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

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

• John J. Tyson
• Virginia Polytechnic Institute
• and State University

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The Virginia Tech Team

• Kathy Chen Jill Sible (Biology)
• Cliff Shaffer Layne Watson (CS)

Collaborators Fred Cross (Rockefeller
Univ) Bela Novak (Tech Univ Budapest)
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Outline

• The biological problem
• BioSPICE tools, especially JigCell
• Future needs

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The fundamental goal of molecular cell biology
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Hanahan Weinberg (2000)
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Kurt Kohn (1999)
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Getting in Touch with Your Inner Yeast
Kurt Kohn (1999)
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Fission Yeast
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Mutant Phenotypes
cdc25 -
wee1 -
wild type
14 mm Short G1 Long G2 Size control at G2/M
7 mm Long G1 Short G2 Size control at G1/S
Very long cells Stuck in G2 Never divide Lethal
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The Modeling Cycle
Data Notebook
Wiring Diagram
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The Modeling Cycle
MONOD
Warehouse
Data Notebook
Wiring Diagram
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The Modeling Cycle
Data Notebook
JDesigner
PathwayBuilder
Wiring Diagram
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The Modeling Cycle
Data Notebook
Wiring Diagram
Jarnac
ModelBuilder
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The Modeling Cycle
Data Notebook
Wiring Diagram
RunManager
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The Modeling Cycle
Data Notebook
Wiring Diagram
LSODA XPP BioNetS
Oscill8
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The Modeling Cycle
Data Notebook
Wiring Diagram
Comparator
BioSenS
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The Modeling Cycle
Data Notebook
Virtual Cell Gepasi
Wiring Diagram
CRNT AUTO
WinPP
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Nick Allen Mark Vass Jason Zwolak Tom
Panning Ranjit Randhawa Bob Ball
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Project Manager
JigCell tools
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Model Builder
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Run Manager
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Comparator
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Wild-type Cell
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GAL-CLN2 cdh1D
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Model Builder
Parameter Values
Run Manager
Comparator
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Local Gradient Search(Levenberg-Marquardt)
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Global DIRECT Search(DIViding RECTangles)
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Global DIRECT Search(DIViding RECTangles)
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Outline

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

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Fission Yeast
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Fission yeast wild type
max
unstable steady state (M)
stable steady state (S-G2)
Active MPF
min
stable steady state (G1)
cell mass
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S
G2
M
G1
S
G2
M
G1
S
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mass/nucleus
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3
2
1
0
CKI
Cdh1
Cdc20
Wee1
Cdc25
Time (min)
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Fission yeast wild type
max
unstable steady state (M)
stable steady state (S-G2)
Active MPF
min
stable steady state (G1)
cell mass
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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
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Fission yeast
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
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Two-parameter Bifurcation Diagram
GENETICS!
wee1OP
Locus of SNICs
wee1 gene expression
wild-type
heterozygote diploid
wee1D
PHYSIOLOGY!
cell mass (a.u.)
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Cyclin gene expression
?
?
cell mass (a.u.)
Oscill8 Emery Conrad
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Growth Patterns in Fission Yeast
OE NE NE OE
NETO
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space
NE
OE
time
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A. with microtubules
orb
NETO
monopolar
bipolar
cell length (µm)
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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
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The End