Metabolic Syndrome workshop

Dec. 13, 2013
Eindhoven University of Technology, Eindhoven
Natal van Riel
Dept. of Biomedica...
Can we link understanding of metabolism and
biochemistry (incl. modeling)
to the multi-omics data that are collected in
in...
Is the time right for application of GSMM‟s
…for a Systems Medicine approach of Metabolic Syndrome?

2007 Recon1
(Duarte 2...
Recon 2
• Genome-Scale Metabolic Model
• Total number of reactions 7,440
• Total number of metabolites 5,063
• Number of u...
Genome-scale metabolic reconstructions
Advantages:
• Especially good coverage of small, monomeric molecules and
central me...
Applications of the global human metabolic
network
“Genome-scale metabolic network reconstructions provide a
platform to i...
Example:
a metabolic perspective on ADHD, autism
• Neurotransmission is disrupted in most psychiatric disorders
• Serotone...
Metabolomics of 24 hour urine
• Metabolomics
(N=362)

• Analysis and
interpretation with
network model
• Recon2, curated f...
HUMETICS HUman METabolic diagnostICS

Network-based analysis
APeT in collaboration with TU/e
Dermois, van den Eijnde et al...
Integration of multi-omics data

(A) Gene
expression
pattern (4
clusters)
(B) Metabolic
network
expression
overlay

/ biom...
Zelezniak et al, 2010, PLoS Comput Biol 6(4): e1000729.
/ biomedical engineering

16-12-2013 PAGE 11
Simulation

/ biomedical engineering

16-12-2013 PAGE 12
COnstraints Based Reconstruction and
Analysis (COBRA) methods
• So far, just the topology
• What about fluxes
• Flux Balan...
Network stoichiometry and Stoichiometric
Matrix
• A hypothetical network

• Stoichiometry matrix

• Stoichiometric model

...
Steady-state („homeostasis‟)
d s (t )

N v ( s ( t )) ˆ 0

dt

Nv

0

metabolite balancing equation
• Set of differential ...
Metabolic Balancing Analysis
• Mass balances (Differential Equations)
• Steady-state (concentrations constant over time), ...
Analyzing pathway diagrams
Two equivalent routes for
converting an input substrate into
an output metabolite

If we know/a...
The conceptual basis of Flux Balance Analysis
With no constraints, the flux
distribution of a biological
network may lie a...
A multi-tissue type genome-scale metabolic
network

• Implications for blood-based metabolic biomarkers
Bordbar, et al., I...
Systems medicine and metabolic modelling

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

1...
Systems medicine and metabolic modelling

/ biomedical engineering

16-12-2013 PAGE 21
/ biomedical engineering

16-12-2013 PAGE 22
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Genome-Scale Metabolic Models and Systems Medicine of Metabolic Syndrome

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workshop on 'The interplay of fat and carbohydrate metabolism with application in Metabolic Syndrome and Type 2 Diabetes', December 12 and 13, 2013, Eindhoven University of Technology

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Transcript of "Genome-Scale Metabolic Models and Systems Medicine of Metabolic Syndrome"

  1. 1. Metabolic Syndrome workshop Dec. 13, 2013 Eindhoven University of Technology, Eindhoven Natal van Riel Dept. of Biomedical Engineering, TU/e, n.a.w.v.riel@tue.nl Systems Biology and Metabolic Diseases
  2. 2. 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 / biomedical engineering 16-12-2013 PAGE 2
  3. 3. Is the time right for application of GSMM‟s …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.) / biomedical engineering 12/16/2013 PAGE 3
  4. 4. Recon 2 • Genome-Scale Metabolic Model • Total number of reactions 7,440 • Total number of metabolites 5,063 • Number of unique metabolites 2,626 http://humanmetabolism.org/ / biomedical engineering 16-12-2013 PAGE 4
  5. 5. 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 / biomedical engineering 12/16/2013 PAGE 5
  6. 6. 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 / biomedical engineering 16-12-2013 PAGE 6
  7. 7. Example: a metabolic perspective on ADHD, autism • Neurotransmission is disrupted in most psychiatric disorders • Serotonergic system malfunctioning • An underlying metabolic cause Yap,et al 2010, J Proteome Res 9(6): 2996 / biomedical engineering 16-12-2013 PAGE 7
  8. 8. Metabolomics of 24 hour urine • Metabolomics (N=362) • Analysis and interpretation with network model • Recon2, curated for tryptophan metabolism Dermois et al / biomedical engineering 12/16/2013 PAGE 8
  9. 9. HUMETICS HUman METabolic diagnostICS Network-based analysis APeT in collaboration with TU/e Dermois, van den Eijnde et al / biomedical engineering 16-12-2013 PAGE 9
  10. 10. Integration of multi-omics data (A) Gene expression pattern (4 clusters) (B) Metabolic network expression overlay / biomedical engineering 16-12-2013 PAGE 10
  11. 11. Zelezniak et al, 2010, PLoS Comput Biol 6(4): e1000729. / biomedical engineering 16-12-2013 PAGE 11
  12. 12. Simulation / biomedical engineering 16-12-2013 PAGE 12
  13. 13. COnstraints Based Reconstruction and Analysis (COBRA) methods • So far, just the topology • What about fluxes • Flux Balance Analysis (FBA) • Flux Variability Analysis (FVA) • … / biomedical engineering 16-12-2013 PAGE 13
  14. 14. Network stoichiometry and Stoichiometric Matrix • A hypothetical network • Stoichiometry matrix • Stoichiometric model d s (t ) N v ( s ( t )) dt with the species concentrations collated in a vector s and the reaction rates in a vector v [ v1 , ..., v 5 ]T / biomedical engineering 16-12-2013 PAGE 14 [ s1 , ..., s 4 ] T
  15. 15. Steady-state („homeostasis‟) d s (t ) N v ( s ( t )) ˆ 0 dt Nv 0 metabolite balancing equation • Set of differential equations  set of algebraic equations with the rates in v unknown 1 1 1 0 0 1 1 0 1 1 0 0 0 0 0 0 0 0 1 1 v1 v2 v3 v4 v5 0 0 0 0 • Here 4 equations (4 species) and 5 unknowns •  an under-determined set of equations •  not a single solution / biomedical engineering 16-12-2013 PAGE 15
  16. 16. Metabolic Balancing Analysis • Mass balances (Differential Equations) • Steady-state (concentrations constant over time), (N v = 0) • A metabolic fingerprint / snapshot v0 Flux space v1 v1 System of algebraic equations v2 v0 v2 An underdetermined system v1 v2 v1 v0 v2 v3 v3 v1 • Measurements to constrain the underdetermined system • Isotopic tracers, e.g. 13C • Solve / simulate with Flux Balance Analysis / biomedical engineering 16-12-2013 PAGE 16
  17. 17. Analyzing pathway diagrams 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 • Can be linked to an objective function to be minimized or maximized in FBA / biomedical engineering 16-12-2013 PAGE 17
  18. 18. The conceptual basis of Flux Balance Analysis 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 N 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 space The network may acquire any flux distribution within this space, but points outside this space are denied by the constraints Orth et al. Nat Biotechnol. 2010; 28(3): 245-248 / biomedical engineering 16-12-2013 PAGE 18
  19. 19. A multi-tissue type genome-scale metabolic network • Implications for blood-based metabolic biomarkers Bordbar, et al., I. (2011) BMC Syst. Biol., 5, 180 / biomedical engineering 16-12-2013 PAGE 19
  20. 20. Systems medicine and metabolic modelling Mardinoglu & Nielsen. J Intern Med 2012; 271:142–154 / biomedical engineering 16-12-2013 PAGE 20
  21. 21. Systems medicine and metabolic modelling / biomedical engineering 16-12-2013 PAGE 21
  22. 22. / biomedical engineering 16-12-2013 PAGE 22
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