humetics 2014 12-10-final

.

Dec. 10, 2014

Natal van Riel, Peter [email protected]

Tel. 5506

GEM-Z 3.109

Dept. of Biomedical EngineeringSystems Biology and Metabolic Diseases

@nvanriel

Metabolic Pathways

• Chemical reactions of metabolism can be considered as

organized into metabolic pathways, in which one chemical is

transformed through a series of steps into another chemical, by

a sequence of enzymes

/ biomedical engineering PAGE 210-12-2014


Metabolic Networks

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 PAGE 412/10/2014

Computational Biology

TOP-DOWN• Bioinformatics

• Data driven

• Statistics

• Biomodeling

• Hypothesis driven

• Knowledge based

BOTTOM-UP



Genome-Scale Metabolic Models

Genome-Scale Metabolic Models


these models include all known metabolic genes corresponding

to metabolic pathways

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.)

2014 iHepatocyte2322(Mardinoglu 2014_Nat Commun)

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/

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



Data Integration and Visualization

Integration of multi-omics data


(A) Gene

expression

pattern (4

clusters)

(B) Metabolic

network

expression

overlay

Dharmawardhana et al. Rice 2013, 6:15

Reporter metabolites

—metabolites with significant collective transcriptional response

in the associated enzyme-coding genes



Red arrows indicate

overexpression of the

associated genes,

blue arrows indicate

underexpression.


Application to Urine Metabolomics

Data Integration


TU/e: Robbin van den Eijnde, Marijke Dermois,

Niels Drost, Peter Hilbers, Natal van Riel

• HUMETICS (HUman METabolic diagnostICS)

• Top-down: bioinformatics

• Bottom-up: modeling and simulation

• Network-based data integration and

analysis (‘middle-out’)

• Genome-Scale Metabolic Model (Recon 2)

• Application: a metabolic perspective on

ADHD and autism (tryptophan pathway)

• APeT (Roosendaal, SME, H. Meijerink)

• Erasmus MC (R.J. Galjaard, Department

of Clinical Genetics)

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

Metabolomics of 24 hour urine


• Metabolomics

(N=362)

• Recon2, curated for

tryptophan metabolism

• Analysis and

interpretation with

network model

Urine metabolite levels

mapped on the tryptophan

pathway in the metabolic

network and levels visualized

using different colors

Dermois et al, 2014

Network-based analysis


APeT in collaboration with TU/e

Dermois, van den Eijnde et al

Results from cluster

analysis mapped on the

tryptophan pathway

facilitate biological

interpretation of data

Sluitstuk | Autisme behandelen met

metabolische routeplanner


http://www.cursor.tue.nl/nieuwsartikel/artikel/sluitstuk-

autisme-behandelen-met-metabolische-routeplanner/

23 januari 2014

humetics 2014 12-10-final

Science

metabolic diseases

metabolic networks3

known metabolic genes

scale metabolic model

integration of omics

multiomics data

associated genes

homologous genes