genome-scale metabolic models and systems medicine of metabolic syndrome

Metabolic Syndrome workshop

Genome-Scale Metabolic Models and Systems Medicine of Metabolic SyndromeDec. 13, 2013Eindhoven University of Technology, Eindhoven

Natal van Riel Dept. of Biomedical Engineering, TU/e, [email protected] Systems Biology and Metabolic Diseases

/ biomedical engineering 08-04-2023

Can we link understanding of metabolism and

biochemistry (incl. modeling)

to the multi-omics data that are collected in

in research projects

and in the clinic of the (near) future

and tendencies towards stratified

and personalized health and healthcare

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Is the time right for application of GSMM’s

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…for a Systems Medicine approach of Metabolic Syndrome?

2007 Recon1(Duarte 2007 PNAS 104(6): 1777)

2010 Hepatonet(Gille 2010 Mol Syst Biol 6:411)

2013 Recon2(Thiele et al. 2013, Nat Biotech.)


Recon 2

• Genome-Scale Metabolic Model• Total number of reactions 7,440• Total number of metabolites 5,063• Number of unique metabolites 2,626

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http://humanmetabolism.org/


Genome-scale metabolic reconstructions

Advantages:• Especially good coverage of small, monomeric molecules and

central metabolism• Comprehensive network topology (wiring)

Limitations:• Manual curration needed of many pathways outside central

metabolism• Weak in polymeric metabolites with large heterogeneity, e.g.,

lipids, lipoproteins

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Applications of the global human metabolic network

“Genome-scale metabolic network reconstructions provide a platform to interpret omics data in a biochemically meaningful manner.”• Four classes of application:

1. Integration of ‘omics’ data for tissue and cell specific network reconstruction,

2. Mapping homologous genes for global mammalian network reconstruction,

3. Contextualization of ‘omics’ data from pathological and drug-treated states,

4. Simulation of pathological and drug-treated states

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Example: a metabolic perspective on ADHD, autism• Neurotransmission is disrupted in most psychiatric disorders• Serotonergic system malfunctioning• An underlying metabolic cause

PAGE 7Yap,et al 2010, J Proteome Res 9(6): 2996


Metabolomics of 24 hour urine

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• Metabolomics(N=362)

• Analysis and interpretation with network model

• Recon2, curated for tryptophan metabolism

Dermois et al


HUMETICS HUman METabolic diagnostICS

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Network-based analysisAPeT in collaboration with TU/eDermois, van den Eijnde et al


Integration of multi-omics data

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(A) Gene expression pattern (4 clusters)

(B) Metabolic network expression overlay

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Zelezniak et al, 2010, PLoS Comput Biol 6(4): e1000729.

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Simulation


COnstraints Based Reconstruction and Analysis (COBRA) methods• So far, just the topology• What about fluxes

• Flux Balance Analysis (FBA)• Flux Variability Analysis (FVA)• …

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Network stoichiometry and Stoichiometric Matrix• A hypothetical network

• Stoichiometry matrix

• Stoichiometric model

with the species concentrations collated in a vector and the reaction rates in a vector

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( ) ( ( ))d t tdt

s Nv s

1 4[ ,..., ]Ts ss1 5[ ,..., ]Tv vv


Steady-state (‘homeostasis’)

metabolite balancing equation• Set of differential equations set of algebraic equations with

the rates in v unknown

• Here 4 equations (4 species) and 5 unknowns• an under-determined set of equations• not a single solution

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( ) ( ( )) ˆd t tdt

s Nv s 0 Nv 0

1

2

3

4

5

1 0 1 1 0 01 1 0 0 0 01 1 0 0 0 00 0 0 1 1 0

vvvvv


• Mass balances (Differential Equations)• Steady-state (concentrations constant over time), (Nv = 0)• A metabolic fingerprint / snapshot

• Measurements to constrain the underdetermined system• Isotopic tracers, e.g. 13C

• Solve / simulate with Flux Balance Analysis

Metabolic Balancing Analysis

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0v 1v

0v1v

2v

0v1v

2v

3v

1v

2v

3v1v

2v

System of algebraic equations

An underdetermined system

Flux space


Analyzing pathway diagrams

• Can be linked to an objective function to be minimized or maximized in FBA

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Two equivalent routes for converting an input substrate into an output metabolite

If we know/assume that the system aims for minimization of total (number of) intracellular fluxes (efficiency), both routes are not equivalent

If the objective is to maximize ATP yield then also only one route will be utilized


The conceptual basis of Flux Balance Analysis

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N

With no constraints, the flux distribution of a biological network may lie at any point in a solution space

Through optimization of an objective function, FBA can identify a single

optimal flux distribution that lies on the edge of the allowable solution space

mass balance constraints imposed by the stoichiometric matrix N + capacity constraints imposed by the lower and upper bounds (ai and bi) are applied to a

network an allowable solution spaceThe network may acquire any flux distribution within this space, but points

outside this space are denied by the constraintsOrth et al. Nat Biotechnol. 2010; 28(3): 245-248


A multi-tissue type genome-scale metabolic network

• Implications for blood-based metabolic biomarkers

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Bordbar, et al., I. (2011) BMC Syst. Biol., 5, 180


Systems medicine and metabolic modelling

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Mardinoglu & Nielsen. J Intern Med 2012; 271:142–154


Systems medicine and metabolic modelling

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genome-scale metabolic models and systems medicine of metabolic syndrome

Health & Medicine

biomedical engineering16

systems medicine

flux distribution

omics data

stoichiometric matrix

objective function

analysis

network