Programming Languages for Programming Languages for BiologyBiology

Bor-Yuh Evan Chang

November 25, 2003

OSQ Group Meeting

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Biological PerspectiveBiological Perspective

F [http://www.nocturnalvisions.freeservers.com/page6.html]FF [Matsudaira et al. Molecular Cell Biology 4.0. Freeman, 2000]

F

FFFF

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Traditional Biological ResearchTraditional Biological Research

• Experiments must focus on a small, specific piece of a system– isolate the variable– feasibility

• Have led to an enormous wealth of (detailed) knowledge but in a fragmented form

Cell Receptor ExpertVirus Expert

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Systems BiologySystems Biology

• Emerging area of biology– study of the relationships and interactions

between biological components– many thousand of molecules interact in

complex series of reactions to perform some function (called a pathway)• e.g., lactose interacting with a receptor

triggers a series of actions to create the enzyme capable of breaking it down into usable form

– “pathways” may overlap

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Approaching Systems BiologyApproaching Systems Biology

• Need a common language of describing/modeling all components of a system– must be modular, compositional, and provided

varying levels of abstraction

• AbstractionAbstraction is an absolute necessity– 1 ribosome (eukaryotic) ¼ 82 proteins + rRNA

• 1 protein ¼ hundreds/thousands amino acids

– 1 membrane ¼ thousands of molecules (lipids, proteins, carbohydrates)

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The Biologist’s ViewThe Biologist’s View

• How do biologists think about or view biological entities (e.g., proteins)?– an entity can interact with certain other types of

entities– an entity can be in a certain “state”– interaction causes some action or state change

• Analogous to a system of thousands of concurrent computational processescomputational processes– Walter Fontana, a theoretical biologist,

examined -calculus and linear logic for describing biological systems (¼1995).

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Example “Textbook” DescriptionExample “Textbook” Description

http://vcell.ndsu.nodak.edu/~christjo/vcell/animationSite/lacOperon/

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Our RoleOur Role

• Finding suitable abstractions for describing computation is our specialty!

• Discovering/proving/checking properties of such descriptions (i.e., programs) is also our specialty!

• Goal:– Find a mathematical abstraction convenient for

describing, reasoning, simulating biological systems• DNA ! string over the alphabet {A,C,G,T}

– enables the use of string comparison algorithms

• Cellular Pathways ! ?

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OutlineOutline

• Why PL is at all related to Biology?

• Previous Abstractions in Biology

• Possible Directions of Work

• PML

• Conclusion

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Previous AbstractionsPrevious Abstractions

• Chemical kinetic models

– can derive differential equations– well-studied, with considerable theoretical basis– variables do not directly correspond with

biological entities– may become difficult to see how multiple

equations relate to each other

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Previous AbstractionsPrevious Abstractions

• Pathway Databases (e.g., EcoCyc, KEGG)– store information in a symbolic form and provide ways

to query the database– behavior of biological entities not directly described

• Petri nets– directed bipartite multigraph (P,T,E) of places,

transitions, and edges; places contain tokens– place = molecular species, token = molecule, transition

= reaction

2

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Previous AbstractionsPrevious Abstractions

• Concurrent computational processes– each biological entity is a process that may

carry some state and interacts with other processes

– each process described by a “program”– prior proposals based on process algebras,

such as the -calculus [Regev et al. ’01]

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Possible Directions of WorkPossible Directions of Work

• Biologically-motivated “process calculi”– finding a suitable machine model to serve as a common

basis for describing biological systems– Cardelli, Danos, Laneve, …

• High-level languages– find suitable high-level languages to make descriptions

closer to informal ones– [Chang and Sridharan ’03]

• Program analyses, simulation, and other tools– simulation will likely be insufficient

• Creating models for obtaining results in biology

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OutlineOutline

• Why PL is at all related to Biology?

• Previous Abstractions in Biology

• Possible Directions of Work

• PML

• Conclusion

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Modeling in the Modeling in the -calculus-calculus

• The -calculus is concise and compact, yet powerful [Milner ’90]– take this as the underlying machine model– not looking for another machine model

• However, it is far too low-level for direct modeling (ad-hoc structuring)

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Informal Graphical DiagramsInformal Graphical Diagrams

Protein

Enzyme Protein Enzyme

Enzyme

Proteink

k-1

kcatsites

domains

rules

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PML: EnzymePML: Enzyme

Enzymebind_substrateparameterized

declared in outer scope

interactions within the complex

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PML: ProteinPML: Protein

Protein Proteinbind_substrate bind_product

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PML: A Simple SystemPML: A Simple System

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Larger ModelsLarger Models

• Modeled a general description of ER cotranslational-translocation– unclearly or incompletely specified aspects

became apparent• e.g., can the signal sequence and translocon

bind without SRP? Yes [Herskovits and Bibi ’00]

• Extended to model targeting ER membrane with minor modifications

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PML: SummaryPML: Summary• Domains

– set of mutually dependent binding sites– defines at the lowest-level the reactions a biological

entity can undergo

• Groups– static structure for controlling namespace– may represent a large biological entity

• large complex, a system, etc.

• [Compartments]– special groups that define boundaries

• Semantics defined via a translation to the -calculus

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PML: SummaryPML: Summary• Benefits

– easier to write and understand because of a more direct biological metaphor

– block structure for controlling namespace and modularity

• Future Work– naming?– proximity of molecules– integrating quantitative information (reaction rates, etc.)– type-checking PML specifications– exceptional / higher-level specifications– graphical and simulation tools

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ConclusionConclusion

• Systems biology needs a mathematical foundation– languages for describing concurrent computation seem

like a step in the right direction

• Status: all very preliminaryall very preliminary– biologically-motivated process calculi

• BioSPI, BioAmbients, Brane Calculus, …

– high-level languages• PML

– analyses and tools (emerging)– creating models for results in biology (emerging)

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ConclusionConclusion

• Abundance of new challenges for PL– language design: biologically-motivated

operators– analysis and simulation: dealing with the scale– …

• How much biology does one need to learn to begin?

Bonus SlidesBonus Slides

CompartmentsCompartments

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CompartmentsCompartments

• Critical part of biological pathways– prevents interactions that would otherwise

occur

• Description of the behavior of a molecule should not depend on the compartment

• Regev et al. use “private” channels in the -calculus for both complexing and compartmentalization

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PML: Simple Compartments ExamplePML: Simple Compartments Example

MolAMolB

bind_a bind_a

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PML: Simple Compartments ExamplePML: Simple Compartments Example

MolAMolB

ER Cytosol

CytERBridge

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PML: Simple Compartments ExamplePML: Simple Compartments Example

MolB

ER Cytosol

CytERBridge MolA

Semantics of PMLSemantics of PML

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Semantics of PMLSemantics of PML

• Defined in terms of the -calculus via two translations– from PML to CorePML

• “flattens” compartments, removes bridges

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Semantics of PMLSemantics of PML

– from CorePML to the -calculus

Syntax of PMLSyntax of PML

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Syntax of PMLSyntax of PML

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Syntax of PMLSyntax of PML

Example: Cotranslational Example: Cotranslational TranslocationTranslocation

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Example: Cotranslational TranslocationExample: Cotranslational Translocation

• Ribosome translates mRNA exposing a signal sequence

• Signal sequence attracts SRP stopping translation• SRP receptor (on ER membrane) attracts SRP• Signal sequence interacts with translocon, SRP

disassociates resuming translation• Signal peptidase cleaves the signal sequence in

the ER lumen, Hsc70 chaperones aid in protein folding

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Example: Cotranslational TranslocationExample: Cotranslational Translocation

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Example: Cotranslational TranslocationExample: Cotranslational Translocation

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Example: Cotranslational TranslocationExample: Cotranslational Translocation

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Example: Cotranslational TranslocationExample: Cotranslational Translocation

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Example: Cotranslational TranslocationExample: Cotranslational Translocation

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Example: Cotranslational TranslocationExample: Cotranslational Translocation

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Example: Cotranslational TranslocationExample: Cotranslational Translocation