Domain-specific Languages for Cellular Interactions

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Domain-specific Languages for Cellular
Interactions

• Bill Harrison
• Department of Computer Science
• University of Missouri at Columbia

This work partially supported by NIH1 R0l
GM62920-04A1, NIH1 P20 GM065762-01A1, the
Georgia Research Alliance and the Georgia Cancer
Coalition.
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Domain-specific Languages for Cellular
Interactions

• Bill Harrison
• Department of Computer Science
• University of Missouri at Columbia

meow!
This work partially supported by NIH1 R0l
GM62920-04A1, NIH1 P20 GM065762-01A1, the
Georgia Research Alliance and the Georgia Cancer
Coalition.
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• Ph.D 2001, UIUC
• Thesis Modular Compilers and Their Correctness
  Proofs
• Thesis Advisor Sam Kamin
• Post-doc, Oregon Graduate Inst. (OGI)
• Three years on Programatica Project
• using Haskell programming language as basis for
  formal methods
• Assistant Professor, University of
  Missouri-Columbia since Fall 2003

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Systems Biology asks

• Can static biological structure be related to
  dynamic biological behavior with mathematical
  clarity, precision, rigor?
• Can biological systems be viewed as the sum of
  their parts?
• Can component-level models be integrated into
  precise system-level models of biological
  behavior?
• What techniques from Mathematics and Computer
  Science apply to this composition problem?

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Rhodobacter Sphaeroides

• Photosynthetic bacterium
• seeks out regions of greater light
• Roughly the size of wavelength of light
• cannot sense local light differences directly
• ? applies random walk

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Simulations of Biological Systems

• Simulations provide qualitative feedback, but are
  not models per se
• how accurate/faithful is a simulation?
• what does the feedback mean?
• can one reason about the biological phenomenon
  based on the simulation?
• can you identify the biology by inspecting the
  text of the simulation program?

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R. Sphaeroides in C

• contains ?1000 LOC
• to understand requires
• expertise in C
• and biological model
• and critical system details
• e.g., how is concurrency implemented?

bool global_stateregister_state(void
apointer) if( number_of_states
mother_of_all_states.size())
mother_of_all_states.resize(number_of_states
1000) mother_of_all_statesnumber_of_states
apointer return true
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R. Sphaeroides in C

• Program structure does not reflect biological
  model
• can you look at the source code and recognize the
  underlying biology?
• ? difficult to comprehend
• and write correctly
• and modify
• and maintain
• and re-use

bool global_stateregister_state(void
apointer) if( number_of_states
mother_of_all_states.size())
mother_of_all_states.resize(number_of_states
1000) mother_of_all_statesnumber_of_states
apointer return true
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System Biology as Programming Language Design

• The Problem
• General-purpose programming languages do not have
  the right vocabulary
• Biological model Concurrent Markov chains
• C classes, pointers, etc.
• nor are they mathematics
• Our Solution Design small, special purpose
  languages with exactly the right vocabulary
• called a Domain-specific Language (DSL)
  Sheard99,Thiemann01,Leijen01
• Mathematical semantics of DSLs gives formal model
  of biology

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Language Model of R. Sphaeroides
cell1 celln
Executing
Produces animation
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Outline

• Language Design and Domain-specific Languages
• design, definition, and implementation
• Systems Biology as Language Design
• Case Study for Rhodobacter Sphaeroides
• Design what are the appropriate abstractions for
  R. Sphaeroides?
• Definition how do we specify exactly what R.
  Sphaeroides programs mean?
• Implementation how do we run R. Sphaeroides
  programs?
• Conclusions

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Cardinal Rule of Language Design
Application Programmers should choose languages
with abstractions most suited to their
task Language designers must provide languages
with those abstractions
Domain
Central Activities
Reasonable Language
System Programming
bit-fiddling
C
Artificial Intelligence
List processing
LISP
System Admin.
Text processing, etc.
PERL
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DSLs are small languages w/ domain abstractions
Ex Parsec Parser DSL
BNF for language
ltStmtgt ? ltidentgt ltExprgt
translates directly
assignStmt Parser Stmt assignStmt do id ?
ident symbol ""
s ? Expr return (Assign id s)
Parsec code
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Why a language and not a library?

• The Slogan What is excluded from a DSL is as
  important as what is included in it
• libraries in a general-purpose language still
  require
• considerable expertise self-discipline on the
  part of the programmer
• Lack of generality in DSL ? fewer things to go
  wrong
• DSL may have desirable properties that a
  general-purpose language will not
• e.g., implementation techniques specialized to
  DSL that do not apply to general-purpose
  languages
• small size makes rigorous specification tractable

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DSL Design

• DSL design for R. Sphaeroides
• what are our domain abstractions?
• How does this organism behave?
• What modeling techniques are used by biologists
  to describe this behavior?

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Bacterial Commands
laze
die
adjust speed
grow
divide
tumble
Probability of growth varies with light
concentration
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Chapman-Kolmogorov Equation
probability of being in state m
probability of transition from i to j
Commonly used framework for modeling
biological systems Bremaud99, Dailey02, Mao02,
Shah00
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Chapman-Kolmogorov Equation
A row in the above matrix encodes the transition
function from state i of a Markov chain
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Bacteria as Markov Chains

• non-deter. state machines with probabilistic
  transitions
• induced by the Chapman-Kolmogorov equation
• Pi,j in terms of environmental factors, organism
• state, etc.
• executing concurrently

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Domain Abstractions for R. Sphaeroides

• Individual cells Markov-chain abstraction
• choose
• P1 ? Action1
• Pn ? Actionn
• Actions Tumble, Divide, AdjSpeed, Laze, Grow,
  etc.
• Concurrency cell1 cell2
• Environmental Factors light, size

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Abstract syntax for CellSys

• choose is our principal domain abstraction
• behaves like the Markov chain transition function
• Cell-level environment variables light, size

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DSL Definition

• Background Programming languages are
  collections of effects
• Java OO Threads State
• LISP Higher-order Functions
• Prolog Backtracking
• Corresponding to each such effect is an algebraic
  construction called a monad
• used for the development of modular semantic
  theories of programming languages Moggi89
• monads may be constructed using monad
  transformers

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Periodic Table of Effects

• Prog. languages are collections of effects
  captured as monads Moggi
• Monads assembled from constructors (monad
  transformers)
• Our view Systems are collections of effects
  captured as monads
• Systems broadly construed
• Compilers Harrison00,98,01,02,
• Secure system software Harrison05,03, and
• Biology Harrison04

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Periodic Table of Effects

• Mathematical definitions for any language created
  by combining MTs
• CellSys StateT ResT ProbT ReactT
• Such definitions are flexible
• modular, extensible, and easily refactored

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DSL definition similar to traditional RTS

• In a traditional RTS
• threads request services like
• send a message
• output on device
• consume resource
• RTS mediates
• ensuring that the threads do not interfere
• global system state remains consistent
• schedules threads

threads
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High-level view of definition

• In CellSys
• Cells are threads with physical components as
  well
• size, velocity,
• cells request services like
• consume nutrients
• move me here
• want to divide
• GE mediates like RTS, also
• preserves physical integrity
• updates global world view
• performs scheduling

cells
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DSL Implementation

• Because CellSys defined in terms of monad
  transformers, may be implemented directly as
  Haskell program
• I.e., monadic language definition may be
  transcribed symbol for symbol into Haskell
• Haskell implementation easily instrumented to
  output system snapshots
• prints out snapshots in POV (Persistence of
  Vision) format converted into MPEG

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Q What are appropriate languages for modeling?

• Integrate techniques from programming languages
• models of concurrency
• language semantics
• i.e., precise, mathematical language definitions
• efficient language implementation
• into special purpose language called a
  Domain-Specific Language
• abstractions taken directly from biology
• ? comprehensible by biologists
• DSLs and DSL programs
• hide technical details irrelevant/uninteresting
  to biologists
• are tunable by computer scientist to reflect
  discovery/refinement
• execute to provide reality check by biologists

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Bioinformatics Computer Science Biology
Computer Science
Biology

• models of concurrency
• efficient implementation
• mathematical models of programs
• reasoning about programs

• organism structure behavior
• modeling techniques
• cellular automata
• systems of PDEs
• numerical techniques

?
?
Hard Problem How do you effect a technology
transfer from CS ? Biology?
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Interdisciplinary Process
CellSys (version 1.0)
Biologist evaluates DSL model for accuracy,
expressiveness, etc.
feedback/discussion
Language expert refactors language as needed
CellSys (version 2.0)
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Summary
Large body of work providing domain abstractions
models
Comprehensibility, Reusability, Ease of Use
systems biology
domain specific languages
modular monadic semantics
Precise description of biological phenomena
through DSL semantics
Harrison Harrison, Domain Specific Languages
for Cellular Interactions in Proceedings of the
International Conference IEEE Engineering in
Medicine and Biology, 2004.