June 22 – 26 , 1998, Dagstuhl Seminar 98251

Modelling and Simulation of Gene and Cell Regulation and Metabolic Pathways


J. Collado-Vides (UNA Mexico), R. Hofestädt (Magdeburg), M. Mavrovouniotis (Evanston), G. Michal (Tutzing)

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The second Dagstuhl seminar for Modelling and Simulation of Gene Regulation and Metabolic Pathways was held from June, 21 to 26, 1998. It was a multidisciplinary seminar with 59 participants from 15 countries. Schloss Dagstuhl workshops in general emphasise computer science, and we are delighted to focus on the rapidly developing links between biosciences and computer sciences. The 1998 meeting is a sequel to the 1995 Dagstuhl seminar on the same topic. Both were generously supported by grants from the Volkswagen Stiftung and the European Community (TMR Grant).

The availability of a rapidly increasing volume of molecular data enhances our capability to study cell behaviour. In order to exploit molecular data, one must investigate the link between genes and proteins; the link between protein structure and protein function; and the concerted effects of many proteins acting on, and interacting with, the mixture of small and large molecules within a cell. This last step is the study of gene regulation and metabolic pathways which was the topic of the Dagstuhl seminar.

The molecular data must be stored and analysed. Database systems for genes and proteins (EMBL, GENBANK, PIR, SWISS-PROT) offer access via internet. In the research field of molecular biology this technique allows the analysis of metabolic processes. To understand the molecular logic of cells we must be able to analyse metabolic processes in qualitative and quantitative terms. Therefore, modelling and simulation are important methods. They influence the domain of medicine and (human) genetics - the microscopic level. Today integrative molecular information systems which represent different molecular knowledge (data) are available. The state of the art is shown by P. Karps system EcoCyc, which represents the metabolic pathways of E. Coli. For every gene or protein within a specific metabolic pathway, EcoCyc presents the access to all corresponding genes and/or proteins. Moreover, the electronical information system KEGG represents all biochemical networks and allows the access to the protein and gene database systems via metabolic pathways. However, both systems are based on the idea of the statical representation of the molecular data and knowledge. The next important step is to implement and integrate powerful interactive simulation environments which allow the access to different molecular database systems and the simulation of complex biochemical reactions.

Molecular information systems for gene regulation and metabolic pathways were one topic of the Dagstuhl seminar. The idea was to discuss the progress of this research field and the integration of the molecular database systems in combination with simulation tools. The organisers of the seminar invited colleagues, who presented their ideas through 42 talks and computer demos.

More than 30 years ago Gerhard Michal started to collect all biochemical reactions. His classification is presented by the Boehringer pathway chart. This data collection was extended by the KEGG research group, which implemented the first electronical representation of this data in 1996. Nowadays all biochemical reactions are available via internet using the KEGG system. KEGG represents links to molecular database systems for genes, proteins, and enzymes, which are elements of metabolic pathways. Thus a link to the EMBL database systems represents more information about a specific gene, and a link to the SWISS-PROT system represents more information about the protein (enzyme).

Regarding the KEGG system the representation of quantitative data and kinetic data is not available today. Furthermore, additional to the molecular data (genes, proteins, and pathways) the first molecular information systems are available which represent data of the cell signals.

Besides the Japanese Cell Transduction Database the GENENET database system is available. Taking regard to both molecular information systems this can be interpreted as the first scientific step in which cell reaction processes are surveyed from the gene regulation process to the cell communication.

For molecular biology the phenomena of gene regulation is the main question. The systematic discussion of this question is based on the electronical representation of the molecular knowledge, which allows the complex analysis of this data. For that reason specific database systems are implemented (OperonDB, TRANSFAC and TRRD). These database systems represent all known operons and the transcriptional factors for E. coli (OperonDB) and eukaryotic cells. Today, two research fields based on this data are supported: The prediction of promoter sequences and the modelling of gene regulation. The prediction of promoter sequences is of importance, because the promoter is the starting signal for a

structure gene which represents the genetic information. The human genome project will sequence the whole genome until the year 2004 (64 * 10**9 base pairs). The next step is to calculate the corresponding genetic map. Therefore, sequence pattern matching algorithms must be developed and implemented. In addition modelling and simulation of gene regulation processes will support the systematic analysis of the metabolic pathways.

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