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Berlin center for genome based bioinformatics koch05
1. Berlin Center for Genome Based Bioinformatics
Bioinformatics, Technical University of Applied Sciences
TFH BIOINFORMATICS
Head
Ina Koch (since 04/2002)
Technical University of Applied Sciences
Seestr. 64
D – 13347 Berlin
Phone: ++49-(0)30-4504 3972
Fax: ++49-(0)30-4504 3959
Email: ina.koch@tfh-berlin.de
http://www.tfh-berlin.de/bi/
Team
Karsten Wenzel (technician, 0.5 position, since
01/2003)
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 43
The 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 main
graduates 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 data
the group two main research directions were pur-
of biological processes has been produced over
sued in the last years, the modelling and analy-
the last years.
sis of biochemical systems and the theoretical
analysis 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 computationally
advices 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 of
with 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 free
Modelling and analysis of of ambiguities.
biochemical systems
Biochemical pathways are modelled at different
Similar 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-
2. 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 a
44 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
3. Berlin Center for Genome Based Bioinformatics
Bioinformatics, Technical University of Applied Sciences
Cottbus. We have provided an approach for Analysis of gene regulatory
model validation of metabolic networks using networks
Petri net theory, which we demonstrate for the
sucrose breakdown pathway in the potato tuber. The understanding of gene regulatory networks
We have started with a hierarchical modelling of is essential for understanding cell processes. A
the 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 in
structure and give insight into complex net Drosophila melanogaster. The processes are
behaviour. 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, signal
main 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 embedded
conservations. The presented detailed discus- in other investigations concerning alternative
sion of occurring T-invariants explains the net splicing and is the first approach for modelling
behaviour 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 net
should be extended by other central metabolic Application of Petri nets to
processes (e.g. glycolysis, respiration, amino medically relevant systems
acid metabolism) to get a deeper insight into the An important aspect of our work caused by strong
whole metabolism in the potato tuber. co-operations with medical research institutes as
Charité and MDC concerns systems of medical
Analysis of interest. Thus, we have analysed the blood
signal transduction pathways clutting process (see Neumann G, Modellierung
biochemischer Abläufe mit Petri-Netzen -
45
The 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 to
in 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 also
species. 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, a
complex mechanisms to control and execute project headed by Astrid Speer of the TFH, the
programmed cell death. The results provide a Duchenne muscle Dystrophy is modelled. This
mathematically 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 work
new insights in this pathway. This work will be influences each other. The application of other
continued 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 metabolism
elling of the interactions in and between the sig- was modelled by differential equations and as
nal transduction pathways in Saccharomyces Petri net (with MDC and BTU). Another recently
cerevisiae (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 students
are in contact with each other. Besides a deeper Implementation of tools for
understanding of these pathways one aim is the analysing biochemical
detailed comparison of both methods in order to systems
see the differences and to check the possibility
We have developed two new tools as help in
of a combination of parts of both approaches.
analysing biochemical systems. One is a simple
4. 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 of
the folding graph B of 1G3E.
5. Berlin Center for Genome Based Bioinformatics
Bioinformatics, Technical University of Applied Sciences
Relevant former
Teaching Publications Scientific Output*
The group is heavily involved in Heiner M, Koch I & Voss K Publications
teaching. Per scientist the teach- (2001). Analysis and Simulation Koch I, Schüler M & Heiner M
ing load ranges from 12 to 16 of Steady States in Metabolic (2005). A Software Tool for Petri
hours per week in each semes- Pathways with Petri Nets. In: Net based based Analysis in Bio-
ter in the accredited MSc course CPN'01-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 CPN
is 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 in
The 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 Theory
on 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, Springer
rithms for theoretical sequence eterious Human Alleles. Hum Verlag, Berlin, 216-237
and structure analysis, and on an Mol Genetics "bf 10"(6): 591-597
introduction into Petri net theory Heiner M, Koch I & Will J (2004).
Koch I (2001). Fundamental Model Validation of Biological
and their applications for model-
Study: Enumerating all con- Pathways Using Petri Nets -
ling and analysis of biochemical
nected maximal common sub- Demonstrated for Apoptosis. J
systems. One module is variable
graphs in two graphs. Theoreti- BioSystems 75(1-3):15-28
for new topics in which industry
cal Computer Science 250:1-30
or research institutes are espe- Koch I, Junker BH & Heiner M
cially interested. This year in this Schuster S, Pfeiffer T, Molden- (2004). Application of Petri net
module 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 breakdown
will be taught. metabolic Networks: Elementary
Flux Modes, Analogy to Petri
pathway in the potato tuber. 47
All 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: Proc
ing 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.
6. 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)
7. Berlin Center for Genome Based Bioinformatics
Bioinformatics, Technical University of Applied Sciences
Böhme, Ulrike: Vorhersage re- Schirmer, Markus: Homology
levanter Methylierungsorte für die Modelling of selected kinase do-
Regulation der Genaktivität, Mas- mains, Master Thesis, Schering
ters Thesis, Max Delbrück Cen- AG and Technical University of
ter for Molecular Medicine (MDC) Applied Sciences 2003
and Technical University of Ap-
Tillack, Thorsten: Entwicklung
plied Sciences 2003
einer Datenbankanwendung für
Bortfeld, Ralf: Conception and molekularbiologische Daten über
implementation of a MySQL Alternatives Spleißen, Diploma
based analysis environment for Thesis in Computer Science,
tissue alternative splicing, Mas- Technical University of Applied
ter Thesis, Max Delbrück Centre Sciences Berlin 01/2003
for Molecular Medicine (MDC)
Boué Stéphanié: Computatio-
and Technical University of Ap-
nal investigation of alternative
plied Sciences, Berlin 2003 (su-
splicing, Master Thesis, Max
pervisor: H. Pospisil, MDC, I.
Planck Institute for Molecular
Koch, TFH)
Genetics 2002
Djoko, Djoko: Theoretische
Untersuchungen zu Cytochrom
P-450 Enzymen mit Methoden Co-operations
der Bioinformatik, Master Thesis, Monika Heiner, Brandenburgi-
Technical University of Berlin and sche Technische Universität TU
Technical University of Applied Cottbus
Sciences, Berlin 2003 (supervi-
sor: L.-A. Garbe, TUB, I. Koch, Ursula Egner, Schering AG
TFH) Denis Thieffry, Claudine Chaoui- 49
Doudieu, Octave Marie Noubi- ya, Mediterranean University
bou: Using sequence informa- Marseille
tion in protein docking proce- Volker Patzel, Max Planck Insti-
dures, Master Thesis, European tute for Infection Biology, Berlin
Media Laboratory Heidelberg
Hiroyuko Ogata, Jean-Michel
(EML) and Technical University
Claverie, CNRS Marseille
of Applied Sciences 2003
Falk Schreiber, Björn Junker, IPK
Köberle, Christian: Systemati-
Gatersleben
sche Analyse von RNA-Struk-
turen mit bioinformatischen Me- Claudia Täubner, TU Braun-
thoden zur Vorhersage von Anti- schweig
sense-Oligodesoxyribonukleo-
Heike Pospisil, MDC Berlin
tiden, Master Thesis, Technical
University of Applied Sciences, Thomas Steinke, ZIB
Berlin 2003 (supervisor: V. Ulf Leser, Institute of Computer
Patzel, MPI-IB, I. Koch, TFH) Science, HUB
May, Patrick: Erstellung einer Cornelius Frömmel, Charité
Online-DB für Proteintopologien
auf der Grundlage eines Edda Klipp, Rainer Spang, Max
graphentheoretischen Algorith- Planck Institute for Molecular
mus, Master Thesis, Technical Genetics
University of Applied Sciences,
Berlin 03/2003
8. Berlin Center for Genome Based Bioinformatics
Scientific Report 2005
50