Berlin Center for Genome Based Bioinformatics Bioinformatics, Technical University of Applied SciencesTFH BIOINFORMATICSHeadIna Koch (since 04/2002)Technical University of Applied SciencesSeestr. 64D – 13347 BerlinPhone: ++49-(0)30-4504 3972Fax: ++49-(0)30-4504 3959Email: firstname.lastname@example.org://www.tfh-berlin.de/bi/TeamKarsten Wenzel (technician, 0.5 position, since01/2003)Stefan Bartel (student)Andrea Sackmann (student, 11/2004-02/2005) Ralf Mehle (student, 04/2003 -08/2003,Sabrina Hoffmann (student, 04/2004-07/2004) 10/2003-12/2003, 10/2004-10/2004)Thomas Runge (student, 02/2004-07/2004) Patrick May (student, 10/2002-01/2003)RESEARCH DIRECTION 43The main goal of the BMBF funding was to es- are divided into special metabolisms or path-tablish a master’s course in bioinformatics for ways, which often correspond to special maingraduates in biological, and medical fields. This functions of the cell, e.g. carbon metabolism,has been done very successfully. Moreover, it energy metabolism, purine metabolism, glyco-was also possible to follow research work at TFH. lytic pathway, and many others. Due to newly developed techniques in experimental biology,Due to the former working field of the head of as microarray analysis, a huge amount of datathe group two main research directions were pur- of biological processes has been produced oversued in the last years, the modelling and analy- the last years.sis of biochemical systems and the theoreticalanalysis of protein structures (see publication To handle the arising data amount it is necessa-list). Following the valuable and constructive ry to represent and store them computationallyadvices of the Scientific Advisory Board of BCB using a unique description of biochemical path-the group has focused its work on the first topic ways. There are several special databases ofwith a main emphasis in modelling medically pathway or interaction data. All of them use dif-relevant systems. The group has made a large ferent description techniques. The most com-contribution for establishing Petri net based tools monly used database, containing many path-in systems biology. ways of different species, is the KEGG Database, but its representation of concurrently behaving pathways by monochromatic graphs is not freeModelling and analysis of of ambiguities.biochemical systems Biochemical pathways are modelled at differentSimilar to computer scientists, biologists use “di- abstraction levels. It must be distinguished be-vide and conquer”-techniques to investigate sub- tween quantitative (kinetic) models and qualita-systems experimentally. Processes in the cell tive (stoichiometric or even purely causal) mod-
Berlin Center for Genome Based Bioinformatics Scientific Report 2005 els. The first ones represent the actual objective As a common intermediate representation we and real purpose in the long-term. The aim of have used Petri nets. They provide a mathemati- these models is to predict the system’s dynam- cally unique representation of biochemical path- ics. Related evaluation methods are typically ways, whereby different biochemical processes based on solutions of systems of ordinary differ- may be depicted hierarchically at different ab- ential equations. Contrary, qualitative models are straction levels. Moreover, established Petri net commonly used only, if kinetic parameters are analysis techniques can be used for the valida- not available or incomplete. All these qualitative tion of qualitative biochemical models, before models are based on more or less graph-theo- they are extended to quantitative ones. Alto- retical descriptions of the system topology, which gether, Petri nets enjoy the following features are defined in case of stoichiometric models by which might be of great help for systems biol- the known stoichiometric equations. ogy: (1) readability - to support understanding, (2) execution (animation techniques) - to expe- Model validation of biochemi- rience a model in order to get really familiar with it, (3) validation techniques - for consistency cal networks applying Petri checks to ensure the model integrity and corre- nets spondence to reality, and (4) analysis techniques With the increasing number of known metabo- - for qualitative as well as quantitative behaviour lites and known interactions between them, vali- prediction. dation of the interaction network becomes more We started the application of Petri nets to bio- and more important. The net behaviour is no chemical systems with well investigated systems more understandable and predictable by using as the glycolysis and pentose phosphate path- human skills only, but available evaluation pack- way in erythrocytes and could confirm the text- ages for quantitative models are not able to book knowledge for these systems. We have check the model for validity. There is a strong used different Petri nets techniques as coloured demand for mathematical methods to validate a44 model for consistency and to answer questions Petri nets (see Runge T, Methodik zur Model- lierung und Validierung von biochemischen Netz- on general structural and dynamic properties as werken mit gefärbten Petrinetzen, dargestellt am liveness, dead states, traps, structural deadlocks, Beispiel der Glykolyse (diploma thesis) and the and invariant properties. Moreover, existing papers presented at CPN Conferences at Uni- methods are dedicated to a certain system type versity Aarhus (Denmark). To analyse much or a certain pathway represented by special larger networks we started to model the whole graphs. Hence, a crucial point seems to be the E.coli metabolism (see Kramer N, Modelling and concise and unambiguous representation of bio- analysis of biological processes using Petri net logical networks to handle computationally these theory (master thesis). The results show the highly integrated networks in an efficient man- modelling and analysis power of Petri nets, but ner. For that purpose, a readable language with also the limits of currently existing tools. From an unambiguous semantics would be of great this work many suggestions arise for further de- help as a common intermediate language to velopments of Petri net theory. avoid the production of just larger patchwork, ex- posed to even more interpretation choices. In- dependently of the given description level and Analysis of metabolic the particular view extension, all pathways ex- networks hibit inherently very complex structures, exploit- In order to prove the modelling and analysis ing all the patterns well-known in software engi- power we have applied Petri net methods in neering as sequence, branching, repetition, and strong co-operation to the experimentally groups concurrency, in any combination. But opposite to other systems, which are of great interest and to technical networks, natural networks tend to where parts of the behaviour are unknown. be much more complex and apparently unstruc- tured, making the comprehensibility of the full Thus, we have modelled and analysed the main network of interactions extremely difficult and carbon metabolism in Solanum tuberosum (po- therefore error-prone. tato) tuber in co-operation with the Max Planck Institute for Plant Physiology Golm and BTU
Berlin Center for Genome Based Bioinformatics Bioinformatics, Technical University of Applied SciencesCottbus. We have provided an approach for Analysis of gene regulatorymodel validation of metabolic networks using networksPetri net theory, which we demonstrate for thesucrose breakdown pathway in the potato tuber. The understanding of gene regulatory networksWe have started with a hierarchical modelling of is essential for understanding cell processes. Athe metabolic network as a Petri net and contin- project has recently been started in co-opera-ued with the analysis of qualitative properties of tion with the Friedrich Schiller-University Jena.the network. The results characterise the net It aims at modelling the splicing processes instructure and give insight into complex net Drosophila melanogaster. The processes arebehaviour. One important technique is the cal- well-characterised, but wide-spread in the litera-culation of the T-invariants as well as P-invari- ture. The Petri net model reflects the interac-ants of a system. The T-invariants reflect the tions between metabolic components, signalmain processes taking place in the metabolic transduction paths, and gene regulatory pro-system in reality. P-invariants reflect substance cesses at mRNA level. This work is embeddedconservations. The presented detailed discus- in other investigations concerning alternativesion of occurring T-invariants explains the net splicing and is the first approach for modellingbehaviour as possible combinations of subpath- such kind of network with Petri nets or qualita-ways, which reflect correctly experimentally tive analysis methods.known results. In the future, the existing netshould be extended by other central metabolic Application of Petri nets toprocesses (e.g. glycolysis, respiration, amino medically relevant systemsacid metabolism) to get a deeper insight into the An important aspect of our work caused by strongwhole metabolism in the potato tuber. co-operations with medical research institutes as Charité and MDC concerns systems of medicalAnalysis of interest. Thus, we have analysed the bloodsignal transduction pathways clutting process (see Neumann G, Modellierung biochemischer Abläufe mit Petri-Netzen - 45The first signal transduction pathway we mod- Hämostase vs. Fibrinolyse vs. Inhibitoren (di-elled represents the basic processes of apoptosis ploma thesis) in co-operation with physicians toin mammalian cells. Apoptosis is an essential yield a valid very large and complex model con-part of normal physiology for most metazoan taining many hierarchy levels, which should alsospecies. Disturbances in the apoptotic process be used in medical research.can lead to several diseases. The signal trans-duction pathway of apoptosis includes highly In co-operation with clinical groups at Charité, acomplex mechanisms to control and execute project headed by Astrid Speer of the TFH, theprogrammed cell death. The results provide a Duchenne muscle Dystrophy is modelled. Thismathematically unique and valid model enabling project started recently and is of great interest,the confirmation of known properties as well as also because theoretical and experimental worknew insights in this pathway. This work will be influences each other. The application of othercontinued to refine the model and to analyse also bioinformatics methods already lead to a publi-quantitative aspects. cation.Another recent work is a diploma thesis on mod- During a PhD thesis the liver cell metabolismelling of the interactions in and between the sig- was modelled by differential equations and asnal transduction pathways in Saccharomyces Petri net (with MDC and BTU). Another recentlycerevisiae (yeast). In the BCB group of Edda started project concerns the modelling of G1/S-Klipp at MPIMG the same pathway is modelled phase in mammalian cells.using different methods. Both diploma studentsare in contact with each other. Besides a deeper Implementation of tools forunderstanding of these pathways one aim is the analysing biochemicaldetailed comparison of both methods in order to systemssee the differences and to check the possibility We have developed two new tools as help inof a combination of parts of both approaches. analysing biochemical systems. One is a simple
Berlin Center for Genome Based Bioinformatics Scientific Report 2005 path-search tool, which allows searching for all Other scientific activities of paths in a biochemical network using a special the group constraint language. This tool is based on the bachelor thesis of Markus Schüler, and is us- Group members are active as referees for sci- able under http://www.sanaga.de/~stepp. entific journals as Bioinformatics, Journal of Theoretical Biology, In Silico Biology, Protein The second tool, which has been developed by Engineering, BioSystems, and for conferences Albert Gevorgyan, represents a complex and as RECOMB 2002, CMSB 2003, ISMB 2005. advanced Petri net editor, which allows the con- They are members of the scientific program com- version of KEGG networks into Petri net models mittee for CMSB 2003 and ISMB 2005. with integrated Petri net analysis techniques and an underlying relational data base system to Based on his master’s thesis Systematische store and search other information as kinetic data Analyse von RNA-Strukturen mit bioinformati- or literature data. In co-operation with Hiroyuki schen Methoden zur Vorhersage von Antisense- Ogata of the Jean-Michel Claverie group at Cen- Oligodesoxyribonukleotiden Christian Köberle in tre National de la Recherche Scientifique (CNRS) co-operation with Max Planck Institute for Infec- in Marseille, France this tool shall be combined tion Biology founded the company Nucleic Acid with their own databases. Design, which designs siRNA structures for func- tional studies. Theoretical analysis of The quality of the scientific work is reflected by the accepted tutorial on “Qualitative Modelling protein structures and Analysis of Biochemical Pathways with Petri In the post-genomic research protein structures Nets” given at ICSB 2004 at Heidelberg and the and their functions play a crucial role. To handle many invited talks given, e.g. at Second Bertinoro the large and complex structure data of proteins Computational Biology Meeting, Bertinoro (Italy), computationally unique descriptions and nota- Dagstuhl-Seminar “Integrative Bioinformatics - 46 tions at different abstraction levels are neces- sary. To define a unique language for protein Aspects of the Virtual Cell”, “Conference BioCon Valley Life Science for the Future”, and various topologies we have developed four linear nota- European universities. tions based on a graph-theoretical description In the future the group wants to combine meth- of protein secondary structure topology (see fig- ods for qualitative analysis with those for quanti- ure). tative analysis to provide practicable tools for the To search for protein topologies we have imple- scientific community. Other tasks will be the con- mented a web-based database Protein Topol- nection of net analysis tools with expression data ogy Graph Library (PTGL), which contains over and the further development of existing models 15.000 protein structure topologies (http:// in co-operation with experimentally working sanaga.tfh-berlin.de/~ptgl/ptgl.html). groups. PTGL is applied in the threading algorithm de- veloped in the BCB group of Thomas Steinke at Zuse Institute Berlin. Other co-operations exist with Davis Gilbert of the University of Glasgow.Left: Structure of the protein 1G3E. Center: Key notation of the folding graph B of 1G3E. Right: The reduced ofthe folding graph B of 1G3E.
Berlin Center for Genome Based Bioinformatics Bioinformatics, Technical University of Applied Sciences Relevant formerTeaching Publications Scientific Output*The group is heavily involved in Heiner M, Koch I & Voss K Publicationsteaching. Per scientist the teach- (2001). Analysis and Simulation Koch I, Schüler M & Heiner Ming load ranges from 12 to 16 of Steady States in Metabolic (2005). A Software Tool for Petrihours per week in each semes- Pathways with Petri Nets. In: Net based based Analysis in Bio-ter in the accredited MSc course CPN01-Third Workshop and chemical Networks. In Silico Bi-in bioinformatics. Moreover, the Tutorial on Practical Use of ology (accepted)group leads the whole course and Coloured Petri Nets and the CPNis responsible for its realisation. Tools, University of Aarhus, Den- Heiner M & Koch I (2004). Petri mark, Jensen K, ed., 15-34 Net Based Model Validation inThe lectures given by the scien- Systems Biology. In: Proceed- (ISSN 0105-8517)tist of the group are focused on ings 25th International Confer-foundations in computer science, Sunyaev S, Ramensky V, Koch ence on Application and Theoryon object-oriented programming I, Lathe III W, Kondrashov AS & of Petri Nets, ICATPN 2004, Bo-in Java, on bioinformatics algo- Bork P (2001). Prediction of Del- logna, Italy, LCNS 3099, Springerrithms for theoretical sequence eterious Human Alleles. Hum Verlag, Berlin, 216-237and structure analysis, and on an Mol Genetics "bf 10"(6): 591-597introduction into Petri net theory Heiner M, Koch I & Will J (2004). Koch I (2001). Fundamental Model Validation of Biologicaland their applications for model- Study: Enumerating all con- Pathways Using Petri Nets -ling and analysis of biochemical nected maximal common sub- Demonstrated for Apoptosis. Jsystems. One module is variable graphs in two graphs. Theoreti- BioSystems 75(1-3):15-28for new topics in which industry cal Computer Science 250:1-30or research institutes are espe- Koch I, Junker BH & Heiner Mcially interested. This year in this Schuster S, Pfeiffer T, Molden- (2004). Application of Petri netmodule molecular modelling and hauer F, Koch I & Dandekar T theory for modelling and valida-statistical applications in medicine (2000). Structural Analysis of tion of the sucrose breakdownwill be taught. metabolic Networks: Elementary Flux Modes, Analogy to Petri pathway in the potato tuber. 47All lectures are regularly evalu- Bioinformatics (in press) Nets, and Application to Myco-ated and have reached top scor- May P, Barthel S & Koch I plasma pneumoniae. In: Procing positions within the university. (2004). PTGL - Protein Topology Germ Conf Bioinf, Bauer EB, Rost U, Stoye J, Vingron M, eds., Graph Library. Bioinformatics Logos Verlag Berlin,115-120 20(17):3277-3279 (ISBN 3-89722-498-4) Popova-Zeugmann L, Heiner M Koch I, Schuster S & Heiner M & Koch I (2004). Modelling and (2000). Using time-dependent Analysis of Biochemical Net- Petri nets for the analysis of works with Time Petri Nets. In: metabolic networks. Workshop Proc Workshop Concurrency, Modellierung und Simulation Specification & Programming, Metabolischer Netzwerke, Hofe- Informatik-Berichte der HUB städt R, Lautenbach K, Lange M, 170(1), Caputh, 136-143 (ISSN eds., Preprint No.10, Faculty of 0863-095X) Computer Science, Otto-von- Rother K, Müller H, Trissl S, Guericke University, Magde- Koch I, Steinke T, Preissner R, burg, 15-21 Frömmel C & Leser U (2004). Columba: Multidimensional Data Integration of Protein Annota- tions. In: Rahm E, ed., Data In- tegration in the Life Sciences, Lecture Notes in Computer Sci- ence 2994, Springer, Leipzig, Germany:156-171 * BCB members are marked bold.
Berlin Center for Genome Based Bioinformatics Scientific Report 2005 Runge T (2004). Qualitative Path Patents / Spin off Reilich, Michael: Simulation Analysis of Metabolic Pathways Steinbeis Transferzentrum Nu- neuronaler Vorgänge in Säugern, Using Petri Nets for Generic Mod- cleic Acids Design (STZ-NAD), Diploma thesis in Technical Com- elling. Technical Report BTU founded in May 2004 by Volker puter Science, Charité and Tech- Cottbus I-03/2004 (ISSN 1437- Patzel and Christian Köberle nical University of Applied Sci- 7969) ences 2004 Runge T (2004). Application of Schelbert, Christian: Structural Coloured Petri Nets in Systems Student Theses Aspects of Alternative Splicing Biology. In: Proc 5th Workshop Effinger, Daniel & Rolschews- using Bioinformatical Methods, CPN, University of Aarhus, 77-95 ki, Johann: Development of a Master Thesis, Technical Univer- dynamic web application: an in- sity of Applied Sciences 2004 Kriventseva EV, Koch I, App- weiler R, Vingron M, Bork P, formation system for pest man- Schramm, Gerrit: MAT - Micro Gelfand MS & Sunyaev S (2003). agement, Master Thesis, Tech- Array Analysis Tool, Master The- Increase of functional diversity by nical University of Applied Sci- sis, Max Delbrück Center for alternative splicing. Trends in ences 2004 Molecular Medicine (MDC) and Genetics 19:124-128 Huber, Florian: Classification of Technical University of Applied EST-tissue information using a Sciences 2004 Sifringer M, Uhlenberg B, Lam- mel S, Hanke R, Neumann B, von directed acyclic graph, Master Waldminghaus, Torsten: In Moers A, Koch I & Speer A Thesis, Max Delbrück Center for silico analysis and selection of (2003). Identification of trans- Molecular Medicine (MDC) and RNA secondary structures, Mas- cripts from a subtraction library Technical University of Applied ter Thesis, Technical University which might be responsible for Sciences 2004 of Applied Sciences 2004 (in co- the mild phenotype in an intra- Kramer, Nina: Modelling and operation with the MPI for Infec- familially variable course of Du- analysis of biological processes tion Biology, Berlin)48 chenne muscular dystrophy. Hu- man Mol Genetics 114:149-156 using Petri net theory, Master Thesis, Technical University of Hettling, Johannes: Ein automatischer Vergleich zwi- Voss K, Heiner M & Koch I Applied Sciences Berlin and BTU schen der Protein Topology (2003). Steady State Analysis of Cottbus 2004 Graph Library und SCOP, Bach- Metabolic Pathways using Petri Neumann, Gerry: Modellierung elor Thesis, Free University of Nets. In Silico Biol 3(3):367-387 biochemischer Abläufe mit Petri- Berlin 2004 (in cooperation with Netzen - Hämostase vs. Fibrino- TFH Berlin, supervisor: I. Koch) Boué S, Vingron M, Kriventseva E & Koch I (2002). Theoretical lyse vs. Inhibitoren, Diploma the- Schüler, Markus: Graphen- analysis of alternative splice sis in Computer Science, BTU theoretische Weganalyse in forms using computational meth- Cottbus and Technical University biochemischen Netzwerken mit ods. Bioinformatics 18(Suppl 2), of Applied Sciences Berlin EPNPSearch, Bachelor Thesis, T. Lengauer, H.-P. Lenhof, eds. Cottbus 2004 Free University of Berlin 2004 (in Runge, Thomas: Methodik zur cooperation with TFH Berlin, Su- Schuster S, Pfeiffer T, Koch I, Modellierung und Validierung von pervisor: I. Koch) Moldenhauer F & Dandekar T (2002). Exploring the pathway biochemischen Netzwerken mit Barthel, Stefan: Eine Schnitt- structure of metabolism: decom- gefärbten Petrinetzen, dargestellt stelle zur Visualisierung daten- position into subnetworks and am Beispiel der Glykolyse, Di- bankbasierter Proteinstruktur- application to Mycoplasma ploma thesis in Computer Sci- topologien, Diploma Thesis in pneumoniae. Bioinformatics ence, BTU Cottbus and Techni- Computer Science, Technical 18(2):351-361 cal University of Applied Sci- University of Applied Sciences ences 2004 Berlin 08/2003 (supervisor: I. Koch)
Berlin Center for Genome Based Bioinformatics Bioinformatics, Technical University of Applied SciencesBöhme, Ulrike: Vorhersage re- Schirmer, Markus: Homologylevanter Methylierungsorte für die Modelling of selected kinase do-Regulation der Genaktivität, Mas- mains, Master Thesis, Scheringters Thesis, Max Delbrück Cen- AG and Technical University ofter for Molecular Medicine (MDC) Applied Sciences 2003and Technical University of Ap- Tillack, Thorsten: Entwicklungplied Sciences 2003 einer Datenbankanwendung fürBortfeld, Ralf: Conception and molekularbiologische Daten überimplementation of a MySQL Alternatives Spleißen, Diplomabased analysis environment for Thesis in Computer Science,tissue alternative splicing, Mas- Technical University of Appliedter Thesis, Max Delbrück Centre Sciences Berlin 01/2003for Molecular Medicine (MDC) Boué Stéphanié: Computatio-and Technical University of Ap- nal investigation of alternativeplied Sciences, Berlin 2003 (su- splicing, Master Thesis, Maxpervisor: H. Pospisil, MDC, I. Planck Institute for MolecularKoch, TFH) Genetics 2002Djoko, Djoko: TheoretischeUntersuchungen zu CytochromP-450 Enzymen mit Methoden Co-operationsder Bioinformatik, Master Thesis, Monika Heiner, Brandenburgi-Technical University of Berlin and sche Technische Universität TUTechnical University of Applied CottbusSciences, Berlin 2003 (supervi-sor: L.-A. Garbe, TUB, I. Koch, Ursula Egner, Schering AGTFH) Denis Thieffry, Claudine Chaoui- 49Doudieu, Octave Marie Noubi- ya, Mediterranean Universitybou: Using sequence informa- Marseilletion in protein docking proce- Volker Patzel, Max Planck Insti-dures, Master Thesis, European tute for Infection Biology, BerlinMedia Laboratory Heidelberg Hiroyuko Ogata, Jean-Michel(EML) and Technical University Claverie, CNRS Marseilleof Applied Sciences 2003 Falk Schreiber, Björn Junker, IPKKöberle, Christian: Systemati- Gaterslebensche Analyse von RNA-Struk-turen mit bioinformatischen Me- Claudia Täubner, TU Braun-thoden zur Vorhersage von Anti- schweigsense-Oligodesoxyribonukleo- Heike Pospisil, MDC Berlintiden, Master Thesis, TechnicalUniversity of Applied Sciences, Thomas Steinke, ZIBBerlin 2003 (supervisor: V. Ulf Leser, Institute of ComputerPatzel, MPI-IB, I. Koch, TFH) Science, HUBMay, Patrick: Erstellung einer Cornelius Frömmel, CharitéOnline-DB für Proteintopologienauf der Grundlage eines Edda Klipp, Rainer Spang, Maxgraphentheoretischen Algorith- Planck Institute for Molecularmus, Master Thesis, Technical GeneticsUniversity of Applied Sciences,Berlin 03/2003
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