1. 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

2. 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 Feb 26;110(9):
Takao and Miyakawa
Genomic responses in mouse models greatly mimic human inflammatory diseases.
Proc Natl Acad Sci U S A Aug 4. pii:

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

4. 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?”

5. Basic Set Concepts (*From Wikipedia)

6. 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.

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

8. 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

9. 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

10. 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

11. 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

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

13. 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”

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

15. 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