Opening lecture at the 2nd International Congress on Precision Medicine in Munich, outlining progress in omics-based biomarkers for rare diseases, biomarker innovation gaps and multi-partner initiatives to bridge those gaps to applications. Also reviewed the highlights of our recently published Handbook of Biomarkers and Precision Medicine.

1. Moving Forward with
Biomarkers in Precision Medicine
alain.vangool@radboudumc.nl
Prof Alain van Gool
Professor Personalized Healthcare
Head Translational Metabolic Laboratory
Strategic advisor of the Executive Board
Radboudumc Technology Centers

2. www.radboudumc.nl
2 Alain van Gool, Relatiedag zorgverzekeraars Radboudumc, Nijmegen, 5 Sept 2019

3. Precision medicine in rare metabolic diseases
Healthy Dutch parents
Son Brian, 2002, low birth weight, lactic acidosis, hypoglycaemia
Intellectual diability, movement disorder, epilepsy
† age 3,5 yr (respiratory failure)
Son Joel, 2009, same clinical phenotype
† age 1,5 yr (epilepsy)
Clinical phenotype:
Suspicion of mitochondrial dysfunction
A short story:
3 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

4. Lab tests • ATP production ↓, Creatine phosphate production ↓
• But OXPHOS enzyme complex I-V normal
• Candidate gene sequencing: no variant
• Mechanism of disease?
• In 2010: Whole Exome Sequencing - WARS2
mutations{medicalxpress.com}
{Rodenburg, Biochim
Biophys Acta, 2016}

5. New mechanism of disease • WARS2 is mtDNA-coded
tryptophanyl-tRNA synthases
• Novel mutation causes
instability of WARS2 protein
• Less charging of Trp-tRNATrp
• New prenatal genetic test !
{Wortmann et al, Human Biology 2017}
5 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

6. Meet & greet @ Translational Metabolic Laboratory
6 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

7. Lessons learned
• Technology innovation is driving impact in personalized
healthcare
• Fast translational of biomarker research to implementation
in academic clinical laboratories
• Crucial to combine different molecular views to understand
human health and disease (X-omics)
7 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

8. Role of molecular biomarkers in Personalized Healthcare
Personalized diagnosis
Personalized therapy
= Personalized healthcare
+Patient participation
X-Omics
Therapy monitoring
8 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

9. Genomic impact in Personalized Health(care)
Personalized medicine:
B-RAFV600E drugs for melanoma
Personalized health:
BRCA-driven preventive surgery
9 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

10. Our functional Omics platforms
Research Biomarkers Diagnostics
Translational Metabolic Laboratory (www.youtube.com/watch?v=yhLbuX0H7rg)
Glycomics/glycoproteomics
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]
Proteomics
Top-down proteomics Functional genomics
Targeted analyses
10 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

11. 11
Uric acid
Human
samples
Plasma, CSF (urine)
Controls vs. patient
QTOF Metabolomics
- Reverse phase liquid chromatography
- Positive and negative mode
- Features
Data analysis
Alignment
Peak comparison
> 10,000 Features
Xanthine
Whole Exome Sequencing
{Karlien Coene
Leo Kluijtmans
Ron Wevers}
Genomics & Metabolomics for Inborn Errors of Metabolism
NRC newspaper 2017

12. 12 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019
Precision medicine in rare metabolic diseases – current
Personalized diagnosis
Genomics
(WES)
Metabolomics
New disease
mechanisms
Personalized therapies
Nature Genetics 2018
NEJM 2014
Nature 2016
NEJM 2014
Genet Med 2017
@Translational Metabolic Laboratory
Glycomics

13. Precision medicine in rare diseases – therapy monitoring
Target range
Eculizumab levels
0 1 2 3 4 5 6 7 8
0
200
400
600
800
1015202530
BS
P1
P2
P3
P4
P5
P6
P7
P8
P9
P10
P11
Intervals (weeks)
Eculizumab(g/mL)
Eculizumab levels
4 5 6 7 81015202530
P1
P2
P3
P4
P5
P6
P7
P8
P9
P10
P11
Intervals (weeks)
Standard infusion intervals (weeks)
{Volokhina et al., Clin Pharmacol Ther, 2017}
{Elena Volokhina, Bert van den Heuvel}
• Soliris (Eculizumab, anti-C5) in
atypical Hemolytic Uremic syndrome
• Life-long weekly infusion of drug
(€500.000/patient/year)
• Collaboration 4 academic hospitals:
(Radboudumc, ErasmusMC, VUMC, UMCG)
• Adjustment of over-dosing
• Reduce treatment after recovery
• Saved 24M euro
(Jan 2016 – Mar 2019, n=37 patients)
13 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

14. Precision medicine in multiple myeloma – therapy monitoring
{Pieter Langerhorst, Jolein Gloerich, Hans Jacobs}
14 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

15. Precision medicine in rare metabolic diseases - future
Personalized diagnosis
Genomics
(WGS)
Metabolomics
New personalized
therapies
Glycomics
Glycoproteomics
Deep Learning
Artificial Intelligence
System biology
Nature Genetics 2016 Pilot 2017
New disease
mechanisms
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Center of Excellence
For Translational Omics

16. However …: Translational innovation gaps !
1. Research to research
2. Research to diagnostics
3. Research to society
{See www.slideshare.net/alainvangool}
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17. Crucial to share best practice in precision medicine !
Maximizing impact without reinventing the wheel
17 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

18. Handbook of Biomarkers and Precision Medicine
70 manuscripts from experts in pharma,
diagnostics, clinic, technology
1. What is a biomarker and their role in drug
development?
2. Biomarkers in preclinical sciences
3. Biomarkers in translational sciences
4. Biomarker-informed clinical trials
5. The road ahead in precision medicine
6. Lessons from the past and pioneers of the
future
7. Emerging technologies
8. The next frontiers in therapeutic target areas
9. Lessons learned and what’s next?
History – Current status – Future
Available @on-line webshops
+ 30% discount for PMBC2019 participants
18 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

19. Biomarker-drug-disease case studies
Emerging biomarkers and Companion Diagnostics
• Oncology
• Melanoma
• Breast cancer
• Lung cancer
• HRD tumors
• AIDS
• Infertility
• Coagulation
• Allergic rhinitis and Asthma
• Autoimmune diseases (RA, SLE)
• Systemic lupus erythematosus
• Cardiovascular disease
• Psychiatric diseases
• Alzheimer’s disease
19 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

20. Biomarker technologies
• Immuno-proteomics
• Targeted proteomics by MS
• Epigenetics
• Non-invasive Imaging
• Metabolomics
• Glycomics
• Proteogenomics
• Mass Spectrometry Imaging
• Next Gen Sequencing
• MicroRNA sequencing
• Microbiome Sequencing
• Data analysis methods
• Omics integration
20 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

21. Lessons learned - collaborations
• Pharma and Diagnostic
processes
• Preclinical
• Translational
• Clinical
• Companion diagnostic
development
• Global collaborations in
translational medicine
• European research
infrastructures
• Public-private partnerships
• USA
• UK
• NL
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22. 22 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019
Lessons learned - quality
• Quality of IVD tests
• Need for standards
• Good reporting practice
• Biobanking guidelines
• Data infrastructures
• Promise of big data analytics
• Health-Technology Assessment

23. Collaboration towards Good Biomarker Practice
{van Gool et al, Nature Reviews Drug Discovery, Apr 2017}
COST action CA16113
http://clinimark.eu
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24. Netherlands X-omics Initiative
Quality
Best practice
Expertise
Standards
FAIR data
Coordinator: Alain van Gool
24 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

25. X-omics research infrastructure
Outreach
• Helpdesk
• Training
• Community
• Demonstrators
o Cell
o Individual
o Population
X-omics
approach
• Data analysis
• Data integration
• Data stewardship
• Study design
• Sample handling
Pushing omics
technologies
• Resolution, sensitivity,
coverage
• Harmonisation,
standardisation, data
FAIR-at-source
25 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

26. X-omics Community
To connect researchers from all over the world,
interested in X-omics research approaches
• LinkedIn
• X-omics festival
Find us on LinkedIn: X-omics community /
https://www.linkedin.com/groups/13739398/
Connect
Discuss
Advise
Inform
Share
Publications
Best practices
Protocols
Trainings
Conferences
26 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

27. X-omics Festival 1 April 2020
• X-omics project kick-off
• Sharing dreams and visions
• Keynote lectures
• Interactive sessions
• Meet & greet experts
• Technology demo’s
Nijmegen, Netherlands
27 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

28. Collaboration in United for Metabolic Disease
• Netherlands multidisciplinary
collaboration
• Clinicians + laboratory
specialists + patients
• Step-wise focus:
1. Awareness
2. Diagnosis
3. Understanding
4. Therapies
5. Care and prevention
• Link to technology in
Netherlands X-omics Initiative
28 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

29. Afterthought: multiple reflections of personal health…
Funhouse mirror effect
• Multiple sources of your data
• Multiple Omics
• Clinical chemistry
• Electronic Patient Dossier
• Wearables
• Digital biomarkers
• Commercial health tests
• Social media
• Surrounding
• Each are a skewed image of you
How to deal with all of this for your personal health(care)?
{Mira Vegter, Hub Zwart, Alain van Gool: submitted}
29 Alain van Gool, 2nd Int Congress on Precision Medicine, Munich, 14 Oct 2019

30. Acknowledgements
Translational Metabolic Laboratory
Hans Wessels
Jolein Gloerich
Dirk Lefeber
Karlien Coene
Leo Kluijtmans
Elena Volokhina
Bert van den Heuvel
Richard Rodenburg
Marcel Verbeek
Dorine Swinkels
Albert Gerritsen
Purva Kulkarni
and others
Edwin Cuppen
Albert Heck
Thomas Hankemeier
Peter Bram ‘t Hoen
Daniella Kasteel
and others
Collaborators/funders
Human Genetics
Helger Ijntema
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
Dapha Habets
Irene Keularts
and others
Rainer Bischoff
Theo Luider
and others