling Cycle Data Notebook Wiring Diagram LSODA XPP BioNetS Oscill8

17. Literature Experimental Databases Differential Equations Parameter Values Simulation Analysis Comparison Data Notebook The Modeling Cycle Data Notebook Wiring Diagram Comparator BioSenS

18. Literature Experimental Databases Differential Equations Parameter Values Simulation Analysis Comparison Data Notebook The Modeling Cycle Data Notebook Virtual Cell Gepasi Wiring Diagram CRNT AUTO WinPP

19. JigCell Nick Allen Mark Vass Jason Zwolak Tom Panning Ranjit Randhawa Bob Ball

20. Project Manager JigCell tools

21. Model Builder

22. Run Manager mutant

23. Comparator Viability = true G1 duration = 35.2 min Mass at division = 1 Viability = false Arrest state = G1 # cycles before arrest = 0

26. division birth M S bud A Wild-type Cell

27. division M S bud? A GAL-CLN2 cdh1D

28. Model Builder Parameter Optimizer Optimum Parameter Values Parameter Values Run Manager Comparator

29. Local Gradient Search(Levenberg-Marquardt)

30. Global DIRECT Search(DIViding RECTangles)

31. Global DIRECT Search(DIViding RECTangles)

34. Outline • The biological problem • BioSPICE tools, especially JigCell • Future needs • Bifurcation analysis • Spatial modeling

35. M M S/G2 M G1 Fission Yeast

36. 1e+0 1e-1 stable oscillation 1e-2 1e-3 1e-4 1e-5 0 1 2 3 4 Fission yeast – wild type max unstable steady state (M) stable steady state (S-G2) Active MPF min stable steady state (G1) cell mass

37. abscissa ordinate P Cdk1 CycB Cdk1 CycB 0 50 100 150 200 250 300 S G2 M G1 S G2 M G1 S 5 mass/nucleus 4 3 2 1 0 CKI Cdh1 Cdc20 Wee1 Cdc25 Time (min)

38. 1e+0 1e-1 stable oscillation 1e-2 1e-3 1e-4 SNIC 1e-5 0 1 2 3 4 Fission yeast – wild type max unstable steady state (M) stable steady state (S-G2) Active MPF min stable steady state (G1) cell mass

39. Nature, Vol, 256, No. 5518, pp. 547-551, August 14, 1975 Genetic control of cell size at cell division in yeast Paul Nurse Department of Zoology, West Mains Road, Edinburgh EH9 3JT, UK wild-type wee1D

40. Fission yeast 1e+0 1e-1 1e-2 1e-3 1e-4 SNIC SNIC 1e-5 0 1 2 3 4 wild type Active MPF wee1D 1e-1 Active MPF 1e-2 1e-3 1e-4 1e-5 0.0 0.5 1.0 1.5 2.0 cell mass

41. Two-parameter Bifurcation Diagram GENETICS! wee1OP Locus of SNICs wee1 gene expression wild-type heterozygote diploid wee1D PHYSIOLOGY! cell mass (a.u.)

42. 2 param bifn diag for Cdc13 Wild type mitotic cycles endoreplication cdc13D cdc13 +/D Cyclin gene expression ? ? cell mass (a.u.) Oscill8: Emery Conrad

43. actin “patches” “tea” mutants “orb” mutants Growth Patterns in Fission Yeast OE NE NE OE NETO

44. Tubulin (a/b dimer) G actin (globular) Microtubule F actin (filamentous) Motor (Tea2) Growth material Landmark (Tea1, Arp2/3) + - - - + - + + + - + - Reaction + Diffusion + Convection Cdc2 CycB Turing pattern Bias

45. NETO space NE OE time

46. A. with microtubules orb NETO monopolar bipolar cell length (μm)

47. A. with microtubules B. without microtubules orb monopolar orb T-shaped NETO curled monopolar bipolar bipolar tripolar cell length (μm) cell length (μm) CFDRC: Andrzej Przekwas

48. The End