Combining Analysis and Combining Analysis and Synthesis in a Model of a Synthesis in a Model of a

Biological CellBiological Cell

Ken Webb & Tony WhiteKen Webb & Tony White

SAC ’04SAC ’04

March 17, 2004March 17, 2004

IntroductionIntroduction

In this presentation I will cover:In this presentation I will cover:1.1. Some backgroundSome background

2.2. CellAK (Cell Assembly Kit)CellAK (Cell Assembly Kit)

3.3. Autopoiesis and SCL (example/test Autopoiesis and SCL (example/test case)case)

4.4. Enhanced CellAKEnhanced CellAK

BackgroundBackground

Started as exercise in bio-inspirationStarted as exercise in bio-inspiration Getting architectural ideas from biology that can Getting architectural ideas from biology that can

be applied to developing complex computer be applied to developing complex computer systemssystems

But there are also aspects of interest to But there are also aspects of interest to members of cell modeling communitymembers of cell modeling community ““Whole-cell modeling” (M. Tomita, E-CELL)Whole-cell modeling” (M. Tomita, E-CELL) ““Grand challenge of modeling multi-cellular Grand challenge of modeling multi-cellular

animal” (D. Harel)animal” (D. Harel) SBML compatible toolsSBML compatible tools

Basic RationaleBasic Rationale

In existing cell/biochem modeling toolsIn existing cell/biochem modeling tools Each object is a separate act of human designEach object is a separate act of human design

Using OO software development techniquesUsing OO software development techniques Process of building complex cell models is easier Process of building complex cell models is easier

for humans (with reuse)for humans (with reuse) CellAK: example of such an OO systemCellAK: example of such an OO system

Can have very large number of componentsCan have very large number of components Paper accepted by journal BioSystemsPaper accepted by journal BioSystems

Enhanced CellAK: introduced in this paperEnhanced CellAK: introduced in this paper Extends CellAK to allow it to model autopoiesisExtends CellAK to allow it to model autopoiesis

CellAKCellAK

An approach to modeling and simulating An approach to modeling and simulating cells, and other similar biological and non-cells, and other similar biological and non-biological entities.biological entities.

Based on:Based on: an object-oriented (OO) paradigm,an object-oriented (OO) paradigm, UML visual formalism,UML visual formalism, ROOM visual formalism.ROOM visual formalism.

Prototype implemented using Rational Prototype implemented using Rational Rose RealTime (RRT)Rose RealTime (RRT)

CellAK – some benefitsCellAK – some benefits

Scalable, through use ofScalable, through use of Object instantiation from classes,Object instantiation from classes, Multiplicity,Multiplicity, Chemical metaphor.Chemical metaphor.

Easy to implement new behaviorEasy to implement new behavior If you know C/C++If you know C/C++

CellAK – Multi-step ProcessCellAK – Multi-step Process

CellAK incorporates a top-down process based on CellAK incorporates a top-down process based on current practice in development of embedded and current practice in development of embedded and real-time systems. Add more detail at each step.real-time systems. Add more detail at each step.

1.1. Identify entities, inheritance and containment Identify entities, inheritance and containment hierarchieshierarchies

2.2. Establish relationships between entitiesEstablish relationships between entities

3.3. Define entity behavior patternsDefine entity behavior patterns

4.4. Implement detailed behaviorImplement detailed behavior

5.5. ValidateValidate

Entities typically all from the biological domain.Entities typically all from the biological domain.

1. UML Inheritance 1. UML Inheritance HierarchyHierarchy

1. UML Containment 1. UML Containment HierarchyHierarchy

1. ROOM Containment 1. ROOM Containment HierarchyHierarchy

2. Relationships between 2. Relationships between entitiesentities

3. Behavior between 3. Behavior between entitiesentities

3. The configured system3. The configured system

3. Detailed entity behavior3. Detailed entity behavior

4. Implement detailed 4. Implement detailed behaviorbehavior

V * SV * Sv = ──────v = ────── Km + SKm + S

// Irreversible, 1 Substrate, 1 Product, 0 Activator, 0 Inhibitor, 0 Coenzyme// Irreversible, 1 Substrate, 1 Product, 0 Activator, 0 Inhibitor, 0 Coenzymecase Irr_Sb1_Pr1_Ac0_In0_Co0:case Irr_Sb1_Pr1_Ac0_In0_Co0: s = sm->molecule[gene->substrateId[0]].get();s = sm->molecule[gene->substrateId[0]].get(); nTimes = enzymeLevel * ((gene->substrateV * s) / (gene->substrateK + s));nTimes = enzymeLevel * ((gene->substrateV * s) / (gene->substrateK + s)); sm->molecule[gene->substrateId[0]].dec( nTimes );sm->molecule[gene->substrateId[0]].dec( nTimes ); sm->molecule[gene->productId[0]].inc( nTimes );sm->molecule[gene->productId[0]].inc( nTimes ); break;break;

5. Validate5. Validate

BioEntityBioEntity

Our name for objects in a model of Our name for objects in a model of biological cells, or other similar biological cells, or other similar complex reactive system.complex reactive system.

May consist of any combination of:May consist of any combination of:1.1. BehaviorBehavior

2.2. Fine-grained structureFine-grained structure

3.3. Other bioEntitiesOther bioEntities

BioEntityBioEntity

BioEntity TypesBioEntity Types

Behavior Fine-grained Structure (FGS)

Contained bioEntities

Examples

Pure Active Object

Enzyme TransportProtein CellBilayer

Pure Passive Object

Cytosol ExtraCellularSolution

Pure Container

EukaryoticCell Cytoplasm

Enhanced CellAK

Cytosol Enhanced CellAK

CellBilayer

AutopoiesisAutopoiesis

““self-making”self-making” All entities in an autopoietic system All entities in an autopoietic system

or network participate in the creation or network participate in the creation and continual transformation of other and continual transformation of other entitiesentities

Based on bottom-up synthesis rather Based on bottom-up synthesis rather than the top-down analysis of than the top-down analysis of original CellAK.original CellAK.

Varela/McMullin SCL ModelVarela/McMullin SCL Model

3 types of randomly moving entities:3 types of randomly moving entities:1.1. CatalystCatalyst CellAK: enzymeCellAK: enzyme

2.2. SubstrateSubstrate CellAK: small moleculeCellAK: small molecule

3.3. LinkLink CellAK: lipidCellAK: lipid

4.4. also Holesalso Holes CellAK: water moleculesCellAK: water molecules

SCL-GROSCL-GRO

source: [17] McMullin, B., and Gross, D. Towards the Implementation of Evolving Autopoietic Artificial Agents. http://www.eeng.dcu.ie/~alife/bmcm-ecal-2001/ bmcm-ecal-2001.pdf

CellAK version of SCLCellAK version of SCL

CellAK was unable to model autopoietic CellAK was unable to model autopoietic systems such as in the SCL model.systems such as in the SCL model.

An enhanced version of CellAK adds An enhanced version of CellAK adds causal dependency to allow this.causal dependency to allow this.

In bioEntities that contain both behavior In bioEntities that contain both behavior and fine-grained structure (FGS), the and fine-grained structure (FGS), the behavior may be at least partly behavior may be at least partly dependent on details of that FGS.dependent on details of that FGS.

BioEntity with DependencyBioEntity with Dependency

Generic BioEntity NetworkGeneric BioEntity Network

SCL BioEntity NetworkSCL BioEntity Network

CellAK – some limitationsCellAK – some limitations

Rigid StructureRigid Structure Unable to evolve novel structure that can Unable to evolve novel structure that can

be incorporated into the running system.be incorporated into the running system. Based on proprietary tool (RRT)Based on proprietary tool (RRT)

But, goal here is to present an approach But, goal here is to present an approach that can be implemented using a variety that can be implemented using a variety of software development languages and of software development languages and tools.tools.

ConclusionsConclusions

CellAK can model biological systems with CellAK can model biological systems with many thousands of componentsmany thousands of components OO/UML top-down decomposition (analysis)OO/UML top-down decomposition (analysis)

Enhanced CellAKEnhanced CellAK Adds greater ability for bottom-up synthesisAdds greater ability for bottom-up synthesis Allows active objects to influence other active Allows active objects to influence other active

objects by effecting their constiuent partsobjects by effecting their constiuent parts Can model autopoietic systems with lots of Can model autopoietic systems with lots of

interdependenciesinterdependencies