1. Nu GO Nutrigenomics: a new way of nutritional sciences.
Un Oslo
Un Munich
Un Florence
Un Balearic Illes
Un Cork
Trinity
Un. Ulster
Rowett
Un Newcastle
Un Reading
IFR
DiFE
Un Krakow
Inserm Marseille
TNO
Un Wageningen
Un Maastricht
EBI Nu GO
Un Lund
Rikilt
Rivm
The EU Network of Excellence
establishing the
European NutriGenomics Organisation
Nutrigenomics:
a new way of nutritional sciences.
the European Nutrigenomics Organisation

2. Mission Statement virtual centre of excellence:
NuGO will form a world-leading
virtual centre of excellence:
the European Nutrigenomics Organisation
to develop and integrate genomic technologies for the benefit of European nutritional science,
to facilitate the application of these technologies,
and to train a new generation of European scientists to use them.
the European Nutrigenomics Organisation

3. 1. The nutrition and health relationship
the European Nutrigenomics Organisation

4. well-being age Nutrigenomics: prevention instead of therapy!
What are the specific nutrition needs in earlier life stages to prevent chronic disease?
Prevention (food)
Therapy (drugs)
age
Adapted from Verrips et al, Cur.op.biotech. 12 (2001)
the European Nutrigenomics Organisation

5. Treatment of early Type 2 Diabetes will have an enormous impact on Health Care :
For real prevention,
we need to act here,
where multiple minor
changes can only be captured
throuhg “omics” approaches
At the time of diagnosis
Patients have lost 50% of their β-cell function
β-cell
Function in %
100 75 50 25
Eye –Retinopathy
Kidney –Nephropathy
Nerves –Neuropathy
Heart disease
Loss of
Homeostasis
Systemic
disease
IGT
Postprandial
Hyperglycemia
Type 2
Diabetes
Phase I
Type 2
Diabetes
Phase II
Type 2 Diabetes
Phase III -8 -2 2 8 14
Years from diagnosis
Lebovitz, Diabetes Rev., 1999

6. “old age disorders” and nutrition
Obesity & related disorders
Diabetes
Cardiovascular Diseases
Osteoporosis
Many forms of cancer (e.g. 60% of colon cancers)
Inflammatory disorders (e.g. arthritis)
Liver disorders
Various bowel disorders
Etc.
the European Nutrigenomics Organisation

7. New approaches needed …
To get nutrition research to merge physiology and biomedical research
To work on disease prevention instead of therapy (which doesn`t work for nutrition)
To tackle the complex genetic differences involved in the nutrition and health relationship
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8. 2. From nutrition to nutritional systems biology
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9. It’s revolution in biological sciences.
And it should also be so in Nutrition …
Gene
enzyme
Hexokinase
ATP
ADP
glucose
Glucose-6-phosphate
Metabolism
the European Nutrigenomics Organisation

10. What about the effect of a big apple pie with lots of
doublewhipped cream, espresso & sugar?
What about the difference between you and me?
hexokinase
ATP
ADP
Glucose
Glucose-6-phosphate
the European Nutrigenomics Organisation

11. the technologies ... proteomics DNA array (transcriptomics)
341
368; ENOA_HUMAN
376; ENOA_HUMAN
407; ENOA_HUMAN
592; KCRB_HUMAN
730; ER60_HUMAN
765
798
902; TCTP_HUMAN
958; GTA1_HUMAN
1277; COF1_HUMAN
807
1035
1088; NDKA_HUMAN
1294; FABL_HUMAN
824
447; CH60 HUMAN
537
76; CH60_HUMAN
800; TPIS_HUMAN
1297; thioredoxin
31; HSP70
g-actin
b-actin
AOP-1
154; ATP-synthetase b-subunit
23; GRP-78
705; Rho GDP
99; Probable disulfide isomerase
914; Natural killer cell enhancing factor 4 5 6 7 66 97 45 30
20.1
14.4 pI Mr
272; GR78 HUMAN
proteomics 10 15 20 25 30 35 40 45 50 55 9 7 6 5 4 3 13 12 11 8 2 1
metabolomics
the European Nutrigenomics Organisation

12. How to approach these issue?
The example of cholesterol homeostasis
the European Nutrigenomics Organisation

13. Example of systems biology approach1)
Induce disease with cholesterol in ApoE3L
High Chol
diet
Low Chol
diet
Control
diet
Statin
Fibrate
LXR
AT2 R
antagonist 2)
All used drugs have anti-atherosclerotic activity but act via different mechanisms.
Specifically interfere in the HC-driven development of the disease
the European Nutrigenomics Organisation

14. Mode of action of drugs used
LXR-activators
(T )
Statins
(Rosuvastatin)
AT2R-antagonist
(Irsebertan)
Fibrates
(Fenofibrate)
blocks
angiotensin II
receptor
inhibits
HMG-Co reductase
Activates PPARa
Activates LXRa/b
Increases HDL-Chol
Stimulates FA uptake and metabolism;
stimulates reverse cholesterol pathway
Anti-inflammatory: in liver and aorta NFkB; AP-1; Stat3
stimulates reverse cholesterol pathway
and bile acid synthesis anti-inflammatory in aorta:
(MMPs, COX-2, IL-6)
Lowers LDL-Chol;
anti-inflammatory in liver and aorta: NFkB, AP-1;
(VCAM,TNFa, MCP-1)
Lowers blood
pressure; anti-inflammatoy
NFkB
(NADP(H) oxidase)
the European Nutrigenomics Organisation

15. Systems Biology: a dynamic approach
Atherosclerosis model:
APOE*3-Leiden
Endpoint:
organs
Disease
Development
Groups:
1: Control diet
2: High cholesterol (HC)
3: HC + PPARa-activator (FF)
4: HC + Statin
5: HC + LXR-agonist
6: HC + AT2R-antagonist
7: Low cholesterol
Over time: plasma samples
CLASSICAL ‘Non-OMICS’:
Score atherosclerosis
Follow plasma markers (TG, Chol, SAA, …)
the European Nutrigenomics Organisation

16. Atherosclerosis model:
Systems Biology: a dynamic approach
Atherosclerosis model:
APOE*3-Leiden
Endpoint:
organs
Disease
Development
Groups:
1: Control diet
2: High cholesterol (HC)
3: HC + PPARa-activator (FF)
4: HC + Statin
5: HC + LXR-agonist
6: HC + AT2R-antagonist
7: Low cholesterol
Over time: plasma samples
CLASSICAL ‘Non-OMICS’:
Score atherosclerosis
Follow plasma markers (TG, Chol, SAA, …)
METABOLOMICS:
LC-MS
the European Nutrigenomics Organisation

17. Atherosclerosis model:
Systems Biology: a dynamic approach
GENOMICS: Affymetrix total genome array
Atherosclerosis model:
APOE*3-Leiden
Statin
Fibrate
LXR
AT2 R
antagonist
LOW
CHOL
Control
Endpoint:
organs
High
CHOL
Disease
Development
Overlap: crucial pathways contributing to disease development
Groups:
1: Control diet
2: High cholesterol (HC)
3: HC + PPARa-activator (FF)
4: HC + Statin
5: HC + LXR-agonist
6: HC + AT2R-antagonist
7: Low cholesterol
Over time: plasma samples
CLASSICAL ‘No-OMICS’:
Score atherosclerosis
Follow plasma markers (TG, Chol, SAA, …)
METABOLOMICS:
LC-MS
the European Nutrigenomics Organisation

18. Metabolomics: Example of a base peak chromatogram obtained by analysis of plasma by the LC-MS lipid platform

19. Example of selected ion chromatograms of several triglycerides

20. Treatment-specific changes (MVA) of plasma lipidsFF HC
Statin
control LC
AT2R 20 40 60 80
100
Heparine-plasma + IS
14.64
14.60
15.13
9.81
7.53
15.35
11.70
9.84
19.40
9.45
19.53
14.19
18.98
7.26
7.19
20.01
15.62
7.65
16.31
10.19
16.84
9.23
8.38
7.04
18.81
20.18
13.40
11.26
8.67
6.77
18.57
20.67
17.21
12.99
21.30
22.76
23.69
24.40
5.30
6.43
14.67
NL:
4.28E6
Base Peak MS
ee346176
LXR
the European Nutrigenomics Organisation

21. Genes of high interest in the processes involved –
Now in their biochemical perspective

22. Role of ZNF202 in atherosclerosis: driver of pre-inflammatory processes

23. SREBP: Key factor in regulation of cholesterol synthesis
insulin
INSIG2 ER
srebf2
SCAP
SREBP
HMG CoA reductase
Ubiquitinat.
Proteas.degradation
Golgi
acetyl CoA carboxylase
Genes for synthesis
of cholesterol,
fatty acids,
triglycerides,
phospholipids
Fatty acid synthase
LDL receptor
SREBP: Key factor in regulation of cholesterol synthesis
(the Goldstein & Brown scheme)
WH, 17 february, 2005

24. A correlation network, based on statistically selected variables (RNA, protein, metabolite)
Node indicates closely regulated part
Box indicates type, up/down
Line indicates relation
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25. Cellular regulatory influence diagrams.
Each gene group is represented by its number, along with those ontology labels that are overrepresented in that gene group.
The mean level of gene group output influences across all 12 target groups is plotted versus the time step.

26. Cartographic representation of the metabolic network of E. coli.
Each circle represents
a module and is
coloured according
to the KEGG pathway classification of the metabolites it
contains. Interactions between modules and nodes
are depicted using lines, with thickness proportional
to the number of actual links.
Inset: metabolic network of E. coli, which contains 473 metabolites and 574 links.
the European Nutrigenomics Organisation

27. Lessons: Merge of physiology and biomedical research
Big machinery needed
Bioinformatics essential
Complexity of nutrition needs systems biology
Early effects need careful description
Multidisciplinary approach – datawarehousing?
the European Nutrigenomics Organisation

28. The future of Nutrigenomics?
brainwash
Nutrition
Nutrigenomics
2004
2005
2006
200X
20XX
the European Nutrigenomics Organisation

29. The future of Nutrigenomics?
“pure
science”
Nutritional systems biology
Nutrigenomics
science
commerce
communication
ethics
(science)
Personalised nutrition
2004
2005
2006
200X
20XX
the European Nutrigenomics Organisation

30. 3. From nutrition to personalised nutrition
the European Nutrigenomics Organisation

31. How to approach these issue?
The example of cholesterol homeostasis
the European Nutrigenomics Organisation

32. Effects of genetic differences on the processes invovled in cholesterol homeostasis
Genetic polymorphism affecting cholesterol homeostasis
Processes involved in cholesterol homeostasis
the European Nutrigenomics Organisation

33. Many differences in the gene exist between humans
Leptin is a protein that tells my brain
that I have enough calories
Identical mice,
except for one gene…
SNPs present in the LEPTIN gene
Many differences in the gene exist between humans
the European Nutrigenomics Organisation

34. the European Nutrigenomics Organisation

35. the European Nutrigenomics Organisation

36. whole-genome patterns of common human DNA variation by genotyping 1,586,383 SNPs
the European Nutrigenomics Organisation

37. Pathological: medical genetics
How to study this genetic component of the nutrition and health relationship?
Pathological: medical genetics
Minor impact genes: genetic epidemiology (cohorts)
More minor impact genes: cohort merging
Multiple minor impact genes (real life): new approach needed (modelling?)
the European Nutrigenomics Organisation

38. Nutrigenomics on the shelves?
the European Nutrigenomics Organisation

39. The nutrigenomics data challenge
Enormous amounts of data and results are and will become available
[Genetic epidemiology, cohort studies, SNP databases, intervention studies, omics data, etc.]
So, we should set up a system to better exploit this: one day, all study data should be available for all nutrition scientists, allowing them (us) to perform “in silico nutritional systems biology”
Advanced information technology:
the Nutrigenomics Information Portal
the European Nutrigenomics Organisation

40. Nu GO the European Nutrigenomics Organisation Un Oslo Un Munich
Un Florence
Un Balearic Illes
Un Cork
Trinity
Un. Ulster
Rowett
Un Newcastle
Un Reading
IFR
DiFE
Un Krakow
Inserm Marseille
TNO
Un Wageningen
Un Maastricht
EBI Nu GO
Un Lund
Rikilt
Rivm
the European Nutrigenomics Organisation

41. central datawarehouseNu GO
Un Oslo
Rowett
Un. Ulster
Un Newcastle
Un Lund
Trinity
DiFE
Un Cork
EBI
IFR
Rivm
Rikilt
TNO
Un Reading
Un Wageningen
Un Maastricht
Un Krakow
Un Munich
Inserm Marseille
Un Florence
central datawarehouse
Un Balearic Illes
the European Nutrigenomics Organisation

42. Federated Database
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43. The key issues: Enormous amounts or data and results
Standardisation of data formats
Federation of databases
Merging of available studies
Perform new studies (partly) based on existing data.
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44. 4. Let`s collaborate and shape this area together.
The big lesson
4. Let`s collaborate and shape this area together.
the European Nutrigenomics Organisation

45. The biomed to nutrition brainwash
Multiple targets, usually with low affinity – systems biology needed
Prevention, not therapy – new biomarkers needed
No disease genes but many minor SNPs – new approach, large numbers
No tradition – brainwash needed
No big money – collaboration needed
Tox based safety assessment – systems biology needed
the European Nutrigenomics Organisation

46. Nu GO Nutrigenomics: a new way of nutritional sciences.
Un Oslo
Un Munich
Un Florence
Un Balearic Illes
Un Cork
Trinity
Un. Ulster
Rowett
Un Newcastle
Un Reading
IFR
DiFE
Un Krakow
Inserm Marseille
TNO
Un Wageningen
Un Maastricht
EBI Nu GO
Un Lund
Rikilt
Rivm
The EU Network of Excellence
establishing the
European NutriGenomics Organisation
Nutrigenomics:
a new way of nutritional sciences.
the European Nutrigenomics Organisation

47. How? Grant for integration – 17.23 ME
No IP barriers – contract signed by all partners, thus all activities and knowledge of all partners can be shared.
Standardization of methods, facilities (e.g. joint Affymetrix platform).
Joint Research Activities: Staff exchange, shift in research topics, etc
Joint information systems
Joint data storage (European Bioinformatics Institute).
the European Nutrigenomics Organisation

48. How (2)? Joint bioinformatics Joint training
Merging 6 obesity & metabolic health cohorts
Linking to funding opportunities
Leading global efforts on nutrigenomics (e.g. metabolomics database)
Etc, etc.
the European Nutrigenomics Organisation

49. The current NuGO structure
Three main areas:
Joint research
Integration
Spreading excellence
- Gut Health
- Metabolic health
- Early life nutrition
- Risk Benefit analysis
- Standardisation
Innovation
Human studies
Animal models
Bioinformatics
Information systems
& databases
- Training
Communication
Society
Commercialisation
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50. The integration process
Year 1
Setting the stage
Year 2
Implement
Year 3
Integrate
Year 4 onwards
Reshape
Research: - who does what?
- what can we do together?
- what are facility and technology needs
Integration - what do we have?
- what do we need?
- what do others need?
Research: - form small functional teams
- develop key emerging areas
- drive technology developments
Integration - standardise / share technology
- new bioinformatics
- data / protocol standards
the European Nutrigenomics Organisation

51. Research themes and groups
Lipid metabolism
Life stage nutrition
Risk Benefit analysis
Metabolic health
Proliferation
Differentiation
Apoptosis
Inflammation
Muscle insulin
resistance
Nutrigenetics
Early biomarkers
Periconceptual
nutrition
Nuclear
transcription
factors
Systems biology
Host-microbe
interaction
Gut Health
Absorption
Genetic epidemiology
Toxicogenomics
Metabolic stress
Adipocyte
fat oxidation
Diabetes II
Carotenoids
the European Nutrigenomics Organisation

52. Where does the money come from?
Partner budget
(non-EU money, >150 m€)
Grant for integration
(EU money, 17.3 m€)
Partner 1 3 2
The grant for integration only pays for a small part of the total budget involved in the consortium nutrgenomics activities
(the “integrating activities”)
the European Nutrigenomics Organisation

53. The world is bigger than Europe...
Un Oslo
Rowett
Un. Ulster
Un Newcastle
Un Lund
Trinity
DiFE
Un Cork
EBI
IFR
Rivm
Rikilt
TNO
Un Reading
Un Wageningen
Un Maastricht
Un Krakow Nu GO
Un Munich
Inserm Marseille
Un Florence
Un Balearic Illes
the European Nutrigenomics Organisation

54. It started small … Dutch Center of Human Nutrigenomics
(established in 2000 by 9 Dutch universities and research institutes)
the European Nutrigenomics Organisation

55. So, do you want to join…?
In changing this dream into a vision into reality?
In establishing a new way of doing nutritional science?
In making this a global effort?
In taking your share in developing this?
NuGO is happy to collaborate with anyone who takes this challenge seriously, since there is a lot of work to be done!
the European Nutrigenomics Organisation