Modelling of Molecular Networks

Organised by
Paulino Gomez-Puertas
Shoshana Wodak
Luis Serrano
Alfonso Valencia
http://www.pdg.cnb.uam.es/GRANADA2002/

Report

Systems biology have recently experimented an increased and substantial interest from different areas in the bioinformatics community, as it clearly posses attractive key challenges and new questions on the nature of the relationships that define the nature of the diverse cell process.
During the 11th to 14th of June in Granada (Spain) we had the opportunity to discuss ideas, available data, and possible methodologies related to this interesting topic in the framework of the European Science Foundation Workshop on "MODELING OF MOLECULAR NETWORKS" (ESF program on "Functional Genomics"). The workshop was organized in three sessions: "combining theoretical and experimental approaches", "networks and computer simulation" and "assembling the puzzle".

In the first session Vincent Schachter (Hybrigenics, France) revised the status of the approaches based on the two-hybrid technique for the construction of interaction networks, as well as the computational approaches for the extension of this information to related organisms, including an insightful discussion of how to use the network information to provide functional annotations. Ann-Claude Gavin (Cellzome, Germany) reported on the technical details of their systematic analysis of protein complexes purified by TAP (tandem affinity purification) of tagged yeast genes, followed by identification of the proteins components of the complexes by MALDI-TOF mass spectrometry. The first reported data includes the identification of approximately 260 complexes corresponding to 2700 proteins. A new release of complexes for an almost complete set of yeast proteins is announced for this year. Shoshana Wodak. (Universite Libre de Bruxelles, Belgium) presented the development of amaze, a database on networks and metabolic, she described the amaze conceptual framework outlining how the analyses of functional networks could be integrated with comparative genome studies to improve the assignment of gene function. Alessandro Guffanti (FIRC Institute of Molecular Oncology, Italy) describes his vision on how biologist would approach the problem of mining sequence data in the context of the analysis of large data sets, while Raik Grunberg (Institut Pasteur, France) talk about approaches for the management of complex data in the framework of the semantic-web initiative. Duncan Davidson (Western General Hospital, UK) described the "Edinburgh Mouse Atlas project", a database and visualization system for the analysis of the morphology of mouse embryos. Particularly interesting was the description of the possibilities for including the information on the distribution of gene products in space and time. Marta Cascante (University of Barcelona, Spain) illustrates how the integration of data in computer models of metabolic profiling can give clues to identify differences between normal and tumour cells which can be exploit in cancer therapy. Using this strategy, she identified the ribose-5-phosphate synthetic pathways can constitute a new target in the treatment of cancer.

In the session on "Networks and computer simulation" Jan Komorowski (Norwegian University of Science and Technology, Norway) introduced a methodology for inducing predictive rule models for functional classification of gene expressions from microarray hybridisation experiments and gene ontology. In addition, he presented "PubGene" a gene network database constructed from statistical coincidence of gene names in paper abstracts. Alvis Brazma (The European Bioinformatics Institute, EBI-EMBL, UK) presented their results on the derivation of gene control networks from the results of gene expression of yeast single gene knockouts. The derived network, that can be described as scale-free network, has interesting properties in particular he described the association between the nodes with a high out-degree of connectivity with transcription factors, and those with high in-degree connectivity with metabolism enzymes. Joaquín Dopazo (Centro Nacional de Investigaciones Oncológicas, Spain) discussed the possibility of inference of positive and negative transcriptional regulation from gene expression data, using the SOTA clustering algorithm, a hierarchical unsupervised growing neural network for analysing gene expression patterns. Hinnerk Boriss (Aarhus University, Denmark) referred to the development of tools for the design of complex networks. Christos Ouzounis (The European Bioinformatics Institute, EBI-EMBL, UK) reviewed their extensive application of gene fusions to the prediction of protein interactions, and their recent application of their clustering techniques ("tribe") to the analysis of protein interaction networks. Alfonso Valencia (Centro Nacional de Biotecnología CNB-CSIC, Spain) offered an integrative point of view of molecular networks, including some aspects of information extraction techniques, including the application to E. coli of the "in-silico two hybrid" and "mirror-tree systems for the prediction of protein interaction partners using information from the corresponding protein sequence families, and the extraction of information from the literature with the "Suiseki" system.

Finally, in the last workshop session, entitled "assembling the puzzle", Victor de Lorenzo (Centro Nacional de Biotecnologia, Spain) introduced the possibilities of bioinformatics approaches to the study of biodegradation, developing systems for automatic extraction of biological information or handling the information on metabolism of toxic compounds in diverse strains and ecosystems and making clusters of knowledge and predictions on novel compounds degradation. Sophia Tsoka (The European Bioinformatics Institute, UK): "Analysis of metabolic enzymes and pathways". Vitor Martins Dos Santos (German Centre for Biotechnology, Germany) shows his initial results on the comparison of the genotype-phenotype relations between two Pseudomona species. Tomasz Zemojtel (Biozentrum, Germany, adds interesting technical details on their set of tools to model enzyme regulation and networks. Yves Moreau (Katholieke Universiteit Leuven, Belgium),presented a Bayesian framework of the analysis and modeling of regulatory networks. Luis Serrano (European Molecular Biology Laboratory, Germany) commented the design and construction of "Smartcell", a framework for whole cell simulation based on simple gene circuits consisting of a regulator and transcriptional repressor modules. Describing the role that negative feedback loops play in gene circuit stability, including their theoretical and experimental approaches toward the modeling of auto-regulatory systems. Hans V. Westerhoff (Vrije Universiteit, The Netherlands) described bioinformatics as an integrative way to analyse data from the biochemistry of cell metabolism in order to obtain complete computer models, or "silicon cells", where to perform simulations of metabolic pathways in a dynamic framework.

The discussions during the meeting allows us to propose four key areas which development would be essential for the future of System Biology:

1.- The need of defining adequate "modules", as units that can be manipulated in relative isolation, are accessible to experimental techniques, amenable to the description in databases, and adequate for the computational simulation. These modules could be species with particularly small genomes, cellular compartments, pathways, processes or complete organs. In the selection of such modules it would be important to keep the balance between the availability of computational and mathematical analysis tools, the amount of information properly stored in databases, and the possibility of accessing the systems with experimental (molecular and cell biology) tools. It is natural to think that the analysis of complete organs will require very complex experimental approaches able to provide a high level of resolution (levels of expression, metabolic analysis, etc), and manipulation and simulation tools, that exceed the current available possibilities. In the other extreme work in simple minimal genomes, may encounter a different type of experimental difficulties, but the results may be easier to analyse with the current techniques. At an intermedium level we can find the stud of well-defined metabolic pathways, that have been demonstrated to be accessible experimentally and of a size appropriated for the accurate mathematical formulation of their control and dynamics.It is interesting that the network of interactions, commonly described by all interacting proteins, and/or all regulated genes, are far too complex for the manipulation. Additional efforts would be required to define isolated regions, with their own internal coherence, which could be analysed experimentally and also manipulated by computation.

2.- Comparative approaches, that have been extremely successful in other fields of biology, and particularly in the bioinformatics approaches to genome analysis, would be also important for the modeling of biological systems. We are convinced that much can be understood by comparing the organization and dynamics of similar systems in different organisms, and/or different stages. Even if it is currently difficult to find comparable datasets for different species, we hope that this situation will change in the near future.

3.- It is important to integrate the appropriated simulation tools in the analysis of complex dynamic networks, since the analytical tools can be the best way of determining the completeness, accuracy and stability of the systems, fulfilling one of the critical needs during analysis. Indeed the work already carried out in the field of metabolic control has been the first one in exploring these new possibilities.

4.- As in many other fields the availability of data repositories, and free access to published experimental information is essential. A need that includes the access to primary data, derived interactions and control networks, computational methods and related software. A problem that cannot be dissociated of the need of creating standards for the description of protein and gene interactions networks, and the experimental (or computational) techniques used to produce them. Different initiatives are well under way for the database storage of expression and protein interaction data.

Overall, the most interesting conclusion of the meeting was that a true interdisciplinary spirit exist around the idea of System Biology, the communication between different fields (experimental approaches, high throughput techniques, bioinformatics, computational biology, mathematical modelling and others) is possible and naturally occurs when the right scientific focus is offered. The hype created around this area offers the unique opportunity of creating a European competitive research program. An opportunity that will have to face the reluctance of more traditional fields very focus on their specialized research.

Participants