Proposed Agent-directed Composition of Biomedical and Simulation Ontologies:
Facilitating Dynamic Hypothesis Instantiation
The T1 Translational Dilemma:
Bottleneck at Evaluating Mechanistic Hypotheses
Question: Can hypothesis evaluation be accomplished in silico?
Proposal: Extend computer-augmented knowledge
representation to computer-assisted hypothesis instantiation
Leveraging Ontologies Expressing Rules and
Capturing Dynamics
Ontologies: Basis of formal knowledge representation in multiple
domains =>
•  Bio-ontologies in Bioportal (Bioportal.org)
•  Modeling and Simulation (M&S) Methods (Ref 1)
Limited expressiveness of Ontologies with respect to Rules =>
Rules necessary to represent Mechanisms
However: content of instances in a M&S Ontology are methods
for instantiating rules!
Proposal: Use the principle of Composability to integrate
biological knowledge expressed using bio-ontologies with
M&S methods drawn from M&S ontologies.
Composability = ability to select and assemble simulation
components in various combinations to meet specific specific
simulation use goals (Ref 1)
The Composition function can be expressed as a planning
task for a semi-intelligent computational agent to semi-
automate the construction of in silico models of
biological hypotheses.
Gary An, M.D. and Scott Christley, Ph.D.
Department of Surgery, University of Chicago, Chicago, IL
The Computational Modeling Assistant (CMA): Steps in Model Construction by the CMA
Rewriting Logic and Reflection using Maude (Ref 2) Biological Model as Maude Logical Statements
• Conversion of statements from the biological
model into logical statements interpretable by
Maude: Logical framework Maude.
based on rewriting logic. • Accomplished by mapping ontology terms into
Maude sorts and ontology relationships into
Maude subsorts.
The CMA uses Maude to: • Biological statements may be deemed invalid
by incorrect specification or insufficient
• Develop rewriting axioms for definition of entity or process in Maude.
mappings between ontologies
and other formal descriptions.
Maude Rewrite/Model Construction Rules
• Determine completeness of
knowledge descriptions. • M&S Ontology is also converted to Maude
sorts and subsorts, represents set of possible
• Enrich knowledge model specifications and simulation methods.
descriptions by accessing • Maude rewrite rules tie biological functions to
specific model rule specifications => expert-
ontologies. defined model construction process.
• Generate model • Rewrite rules identify possible model
specifications, and expand depending upon
specifications for possible
content of statement, e.g. “diffuse” incorporates
simulations. space and therefore specifies “PDE” rather
• Generate simulation code than “ODE”.
(future). Model Specification
• Construction of the model specification is a
planning task.
• The initial state = biological model as set of
Maude logical statements
Biological Example: Gut Mucus Dynamics (Ref 3) • The goal state = model specification where all
of the statements from the conceptual
biological have been accounted for
“Loose” Mucus: Portion of mucus layer • The CMA uses the Maude search command
populated by gut bacteria to find all possible solutions (plans) to complete
model specifications from the initial biological
statements.
“Firm” Mucus: Tightly cross-linked, adherent to
Future Directions
Epithelial Cells, barrier to bacteria
Colonic Epithelium •  Need to expand development of ontologies/formal specification
of M&S methods (far behind Biomedical community).
Question: What leads to stratification of the mucus layer? •  Establish parsers and interpreters to Biomedical Markup
To examine this 1.  goblet cell [GO:0005623] has [GO:has_part] muc2 11.  A protein and B protein bind [SBO:0000177] to form AB Languages (SBML, CellML).
gene [SBO:0000243]. complex [SBO:0000296].
question we 2.  Muc2 gene is transcribed [SBO:0000183] into muc2
mRNA [SBO:0000278].
12.  Goblet cell secretes AB complex into extracellular
space.
•  Implement biological systems requiring hybrid models
generate a 3.  Muc2 mRNA is translated [SBO:0000184] into muc2
protein [SBO:0000252].
13.  Extracellular AB complex diffuses [REX:0000122].
14.  Extracellular AB complex disassociates [SBO:0000180]
(concurrently using different M&S methods).
mechanistic 4.  goblet cell [GO:0005623] has [GO:has_part] A gene
[SBO:0000243].
into extracellular protein A and B.
15.  Extracellular A protein diffuses [REX:0000122]. •  Automate simulation code generation from model specification.
5.  A gene is transcribed [SBO:0000183] into A mRNA 16.  Extracellular B protein diffuses [REX:0000122].
hypothesis of
References
[SBO:0000278]. 17.  Extracellular A protein decays [SBO:0000179].
6.  A mRNA is translated [SBO:0000184] into A protein 18.  Extracellular B protein decays [SBO:0000179].
mucus dynamics [SBO:0000252].
7.  goblet cell [GO:0005623] has [GO:has_part] B gene
19.  Extracellular muc2 protein forms inner mucus layer
[GO:0070702].
1.  Benjamin, P., Patki, M. and Mayer, R. (2006) “Using Ontologies for Simulation Modeling.” Proceedings of the 2006
expressed as a [SBO:0000243].
8.  B gene is transcribed [SBO:0000183] into B mRNA
20.  Extracellular A protein cleaves [SBO:0000178]
extracellular muc2 protein. Winter Simulation Conference. 1151-1159.
2.  Clavel, M. et al. 2007. All About Maude - A High-Performance Logical Framework: How to Specify, Program, and
series of statements [SBO:0000278].
9.  B mRNA is translated [SBO:0000184] into B protein
21.  Cleaved extracellular muc2 protein forms outer mucus
layer [GO:0070703]. Verify Systems in Rewriting Logic. Springer.
[SBO:0000252]. 22.  Colon epithelium [FMA:Epithelium_of_colon] is a 2D
= Biological Model 10.  Goblet cell secretes [GO:0046903] muc2 protein into plane of cells. 3.  Johansson, M.E.V., Holmen Larsson, J.M. and Hansson, G.C. The two mucus layers of colon are organized by the
MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. PNAS 2010. 5(8):12238e.
extracellular space [GO:0005615].