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CASyM training event -

Systems Medicine of Multifactorial Disorders workshop & tutorial and 8th CFGBC symposium REPORT

12 - 15 June, 2013 Ljubljana, Slovenia

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CASyM training event: Systems Medicine of Multifactorial Disorders workshop & tutorial and 8th CFGBC symposium

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Publisher

CASyM administrative office Project Management Jülich, Forschungszentrum Jülich GmbH [email protected]

Authors

Jure Ačimovič, Marc Kirschner, Damjana Rozman Supplement: Hans V. Westerhoff Pictures

Jure Ačimovič, Žiga Urlep

Date 24 July 2013

Please take note that the content of this document is property of the CASyM consortium. If you wish to use some of its written content, make reference to: CASyM report: Systems Medicine of Multifactorial Disorders workshop & tutorial and 8th CFGBC symposium, Ljubljana, June 2013.

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mailto:[email protected]


TABLE OF CONTENTS

1 INTRODUCTION ...................................................................................................................... 3

2 PROGRAMME ......................................................................................................................... 5

3 EVENT OUTCOME ................................................................................................................. 10

3.1 General information .......................................................................................................... 10

3.2 Survey statistics.................................................................................................................. 11

3.2.1 Workshop ....................................................................................................................... 11

3.2.2 Tutorial ........................................................................................................................... 12

3.2.3 Open questionnaire ........................................................................................................ 13

3.3 Systems Medicine Education Round Table ........................................................................ 14

3.4 Tutorial & ECTS/CME credits.............................................................................................. 17

4 LIST OF PARTICIPANTS ......................................................................................................... 20

5 ACKNOWLEDGEMENTS ........................................................................................................ 24

6 APPENDIX ............................................................................................................................. 26

6.1 Assessment by prof. dr. Hans V. Westerhoff ..................................................................... 26

6.2 Survey and questionnaire .................................................................................................. 28

6.3 Examination questions (ECTS credits)................................................................................ 30

6.4 Grading criteria (ECTS credits) ........................................................................................... 35

6.5 Application procedure for ECTS ......................................................................................... 36

6.6 Application procedure for CME ......................................................................................... 38

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1 INTRODUCTION

The Coordinating Action Systems Medicine (CASyM) represents an activity of a multidisciplinary European consortium that has been tasked with developing an implementation strategy (road map) for Systems Medicine. CASyM is supported by the FP7-Directorate-General for Research and Innovation of the European Commission. The present report on the first training event “Systems Medicine of Multifactorial Disorders workshop & tutorial and 8th CFGBC symposium” is part of the CASyM work package 2 – “Multidisciplinary training in systems approaches for the next generation of scientists and MDs”.

According to the participants’ opinions, the meeting was an exciting Systems Medicine symposium, which truly presented the highlights of interdisciplinary research, bridging biology, medicine and clinics with mathematics and information sciences. The invited lectures, poster presentations and other discussions provided state of the art information from the above fields and more particularly on their integration.

In addition to the training event of CASyM, the meeting also represented an important networking platform for relevant initiatives and was supported by the European Research Infrastructure programme’s ISBE (Infrastructure for Systems Biology Europe) and ELIXIR (the European life-science Infrastructure for Biological Information). Within the workshop/tutorial also ESR and ER students of the FP7 ITN FightingDrugFailure have been trained. This joint Slovenian-EU partnership is of particular importance for the Slovenian local organizers, who joined the forces from academic, research, clinical and SME settings. The CASyM event was a pilot in the sense of being a “systems biology and systems medicine training proof of concept” upon which additional and similar events will build as a part of the proposed implementation actions. According to the questionnaires, the attempts were very successful and useful for all participants and the trainees. Such meetings are planned to become a tradition within the CASyM European training scheme. In addition to the research symposia “From Omics to Understanding the Model Biological Systems” and “Systems Medicine of Multifactorial Disorders”, such as cancer, metabolic, liver and brain diseases, diseases linked to immune system, etc., we had a session where the participating European programmes (CASyM, ISBE, ELIXIR) were presented. Additionally, there was an important round table discussion of Systems medicine training initiatives in the USA and in Europe that is reported in detail in Chapter 3.3.

After the 2-day workshop with cutting edge systems biology and systems medicine lectures and poster presentations, the meeting continued in a 2-day systems medicine tutorial for a limited number (14) of participants, where attendees got hands-on experience in various mathematical and informatics approaches to medical relevant questions from 6 renowned European clinicians and scientists and Slovenian co-tutors. Importantly, the workshop and tutorial were accredited with 5 ECTS (European Credit Transfer System), 20 CME (Continuous Medical Education) and 20 SILM (Professional Education for Laboratory Medicine) points, which may well have been awarded for the first time in Europe for systems medicine in particular.

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The meeting was attended by 108 participants from 9 countries. 10 of them were medical doctors. One was a 3rd year student of medicine that already completed undergraduate studies of electrical engineering. Due to timing of the meeting in high examination period we were unfortunately unable to attract more undergraduate medics. Six participants received ECTS credits and five participants CME credits.

Figure 1: Students and tutors of the Ljubljana Systems Medicine tutorial.

A more detailed report regarding the systems medicine education and training perspectives and hurdles is detailed in Chapter 3.4. In addition to the report the assessment by Hans V. Westerhoff, a systems biologist and representative of ISBE, who participated as speaker and tutor on the entire 4-day workshop and tutorial event, is presented in Appendix 6.1. This assessment presents important insight with crucial messages related to systems medicine, to which the other authors of this report subscribe.

Figure 2: Hans V. Westehoff

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2 PROGRAMME

Wednesday, June 12, 2013 8:00 - 9:00 Registration

9:00 - 9:15 Opening Ceremony From 'omics' to Biological Knowledge in Model Systems Bioinformatics Chairs: K. Gruden, J. Schuchhardt 9:15 - 9:45 J. Schuchhardt, Germany: From arrays to reads: statistical aspects of using high

throughput data in systems medicine 9:45 – 10:00 Š. Baebler, Slovenia: Translational research in agriculture: from arabidopsis to

potato

10:00 - 10:15 J. Levatić, Slovenia: Network reconstruction and gene function prediction from time-series gene expression data about of potato defence response

10:15 - 10:30 D. Kocev, Slovenia: Finding drug targets for Tuberculosis and Salmonella by analyzing data from compound screens and public biological databases

10:30 - 10:45 M. Žitnik, Slovenia: Data fusion for Dictyostelium bacterial response gene prioritization

10:45 - 11:15 Coffee Break Omics and Functional analysis Chairs: R. Komel, C. Gostinčar 11:15 - 11:30 S. Berne, Slovenia: Fungal candidate genes implicated in plant pathogenesis

identified via genome and transcriptome analysis

11:30 - 11:45 D. Dobnik, Slovenia: Role of microRNAs in potato-PVY interaction

11:45 - 12:00 J. Šuštar-Vozlič, Slovenia: Proteomic analysis of drought stress response in common bean, Phaseolus vulgaris L.

12:00 - 12:15 S. Mandelc, Slovenia: Proteomics of hop after infection with plant pathogen Varticillium albo-atrum

12:15 - 13:35 Lunch Buffet & Poster Viewing

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Genomics Chairs: U. Petrovič, J. Šuštar-Vozlič 13:35 – 14:05 J. Zajc, C. Gostinčar, M. Lenassi, Slovenia: Genomics of halophilic and halotolerant

fungi

14:05 – 14:15 J. Jakše, Slovenia: NGS sequencing for new phytopathogen discovery

14:15 – 14:25 D. Kutnjak, Slovenia: Constructing complete viral genomes from plant defense molecules: a case study of Potato virus X (PVX)

14:25 – 14:30 Short Break Systems Medicine of Multifactorial Disorders

European Infrastructures and Coordinated Actions Chair: M. Šabec 14:30 - 14:45 H. V. Westerhoff, NL/UK: The Infrastructure for Systems Biology Europe (ISBE)

14:45 - 15:00 M. Kirschner, Germany: Coordinated Actions for Systems Medicine (CASyM)

15:00 - 15:15 N. Blomberg, UK: ELIXIR: the European life-science infrastructure for

biological information 15:20 – 15:30 Coffee Break From Microarrays to Understanding Diseases Chairs: M. Kirschner, D. Rozman 15:30- 15:55 E. Vrtačnik Bokal, R. Devjak, Slovenia: Cumulus cells gene expression profiling to

improve in vitro fertilization

15:55 - 16:20 B. Peterlin, A. Maver, Slovenia: Synthesis of heterogeneous genomic data in discovery of genetic factors for multifactorial diseases

16:20 – 16:45 J. Marc, Slovenia: System medicine diagnostics and pharmacogenomic markers of osteoporosis (ESPT talk)

16:45 – 17:10 T. Battelino, Slovenia: Closed loop insulin delivery

17:10- 17:30 Coffee break

17:30 - 18:10 D. Duffy, T. Schwarzl, Ireland: Omics of Mycs: Application of omics technologies to elucidate the MYCN transcriptional network in neuroblastoma

18:10 – 18:50 V. Turcanu, UK: Systems medicine of peanut allergy (talk via Skype) 19:00 - 21:00 Get Together with Posters

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Thursday, June 13, 2013

Systems Medicine in Clinical Research Chairs: S. Vasudevan, B. Peterlin 8:30 - 9:10 M. Benson, Sweden: Systems medicine to individualise medicine - an

introduction

9:10 - 9:50 D. Harrison, UK: Systems Pathology: how much more can tissue tell us?

9:50 - 10:15 V. Dolžan, L. Lusa, Slovenia: Translating pharmacogenetics to clinical practice

10:15 - 10:40 Coffee Break

Systems Medicine of Cancer Chairs: R. Komel, L. D'Allesandro 10:40 - 11:20 J. Clairambault, France: Optimising cancer pharmacotherapeutics using

mathematical modeling - a systems medicine approach

11:20 - 12:00 S. Vasudevan, USA: Systems Medicine approach to understanding pancreatic cancer

12:00 – 12:25 S. Parodi, Italy: Two systems-medicines-perspectives in oncology

12:25 - 13:40 Lunch Buffet

Mathematical and Animal Models Chairs: D. Harrison, L. Lusa 13: 40 - 14:20 H.V. Westerhoff, NL/UK: The virtual patient

14:20 - 15:00 L. d'Alessandro, S. Hoehme, Germany: The role of HGF in Liver Regeneration (The

Virtual Liver Network talk)

15:00 - 15:25 D. Rozman, P. Juvan, Slovenia: From mouse models to human liver diseases: a statistical modelling approach

15:25 – 15:45 Coffee Break

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Systems Medicine Education Round Table Chairs: M. Benson, D. Harrison, D. Rozman 15:45 – 16:00 16:00 – 17:30

S. Vasudevan (USA): The Georgetown University graduate programme in Systems Medicine Discussion with the CASyM systems medicine education panel and the audience

17:30 – 20:00 Ljubljana Guided Walking Tour

20:00 - 22:00 Dinner for Speakers and Tutors Friday, June 14, 2013 Tutorials – Day 1 9:00 - 11:00 D. Harrison: When is enough data too much?

Co-tutor: R. Košir, Slovenia

Coffee in the Room

11:00 - 13:00 J. Clairmbault: PK-PD models for (chrono) therapy optimization in cancer treatments Co-tutor: M. Goličnik, Slovenia


14:00 - 16:00 G. Baier: Modelling for medical applications Co-tutors: L. D'Allessandro, Germany; A. Belič, Slovenia

Coffee in the room

16:00 - 18:00 M. Benson, Sweden, V. Dolžan, Slovenia: Students' oral poster presentations & discussions

18:00 – 20:00 Free Time

20:00 Dinner

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Saturday, June 15, 2013 Tutorials – Day 2 9:00 - 10:30 H. V. Westerhoff, NL: Truly individualized systems medicine: A hands-on tutorial

where participants will resolve paradoxes by using the virtual twin/digital-me Co-tutor: P. Juvan, Slovenia

Coffee in the Room

10:30 - 12:00 P. Dovč. G. Gorjanc, Slovenia: Searching for runs of homozygosity: A strategy for recessive diseases


13:00 – 14:30 J. Schuchhardt, Germany: Public tools and databases for working with high-throughput data Co-tutor: M. Petek, Slovenia

14:30 - 15:30 ECTS tests

15:30 – 16:00 ECTS, CME, SILM questionnaires

16:00 - 17:00 Closing Ceremony with Delivery of Certificates

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3 EVENT OUTCOME

3.1 General information

Gender was well balanced with 48 females and 60 males among the 108 participants (Figure 1). 37 invited speakers and 6 tutors (Figure 3) from all over Europe and the rest of the world presented highlights of interdisciplinary research, bridging biology, medicine and clinics with mathematics and information sciences in the workshop and tutorial. Among the participants were Principal Investigators, MDs, postdoctoral researchers, PhD students and commercial employees. The majority of participants were from Slovenia followed by Germany, Italy, UK, France, Netherlands, Sweden, USA and Brazil.

Figure 3: Workshop participants according to gender, position, registered for and country (n = 108).

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3.2 Survey statistics

Questionnaires were given to each participant (Appendix 6.2) and here we summarize the outcome:

3.2.1 Workshop

Figure 4: Workshop survey questions and the distribution of answers (n = 21).

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3.2.2 Tutorial

Figure 4 continued: Workshop survey questions and the distribution of answers (n = 21).

Figure 5: Tutorial survey questions and the distribution of answers (n = 14).

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3.2.3 Open questionnaire

Outcome of an open questionnaire for participants attending the workshop (n = 22). Answers were grouped and summarized accordingly.

1. What made you chose to attend the current workshop and what was the initial source of information? Proximity of location; Invited lecturer; Recommendation from supervisor

2. What kind of association do you combine with Systems Medicine?

Systems Biology approach; Organisms as a whole

3. Where do you see the beneficial aspects of Systems Medicine? Treating multifactorial diseases

4. According to your opinion, in which disease area could Systems Medicine have the most impact?

Cancer, multifactorial diseases

5. Have you visited the CASyM website? 50% YES, 50% NO.

6. What do the following terms mean to you - please try to give a short definition:

Systems Medicine: Systems Biology approach in medicine

Systems Biology: A holistic view of organisms, biological processes; Interpretation of

OMIC approaches in biological systems

Personalized Medicine: Patient tailored treatment/therapies and diagnostics

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3.3 Systems Medicine Education Round Table

Give medicine back to the doctors!

Minutes of the Systems Medicine Education Round Table (RT), Ljubljana June 13, 2013 by M. Kirschner.

Introduction

To set the scene, the RT was introduced by a plenary presentation from S. Vasudevan, Georgetown University, Washington DC, presenting the only complete Systems Medicine undergraduate training program so far.

This novel program (dual MD/MS Systems Medicine) aims at educating a new type of physician, trained in computational sciences and “omics” technologies with a comprehensive understanding to systems approaches.

The program offers a range of relevant course modules covering the following topics:

Biomedical informatics Translational bioinformatics Critical reading Systems biology & related technologies Clinical metabolomics Introductory biostatistics

Figure 6: D. Harrison chairing the Systems Medicine Round Table, together with Soona Vasudevan, Damjana Rozman and Mikael Benson.

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Summary of statements and comments by the audience Undergraduate training for MD´s in Systems Medicine is very difficult to achieve since the curricula are traditional and not very flexible. In contrast, training at the MD level could be implemented much more easily. The question of teaching either general concepts or specific tools (or both) of Systems Medicine during training was regarded as an important point of the discussion, since not every MD student will receive a systems master training education and there seemed to be a conceptual problem in the community about what 4P and Systems Medicine indeed is. It was concluded that the introduction of Systems Medicine general concepts into MD training is absolutely necessary, since MDs need to understand biological networks in order to properly understand the pathology of diseases. Teaching systems approaches would result in a much better medical education of medical doctors. Therefore it is necessary to integrate more Systems Biology as well as actual modelling courses into each new training concept (e.g. Georgetown University). In this sense Georgetown University aims at integrating the IBM Watson computer/device into their Systems Medicine training concept. The comment was made, that the Systems Medicine graduate program of the Georgetown University could benefit from integrating more Systems Biology approaches into their curriculum. However, the creation of new course modules was regarded as difficult. Emphasis was also put on the introduction of interactive tools. These tools could feature visualizations of organs, tissues, cells, etc. and demonstrate effects of pharmaceutical active substances in an open and accessible way. With regards to mathematical modelling, such tools could also display the usefulness of mathematical models within routine clinical practice. The doctor-patient relationship would benefit very much from integrating such medical imaging and visualization systems into the clinical routine. The Round Table Chairs also asked the audience about their personal opinion of how Systems Medicine could be introduced into current curricula, with the following ideas emerging from the audience:

By offering proper Systems Medicine training concepts By clearly defining achievable aims and goals By making sure that everyone involved “speaks the same language” (e.g. MDs, statisticians,

modellers, bioinformatics need to make sure that they communicate on a common base) By using already existing and user-friendly analytical tools By convincing MDs that a systems approach is indeed useful The fact that many MDs have a very high work load (“too busy”) and that they have to follow

many different guidelines might not allow additional space needed for the implementation of a systems approach

Medical curricula are too busy and cannot be loaded with extra courses unless something old is abandoned or unless the Systems Medicine training can teach more efficiently and attractively the same material that was taught previously. Examples are anatomy, pathology and biochemistry which can be taught in a much more lively and disease-oriented way by using systems medicine modelling related to the Virtual Patient. In this sense the comment was made that the Faculty of Medicine in Ljubljana is underway in adapting the MD curriculum by offering systems medicine related courses of choice.

By offering interesting research projects. However, MDs are very much interested towards becoming a surgeon with focus on operations and might therefore not be interested in research

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projects. Yet, systems medicine is now developing with computer assisted real time prediction of best ways to excise tumour in tissue saving contexts, and this may well generate much interest.

MDs and the current curricula in many countries are not open to new approaches, which might threaten the implementation of Systems Medicine.

The “establishment” in the medical community was regarded a problematic, since it wouldn´t allow introduction of new concepts into medical curricula.

Figure 7: The round table discussion attracted the medical doctors.

The opinions above met the following comments:

Doctoral level students in Sweden (Linköping University) are very interested and show a strong motivation for systems approaches.

MD curricula need to be made more attractive by replacing various existing courses and by clearly defining new courses with focus on the master level.

The medical educational system is very guideline-fixed and Systems Medicine might not be able to enter such guidelines.

MDs hardly talk about modelling in the context of Systems Medicine. What is often referred to is statistics. This seems to be a common misconception of what mathematical modelling based on systems approaches, is, and could mean for medicine.

E-learning interest groups of the UK could be a valuable example to define what is actually needed for systems based training/education.

The Round Table discussion was ended with the following two statements from Hans Westerhoff and Mikael Benson, which represent a critical view of the on-going debate about the understanding of the meaning of Systems Medicine by clinical doctors:

Give medicine back to the doctors! Systems Medicine is very close to clinical medicine!

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3.4 Tutorial & ECTS/CME credits

Introduction

Jointly, 14 participants attended the tutorial where 9 tutors and 6 co-tutors were at the students’ disposal. In most cases the tutors were professors from foreign institutions who were responsible for covering their topic and for the preparation of the materials for students in advance. Please click here to get access to the course material.

All students were requested to use their own laptop computers, and all necessary academic programmes were available for downloading and installing on their computers in advance. Each student was supposed also to present a poster that was exposed during the entire 2-day lasting tutorial. Some of these posters were selected for oral presentation. In addition to stimulate participants to participate in the students-tutors discussions and to engage in the hands-on work with the computer programmes and applications, the students were not only graded regarding their poster presentations but also in a final test, which was required for obtaining the ECTS credits.

Figure 8: Certificates of ECTS credits for systems medicine.

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http://cfgbc.mf.uni-lj.si/2013anniv8casym/On_line_material


Tutorial structure

PART 1 – Lectures and interactions with students

The tutorial started with a challenging talk of D. Harrison, who interactively discussed with students on the relativity of scientific perception in the systems pathology area, and how much caution is needed to avoid seemingly simple interpretations that might be totally wrong.

The tutorial of J. Clairmbault was about the PK-PD models and their usability for chronotherapy. The tutorial was mathematically too demanding, with no hand-outs and the major part of the students missed the message. This is a weak point as chronotherapy represents an important part of applicative systems medicine with already proven success stories.

G. Baier and L. d’Allesandro presented modelling for medical applications which was interesting and well taken, although too theoretical for life-science-oriented students and without hand-outs.

The general opinion of participants was that H. Westerhoff presented the best tutorial session with the most practical applications. He dealt with Interrogating a simple MAP kinase model in a silicon cell model with a superb hand-out that allowed students to follow the text and ‘play’ with the model simulations independently. The students logged-on the tutors’ website and ran the model simulation. The hand-out drove them through several steps, at each step asking a physiologically relevant question that the model was able to answer with the input of proper model parameters. The role of the tutor was to initially explain the basics of the model and of the physiological questions, and then, together with co-tutor, to interactively help students during discovering the model. Hand-outs of the tutorial as well as the programme may he shared during future CASyM training events and are available upon request from H. Westerhoff.

The tutorial session of P. Dovč and G. Gorjanc dealt with searching for homozygosity runs as a strategy to discover recessive diseases. It was a good hands-on tutorial.

The last tutorial was presented by J. Schuchhardt, a tutor representing a SME providing modelling software. Using a good hand-out, he interactively introduced students with public software tools and information databases, and later on students practised hand-on examples under the tutor’s supervision.

PART 2 - Oral presentations

A very good part of the tutorial were oral poster presentations. The selected students had a limited set of time (10 min) for their presentation, but the tutors M. Benson and V. Dolžan, both MDs, were nevertheless successful in running an active discussion among students. The common opinion was that presentations were on a high scientific level and also technically well presented. Students were encouraged to ask questions in the discussion, which was achieved successfully.

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PART 3 - Exam

The tutorial event finished with an hour-lasting multiple choice question exam, where each tutor prepared 2 – 3 questions from her/his part. The test was taken only by students who enrolled for the ECTS credit points. All other participants received a certificate of attendance. The certificate helps students/participants to get their training approved by their local Universities (ECTS) or by their local professional societies (CME for medical doctors, SILM for clinical laboratory medicine).

The examination questions and grading criteria are appended to this document (Appendix 6.3 and 6.4, respectively). All students who took the exam passed it and succeeded with the following final score: 96%, 92%, 90%, 90%, 86% and 86%. Among them, one student was a 3rd year medicine student who previously completed University studies of electrical engineering. There was also one medical doctor in post-doctoral training. Other students were Ph.Ds. from biochemistry (2) and computer and information sciences (2).

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4 LIST OF PARTICIPANTS

PARTICIPANTS

SURNAME FIRST NAME LEGAL ENTITY

Ačimovič Jure Faculty of Medicine, University of Ljubljana, Slovenia Azevedo Sandra Federal University of Rio de Janiero, Brazil Baebler Špela National Institute of Biology, Slovenia Baier Gerold University College London, UK Battelino Tadej Faculty of Medicine, University of Ljubljana, Slovenia Belič Aleš Faculty of Electrical Engineering, University of Ljubljana, Slovenia Benson Mikael Centre for Individualised Medicine, Linköping University, Sweden Berne Sabina Faculty of Medicine, University of Ljubljana, Slovenia Blomberg Niklas ELIXIR Hub, UK Bokal Vrtačnik Eda University Medical Centre Ljubljana, Slovenia Breskvar Katja University of Ljubljana, Slovenia

Burnik Papler Tanja Department of Obstetrics and Gynecology, University Medical Centre Ljubljana, Slovenia, Slovenia

Chersicola Marko Nacional Institute of Biology, Slovenia Clairambault Jean INRIA and UPMC, France Coll Rius Anna National Institute of Biology, Slovenia Čeh Simon Chemass d.o.o., Slovenia D'Alessandro Lorenza A, German Cancer Research Center - DKFZ, Germany Debeljak Nataša Faculty of Medicine, University of Ljubljana, Slovenia Dermastia Marina NIB, Slovenia Devjak Rok University Medical Centre Ljubljana, Slovenia Dobnik David National Institute of Biology, Slovenia Dolžan Vita Faculty of Medicine, University of Ljubljana, Slovenia

Dovč Peter University of Ljubljana, University of Ljubljana, Medical Faculty, Slovenia

Drnovšek Olup Brigita University Medical Centre Ljubljana, Slovenia Duffy David J. University College Dublin, Ireland Dzeroski Saso Jozef Stefan Institute, Slovenia Erčulj Nina Roche d.o.o., Slovenia Fabjan Teja Univerzitetni klinični center Ljubljana; Poliklinika, Slovenia

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Finžgar Miha Faculty of Medicine, University of Ljubljana, Slovenia Goličnik Marko Faculty of Medicine, University of Ljubljana, Slovenia Gorjanc Gregor Biotechnical Faculty, Slovenia Gostinčar Cene Biotechnical Faculty, University of Ljubljana, Slovenia Grošelj Urh University Children's Hospital Ljubljana, Slovenia Gruden Kristina National Institute of Biology, Ljubljana Gutiérrez Mariscal

Francisco Miguel Faculty of Medicine, University of Ljubljana, Slovenia

Hafner Mateja Faculty of Medicine, University of Ljubljana, Slovenia

Harrison David Medical & Biological Sciences, University of St Andrews, United Kingdom

Hevir Neli Faculty of Medicine, University of Ljubljana, Slovenia Hoehme Stefan Interdisciplinary Center for Bioinformatics, Germany Horvat Simon Biotechnical Faculty / National Institute of Chemistry, Slovenia Jakše Jernej Biotechnical faculty, University of Ljubljana, Slovenia Jančar Nina University Medical Centre Ljubljana, Slovenia Javornik Branka University Ljubljana Biotechnical Faculty, Slovenia Jenko Barbara Faculty of Medicine, University of Ljubljana, Slovenia Juvan Peter Faculty of Medicine, University of Ljubljana, Slovenia Kirschner Marc Forschungszentrum Jülich GmbH, Germany Klančar Gašper UMC Ljubljana, Slovenia Klavzar Helena Faculty of Medicine, University of Ljubljana, Slovenia Kocev Dragi Jožef Stefan Institute, Slovenia Kogovšek Polona National Institute of Biology, Slovenia Količ Rok Kemomed d.o.o., Slovenia Komel Radovan Faculty of Medicine, University of Ljubljana, Slovenia

Košir Rok Faculty of Medicine, University of Ljubljana & Diagenomi d.o.o., Slovenia

Kutnjak Denis National Institute of Biology, Slovenia Kužnik Marjan Faculty of Medicine, University of Ljubljana, Slovenia Lah Turnšek Tamara National Institute of Biology, Slovenia Lanišnik Rižner Tea Faculty of Medicine, University of Ljubljana, Slovenia Lazar Ana National Institute of Biology, Slovenia Lenassi Metka Faculty of Medicine, University of Ljubljana, Slovenia Leskošek Brane Faculty of Medicine, University of Ljubljana, Slovenia

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Levatić Jurica Jozef Stefan Institute, Slovenia Lewińska Monika Faculty of Medicine, University of Ljubljana, Slovenia Logonder Uroš Roche d.o.o., Slovenia Lorbek Gregor Faculty of Medicine, University of Ljubljana, Slovenia Lusa Lara Faculty of Medicine, University of Ljubljana, Slovenia Mandelc Stanislav Biotechnical Faculty, University of Ljubljana, Slovenia Mandić Maja Veterinary Faculty, Slovenia Marc Janja Faculty of Pharmacy, University of Ljubljana, Slovenia Maver Ales University medical centre Ljubljana, Slovenia Medved Anja Biomedis M.B. d.o.o., Slovenia Miljkovic Dragana Jožef Stefan Instutute, Slovenia Naik Adviti Faculty of Computer Sciences and Informatics, Slovenia Novak Metka National Institute of Chemistry, Slovenia Pajič Tadej UKC Ljubljana, Slovenia Parodi Silvio University of Genoa, Italy, Italy Perin Petra Faculty of Medicine, University of Maribor, Slovenia Petek Marko National Instutute of Biology, Slovenia Peterlin Borut University medical centre Ljubljana, Slovenia Petrovič Uroš Jožef Stefan Institute, Slovenia Plemenitaš Ana University of Ljubljana, Faculty of Medicine, Slovenia Podpečan Vid Jožef Stefan Instutute, Slovenia

Prosenc Zmrzljak Uršula Faculty of Medicine, University of Ljubljana & Institute of Oncology, Slovenia

Ramšak Živa National Institute of Biology, Slovenia Remškar Janez Institute of Oncology Ljubljana, Slovenia Rozman Damjana Faculty of Medicine, University of Ljubljana, Slovenia Rugel Bojan ITAG d.o.o., Slovenia Schuchhardt Johannes MicroDiscovery GmbH, Germany Schwarzl Thomas University College Dublin, Ireland Slak Janez ARRS, Slovenia Slavkov Ivica Jožef Stefan Institute, Slovenia Stare Tjaša National institut of biology, Slovenia Šabec Marta Ministry of Education, Science and Sport, Slovenia Šuput Dušan Faculty of Medicine University of Ljubljana, Slovenia

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Šuštar Vozlič Jelka Agricultural Institute of Slovenia, Slovenia Tanevski Jovan Jožef Stefan Institute, Slovenia Traunšek Urban ITAG d.o.o., Slovenia Trošt Nuša Faculty of Medicine, University of Ljubljana, Slovenia Trošt Nina Faculty of Medicine, University of Ljubljana, Slovenia Turcanu Victor King's College London, UK Urlep Žiga Faculty of Medicine, University of Ljubljana, Slovenia Westerhoff Hans V. Universities of Amsterdam (NL), University of Manchester (UK) Vasudevan Sona Georgetown University, USA Vavpetič Anže Jožef Stefan Institute, Slovenia Zajc Janja Biotechnical Faculty, University of Ljubljana, Slovenia Zhang Huan Faculty of Health Sciences, Linkoping University, Sweden Zore Andrej University Medical Centre Ljubljana, Slovenia

Zupan Blaž Faculty of Computer and Information Science, University of Ljubljana, Slovenia

Žitnik Marinka Faculty of Computer and Information Science, University of Ljubljana, Slovenia

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5 ACKNOWLEDGEMENTS

The event “Systems Medicine of Multifactorial Disorders workshop & tutorial and 8th CFGBC symposium” is part of the CASyM work package 2 – “Multidisciplinary training in systems approaches for the next generation of scientists and MDs”.

CASyM is funded by the European Union, Seventh Framework Programme under the Health Cooperation Theme and Grant Agreement # 305033.

STEERING COMMITTEE

The following officials, as part of the Scientific Steering Committee, are involved in the scientific coordination of CASyM:

Charles Auffray - European Institute for Systems Biology & Medicine - EISBM, France Mikael Benson (Deputy Speaker) - Linköping University Hospital, Sweden Rob Diemel - The Netherlands Organisation for Health Research and Development, The Netherlands David Harrison (Speaker) - University of St. Andrews, United Kingdom Walter Kolch - University College Dublin, Ireland Frank Laplace - Federal Ministry of Education and Research, Germany Francis Lévi - Institut National de la Sante et de la Recherche Medicale, France Damjana Rozman (Deputy Speaker) - University of Ljubljana, Faculty of Medicine, Slovenia Johannes Schuchhardt - MicroDiscovery GmbH, Germany Olaf Wolkenhauer - Dept. of Systems Biology & Bioinformatics University of Rostock, Germany ADMINISTRATIVE OFFICE (COORDINATION)

Marc Kirschner - Project Management Jülich, Forschungszentrum Jülich GmbH, Germany

INTERNATIONAL SCIENTIFIC COMMITTEE

Damjana Rozman, chair - University of Ljubljana, Faculty of Medicine, Slovenia Kristina Gruden, chair - Dept. of Biotechnology & Systems Biology, National Institute of Biology, Slovenia Gerold Baier - University College London, UK Mikael Benson - Linköping University Hospital, Sweden Vita Dolžan - University of Ljubljana, Faculty of Medicine, Slovenia David Harrison - University of St. Andrews, United Kingdom Marko Goličnik - University of Ljubljana, Faculty of Medicine, Slovenia Walter Kolch - University College Dublin, Ireland Radovan Komel - University of Ljubljana, Faculty of Medicine, Slovenia Francis Levi - Institut National de la Sante et de la Recherche Medicale, France Uroš Petrovič - Jožef Stefan Institute, Slovenia Hans V. Westerhoff - University of Amsterdam and VU University Amsterdam, Netherlands and the University of Manchester, UK Olaf Wolkenauer - Dept. of Systems Biology & Bioinformatics University of Rostock, Germany Eda Vrtačnik Bokal - University Medical Centre Ljubljana, Slovenia Brigita Drnovšek Olup - University Medical Centre Ljubljana, Slovenia

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ORGANIZING COMMITTEE

Jure Ačimovič, chair - University of Ljubljana, Faculty of Medicine, Slovenia Helena Klavžar, treasurer - University of Ljubljana, Faculty of Medicine, Slovenia Marina Dermastia - National Institute of Biology, Slovenia Vita Dolžan - University of Ljubljana, Faculty of Medicine, Slovenia Marko Goličnik - University of Ljubljana, Faculty of Medicine, Slovenia Kristina Gruden - National Institute of Biology, Slovenia Mateja Hafner - University of Ljubljana, Faculty of Medicine, Slovenia Peter Juvan - University of Ljubljana, Faculty of Medicine, Slovenia Rok Košir- University of Ljubljana, Faculty of Medicine & Diagenomi d.o.o., Slovenia Damjana Rozman - University of Ljubljana, Faculty of Medicine, Slovenia Eda Vrtačnik Bokal - University Medical Centre Ljubljana, Slovenia Uršula Prosenc Zmrzljak - Institute of Oncology Ljubljana, Slovenia

Figure 8: The Local Organizing Committee. From left: Rok Košir, Mateja Hafner, Helena Klavžar, Uršula Prosenc Zmrzljak, Jure Ačimovič, Damjana Rozman, Peter Juvan.

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6 APPENDIX

6.1 Assessment by Hans V. Westerhoff

Westerhoff’s conclusions about training during the CASyM workshop

Remark: The comments below are based on the CASyM training session, a bilateral discussion with David Harrison and on the actual experience with the tutorial. The authors of the report agree with the general content.

1. Many physicians think they are too busy to be trained and to use systems medicine: Hence the training should be extremely user friendly, be useful immediately, and save rather than cost time. No extra expertise (such as knowing how to model) should be needed. The Westerhoff tutorial on Saturday morning may be a bit gauged into this direction: there participants interrogated models without having to do any programming. Yet also this course needs improvement in terms of being more related to disease rather than pathways only.

2. Medical curricula are full; nothing can be added. However, some of these curricula still contain anatomy, biochemistry, cell biology, physiology, immunology where the student has to learn very much by heart, for instance the entire glycolytic pathway, TCA cycle, PP Pathway, the anatomy of the colon, heart etc. Study time may be reduced by substituting part of this memorization by the ability to call-up a model on the physician’s mobile phone, I-pad, i.e. to practice computer use in this sense and then to interrogate this model. The concept is that now the student only needs to learn one pathway and one organ anatomy by heart (to learn the essence of pathways and of anatomy) and then to learn how to get this type of information from the model for other pathways and organs and how to interpret that information.

3. At present physicians are often a ‘machine’ that for a disease that is diagnosed by a lab as one of the standard diseases, prescribes a therapy that is completely specified by a protocol. There is in fact no possibility for personalization, e.g. to take into account that a specific patient lives alone, needs to feed her cat twice a day, for which she has to climb two stairs in her house; or her personal genome sequence and metabolic map and her family history in more detail. The virtual patient environment would weigh all such factors and come with a more personalized therapy proposal, which the physician then has to obtain (by interrogating the model and interpreting the answers). Consequently, Systems Medicine will give Medicine back to the physicians, retrieving it from the world of protocols.

4. Many physicians are not interested in knowing about mechanism of disease or of the drug. They just want to know whether the drug works and whether they should prescribe it. Here systems medicine and the virtual patient model would be able to involve a model to make predictions, whilst checking these with predictions with previous therapies of patients of the same physician (he may have forgotten the details) and of patients of thousands of colleagues of the physician. The physician (plus the patient) would still be in control because he is interrogating the computer model.

5. Physicians would much like to have a model that can be run as a movie to show to the patients how the therapy the physicians proposes will work and what the disadvantages and advantages are of the

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therapy and of alternative therapies. In order to save time, the physician would let the patient work with the model for an hour or so in the physician’s absence and then discuss conclusions and unclarities in 10 minutes.

6. Knowledge and learning are being revolutionized. Learning by heart will largely disappear. Learning how and what to ‘’click’’ will become much more important. These developments will be integrated in the systems medicine environment.

7. There is a dearth of teaching material for systems medicine. CASyM needs to support the development of teaching modules; such as some of the ones practiced at the Lubljana tutorials. Some of this should also be developed as e-courses, other for courses such as the FEBSSysBio courses and others as a travelling lecture and hands-on computer-practical course.

8. CASyM could perhaps organize a low key work meeting between physicians and programmer-teachers of systems medicine, in order to test the computing courses already available (such as the one taught by Westerhoff in Lubljana) for physician and patient user friendliness and in order to define new training modules.

9. CASyM could perhaps also facilitate the interaction between the European Association for Personalized Medicine (EAPM) and the systems medicine community. EAPM should become visible in the roadmap.

10. CASyM should get together European and national funders and a group of leading scientists in systems medicine (or medicine and systems biology) at a work meeting to discuss future modes of funding, ending the cottage industry mode of biology and starting up BIG systems medicine. Experiences with SysMO, ERASysBio, ITFoM, BRAIN should be learnt from and ways should be developed to alleviate the impossibility of transnational funding.

11. ITFoM and VPH have decided to continue to integrate activities towards the R&D for and around virtual twins/digital-me’s. CASyM could assist these groups with organizing this future. The virtual patient could become part of CASyM’s roadmap. CASyM could also try to connect this up with the Virtual Liver Network (VLN).

12. The ESFRI research infrastructure ISBE could also use some help from CASyM, particularly where it addresses the systems medicine side of systems biology. CASyM could also help define the relationships with and between ISBE and ELIXIR in the area of systems medicine.

13. CASyM could perhaps organize a get together between a few captains of relevant industry and leaders of large, running systems-medicine related projects (e.g. VLN).

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6.2 Survey and questionnaire

Systems Medicine of Multifactorial Disorders Workshop & tutorial and 8th cfgbc symposium

Overall evaluation I totally agree I agree Neutral I decline

I would not recommend

it

The training event was helpful for my future career and I would recommend it to fellow students.

Organization

The event was well organized

Course rooms were well equipped with appropriate media technology

I could find specific courses easily

Courses started and ended in time

Speaker/Tutors

Topics were well addressed

Presentations were of high quality

Speaker/Tutors were well prepared

Speakers interacted well with audience

Discussions

I could follow the discussions

I did make a contribution to the discussion

The discussions were well chaired

Practical courses

The offered courses were useful

Computational tools were useful

Databases were useful

Male undergraduate MD

Female graduate PhD

no

statement Master

Please state your

nationality:

Please state your

course of study:

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OPEN QUESTIONNAIRE

1. What made you chose to attend the current workshop and what was the initial source of

information?

2. What kind of association do you combine with Systems Medicine?

3. Where do you see the beneficial aspects of Systems Medicine?

4. According to your opinion, in which disease area could Systems Medicine have the most impact?

5. Have you visited the CASyM website?

6. What do the following terms mean to you - please try to give a short definition: Systems Medicine: __________________________________________________________

Systems Biology: ____________________________________________________________ Personalized Medicine: ________________________________________________________

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6.3 Examination questions (ECTS credits)

CASyM Training Event – Ljubljana, June 15, 2013

Final Exam Your Name: ____________________

There are a total of 4 pages of this exam. Look over the entire exam before starting. The exam is worth 50 points, divided into 15 questions. You have 60 minutes for this exam. Plan your time accordingly, and circle the correct answers. There is one correct answer to each question unless stressed otherwise.

1. The one gene-one function paradigm has been depicted as:

Nutrient 1 Gene 1 function 1




Answer the questions now:

An organism with 100 functions should have 100 genes; Yes No

Every disease needs at least two mutations before it sets in; Yes No

For a single disease there can only be one gene mutation that causes it, although there can be multiple nutrition defects that cause it; Yes No

2. Now please engage in a mind shift, away from that paradigm, towards a systems biology paradigm, where networks are more like this:

Nutrient 1 Gene 1 Gene 2 Gene 3 function 1

Nutrient 2 Gene 1 Gene 4 Gene 5 function 2

Nutrient 3 Gene 3


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Answer the questions now:

An organism with 100 functions should have 100 genes; Yes No

A disease may need at least two mutations before it sets in; Yes No

For any single disease there can only be one gene mutation that causes it, although there can be multiple nutrition defects that cause it; Yes No

3. We are considering the following metabolic pathways (where ‘gene’ represents the corresponding enzyme):

Food 1 Gene 1 Gene 2 Gene 3 function 1

How can one determine whether gene 1 is indeed the rate limiting step of the pathway?

By deleting the gene. If the flux disappears, the enzyme corresponding to gene 1 was the rate-limiting step. Yes No

By removing 10 % of enzyme 1 and determining the flux change. Yes No

By seeing whether reaction 1 consumes ATP? Yes No

A crucial experiment with mitochondria has been reported measuring the effect of various inhibitors on respiration. Did that experiment show that there was indeed, as then expected, a single step that limited respiration? Yes No

4. The following statements are almost always correct/incorrect:

The first step in pathways is always the rate-limiting step. Correct Incorrect

A step in a pathway is regulated either at the metabolic or at the gene-expression level, never at both. Correct Incorrect

Systems medicine for human metabolism is still very far away. Correct Incorrect

The flux control coefficients measure the extent to which an enzyme concentration is determined. Correct Incorrect

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5. Which of the below components does 'systems' biomedical research not necessarily need?

a) A working hypothesis.

b) A mental model.

c) A computer simulation.

d) Experimental data.

e) A mathematical model.

6. In cell signalling, the activation dynamics of a signalling molecule is not

characterized by its …

a) timing.

b) amplitude.

c) duration.

d) steady state.

e) molecular weight.

7. The choice of mathematical modeling approaches depends both on the biological system and the biological question. Which of the following statements is true?

a) MicroRNA expression profiling cannot be used for network modelling.

b) Cell population data is sufficient for spatio-temporal modelling.

c) To perform dynamic pathway modelling, concentrations, binding affinities and reaction rates have to be determined or estimated.

d) Ordinary differential equations cannot describe mass-action kinetics of pathway.

e) For multi-scale modelling only time-resolved immunoblotting data is required.

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8. Runs of homozygosity are

a) loci with strictly recessive mode of inheritance.

b) genomic regions which contain disease genes.

c) highly conserved genomic regions.

d) longer genomic regions, where an individual or a group of individuals are homozygous.

9. Two alleles are identical by descent if

a) they are copies of the same ancestral allele.

b) they have the same nucleotide sequence.

c) we can both trace more than 5 generations back in the pedigree.

d) they appear in the same population.

10. Why are long stretches of autozygosity good candidates for causal regions for recessive diseases?

a) Because the diseases are allways caused by recessive alleles

b) Because recessive diseases are caused by autozygosity for the disease allele

c) Because the disease alleles always ocuppy long genomic regions

d) Because autozygosity is often associated with autoimmunity

11. Formalin fixed, paraffin embedded human tissues is least suitable for isolation of which one of the following:

a) DNA. b) mRNA. c) Protein. d) MicroRNA.

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12. Optimising drug delivery in pharmacological treatments of cancer needs a mathematical formulation in terms of an objective function and constraint functions; the main pitfalls encountered in the clinic, that determine the design of such constraint functions are (choose two correct answers)

a) non-observance of the treatment due to hardly understandable prescriptions.

b) unrealistic scheduling of drug delivery regimens with respect to the presence of the nursing staff.

c) emergence of drug-resistant populations of cancer cells.

d) unwanted toxic side effects in populations of healthy cells.

13. Biological variability in cell populations can be taken into account in models by

a) introducing uncertainty by adding additive noise in the second member of ODEs.

b) introducing uncertainty by adding additive noise on the parameters of ODEs.

c) representing the cell population by a PDE structured according to a chosen biological variable.

d) using cellular automata to simulate cell population growth.

14. Which two public databases should be consulted for finding microarray data? (choose two correct answers)

a) OMIM database

b) ArrayExpress database

c) dbSNP

d) GeneExpressionOmnibus (GEO)

e) Protein Data Bank (PDB)

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15. Which fact can lead to wrong interpretation of genomic SNPs on protein (amino acid) level?

a) Gene function is sometimes difficult to predict.

b) A gene may be transcribed and translated from the forward or the reverse genomic strand.

c) Epigenetic changes may influence gene function.

d) Every gene has its own genetic code.

e) None of the above is true.

6.4 Grading criteria (ECTS credits)

Active participation Poster, Abstract, Presentation Exam Total 20 30 50 100

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6.5 Application procedure for ECTS

Subject: Request to obtain the ECTS for the international workshop "Systems medicine of multifactorial disorders"

Ljubljana, 28.2.2013

Dear Sir or Madam,

Centre for Functional Genomics and Bio-Chips (CFGBC) is a consortium based infrastructure centre. It was established by the Slovenian Consortium for Biochips, the network of Slovenian academic institutions, research institutes, clinical centres and pharmaceutical industry with 16 members in total, which are engaged in the research of biochemistry and molecular biology, genetics, and other approaches of Post-genomic era. Every year in June CFGBC organizes international Symposium and the accompanying scientific workshop with foreign and domestic lecturers. Around 100 participants from Slovenia and abroad participated the Symposium and workshop in the past years.

The Symposium and workshop entitled "Systems medicine of multifactorial disorders" will take place in Ljubljana, Slovenia, from 12 to 15 June 2013 at the Faculty of Medicine, University of Ljubljana. Chairs of the International Scientific Committee are prof. dr. Damjana Rozman (Faculty of Medicine, University of Ljubljana) and prof. dr. Kristina Gruden (National Institute of Biology). The Scientific Committee is composed of recognized experts from Slovenia and abroad. All lecturers have extensive and highly cited bibliography in the corresponding field. Symposium and workshop is an excellent opportunity for social networking of young future scientists with senior colleagues and to exchange knowledge and experience.

Center za funkcijsko genomiko in bio-čipe

Inštitut za biokemijo Zaloška 4, 1000 Ljubljana

tel. 543 7590, fax. 543 7588 http://cfgbc.mf.uni-lj.si/

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http://www.nib.si/index.php


The Symposium will take place on the first day of the event followed by a three day workshop. Workshop topics will include:

• Systems medicine approaches to search for diagnostic markers and therapeutic targets in clinical trials

• Determination of the appropriate amount of data (can there be too much data?) • Pharmacotherapeutics optimization in the treatment of cancer using mathematical modelling • The “Virtual patient” project • The “Virtual Liver” project – network elucidation to determine the role of HGF in liver

regeneration • Principles of RNA sequencing and bioinformatics analyses • PK-PD models for optimization of the therapy of cancer • Mathematical modelling for applications in Medicine

The 2-day Systems Medicine tutorial that will follow the workshop is dedicated primarily to doctoral and post-doctoral students, medical doctors and other medical professionals. A poster is obligatory for participants attending the tutorial. Tutorial will include problem-based discussions, active participation in Systems Medicine based exercises (experimental approaches, databases, computation tools, etc.), and oral presentation of participant’s posters. 15 hours of lectures and 15 hours of practical work will be carried out through the entire event. The number of participants is limited and the candidates will be selected on the basis of their curriculum vitae and poster abstract. Since the tutorial materials will be available on-line beforehand, participant’s individual work is expected prior to the event start. The acquired knowledge will be examined at the end of the tutorial. Participants will receive a certificate of attendance and results of examination.

We kindly ask the Programme council of doctoral studies of Biomedicine to accredit the Symposium and workshop with ECTS points and to approve the course as an elective course for the students participating the event. We suggest accrediting the elective course with 5 ECTS points.

Yours sincerely,

Prof. dr. Damjana Rozman and prof. dr. Kristina Gruden, Chairs of the International Scientific Committee

Attachments:

1. First Announcement 2. Draft programme

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6.6 Application procedure for CME

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