Introducing the innovations we plan to do in the Netherlands X-omics Initative, together with other X-omics consortium members, at a dedicated X-omics workshop at the annual congres of the Netherlands Chemistry society.

1. Innovation within the
Netherlands X-omics Initiative
Prof Alain van Gool
Professor Personalized Healthcare
Head Translational Metabolic Laboratory
Strategic advisor of the executive board
Coordinator Radboudumc Technology Centers
CHAINS 2018
4 Dec 2018, Veldhoven

2. www.radboudumc.nl

3. Role of molecular biomarkers in Personalized Healthcare
Personalized diagnosis
Personalized therapy
= Personalized healthcare
+Patient participation
X-Omics
Therapy monitoring
3 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

4. Genomic impact in Personalized Health(care)
Personalized medicine:
B-RAFV600E drugs for melanoma
Personalized health:
BRCA-driven preventive surgery
4 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

5. Genomics developments
More and longer reads at lower costs
5 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

6. Diagnostic progress by Whole Exome Sequencing
Human Genetics Nijmegen (Lisenka Vissers, Marcel Nelen, Han Brunner et al)
Retrospective analysis of Intellectual Disability cohort (n=150)
Sanger sequencing
Gene-by-gene
5.4 tests / patient (1-28)
Whole Exome Sequencing
All genes at once
1 test / patient
6 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

7. Next: Whole Genome Sequencing
Circus plots of Whole Genome Sequences of two metastatic cancer patients
Source: prof Edwin Cuppen, Hartwig Medical Foundation
7 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

8. Interpretation of genetic variants becomes the issue
“Functional studies can be a powerful tool in
support of pathogenicity”
Richards et al., Genet Med. (2015)17:405-24
Variant classification:
1. Benign
2. Likely benign
3. Uncertain significance
4. Likely pathogenic
5. Pathogenic
Guidelines American College of Medical Genetics and Genomics (ACMG)
More sequence data =
more unknown variants
8 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

9. The DNA-RNA-protein-metabolite dogma
Text book
DNA
RNA
Protein
Metabolite
Reality
{Karr, Cell 2012}Environment
9 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

10. Complexity in protein biology
21.000 genes
1.000.000 -2.000.000
protein forms
N-Glycosylation
Truncation
Phosphorylation
Acetylation
Ubiquitination
…
10 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

11. Our functional Omics platforms
Research Biomarkers Diagnostics
Translational Metabolic Laboratory (www.youtube.com/watch?v=yhLbuX0H7rg)
Glycopeptidomics
500
1000
1500
2000
m/z
5 10 15 20 25 30 35 40 Time [min]
Metabolomics
400
600
800
1000
1200
1400
m/z
10 20 30 40 50 60 Time [min]
Bottom-up proteomics
Glycomics
Top-down proteomics Functional genomics
11 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

12. 12 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018
Uric acid
Human
samples
Plasma, CSF (urine)
Controls vs. patient
QTOF Mass Spectrometry
- Reverse phase liquid chromatography
- Positive and negative mode
- Features
XCMS
Alignment
Peak comparison
> 10,000 Features
Xanthine
Whole Exome Sequencing
Karlien Coene
Leo Kluijtmans
Ron Wevers
Genomics & Metabolomics

13. Genomics & Glycomics
SLC8A6
GlycoModelControl(n=40)
SLC10A7-CDG
(n=4)
O
therCDG
-II(n=21)
-150
-100
-50
0
50
100
P33
P32
P17
P39
Modelvalues
99 patients; 47 without known gene defect
- Glycomics profiling on 99
- Intact transferrin glycoprofiling on 99
- Whole Exome Sequencing for 32 cases
PGM1: New Eng J Med 2014
Man1B1: Brain 2014
More subtle changes: here
(manuscript in prep)
Dirk Lefeber
Monique van
Scherpenzeel
13 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

14. Genomics & Glycoproteomics
• Mass spectrometry analysis of glycoproteins in human plasma
• 1/20 microliter analysis: detection of 1.000.000 signals in one scan (1,4 Gb)
• ~40.000 peptides of which >80% contain sugar modification
• Potential to screen patients and identify new biomarkers?
500
1000
1500
2000
m/z
5 10 15 20 25 30 35 40 Time [min]
Proof of principle study:
Biomarkers !?
Hans Wessels, Alain van Gool, Dirk Lefeber
14 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

15. Functional genomics
functional validation
of variants with unknown
significance
CRISPR/Cas9
rescue
biomarkers
animal model
iPSC
+nGFP +nGFP +TAZ
contr BTH BTH
PTPS deficiency PTPS deficiency-Corr#1
TH/βIII-tubulin/DAPI
complementation
Control clpb MO
mdh1Δ
mdh1-P128L
mdh1-P202L
mdh1-G30R
hMDH2
MDH1
-
YPD
fermentation
YPD
respiration
α-actinin
α-ManNAc
CH3
β-ManNAc
CH3
2.10 2.05 2.00
{Rodenburg,
J Inherit Metab Dis, 2018}
micro-organism model
Richard Rodenburg
Omar Tutakhel
15 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

16. Precision medicine in genetic-metabolic disease – current
Personalized diagnosis
Genomics
(WES)
Metabolomics
(IEM panel)
New disease
mechanisms
Personalized therapies
Nature Genetics 2018
NEJM 2014
Nature 2016
NEJM 2014
Genet Med 2017
16 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

17. Diagnostic glycoproteomics pipeline
Comprehensive QC analytics

18. Diagnostic glycoproteomics pipeline
Comprehensive QC analytics

19. Precision medicine in genetic-metabolic disease - future
Personalized diagnosis
Genomics
(WGS)
Metabolomics
(more panels)
New personalized
therapies
Glycomics
Glycoproteomics
Deep Learning
Artificial Intelligence
System biology
Nature Genetics 2016 Pilot 2017
New disease
mechanisms
19 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

20. Progress further through collaboration
European networks
national
local
20 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

21. National large-scale scientific infrastructures
www.nwo.nl21 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

22. Netherlands X-omics Initiative
www.x-omics.nl
• Access
• Helpdesk / training
• Collaboration
22 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

23. 23 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

24. Netherlands X-omics Initiative
Push omics
technologies
• Resolution
• Sensitivity
• Coverage
Genomics
Proteomics
Metabolomics
• Quality
• Standards
• Data FAIR
at source
X-omics
• Study design
• Sample handling
• Data cataloging
• Quality
• Expertise
• Best practice
• Data integration
• Data analysis
• Best practice
• Access
• Helpdesk / training
• Collaboration
24 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

25. X-omics demonstrators
www.x-omics.nl
1. Cell/organoid
• Understanding cancer drug response and resistance
• Drug-induced dynamic pathway analysis
2. Individual
• Understanding personalized differences in rare diseases
• Systemic changes to biological challenges
3. Population
• Understanding genetic variants in Dutch population
• Statistical correlations
To showcase and field test new X-omics capabilities
25 Alain van Gool, CHAINS 2018, Veldhoven, 4 Dec 2018

26. Objectives next years
www.x-omics.nl26 Alain van Gool, Benelux Precision Medicine Forum, Utrecht, 13 June 2018
1. Advancing X-omics technologies far
beyond state-of-the-art
2. Realizing a genuinely integrated X-omics
infrastructure in Netherlands
3. Use infrastructure for new biology
Consortium kick-off
Nijmegen, 14 Sept 2018
Other
networks,
infrastructures,
cohorts,
projects

27. Acknowledgements
Translational Metabolic Laboratory
Hans Wessels
Dirk Lefeber
Karlien Coene
Leo Kluijtmans
Richard Rodenburg
Jolein Gloerich
Anouk Suppers
Purva Kulkarni
Albert Gerritsen
Roel Tans
Esther Willems
Ron Wevers
and others
Edwin Cuppen
Albert Heck
Thomas Hankemeier
Peter Bram ‘t Hoen
Daniella Kasteel
and others
Collaborators/funders
Human Genetics Nijmegen
Marcel Nelen
Alexander Hoischen
Lisenka Vissers
Christian Gillisen
Han Brunner
and others
alain.vangool@radboudumc.nl
www.radboudumc.nl/en/people/alain-van-gool
www.slideshare.net/alainvangool
CarTarDis
Irene Keularts
Hans Scheffer
and others
Rainer Bischoff
Theo Luider
and others