Interactive lecture with a large group of healthcare professionals, scientists and patients to illustrate developments in personalized healthcare and the role of technology to support science, innovations and medical impact. (slides in English)

1. ‘Personalized Health(care) doe je samen’
Prof Alain van Gool +
Radboud Grand Round
22 Augustus 2016

2. My path 1989-now
• Molecular biology
• Mechanisms of disease
• Biomarkers
• Omics / technologies
• Translational medicine
• Personalized healthcare
Senior Scientist Integrator Biomarkers
Scientific lead DTL-Technologies
Head EATRIS Biomarker Platform
Professor of Personalized Healthcare
Head Radboud Center for Proteomics, Glycomics & Metabolomics
Coordinator Radboud Technology Centers
2 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

3. Consider individual differences in life science research
3
3 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

4. Source: Chakma, Journal of Young Investigators, 16, 2009
Principle of Personalized Medicine
4
• The right drug for right patient at right dose at right time
• Molecular biomarkers as key drivers of patient selection
• = Precision medicine or Targeted medicine
4 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

5. Example: Personalized medicine in melanoma
B-RAFV600E mutation Strong growth of cell Growth of tumor
• B-RAFV600E cells always grow and become cancer cells
• RAF inhibitors will block pathway, block cell growth
and inhibit cancers that have a B-RAFV600E mutation
• 60% of melanoma patients have B-RAFV600E mutation
• Basis for a personalized medicine !
5 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

6. Personalized medicine in melanoma
Treat patients with
B-RAFV600E mutation Inhibit growth of cell
Patients live longerTumors disappearCells stop growing
B-RAFinhibitor
6 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

7. Emerging Personalized / Precision / Targeted Medicine
2010:
5%of drugs in pipeline had companion diagnostic biomarker test
2015:
80%
50%
7 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

8. 8
Optimal Personalized / Precision / Targeted Medicine

9. People are more than linear pathways
{Source: Barabási 2007 NEJM 357; 4}
• People are different
• Different systems and networks
• Different risk factors
• Different preferences
9 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

10. Societal need in efficient personalized health(care)
{Source: prof Jan Kremer}
Towards cost effective care, less cure
10 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

11. Highest need in efficient personalized health(care)
It’s personal !
‘I want to stay healthy.’
‘If not, how do I get healthy?’
11 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

12. 3 key aspects of personalized health(care)
‘I want to stay healthy. If not, how do I get healthy?’
1. What to measure?
2. How much can it change?
3. What should be the follow-up for me?
12 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

13. 1. What to measure?
Exponential technological developments
• Next generation sequencing
• DNA, RNA
• Risk analysis and therapy selection
• Mass spectrometry
• Proteins, metabolites
• Monitoring of disease and treatment effects
• Imaging
• Non invasive images, real time
• Spatial view of intact organs and organisms
500
1000
1500
2000
m/z
5 10 15 20 25 30 35 40 Time [min]
13 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

14. Crash course in molecular biology
DNA, protein, cell, tissue, system biology
14 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

15. Advances in mass spectrometry
• Mass spectrometry analysis of glycoproteins in human plasma
• 0,05 microliter analysis: detection of 1.000.000 signals in one scan (1,4 Gb)
• ~40.000 peptides of which >80% contain sugar modification
• Diagnose 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:
{Hans Wessels, Monique van Scherpenzeel, Dirk Lefeber, Alain van Gool}
Biomarkers !?
15 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

16. Innovation in protein biomarker diagnostics
Current diagnostic protein assays:
• Mostly protein abundance
Emerging:
• Post-translational modifications
• Intact proteins
• Protein complexes
16 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

17. New diagnostic glycoprotein biomarker
• Rare metabolic disease cases (liver disease and dilated cardiomyopathy)
• Combination glycoproteomics and exome sequencing
• Identification of deficient enzyme in glycosylation pathway
• Outcome 1: Explanation of disease
• Outcome 2: Dietary intervention as succesful personalized therapy
• Outcome 3: Glyco -transferrin profile developed as diagnostic mass spec test
{Monique van Scherpenzeel, Dirk Lefeber}
17 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

18. 18 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016
Intact protein analysis
Bottom-up proteomics
Top-down proteomics
{Hans Wessels, Alain van Gool}

19. Intact complexome proteins as new biomarker?
• Native tissue biopsies
• Isolate intact membrane complexes
• Separate and isolate complexes using native gels
• LC-MS/MS analysis of intact proteins
• Data analysis
Tissue 1
(n=3)
Tissue
2 (n=3)
Subunit
Subunit – tissue 1
Subunit – tissue 2
• Identified protein sequence of subunit
• Deduce simulated sequences from database
• Determine fit with experimental data
19
{Hans Wessels, Susanne Arnold, Uli Brandt, Alain van Gool}

20. 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
Next generation metabolic screening
Xanthine
Whole Exome Sequencing
{Leo Kluijtmans, Ron Wevers (TML) + Genetica}

21. Challenge: translate laboratory to society
• Heart beat
• Steps / movement
• Glasses water/coffee• 1.000.000 molecules per analysis
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22. 22
New data
(generators, owners)
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23. What does my DNA tell me?
23% chance blond hair 3.1% Neanderthaler DNA
23 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

24. Genetic risk lung cancer
→ don’t smoke !
What does my DNA tell me?
No expected adverse reaction
to Warfarin
24 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

26. Need for optimal quality in health biomarker analyses
Test, interpret, advice
“Post-traumatic Test Syndrome” ?
26 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

27. Try-outs at REshape Center of Health(care) Innovation
Lucien Engelen

28. … but not all data is useful data !

29. 3 key aspects of personalized health(care)
‘I want to stay healthy. If not, how do I get healthy?’
1. What to measure?
2. How much can it change?
3. What should be the follow-up for me?
29 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

30. healthy disease disease +
treatment
2. How much can it change?
Subgroups
100%
Individual
Population
30 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016
Past
Present
Future

31. Personalized health(care) model
Personalized
Intervention
of patients-like-me
Personal thresholds
of persons-like-me
Big
Biomarker
Data
Molecular
Non-molecular
Environment
…
HomeostasisAllostasisDisease
Time
Disease
Health
Selfmonitoring
Adapted from Jan van der Greef, TNO
Personal profile
Personalized health
Personalized medicine
31 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

32. 3 key aspects of personalized health(care)
‘I want to stay healthy. If not, how do I get healthy?’
1. What to measure?
2. How much can it change?
3. What should be the follow-up for me?
32 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

33. 3. What should be the follow-up for me?
Personal profile data
Knowledge
Understanding
Decision
Action
33 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

34. Daily views of molecular system biologists
β-cell Pathology
gluc Risk factor
{Source: Ben van Ommen, TNO}
therapy
34 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

35. Translation is key in Personalized Healthcare !
“I’m afraid you’re
suffering from an
increased IL-1β and
an aberrant miR843
expression”
Adapted from:
?
35 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

36. 36 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016
Translating Personalized Health(care) in society

37. We need a personalized data-driven GPS for health
• Monitor on background
• Alert when you are at risk
• Advice what to do
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38. Translational medicine using simulation + feedback
Simulating YOUR health + Personalized advice + Feedback
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39. Personalized Healthcare @ Radboudumc :
Focus on the end user: the patient / citizen
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40. Patient
Radboud
Personalized Healthcare
A significant impact
on healthcare
Molecule
Population
40 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

41. Personalized Healthcare @ Radboudumc
People are different Stratification by multilevel diagnosis
+Patient’s preference of treatment
Exchange experiences in
care communities Select personalized therapy
Population
Man
Molecule
41 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016www.radboudumc.nl/Research/Pages/PersonalizedHealthcare

42. Be proud of what we achieve !
42 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

43. Research themes and institutes
www.radboudumc.nl/Research/Themes/Pages/default.aspx
43

44. Orientation across the spectrum
from molecule to man to population
Orientationacross
thespectrumofdiseases
PI
Research theme
TechnologyCenters
Research support by Technology Centers
44
www.radboudumc.nl/research/technologycenters

45. Radboudumc Technology Infrastructure
Get organised:
1. What technological expertise do we have and should we have ?
2. How should we organise this ?
3. How will we communicate this ?
45 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016

46. www.radboudumc.nl/research/technologycenters
46
Genomics
Bioinformatics
Animal
studies
Stem
cells
Translational
neuroscience
Image-guided
treatment
Imaging
Microscopy
Biobank
Health
economics
Mass
Spectrometry
Radboudumc
Technology
Centers
Investigational
products
Clinical
studies
EHR data
analysis
Statistics
Human
performance
Data
stewardship
Molecule
Flow
cytometry
3D lab

47. About 280 dedicated people working in 19 Technology Centers, ~1800 users (internal, external), ~150 consortia
www.radboudumc.nl/research/technologycenters/47
• Proteins
• Metabolites
• Drugs
• PK-PD • Preclinical
• Clinical
• Behavioural
• Preclinical
• Animal facility
• Systematic review
• Cell analysis
• Sorting
• Pediatric
• Adult
• Phase 1, 2, 3, 4
• Vaccines
• Pharmaceutics
• Cyclotron
• Radio-isotopes
• Malaria parasites
• Management
• Analysis
• Sharing
• Cloud computing
• DNA
• RNA
• Internal
• External
• Early HTA
• Evidence-
based surgery
• Field lab
• Statistics
• Biological
• Structural
• Preclinical
• Clinical
• Economic
viability
• Decision
analysis
• Experimental design
• Biostatistical advice
• Electronic Health
Records
• Transmural
translation
• Best practice
• In vivo
• Functional
diagnostics
• iPSC
• Organoids
• 3D imaging
• 3D printing
• Virtual reality

48. Working with/within other networks
Region, nation, Europe, world
48
Peggy Manders
Gerhard Zielhuis
Peter Friedl
Otto Boerman
Alain van Gool (Scientific Lead Technologies)
RADBOUD RESEARCH FACILITIES
Otto Boerman (Head Imaging Platform)
Alain van Gool (Head Biomarker Platform)
Via DTL
Grootschalige
Wetenschappelijke
Infrastructuur

49. Acknowledgements
Ron Wevers
Jolein Gloerich
Hans Wessels
Dirk Lefeber
Monique Scherpenzeel
Leo Kluijtmans
Lucien Engelen
Nathalie Bovy
Paul Smits
Maroeska Rovers
Bas Bloem
the Technology Centers
and many others
www.radboudumc.nl/personalizedhealthcare
www.radboudumc.nl/research/technologycenters
www.radboudresearchfacilities.nl
alain.vangool@tno.nl
alain.vangool@radboudumc.nl
www.linkedIn.com
www.slideshare.net/alainvangool
Many collaborators and funders
Jan van der Greef
Ben van Ommen
Ivana Bobeldijk
Lars Verschuren
Marjan van Erk
Peter van Dijken
Heleen Wortelboer
Wessel Kraaij
Peter Wielinga
Ronald Mooij
Suzan Wopereis
and many others
CarTarDis
49 Alain van Gool, Radboudumc Grand Rounds, 22 Aug 2016