Title: Cellerator: A System for Simulating Biochemical Reaction Networks
1Cellerator A System for Simulating Biochemical
Reaction Networks
Jet Propulsion Laboratory California Institute of
Technology
bshapiro_at_jpl.nasa.gov
2Part of a Biochemical Network
From Kohn (1999) Molecular interaction map of
the mammalian cell cycle control and DNA repair
systems. Mol Biol Cell 102703-2734
3Biochemical Networks Are...
- Complex
- Mutually interacting
- Large
- Number of reactions grows exponentially with
number of states - Best understood pictorially
- Best described quantitatively by a large system
of differential equations (ODEs)
Need to translate pictures to ODEs
4Online network databases exist ...
http//www.genome.ad.jp/kegg/
5... but mathematical simulations of these
networks are hopelessly naive...
6A
B
C
Input Canonical Form Biochemical Notation
Output Canonical Form System of ODEs
Activity (e.g., Cell Division)
Solver
Concentrations vs. Time
7Caltech ERATO Simulator Architecture
A
GUI and Modeling meta-language
B
C
Text Transfer Protocol
XML based protocol
Application
Application
Application
Application
Exploratory Research for Advanced Technology
(Japan Science Technology Corporation)
http//www.systems-biology.org
Application
8A simpler network for cell division
CCyclin enzyme that gets things going MMPF
promoting factor. MgtThreshold induces cell
division XCyclin Protease enzyme that breaks
down C
Goldbeter, A (1991) A minimal cascade model for
the mitotic oscillator involving cyclin and cdc2
kinase. PNAS 889107-9111
9Equations and prections of Goldbeter Mitotic
Oscillator
10Cellerator canonical form for input
Reactions are input with a biochemical based
notation
Prints out ODES
STN reaction, rate-constants, reaction,
rate-constants, interpretSTN Simulation
predictTimeCourseSTN, options
Returns tables of values as a function of time,
with optional plots
11Cellerator input/output for Goldbeter Mitotic
Oscillator
12(No Transcript)
13The Basis of Cellerator Chemical Reactions
- Simple
- Cooperative
- Conversion
- Creation, Degradation
- Enzymatic
- Reversible Enzymatic
- Transcription (Gene ? RNA)
- Post-transcriptional Processing
- Translation (RNA ? Protein)
- Diffusion
- and more ...
14Translation of Biochemical Formula to ODE
rate constant
Concentrations
- Law of Mass Action
- Two-way Reaction
- Complex reactions built from simple reactions
is described by
Similar ODEs can be written for B and C
is described by
15Enzyme Kinetic (Catalytic) Reaction
- Enzyme E catalyzes the production of product P
from substrate (source) S - Write more compactly as
3 Reactions written two different ways
Explicit
Hidden
Cellerator syntax for this set of reactions
Rate constants
16Two-way catalytic reaction
- A second enzyme F catalyzes the reverse reaction
- Total of Six Elementary Reactions
- Write more compactly as
Explicit
Rate constants
Hidden
Cellerator syntax for this set of reactions
17Canonical Forms for Translation Chemical
reactions
- Input Canonical Form for Chemical Reaction
- Output Canonical Form Terms in an ODE
18Cellerator Arrows Law of Mass Action
19Cellerator Arrows Catalytic Reactions
20Cellerator Arrows Transcriptional Regulation
21 INPUT
OUTPUT
MAP Kinase Cascade
22MAP Kinase in Scaffold
23The combinatoric explosion
24(No Transcript)
25IP3 Calcium Receptor
26IP3 Calcium Receptor (continued)
27Repressilator
28Repressilator
29Object Oriented ImplementationDomains and
Fields
- Domain object
- Field function that maps domains to R
- Field of Domains maps domain elements to domains
- Example
- graphDomain represents tissue
- node Domains cells
- neighborsg,n returns a list of nodeDomains that
are neighbors of node n n in graph g
30Multicellular Organisms
31Myogenesis Collaboration with Laboratory Dr.
Barbara Wold (Chris Hart), Caltech
32Plant Growth Collaboration with Laboratory Dr.
Elliot Meyerowitz, Caltech
33Secondary Leukemia Collaboration with City of
Hope National Medical Center (NASA/BSRP)
Focus Pathogenesis of myelodysplasia acute
myeloid leukemia following high-dose
chemo/radiotherapy and autologous peripheral
blood stem cell transplantation for treatment of
Hodgkins disease and non-Hodgkins lymphoma
34JPL Collaborations using Cellerator
- Effects of microgravity during space flight on
bone and muscle development (Caltech, JSC, and
UCI) - Development of childhood leukemias (Caltech,
Childrens Hospital of LA, and UC, Irvine) - Description of core signal transduction units
(Johns Hopikins) - Improving algorithms for micro-array data
analysis (Caltech, Harvey Mudd) - Systems Biology Workbench (Caltech, JST/Erato)
35Acknowledgements
- Eric Mjolsness - UC, Irivine
- Andre Levchenko - Johns Hopkins University
- Barbara Wold - Caltech
- Elliot Meyerowitz - Caltech
Original Developers