Systems Biology in Medicine
8-10 May 2008
Barcelona, Spain

Organiser:

Pablo Villoslada, Center for Applied Medical Research, University of Navarra, Pamplona, Spain

Draft Report

Summary

Systems biology (SB) is a growing area that aims to understand biological systems at a holistic level. SB integrates theoretical and experimental research. SB has applications in various areas related to medicine including development of new diagnostic methods, improvement of drug target identification and prognosis assessment. In particular SB is well positioned to respond to the increasing need of personalized medicine in complex diseases like cancer or autoimmune diseases. However little is known in the medical profession about the theories and techniques behind SB. The objective of the workshop was to establish a permanent link between medical doctors and SB scientists fruitful for
both fields. In a clinical environment (Hospital Clinic Barcelona) outstanding speakers from five European countries discussed the foundations of systems biology and its implications in medical practice. Nearly 60 participants with different backgrounds assisted to the workshop and engaged in stimulating talks regarding the benefits and obstacles that SB will encounter in its approximation to the daily care of individual patients. This ESF sponsored meeting covered hot topics ranging from network biology to metabolomics. The organizing committee is very pleased with the results of the workshop and looks forward to repeat this experience on a regular basis.

Scientific Content

The Workshop Systems Biology in Medicine was organized to cover the principles behind SB and the current initiatives to implement SB in medical practice. According to this objective the OC designed a program that were attractive to scientist from different disciplines including medical doctors, mathematicians and engineers.

Foundations of systems biology

In this module professor Garcia-Ojalvo, Sole and Bruggeman explained in a concise and clear manner difficult contents such as dynamical systems theory and network theory. The topics developed included non-linear dynamics, the effect of noise in eukaryotic and prokaryotic systems as well as the more important concepts in biological networks needed to understand the current research in SB. The leading theme in this session was complexity and specially complexity in biological systems. The material covered in “Foundations of Systems Biology served as an orientation to highlight the need of an integral in contrast of a reductionist approach to understand the origin and way to treat complex diseases.

Applications of SB: Fundamental biology

SB can be viewed as a kind of invigorated physiology. Taking advantage of high efficiency technology able to measure in a single experiment the gene expression or metabolic profile of an entire cell, SB is capable to describe and in the near future to predict the behavior of biological systems in response to external or internal stimuli. But to succeed in this end, SB also needs a theoretical frame rooted in quantitative sciences like mathematics and physics. During this session, experts in metabolomics, network biology and computational modelling discussed the relation between structure and function in biological networks, the mathematical tools required to asses the dynamics of a network and the effects of interventions on links or nodes of such networks. A continuous topic during the talks was robustness defined as the property by which a specific system responds to a perturbation with minimal or none loss of functionality. The speakers also reviewed the methods available to evaluate the accuracy of computational models and the necessity to compare and improve these models with experimental data.

Finally, at the end of the afternoon, an interesting talk presented SB as a paradigm shift in our approximation to diagnose and treat complex diseases. Applications of SB: Fundamental physiology Biochemical networks can be considered information processing devices that sense the environment and produce a response according to the internal state of the network. Biochemical networks (metabolic networks, signal transduction networks) are ideal candidates for drug discovery experiments. In particular some groups of nodes organize in a constant structure that results in a constant function. The elucidation of the topology and dynamics of these network motifs represents a breakthrough in the application of SB in medical practice.

In the module “Fundamental physiology” the speakers considered the basics of signal processing in biological systems with an emphasis on how aberrations in this function could lead to the appearance of disease. They also evaluated the utility of SB in drug discovery and especially how can SB reduce the cost and time in drug development.

A permanent limitation in clinical practice is how to assess the response to a drug. In last years there has been a considerable interest in the development of gene, metabolite or protein markers, collectively known as biomarkers, to predict the utility or toxicity of a drug in an individual patient. During this session a successful experience in the development of a biomarker for liver disease illustrated the power of SB when applied in clinical settings. Pathophysiology of diseases

The most prevalent diseases (cancer, autoimmune diseases) are complex diseases. With complex we mean that they are the result of multiple interacting components whose collective properties cannot be explained from the study of each component in isolation. Defect in various levels, from genes to cells can lead to complex diseases.

In particular SB is well positioned to address these questions.
• How combination therapy will be more beneficial than single interventions and which side effects are expected with combination therapy?
• How to develop reliable and easy to use biomarkers to follow treatment efficacy?
• What are the rate-limiting steps in complex diseases pathogenesis?

In the module “Pathophysiology of diseases” the speakers described how SB could respond to the questions stated above. A case study in cancer metabolomics exemplifies how the combination of a clever hypothesis with SB methods is able to identify a new kind of targets for cancer therapy.

Invited lectures

In the morning of the last day, invited speakers discussed applications that covered and summarized much of the contents reviewed in the previous days.

One interesting talk explained the electrical activity of the heart, suggesting useful interventions to treat Brugada Syndrome based on the emerging properties that exhibit cardiac cells when they work in a synchronized manner.

Assessment of the results & impact of the event

The workshop was an academic success. During the three days of the event the quality of the talks promoted the interaction between speakers and participants and facilitated the establishment of collaborations among basic and clinical oriented research groups. The clear definition of modules in the programme improved the comprehension of difficult contents, especially those related to network biology and nonlinear dynamics essential to SB appreciation. The speakers illustrated with detail the relation between SB and clinical practice in several medical disciplines like immunology, cardiology, endocrinology and oncology. They also explained the technology and skills required to succeed in SB.

It is important to highlight that the meeting was held in a clinical setting where SB is heralded to have its more profound impact. The organizing committee strongly believes that this ESF workshop will become a reference in the public awareness of SB as an essential discipline in the medical armamentarium against complex diseases. The committee also recognizes the necessity of this kind of meeting to promote the education of scientists well trained in quantitative and experimental methodologies essentials for SB development. In particular the OC seeks the involvement of more medical doctors proficient in SB theories and techniques.

Programme

Introduction to System Biology

1. Foundations of Systems Biology: System theory, Non-linear dynamics and Chaos, Information theory, Control theory, Complexity theory, Computational theory
2. Fundamental biology: myths and challenges
3. Basics Concepts in System Biology related to medical practice: Robustness, Evolvability, Steady states, Structural stability, Modularity, Emergent properties
4. Fundamental Biology Biological Networks (genome, transcriptome, proteome, metabolome,
etc.)
a. Metabolic fluxes
b. Signalling pathways
c. Development
d. Cell cycle
e. System neuroscience
f. System immunology

Systems Biology in Medicine

1. Pathophysiology of complex diseases
a. Cancer
b. Metabolic diseases: Obesity and diabetes
c. Neurological diseases
d. Autoimmune diseases
e. Chronic respiratory diseases
f. Cardiology

2. SB approach to therapy
g. SB in drug discovery
h. System based therapy and personalized medicine
i. Biomarkers

Schedule

Day 1 - 8 May

Foundations of systems biology
9:00 – 9:30 Welcome: description of the workshop objectives and activities JM Pique & Teresa Estrach
9:30 – 10:30 Dynamical systems theory Jordi García-Ojalvo
10:30 – 11:00 Coffee break
11:00 – 12:00 Complex Systems Ricard Sole
12:00 – 13:00 Eukaryotic Systems Biology: network approaches to predict and to explain
Frank Bruggeman

13:00 – 13:30 Lunch

Applications of SB: Fundamental Biology
13:30 – 14:30 Biological networks: their structure, function and evolution Ricard Sole
14:30 – 15:30 Metabolic fluxes Frank Bruggeman
15:30 – 16:00 Coffee break
16:00 – 17:00 Comparing models in bioinformatics and systems biology Olaf Wolkenhauer
17:00 – 18:00 System Biology and Innovation in Biomedicine: towards a new paradigm Albert Barbera

Day 2 - 9 May

Applications of SB: Fundamental physiology
9:00 – 10:00 Unravelling neurological diseases with systems biology Pablo Villoslada
10:00 – 11:00 Systems Biology and it's usage for drug R&D Igor Goryanin
11:00 – 11:30 Coffee break
11:30 – 12:30 Biomarkers discovery for stratified medicine Fernando Corrales
12:30 – 13:30 Signaling pathways and information processing Tibor Kalmar
13:30 – 14:30 Lunch & Poster session

Pathophysiology of diseases
14:30 – 15:30 Cancer: Multiple perturbations on cancer cell metabolic pathways as new targets for novel designed therapies Marta Cascante
15:30 – 16:30 Boolean networks as predictive models for biochemical networks: Chances and Limitations Stefan Bornholdt
16:30 – 17:00 Coffee-break
17:00 – 18:00 Chronic respiratory diseases Josep Roca
18:00 – 19:00 Proteomics in obesity research Silvia Barcelo
Poster display All day Susana Kalko

Day 3 - 10 May

Invited lectures
9:00 – 09:45 Action potential propagation Jean Bragard
09:45 –10:30 A genomic analysis of transcriptional regulation of the human genome Nicholas Luscombe
10:30 – 11:00 Coffee-break
11:00 -11:30 Emergent Activity in the Cerebral Cortex Network Maria V. Sanchez-Vives
11:30 – 12:15 Promoting, maintaining and filtering noise during embryonic development Tibor Kalmar
12:15 – 13:00 Complex Networks and Bibliome Informatics: applications to computational biology Luis Rocha
13:00 Lunch and Farewell