The Mapping Problem: How do experimental biological models relate to each other, and how can dynamic computational models be used to link them? Gary An, MD University of Chicago 2014 MSM Consortium Satellite Sept 5, 2014 Bethesda, MD

A Tale of Two Mappings Seok, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3507-12. Takao and Miyakawa Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2014 Aug 4. pii: 201401965.

The Multi-scale Translational Challenge Barriers to Understanding Multiscale/ MultiStep Investigation Organism Organs Tissues Cells Molecules Genes

Biological Experimental Workflow In vitro In vivo Clinical Where “ “ represents inferred knowledge Q1: What is the justification for this translation of knowledge? Q2: What is “similar?”

Basic Set Concepts (*From Wikipedia)

Biological Paradigm (Legacy of Zoology) “Animals are classified as follows: 1. those that belong to the Emperor, 2. embalmed ones, 3. those that are trained, 4. suckling pigs, 5. mermaids, 6. fabulous ones, 7. stray dogs, 8. those included in the present classification, 9. those that tremble as if they were mad, 10. innumerable ones, 11. those drawn with a very fine camelhair brush, 12. others, 13. those that have just broken a flower vase, 14. those that from a long way off look like flies. Celestial Emporium of Benevolent Knowledge – Jorge Luis Borges' fictional taxonomy of animals from his 1942 short story The Analytical Language of John Wilkins.

Bio Paradigm 1: Sets of Components (Detailed Descriptive) In vitro In vivo Clinical Components Components ? ? Partial Functions at best because Bio Models are Opaque

Bio Paradigm 2: Sets of Functions/Behaviors In vitro In vivo Clinical Injective Injective ? ? Mapping More Conserved/Preserved* Q: What is the “nature” of the injection? => Identify the Description of the Behavior/Function *Note: This does not mean components are not included, but rather are abstract representational components

The Role of Modeling Part 1 In silico PS1 Bio Model Explicit Injection This Injective function is Explicitly Described (Model specification/structure) As a Dynamic Model, the In Silico Model represents behavior

The Role of Modeling Part 2 In vitro ? In vivo ? Clinical Injective Injective Explicit Injection Explicit Injection Explicit Injection In Silico PS1 In Silico PS2 In Silico PS3 Bijective Bijective

The (Potential) Danger of Modeling In silico #2 Bio Model Bijective Higher Fidelity directed of Bio Proxy Models move towards Bijective Relationship (Output vs. Generative) Risk: Too closely approximates non-mapping Bio Proxy Models => Can’t Serve as Bridge

The Failure of Modeling ? ? In vitro In vivo Clinical Injective Injective Bijective Bijective Bijective In Silico #1 In Silico #2 In Silico #3 ? ?

The Translational Goal of Modeling In vitro In vivo Clinical Injective Injective In Silico PS(n) Q: Can the In Silico Model now be used to explore behavior space not reachable by In vitro/In vivo Models? A: I claim “Yes”

Modeling for Personalized Medicine Patient 1 Patient 2 Patient 3 Injective Injective In Silico PS(n) Embrace Heterogeneity!

Take Home Points Behavior/Function Maps highly conserved Dynamic In Silico Models serve as bridges Conserved In Silico Model Structure => Encapsulate Transferable Knowledge/Hypothesis of Mechanism Output Heterogeneity => Different Parameters Component Mapping now related to role in Behavior Generation In Silico Models for Bridging cannot be made too precise => over tuned/fit/mapped Explains/Utilizes Biological Heterogeneity Pathway to Translation and Personalization