the mapping problem : how do experimental biological models relate to each other, and how can...
TRANSCRIPT
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, MDUniversity of Chicago
2014 MSM Consortium SatelliteSept 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 MiyakawaGenomic 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
Organism
Organs
Tissues
Cells
Molecules
Genes
Barriers to Understanding
Multiscale/MultiStep
Investigation
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 Clinica
lInjective 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 Mode
l
ExplicitInjection
• 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
? ?
In Silico PS1
In Silico PS2
In Silico PS3
Bijective Bijective
Explic
itIn
ject
ion
Explic
itIn
ject
ion
Explic
itIn
ject
ion
The (Potential) Danger of Modeling
In silico #2
Bio Mode
lBijective
• 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
? ?In
Silico #1
In Silico #2
In Silico #3
Bije
ctiv
e
Bije
ctiv
e
Bije
ctiv
e
? ?
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 PointsBehavior/Function Maps highly conserved
Dynamic In Silico Models serve as bridgesConserved In Silico Model Structure => Encapsulate Transferable Knowledge/Hypothesis of MechanismOutput Heterogeneity => Different ParametersComponent 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
