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Translational Systems Biology of Acute Translational Systems Biology of Acute Inflammation:Inflammation:
Addressing the Translational Dilemma Addressing the Translational Dilemma by Avoiding Ill-Posed Questionsby Avoiding Ill-Posed Questions
2014 Multi-scale Modeling Consortium Meeting2014 Multi-scale Modeling Consortium Meeting
September 3, 2014September 3, 2014
Bethesda, MDBethesda, MD
Gary An, MDGary An, MD
Associate Professor of SurgeryAssociate Professor of Surgery
Department of SurgeryDepartment of Surgery
University of Chicago, Chicago, ILUniversity of Chicago, Chicago, IL
Wandling and An, WJ Emer Surg, 2010
U.S. FDAU.S. FDA““Critical PathCritical Path”” Document Document
March 2004 “Innovation or Stagnation”
The Multi-scale Translational Challenge
Organism
Organs
Tissues
Cells
Molecules
Verticaland
ParallelCoupling
OutputGenes
Barriers to Understanding
The Translational DilemmaThe Translational Dilemma
Traditional Scientific Cycle
Scientific Cycle in Data-Rich, High-throughput Environment
Increasing Dimensionality of
Data
Increased Complexity “Systems Diseases”
“”“”
“In that Empire, the Art of Cartography attained such Perfection that the map of a single Province occupied the entirety of a City, and the map of the Empire, the entirety of a Province. In time, those Unconscionable Maps no longer satisfied, and the Cartographers Guilds struck a Map of the Empire whose size was that of the Empire, and which coincided point for point with it. The following Generations, who were not so fond of the Study of Cartography as their Forebears had been, saw that the vast Map was Useless...”
““””
The Importance of The Importance of ““DynamicsDynamics”” Dynamic => System evolves over timeDynamic => System evolves over time Mechanistic => Approximations of Cause and Mechanistic => Approximations of Cause and
EffectEffect Need to capture movement from Health to
Disease…
Disease as a specific Disease as a specific Dynamic StateDynamic State
Same underlying processes =>Same underlying processes =>
Different conditions =>Different conditions =>
Different behaviors =>Different behaviors =>
Different Phenomena => Different Phenomena => HeterogeneityHeterogeneity
Dynamic Knowledge Representation with Agent-based Modeling
ABMs of Global Systemic Inflammation, circa ABMs of Global Systemic Inflammation, circa 19901990– Endothelial/Blood interfaceEndothelial/Blood interface– Activation/Propagation of InflammationActivation/Propagation of Inflammation– Endothelial Cells and White Blood CellsEndothelial Cells and White Blood Cells
Examine Overall Dynamics of SIRSExamine Overall Dynamics of SIRS What are the Clinical Phenotypes of Interest?What are the Clinical Phenotypes of Interest?
An, Shock Oct, 2001 and An, Critical Care Medicine Oct, 2004
Model of Global Inflammation, Model of Global Inflammation, circa 1990circa 1990
List of In-Silico ExperimentsList of In-Silico Experiments
Results of In-Silico Experiments Results of In-Silico Experiments in Infectious Mode (n=100)in Infectious Mode (n=100)
Results from In Silico TrialsResults from In Silico Trials No mediator-based intervention led to No mediator-based intervention led to
statistically significant improvementstatistically significant improvement Outcome could be changed => Antibiotics did Outcome could be changed => Antibiotics did
improve survivalimprove survival
Interventions led to short term effects that rapidly Interventions led to short term effects that rapidly reversed => reversed => ““Pebble in the streamPebble in the stream”” The problem was not parallel pathway redundancy, The problem was not parallel pathway redundancy, rather temporal, structural robustnessrather temporal, structural robustnessSystems Systems ““dieddied”” because they could not clear initial because they could not clear initial damagedamageMore vigorous response => Better survival (as long as More vigorous response => Better survival (as long as cellular-based) => Fletcher, et al ScTM 2014, 6(249)cellular-based) => Fletcher, et al ScTM 2014, 6(249)
Qualitative Dynamic Knowledge Qualitative Dynamic Knowledge RepresentationRepresentation
Instantiation of conceptual models = Instantiation of conceptual models = ““Thought Thought ExperimentsExperiments””
Provide means of Provide means of ““pre-testingpre-testing”” hypotheses and hypotheses and conceptual modelsconceptual models
Advances knowledge via Advances knowledge via
=> nullification of flawed hypotheses*=> nullification of flawed hypotheses*
=> identification of => identification of ““plausibleplausible”” conceptual conceptual modelsmodels
*Exclude whole classes of hypotheses at time *Exclude whole classes of hypotheses at time of candidate discovery!of candidate discovery!
Managing the Incompleteness of Managing the Incompleteness of KnowledgeKnowledge
Knowledge will always be incompleteKnowledge will always be incomplete What extent of knowledge is sufficient?What extent of knowledge is sufficient? What is the basis of the rules => what is What is the basis of the rules => what is
the literature?the literature? Incomplete Rules => Did you leave Incomplete Rules => Did you leave
something out? something out? Modeler Bias => Why did you choose what Modeler Bias => Why did you choose what
you chose?you chose?
““All models are wrong, some are All models are wrong, some are useful…useful…””
Computational Modeling Assistant (CMA)Computational Modeling Assistant (CMA)Semi-automating Hypothesis EvaluationSemi-automating Hypothesis Evaluation
What does this all get you?If Model Behavior matches real world observationsThe “Thought Experiment” is a Plausible representation of the “real world”Look for ways to “break” it
If Model Behavior does not match real world observationsRe-examine underlying assumptions Utilize Modularity for differential fitnessScience Progresses via Hypothesis Nullification
“It ain't what you don't know that gets you into trouble. It's what you know for sure that just
ain't so.” -- Mark Twain
An, Science Translational Medicine, 2010
““Knowledge Ecologies:Knowledge Ecologies:”” Science as Evolution Science as Evolution
Coming Fall 2014
FinisFinis