Systems BiologyResults, Progress and Innovations from BMBF Funding
ImprintPublished byForschungszentrum Jülich GmbHProject Management Jülich (PtJ)52425 JülichOrdersIn writing to the publish...
Systems BiologyResults, Progress and Innovations from BMBF Funding
2                                                                                                PReFacePrefaceSystems bio...
PReFace                                                                                                                   ...
4                                                                   contentSContentsPrefaceHans V. Westerhoff             ...
contentS                                                                                           5Targeting Parkinson’s ...
6                                                        PRogReSS and InnovatIon thRough SySteMS BIologyProgress and Innov...
PRogReSS and InnovatIon thRough SySteMS BIology                                                                      7ing ...
8                                                                    PRogReSS and InnovatIon thRough SySteMS BIology    Ap...
PRogReSS and InnovatIon thRough SySteMS BIology                                                                           ...
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Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
Report on System Biology Funding from BMBF
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Report on System Biology Funding from BMBF

  1. 1. Systems BiologyResults, Progress and Innovations from BMBF Funding
  2. 2. ImprintPublished byForschungszentrum Jülich GmbHProject Management Jülich (PtJ)52425 JülichOrdersIn writing to the publisherProject Management Jülich (PtJ)Außenstelle BerlinPO Box 61024710923 BerlinPhone: +49-30-20199-457Fax: +49-30-20199-470E-Mail: ptj-bio@fz-juelich.deInternet: www.fz-juelich/ptj/systembiologieSupervision ContentsDr. Sigrid Grolle, Dr. Gisela Miczka (PtJ), JülichEdited byDr. Stefanie Reinberger, HeidelbergTranslationLanguage Services, Central Library, Forschungszentrum Jülich GmbHLayoutFOCON GmbH, AachenPrintBonifatius GmbH, Druck Buch Verlag, PaderbornAs of Jülich, Berlin 2008Photo creditsDerichs Kommunikation GmbH, Jülich: Cover pictureFurther photos and figures are provided from the respective authors (q.v.)
  3. 3. Systems BiologyResults, Progress and Innovations from BMBF Funding
  4. 4. 2 PReFacePrefaceSystems biology is working Systems biology began well before the turn of The functioning of living organisms does notthe century in the USA and in Japan. Its empirical only depend on their individual components butmolecular genetics/genomics roots were more also on the interactions between these components,American, its physical chemistry/mathematical i.e. on dynamic networking. For good reasons,biology roots, including non-equilibrium molecular biology focuses on individual macro-thermodynamics and metabolic control analy- molecules. One paradox is therefore that systemssis, more European. Hybridization arrays, QPCR, biology needs to interface actively with molecular2-D electrophoresis, chromatography plus 2-D biology, which itself shies away from studyingmass spectrometry, and quantitative microscopy interactions and networking. Systems biologyenable the quantification of changes in concen- also needs to interface strongly with physiology,trations of molecules and thus represent an ad- which itself frowns upon an analytical approachditional basis for systems biology. Even if Europe based on individual components. Tuned to thehas a historical lead in some of these, the major simplest possible systems and linear approxima-initiatives in systems biology started in the USA tions thereof, mathematics and physics considerand Japan. There the time was ripe for systems biology a mere set of special cases, too complexbiology whilst Europe was more sceptical with to resolve. Systems biology needs to integraterespect to new research and development. and add to these three paradoxical approaches. This barrier was overcome by the first major Quite a number of research programmescoherent systems biology research programme in throughout the world call themselves systemsEurope, which started in 2004. The programme biology, but do not integrate these threewas ‘HepatoSys’, funded by the Federal Ministry approaches. Some merely calculate theoreticalof Education and Research (BMBF). In the follow- behaviour that may not actually function. Othersing year, the UK BBSRC and EPSRC funded research collect data without interpreting how functionscentres and doctoral training centres for systems arise from interactions. The BMBF researchbiology. The BMBF then funded four such research programmes, and certainly HepatoSys, integratecentres (FORSYS) in 2007. Setting up further fund- the three approaches, and with appreciable success.ing priorities (QuantPro, FORSYS Partner), BMBF The preparatory committees and the internationalcontinued to propel German systems biology steering committees worked hard to bring aboutforward, also by supporting the training of young this integration. The committees had to rejectscientists. At the same time BMBF announced a excellent research that lacked integration per-transnational research programme on microbial spectives, and they insisted on the integration ofsystems biology (SysMO) with the Netherlands, distinct proposals. Both types of action are unusualthe UK, Austria, Norway and Spain. In 2008 many in evaluating and advising on scientific research.additional systems biology research programmes The paradigm shift effected by systems biologyare now running in Europe, including Germany, implies that the success of systems biology pro-where the new funding priority MedSys will fund grammes should be judged by more stringentapplied systems biology in medical research. criteria than the success of traditional research
  5. 5. PReFace 3programmes. Of course, the research should be BMBF is to be complimented on the importantexcellent, as judged from the discoveries and ap- role it has played in the emergence of systemsplications. In addition, the programmes should be biology. Japan and the USA may have been firstdistinguished from the traditional research pro- to engage in systems biology, but BMBF has nowgrammes in molecular biology, mathematics and put Europe into a leading position with the firstphysiology. Research that is excellent in terms of and by far the largest, truly integrated systemsmolecular biology but not in terms of mathematics biology programmes. The integration of themay not be regarded as excellent systems biol- various disciplines dealing with various aspects ofogy. On the other hand, the highest excellence in the human cell is of tremendous importance forsystems biology may conflict with the paradoxical health, disease and drug effectiveness. BMBF hasstandards of the two neighbouring disciplines. For also promoted the standardisation that is abso-the steering committee, this makes life difficult, lutely essential for the life sciences and for theas the quality of research proposals/reports can- ‘silicon human’ of the future. In addition, it hasnot be assessed from the number of publications enabled scientists to make scientific discoveriesin journals with high impact in molecular biology, that could not otherwise have been made.or in conference proceedings in engineering. I invite you to study this brochure, and to assess Another paradox relates to the involvement of and enjoy the progress made by systems biologyindustry in systems biology programmes. The phar- in Germany. Systems biology is working, also inmaceutical industry understands why one should Europe.look at disease and drug safety from the perspectiveof networks. However, since systems biology dealswith entire networks, the best expertise needs to beengaged; involving too many research groups forthe intellectual property to remain exclusive. Thepharmaceutical industry will only become involvedwhen research starts to become applicable. Then Hans V. Westerhoffthey plan defined bilateral projects with academicresearch groups. These kinds of projects are ex-pected for the funding priority MedSys, and may Hans V. Westerhoff is AstraZeneca Professor of Systems Biology andnow also become possible for Hepatosys. Systems Director of the Doctoral Training Centre for Integrative Systemsbiology is a matter for large-scale public funding in Biology from Molecules to Life (ISBML), Manchester, UK. Furthermore,order to support new application-relevant research he is Professor of Molecular Cell Physiology at the Free Universityprogrammes in their early phases. Amsterdam and is Chairman of the “HepatoSys” Steering Committee.
  6. 6. 4 contentSContentsPrefaceHans V. Westerhoff 2Contents 4Progress and Innovation through Systems BiologyG. Miczka 6HepatoSys – Systems Biology of Liver CellsHepatoSys - Systems Biology Studies of Liver Cells (Introduction)U. Heisner 10Robustness of the Drug Detoxification Metabolism in Liver CellsM. Reuss, J. Bucher, U.M. Zanger 12A Circuit Diagram for BiotransformationK. Mauch 14High Tech for Liver CellsM. Athelogou, G. Schmidt, F. Owen 16The Endocytosis Transport Network/SystemM. Zerial, J. McCaskill, A. Deutsch 18Iron NetworkJ.G. Reich, M. Muckenthaler, M. Hentze 20Central Data ManagementH.-P. Fischer, D. Bannasch 22Liver Cells in CultureJ. G. Hengstler 24Feedback for Liver RegenerationU. Klingmüller, S.Dooley, J. Timmer 26Liver Regeneration – A Unique PhenomenonD. Drasdo, S.Höhme 28HepatoNet - Modelling the Liver MetabolismH.-G. Holzhütter, K. Hübner, S. Hoffmann 30FORSYS – Centres of Systems BiologyFORSYS – Research Units on Systems Biology (Introduction)B. Regierer 32
  7. 7. contentS 5Targeting Parkinson’s DiseaseR. Baumeister, E. Schmidt 34The Cell’s Suicide ProgrammeR. Eils 36On the Track of Molecular SynergismsW. Weckwerth 38Microbes and Men – A Complicated CoexistenceM. Naumann, R. Poltz 40QuantPro – Quantitative Analysis for the Description of Dynamic Processes in Living SystemsQuantPro – Quantitative Analysis for the Description ofDynamic Processes in Living Systems, (Introduction)Y. Pfeiffenschneider 42Biomarkers for Potato BreedingP. Geigenberger 44Transport Systems in the LiverU. Pehl 46The Light Processing NetworkD. Osterhelt , M. Ueffing 48SysMO – Systems Biology of MicroorganismsSysMO – Systems Biology of Microorganisms (Introduction)M. Heidelberger 50Lactic Acid Bacteria in ComparisonU. Kummer, B. Kreikemeyer 52Stress in BacteriaV. Martins dos Santos 54Clostridium acetobutylicum – a Response to Dwindling Crude Oil ReservesP. Dürre, A. Ehrenreich 56ERASysBio – 13 Countries Coordinate their Funding ActivitiesV. Simons 58Data and Facts on Funding for Systems Biology in GermanyE. Stüttgen 59
  8. 8. 6 PRogReSS and InnovatIon thRough SySteMS BIologyProgress and Innovation through Systems Biology In all societies, innovations form the basis for is an iterative process between laboratory experi-progress and development. Innovations ensure ments and mathematical modelling. The result ofcontinuous growth, prosperity and international this process is an optimised mathematical modelcompetitiveness. The Federal Government’s High- describing the behaviour of a given biologicalTech Strategy for Germany is therefore specifically system in a defined environment. This thus facili-promoting research fields with a high innovation tates predictions about the behaviour of the systempotential. This also includes the relatively young under the influence of internal and external factors.discipline of systems biology. After the widespread introduction of the What is systems biology?methods of molecular biology in medicine and Systems biology is characterised as the quantita-biology, systems biology is regarded as the second tive analysis of dynamic interactions between thekey technology for achieving progress in the life components of a biological system with the aimsciences. At the same time, it forms the basis for of understanding the behaviour of the system as aexploiting new innovation potential in the whole and enabling predictions of its behaviour toknowledge-based bioindustry. be made. to this end, mathematical concepts are applied to biological systems so that an iterativeWhat is systems biology? process takes place between laboratory experiments and computer modelling. In the past, the individual research disciplinesin the life sciences primarily focused on investigat-ing process flows down to the molecular details. Ina descriptive approach directed at achieving high Benefits of systems biologyquality and molecular details, a wealth of data wasgenerated concerning single cell components or With its new concept, systems biology has thefunctions. However, the interaction of these mol- potential to radically change the life sciences andecular structures is highly dynamic and is control- to provide completely new findings for biomedicalled by cross-linkages with all cellular hierarchies. research and for biotechnology in industry andIn order to understand such a biological system agriculture. Working with models and computeras a whole, it is necessary to have a quantitative simulations offers the opportunity of proceed-understanding of the processes taking place in ing in a targeted manner. Instead of looking forit. This is the starting point for systems biology. the proverbial needle in a haystack, the mostThe aim of the systems biology research approach probable processes can be calculated and ex-is to understand the behaviour, the dynamics of a periments tailored accordingly. Systems biologybiological system, for example a metabolic path- thus offers the opportunity of raising knowledgeway, a cell organelle or - in the distant future - a of dynamics and the interaction of vital func-whole cell or organism in its entirety. This requires tions to a completely new plane and of exploit-the linkage of all molecular biology data from the ing new potential for innovation in medicine,level of the genome, through the transcriptome the pharmaceutical industry, the chemicaland the proteome, up to and including the met- industry and the biotechnology industry.abolome, the analysis of interaction patterns and The application of computer models may in future,also data integration with the aid of mathematical for example, serve to find new targets for treatingmethods. A basic prerequisite for systems biology diseases or forecasting possible side effects of newapproaches is therefore the interdisciplinary active substances. Drug development will thuscollaboration of researchers from the fields of become more effective and safer and, moreover,biology, chemistry, medicine, computer science, permit animal experiments to be restricted to amathematics, systems science and also engineering. minimum. In the same way, biological applicationsThe heart of the systems biology research approach can be specifically optimised, for example increas-
  9. 9. PRogReSS and InnovatIon thRough SySteMS BIology 7ing the productivity of cell systems for certain biology in Germany. This support measure consistssystems and also the development of novel synthesis of two components. The “FORSYS Cooperations”techniques. First applications are already beginning provide support for a transfer of know-how be-to emerge in the ongoing research projects. tween the existing FORSYS centres and partners from academia and industry and lay the founda-Support measures implemented by tion for the establishment of further competencethe Federal Ministry of education and Research nodes for systems biology in Germany. The “FORSYS Young Investigators Groups“ give young scientists Systems biology requires altered research the opportunity to conduct independent researchstructures in science and industry, new cooperation and thus to exploit their creative potential.models and a new quality of interdisciplinary andinterindustrial collaboration in a national and inter-national framework. The Federal Ministry of Educa- Peter gruss, President of the Max Planck Societytion and Research (BMBF) recognised this at an earlypoint and is reacting to these constraints. As part “the systems biology research approach in the lifeof the Federal Government’s High-Tech Strategy, sciences will have a decisive influence on progress init is undertaking a selective expansion of systems biology and medicine.”biology support measures and the establishmentof relevant research and funding structures on anational and international level. These measures The support measure “Medical Systems Biology –are being taken within the context of lines of action MedSys” announced early in 2008 focuses on theplanned or implemented by the federal states, the application potential of systems biology for medi-Helmholtz Association, the Max Planck Society and cine and drug development. Apart from academicother research and funding organisations in this research groups, it therefore primarily targets cor-field. porate research departments in the pharmaceutical and biotechnology industries, which are concerned, Back in 2001, BMBF initialised funding of this among other things, with the development ofinnovative research field in Germany with its call patient-related tools for diagnosis and treatment orfor proposals for “Living Systems – Systems Biology”. the application of systems biology approaches forThe resulting pilot project “Systems Biology of the increasing the efficiency of clinical trials.Liver Cell - HepatoSys“ has now developed into a Systems biology also plays a not inconsiderablenationwide network of expertise which also enjoys part in the support measure on the topic ofinternational recognition. “BioEnergy 2021 – Research on Utilising Biomass“ The support programme “Research Units of announced at the beginning of 2008. The “SystemsSystems Biology- FORSYS” created the decisive basis Biology for Bioenergy” module will fund researchfor systems biology in Germany. The establishment projects that contribute towards optimising crops asof the four FORSYS centres in Freiburg, Heidelberg, energy plants.Magdeburg and Potsdam in 2007 improved thesituation for systems biology, with respect to both The discussion is currently focusing on furtherstructure and content. The FORSYS centres ensure research measures including the expansion of thethat the interdisciplinary collaboration essential for methodological and technological basis for systemssystems biology is available “under the same roof”, biology, for which the foundation was laid by theand that there is a local concentration of research research priority “Quantitative Analysis to Describeexpertise that also provides training opportunities the Dynamic Processes in Living Systems – Quant-for young scientists. Pro” that started in 2004. In addition, attention The support measure announced in 2007 is also being paid to exploiting the potential of“Partners for Research Units of Systems Biology – systems biology research for other fields ofFORSYS Partners” further strengthened systems application (e.g. for health in ageing).
  10. 10. 8 PRogReSS and InnovatIon thRough SySteMS BIology Apart from national commitments, the Federal The Federal Research Ministry is also involved inResearch Ministry is also involved in the develop- planning a large-scale European project on thement of European support measures for systems “Systems Biology of the Metabolic Syndrome” that isbiology. For example, in 2006 as part of the ERA-Net scheduled to be launched in 2009.ERASYSBIO, the transnational support measure The strategy paper “Systems Biology in the Euro-SysMO (Systems Biology of Microorganisms) was pean Research Area” was published in April 2008agreed jointly with six European partners. Funding by ERA-Net ERASYSBIO as a basis for the furtherof the transnational collaborative projects began in harmonisation of funding policy for systems biology2007 and due to the success of these projects will be in Europe.continued beyond 2010.Schematic representation of the iterative cycle of experiment andmodelling in systems biology. Karl-heinz Maurer, henkel Kgaa düsseldorf “Systems biology is becoming increasingly important in henkel research in terms of the technological application and control of microorganisms, and in the long-term, in order to establish in vitro test systems on the basis of skin cells. We use systems biology approaches to optimise the efficiency and quality of microbial fabrication processes for technical enzymes. We look at microorganisms that colonise our bodies and use methods from systems biology to work on the influences that the growth and formation of relevant metabolites have as a result of specific principles. In the long-term, we want to use the basic principles of the systems biology of skin cells in tissue models and cell cultures to develope alternative methods to replace animal Bilateral support measures for Medical Systems experiments.”Biology were started with Slovenia in 2007. Othercooperative projects are planned with Austria fromspring 2008. Furthermore, another European support meas-ure for systems biology is under preparation as partof ERASYSBIO, which is receiving major supportfrom Germany and the UK. With these supportmeasures, BMBF is pursuing the goal of specifi-cally strengthening national research and fundingpriorities in the field of systems biology by interna-tional networking and of promoting cooperationbetween systems biology centres, which are at themoment mainly located in the Netherlands, the UKand Germany.
  11. 11. PRogReSS and InnovatIon thRough SySteMS BIology 9Summary In this way, the competitiveness of Germany will be sustained in the field of the life sciences and With its early and comprehensive support for cooperation between academic and industrialsystems biology, BMBF has helped Germany to research specifically promoted.establish a leading position in this important Practical applications of the systems biologyresearch field that has great future potential. The research approach are already foreseeable in thetotal BMBF funding of systems biology is € 37 million fields of biotechnology and medicine. Since 2004,per year for national and international support the first companies – mainly small and medium-measures. sized enterprises (SMEs) – have already become The aim of the BMBF’s coordinated research and involved in this research as pioneers in systemsfunding measures is to support the establishment biology. The increasing maturity of systems biologyof the research infrastructure required for systems is manifested in the growing number of researchbiology together with major actors in Germany and partners from the pharmaceutical industry, theEurope. It is taking up central research fields and biotech industry and other sectors who recognisetopics which are of major significance for progress opportunities for the medium- and long-termin the life sciences and for exploiting new inno- development of new areas of business.vation potential and contributes significantly to thetraining and encouragement of young scientists. Gisela Miczka, Projektträger Jülich (PtJ) On the Internet: www.fz-juelich.de/ptj/systembiologie Fascination Systems Biology Dr. Vytaute Starkuviene-Erfle has been head of the Young Inves- chemistry or even quantum physics. This gives us an overall picture tigators Group “Screening of Cellular Networks” since autumn of what’s going on – it doesn’t just show us how a single protein 2007, which is part of the VIROQUANT centre in Heidelberg. She behaves, but rather how the whole system or at least a part of it spoke about her enthusiasm for systems biology and the excellent behaves. That’s absolutely fascinating. Systems biology has the opportunity to work in such a research centre. potential to help us understand every system, every organism in its entirety and complexity at some point in time. At the moment, When did you become interested in systems biology? we’ve only just begun, but the process of getting to this stage alone It was during my time as a postdoc at EMBL in Heidelberg. I had is very captivating. established high-throughput assays for studies on trafficking mechanisms in mammalian cells. In doing so, I began to under- What does it mean for you to head a Young Investigators Group stand the significance of being able to analyse many components in the VIROQUANT centre? at the one time instead of concentrating on single proteins, which As soon as they have penetrated the host cell, viruses become is what I was familiar with from my earlier work. So that’s why I involved in a number of cellular processes and therefore influence decided to orient myself in the direction of systems biology. the entire system of the cell. VIROQUANT investigates these pro- cesses and this information is what attracts me. In the BIOQUANT What is so fascinating about systems biology? building in Heidelberg, I work side-by-side with virologists and cell Systems biology throws light on a specific issue from all sides – both biologists, as well as with mathematicians, bioinformaticians, and from the level of the gene and the protein right up to the effects in modellers. We have lively discussions and our cooperations are ex- the system and vice versa. It accounts for a wide variety of factors in tremely fruitful. This is the only way that systems biology can really this process, and can be expanded to areas where classical biology function well. I believe that my research benefits from this to a large was not admitted in the past, such as biophysics, bioorganic degree and I hope that I too can contribute a great deal.
  12. 12. 10 hePatoSySHepatoSysSystems biology studies of liver cells With its call for proposals for “Living Systems– Systems Biology” in 2001, the Federal Ministry of othmar Pfannes, genedata ag BaselEducation and Research (BMBF) gave the go-aheadfor the funding of systems biology in Germany. “In the decades to come we will see many innova-HepatoSys – a national network of expertise for re- tions that are based on systems biology research.search into liver cells – was initiated in 2004. Today, these novel products and processes will have aHepatoSys is the largest systems biology consortium global impact on our way of life. Information andworking on interdisciplinary principles anywhere communication technology in particular will havein the world. to solve enormous challenges, but also benefit from The liver is the central metabolic organ in verte- very promising business opportunities. as a growingbrates and is in many respects a very special organ. company with global focus, genedata concentratesEach day, it synthesises, converts or degrades more on establishing a strong position in this emergingthan 10,000 substances and thus contributes to the systems biology based market. the hepatosysutilisation of food and purifying the body of meta- project is a key element in this strategy.”bolic products, drugs, alcohol and other harmfulsubstances. As the largest gland in the body, in 24hours it produces almost a litre of bile and thus as- The HepatoSys network of expertise investigatessists the body’s digestive system. The organ serves to regeneration, differentiation, endocytosis, detoxi-store glucose and vitamins and also produces vital fication and the iron metabolism in liver cells. Toproteins such as the blood clotting factors. The liver this end, experimental research teams from biol-is furthermore characterised by its unique ability ogy, chemistry, pharmacology and medicine workto regenerate itself almost completely after dam- hand in hand with representatives of theoreticalage by injury or toxic agents. Hepatocytes express physics, mathematics and with computer scientistsmore genes than most other types of tissue in the and engineers. The long-term objective is to createmammalian organism. They therefore have a very a model for predicting vital processes in the liver,wide range of enzymes and metabolic networks. which would represent an enormous increase in knowledge for medicine and pharmacology. Drugs can be developed more efficiently and economi- cally with the aid of such tools. In silico models open up new possibilities of individualising treat- ments and significantly reducing the number of animal experiments in drug development. no content without structure – the development of hepatoSys During the first funding phase of the Hepa- toSys consortium from 2004 to 2006, attention was initially focused on creating a functioning infrastructure. Today, more than 40 teams work in HepatoSys in the four regional networks of detoxification, iron metabolism, endocytosis and regeneration in addition to the two platforms of cell biology and modelling using comparable cells according to jointly agreed lab protocols.
  13. 13. hePatoSyS 11 the other side of the fence There is a very high level of knowledge trans- fer in the HepatoSys consortium due to the inter- disciplinary collaboration and the numerous external cooperation. A steadily increasing number of companies are joining the association. This devel- opment is encouraged by the fact that the regional networks are located at important biotechnology sites throughout Germany. For example, the regen- eration network has its main sites in Freiburg and Heidelberg in the immediate vicinity of the world- famous hospitals in Heidelberg and Freiburg and also close to BioValley e.V., an association bringing together industrial companies and research insti- tutions in Germany, France and Switzerland. The detoxification network maintains close contacts with the process engineering industry in the Stuttgart region. The iron regulation network col- laborates closely with the Charité university hospi- tal in Berlin and the Heidelberg university clinic. The network of expertise is also very well known outside Germany. In 2006, HepatoSys attracted The important results, laboratory regulations international attention as the organiser of the firstand background information are made accessible to “Systems Biology of Mammalian Cells” (SBMC)all members of the network by means of central data conference. At the beginning of 2008, the Healthand knowledge management. The second funding Programme of the European Union grantedperiod started at the beginning of 2007. Until 2009, funding for a HepatoSys project devoted to studyingall activities are focused on result-oriented research. cancer of the liver. This project, which will be start- The project is monitored by an international ing in October 2008, means that the HepatoSyspanel of high-calibre experts who provide valu- network of expertise is extending its activities onable stimulus for further developments. Hepato- the European level.Sys is steered by a project committee consistingof the coordinators and representatives of thenetworks and platforms. The project committeetakes up the recommendations of the steeringcommittee and is responsible for implementingthe milestone planning. The project committeecoordinates the interdisciplinary collaboration, author:organises the dates and keeps itself informed ofthe scientific progress made in the consortium. In Dr. Ute Heisnerorder to handle the wide range of organisational Systems Biology of Liver Cells - HepatoSystasks, the project committee has a central project Central Project Managementmanagement unit. In addition, each network and Institute for Physics, University Freiburgplatform has its own local project management. Phone: +49(0)761-203 5803 www.systembiologie.de www.hepatosys.de ute.heisner@fdm.uni-freiburg.de
  14. 14. 12 hePatoSySRobustness of the DrugDetoxification Metabolism in Liver CellsCompensation for genetic polymorphisms and environmental influences indegrading xenobiotics in the liver Humans and animals are subjected to perma- the metabolic network structurenent exposure to different kinds of xenobioticsubstances, including plant toxins, medicinal drugs, For the characterisation of the catalytic proper-and environmental poisons. In vertebrates, the liver ties of the CYP450 system, we chose dextromethor-has the task of making these substances water-solu- phan, a cough suppressant, and propafenone, anble and thus preparing them for excretion. In hepa- anti-arrhythmic agent as model substances. In ordertocytes, this process consists of a complex sequence to identify the CYP450 variants involved in convert-of reaction steps (biotransformations) that are cata- ing these substances, we first conducted activitylysed by an extensive enzyme system, in particular measurements of recombinant enzymes. On thisby the cytochrome P450 monooxygenases (CYP450). basis, we established the topological structure of Caused by a number of variations in genetic the metabolic system: it is a multi-reactive system inmake-up, so-called genetic polymorphisms, and as which individual isoenzymes have an overlappinga result of illness or environmental factors such as substrate specificity.the intake of food and drugs, these enzymes exhibita pronounced interindividual variability in theirexpression and functionality, in other words in howmuch of the effective enzyme is available in the cell. So that the metabolism of xenobiotic substancesprogresses smoothly, it must be “robust” comparedto the individual factors of influence. Robustnessis a central concept in the systems-theory analysisof networks. It describes how well a system cancompensate for disturbances that have eitherbeen caused internally, for example as a resultof mutations, or externally, for example throughenvironmental influences. Experimental and Model structure of the drug detoxification metabolism of the sub-theoretical groups within the HepatoSys Compe- strates dextromethorphan (DTM) and propafenone (PPF) for the phase Itence Network are working on our project, which metabolites and CYP450 enzymes involved in the complete isoenzymeaims to mathematically model and simulate the model (left) and in the reduced model (right).detoxification metabolism of drug substances. Aspart of this project, we are studying how the large Both of the model substrates were degraded by avariability of the CYP450 system is compensated. number of enzyme variants. This redundancy is extremely important for the robustness of the system. It increases the number of possible degrada- tion pathways and reduces the risk that the loss of an individual CYP could endanger the functional performance of the degradation. This becomes clear through a comparison with a reduced model in which each reaction step is only realised by the most active “master” isoenzyme. In this case, the loss of an individual enzyme would have a more drastic effect on the degradation of xenobiotic substances. In order to identify the parameters of the mathe- matical model, we conducted experiments onIn the liver, cytochrome P450 monooxygenases are responsible for the microsomal fractions, membrane-limited vesiclesdegradation of xenobiotic substances. Here, the percentage distribu- from human liver tissue, in which CYP450 agentstion of different CYP450 agents is shown. were anchored. We determined the formation rates of the degradation products for different starting
  15. 15. hePatoSyS 13 new. The advantage of systems biology analyses lies in the fact that many different conditions can be simulated with the models created. In the future, this could help us to gain a better understandingThe inter-individual differences in the CYP isoenzyme concentration is of the circumstances under which the robustnessreflected in the half-life for substrate degradation. The example shows of the system is no longer sufficient to perform anthe simulation profiles for two different livers. adequate detoxification, or to simulate the degra- dation of new substances under different conditionsconcentrations of the model substrates - individu- in early phases of drug development.ally or in combination. On the basis of these data, Furthermore, we want to link other systemsmodel parameters such as the maximum enzymatic biology model assemblies, which contain the genedegradation rate were estimated with the aid of regulation of the CYP450 enzymes, or relevantwhat is known as an evolutionary algorithm. aspects of the central carbon metabolism of the cell, The results show that the parameters - compa- and thus achieve a comprehensive modelling andrable with the interindividual differences in CYP simulation of the degradation processes of drugconcentrations and activities - may vary strongly substances in the liver cell.in the isoenzyme model. Despite high variable pa-rameters, a constant good adaptation was achieved,which can be interpreted as the maintenance of thefunctionality of the drug detoxification metabolism. authors:Robustness with respect to Prof. Matthias Reuss is Director of theinter-individual variability Institute of Biochemical Engineering at the University of Stuttgart. His research Using model simulations of substrate degra- interests include systems biology and itsdation, we investigated how well protected the possible applications for biotechnologyCYP450 system is against inter-individual vari- and medicine.ability. In order to do so, we selected the data of 150 Phone: +49(0)711-68 564 573individual isoenzyme concentrations in the liver cell reuss@ibvt.uni-stuttgart.defrom a comprehensive liver bank and integratedthem into the reaction kinetics in the model simula- Dipl.-Ing. Joachim Bucher studied processtions. engineering at the University of Stuttgart The following is true of the robustness of the and is currently completing his Ph.D. atmetabolism of drug substances: the smaller the the Institute for Biochemical Engineer-deviations of the half-lives of the substrate degrada- ing, University of Stuttgart, in the field oftion, the more robust the system. It was shown that systems biology.the complete isoenzyme model exhibited a lower Phone: +49(0)711-68 566 324variance of half-lives than the reduced model, bucher@ibvt.uni-stuttgart.dewhich lacked isoenzymes that appeared to be lessimportant but were critical for redundancy. The Prof. Ulrich Zanger is head of the researchredundancy of the isoenzymes therefore represents field of Molecular and Cell Biology at thea decisive factor for the compensation of individual Dr. Margarete Fischer-Bosch Institute ofdifferences. Clinical Pharmacology in Stuttgart. For the last 20 years, he has been workinga variety of possible applications on drug metabolism and genetic poly- morphisms. That the CYP450 system represents an extremely Phone: +49(0)711-81 013 704diverse and robust chemical defence system is not uli.zanger@ikp-stuttgart.de
  16. 16. 14 hePatoSySA Circuit Diagram for BiotransformationDynamic flux analysis of the central metabolism in human hepatocytes The enzyme system of the central metabolism results reflect the actual situation at a selectedplays an important role in the functioning of an point in time. For this purpose, researchers at theorganism. It supplies energy equivalents that make Institute of Biochemical Engineering in the Uni-it possible for vital processes to occur and it also versity of Stuttgart apply an ingenious procedureallows the biotransformation of endogenous and which involves briefly treating hepatocytes thatforeign substances so that these can be eliminated have been quickly separated from the mediumfrom the body. The mathematical description of with water at a temperature of over 90 degreesthis enzyme system represents a decisive basic Celsius. This inactivates enzymes ensuring that theprinciple for predicting the dosage of medications. metabolites are not degraded further. With theThe objective of our research project is therefore to heat treatment, we simultaneously achieve a cellcreate a type of circuit diagram that quantitatively disruption that releases intracellular metabolites.records the transformation of the components Following this, colleagues in the Dr. Margareteinvolved in the central metabolism. Coordinated Fischer-Bosch Institute of Clinical Pharmacology,by Insilico Biotechnology AG, Stuttgart, a team Stuttgart, determine the amount of metabolitesof chemists, biologists, engineers, and computer in the samples. In order to do so, they combine gasscientists analyse the activities of the central chromatography and high performance liquidmetabolism and integrate the data into a computer chromatography with mass spectrometry. Themodel before they simulate the behaviour of the highly sensitive measuring procedure does not justmetabolism with the aid of supercomputers. guarantee a precise determination of the metabo- lites; it also allows the detection of isotopes, which are labelled compounds that only differ from unlabelled compounds by their mass numbers. In this manner, it is also possible to investigate conversions in parallel metabolic pathways.Metabolic network of human hepatocytes (circles symbolise metabo-lites, enzyme-catalysed reactions are represented by rectangles). Fromthe modelling and simulation environment, precise mathematicalequations for the components are formulated, evaluated andcompared with experimental data.Following metabolic pathways We have already succeeded in integratinga few hundred enzyme-catalysed reactions andmore than 400 metabolites, in other words the The determination of intracellular metabolite concentrations requiresdegradation products and intermediate degrada- precise analysis. A combination of high-pressure liquid chromatogra-tion products of biochemical metabolic processes, phy and mass spectrometry is, for instance, used for this purpose.into the model system. In quantifying intracellularmetabolite concentrations, it is essential that themetabolism of cells be stopped immediately aftersampling. This is the only way of ensuring that our
  17. 17. hePatoSyS 15 For example, we use glucose labelled with13C carbon atoms and trace the distribution dy-namics of the heavy isotope in the glucose deg-radation products. Computer simulations on thebasis of these studies then allow us to calculatemetabolic fluxes in parallel pathways and reac-tion cycles. Using this method, we succeeded forthe first time in determining the production ratesof NADPH - an important cosubstrate for medi-cation degradation in the liver - in hepatocytesusing the pentose phosphate pathway. We nowknow that NADPH is not a limiting factor for theapplication and disposal of therapeutic agents.Metabolic dynamics afterthe administration of medication During the first project phase in the period 2004to 2006, the focus was on the analysis of station- Computer simulation of the time course of selected metabolites afterary metabolic fluxes in the central metabolism excitation of the system by a sudden reduction in the external nutrientof hepatocytes. On this basis, we will direct our concentration.attention in the second phase from 2007 to 2009to the metabolic dynamics after the administra-tion of cholesterol-lowering drugs. The aim is to procedures known as evolution strategies in orderdescribe the effect of these therapeutic agents to determine the unknown parameters. The resultsmechanistically on a metabolic level and to predict previously obtained with this procedure are en-the influence of the medication dosage. We want couraging. With one of the first dynamic models,to know how the enzymes involved control the we thus succeeded in achieving good agreementproduction of cholesterol and how side effects can between the simulated and measured metabolitebe avoided. Furthermore, we are interested in the concentrations. This model is available to HepatoSyseffect the substances have in people with different project partners so that further models can be incor-genetic backgrounds so that we will be able to take porated.steps towards creating individualised treatments.In this way, we are making an economically rel-evant contribution to reducing the amount of time author:and the high costs involved in studies that aim todetermine the appropriate medication dosage. Klaus Mauch is co-founder and CEO of In cooperation with other partners in the Insilico Biotechnology AGNetwork Detoxification from the Stuttgart group Phone: +49(0)711-674 2164involved in HepatoSys, we are working on a model klaus.mauch@insilico-biotechnology.comsystem which can be used to predict the optimum www.insilico-biotechnology.comdosage of medication using a computer. The firststep requires experiments for recording the dynam-ics of the central metabolism after the administra-tion of the active ingredient and then imaging them Projectpartners involved: Insilico Biotechnology AG (Klaus Mauch),using the computer. Since the kinetic parameters Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology (Utefor the majority of the enzyme reactions involved Hofmann), Institute of Biochemical Engineering in the University ofare unknown, we use sophisticated estimation Stuttgart (Klaus Maier, Anja Niebel, Gabriele Vacun, Matthias Reuss).
  18. 18. 16 hePatoSySHigh Tech for Liver Cellsautomated image analysis of endocytosis As part of the HepatoSys initiative, the Endocy- erating semantic networks that describe objects.tosis Network (EndoSys) focuses upon analysis of In simple terms, a cell, for example, is representedendocytosis and its influence on signal transduction together with its properties such as size or shape,using systems biology. The members of the con- and these attributes are linked hierarchically (“thesortium, for instance, investigate the formation of cell is large, elongated and granulated”). Thesevesicles (cell compartments enclosed by the cyto- hierarchies are then in turn linked and they collec-plasmic membrane with which membrane proteins tively form a network - the cognition network.or nutrients are ingested into the cell), and how Considering the example of a liver cell, im-the vesicles are transported within the cell. These aged with the aid of a confocal microscope, theinvestigations produce large quantities of very network has the following structure: the lowestheterogeneous image data, such as two- or three- level contains pixels as objects, which are com-dimensional microscopic images of hepatocytes bined on the next higher hierarchical level to formand their components, as well as simulated image larger units such as cell nuclei, endosomes anddata of different biological processes. Relevant cytoplasm; these are further combined into ob-parameters for investigation are simultaneously de- jects representing individual hepatocytes, whichtermined using both experiments and simulations. are finally combined into groups of liver cells. This As the technology partner of the HepatoSys procedure can be further continued, for example,network, Definiens AG Munich has the task of by combining clusters of cells into organs andgenerating automated image analysis so as: to en- organs into organisms. If the necessary data is notable these heterogeneous datasets to be combined; present in a single image, it is possible to relateto generate parameters from the experimental the contents of several images. Metadata such asimage files; and, conversely, to produce simulated measurement information can also be utilised.images from the experimental measurements. From the image to the parameter and simulation – and back again Cognition Network Technology can be used to analyse both image data (e.g. three-dimensional images of hepatocytes) and results from modelling and simulations (e.g. the modelling of endocytotic processes). In the case of microscopic images, information is recorded such as the following:Image analysis of three-dimensional (confocal) pictures of a hepato- • the segmentation and classification ofcyte based upon Definiens Network Technology (red: cell nucleus; individual hepatocytes, cell nuclei, vesicles,blue: marker; green: cytoplasm; yellow: cell boundary for the endosomes and cytoplasm;membrane representation; image data: Steven Dooley). • the detailed description of hepatocytes and their contents;Recognition technology • the quantitative description of the mutual relations between the objects involved, Originating from the idea of mapping elemen- such as the distance of endosomes from thetary mechanisms of human perception simply cell nuclei.and naturally into an image analysis process, GerdBinnig and his team developed Definiens Cognition In simulations like those involving vesiclesNetwork Technology. It is based upon the concept of during endocytosis, point coordinates are availableinformation processing through cognition net- which describe the image e.g. its extent andworks. This image analysis process involves gen- orientation in space. Similarly, data from
  19. 19. hePatoSyS 17 developed by Definiens are used to analyse these data sets, to record them quantitatively and to extract information from them. The algorithms, which were first developed for small volumes of data, can then be adapted to the requirements of large volumes of data. Benefits of this approach using Cognitive Network Technology include: good transferability and high precision in applying the image analysis approach to a large number of im- age files; full-automation; user-friendly software that is easy to operate; and an implementationImage analysis of three-dimensional (confocal) pictures of hepatocytes that is flexible and adapts easily to changing usage(white: individual endosomes; magenta: cell nuclei; green: cytoplasm; patterns. The algorithms that Cognition Networkimage data: Marino Zerial). Technology employ for image and table analysis will in future also be used to investigate other cell types.experiments and statistical analyses can be used tocompile simulated images. Since information from “real” and simulatedimages and also experimentally-obtained data canbe processed at one common level, these differenttypes of information can be interconverted e.g. in-formation from a confocal image can be convertedinto experimental data in order to produce a simu- authors:lation. Experiment, modeling and simulation canbe linked in this way and the parameters resulting Dr. Maria Athelogou, is senior researchfrom the analysis can be used to optimise experi- scientist with Definiens AG and isments and models. concerned with project management and image analysis. Phone: +49(0)89-231 180 14 mathelogou@definiens.com www.definiens.comImage analysis of three-dimensional simulated image data. The Dr. Günter Schmidt is senior researchfigure shows a time sequence from the development of vesicles scientist at Definens AG and addressesduring a simulation. Each individual vesicle is represented by a dif- issues of software development and im-ferent colour. In the Definiens image analysis platform, images are age data analysis.automatically generated from the point coordinates of the simulated Phone: +49(0)89-231 180 15vesicles and then analysed via Cognition Network Language (CNL) gschmidt@definiens.comrules (Simulation: J. S. McCaskill).large volumes of data and Owen Feehan concentrates on softwarevarious types of cells development and image data analysis. Phone: +49(0)89-231 180 97 In order to investigate the endocytotic proc- ofeehan@definiens.comesses in liver cells, Endocytosis project partnershave developed assays that have to be performed inextensive screening programmes, thereby gener-ating large quantities of data sets. The algorithms
  20. 20. 18 hePatoSySThe Endocytosis Transport SystemMolecular switches control material transport inside the cell Endocytosis is a central cellular process in which for example, collections of proteins at the molecularmembrane components and dissolved substances level and surface elements of vesicle membranes atare taken up by the cell surface. In this process, the the next higher level – are regarded as a hierarchycell membrane folds around the object thus form- of container systems. The individual containers areing vesicles which transfer their cargo to a set of loaded with molecular structures of the next lowerintracellular membrane compartments that consti- level. The simulation therefore bridges the gaptute the endosomal transport system. Depending between molecular processes such as theon the purpose, the endocytosed cargo, it is either interaction of proteins on the vesicle membranerecycled or degraded within the cell. Endocytosis and the dynamic processes on the level of completecontrols processes such as nutrient uptake, protein endosomes, for instance for the processes oftransport within the cell and the signalling response membrane deformation, membrane fusion andto growth factors and hormones. Diseases such as protein exchange. For the first time, a systematicAlzheimer’s, asthma or viral and bacterial infections and molecular-based simulation platform has beenhave been associated with defects in this transport established combining the chemical kinetics andsystem, which makes endocytosis important and physical self-organisation of structures for a spatial-interesting from a biomedical perspective. ly and temporally resolved investigation of cellular To date, the mechanisms underlying endocytosis processes. This method will be of major importanceremain largely unexplored. At present, there is no for future computer-based studies of endocytosis inpossibility of predicting the course of endocytosis liver cells in systems biology but the simulations canunder different physiological and pathological also be systematically adapted to many differentconditions. Within the general frame of Hepato- problems.Sys, the aim of the EndoSys network is to analyseendocytosis and its influence on cellular signallingnetworks by a systems biology approach, focus-ing on liver cells. The ultimate goal is to developboth specific mathematical models and a generalsimulation platform. This will serve for a quantita-tive prediction of endocytotic processes and signaltransduction in hepatocytes under predefinedphysiological or pathological conditions. Primary mouse hepatocytes with endosomes under the microscope.Simulation platforms for endocytosis Early endosomes are stained green, late endosomes red and the cell nuclei glow blue. In systems biology, the analysis of endocytosisin liver cells presents us with entirely new chal- new organisation principlelenges. Current studies demonstrate that molecularreactions as well as changes in transport and shape To gain a full understanding over and abovein cellular compartments such as endosomes are this, we must also unravel interested in the preciseclosely coupled. The necessary integration includes molecular mechanisms underlying endocytoticchemical activities on several spatial levels - starting material transport. To this end, at Dresden Univer-with individual molecules, via supramolecular proc- sity of Technology we have translated the molecularesses, up to the dynamics of compartments, such as switches that regulate the transport between earlyprotein sorting by vesicle budding and finally the and late endosomes into a system of partial differ-entire cell. ential equations. These can be used to represent, for In order to improve our understanding of these example, the concentration of typical key regula-processes, within the EndoSys network at the Ruhr tory proteins – Rab5 for early endosomes, Rab7 forUniversity in Bochum we are developing a novel late endosomes – as a function of time and positionhierarchical simulation platform. Complex objects – on the vesicle membrane.
  21. 21. hePatoSyS 19 By a combination of modelling, model analysis, simulation, living cell microscopy and observation of individual endosomes in image sequences we succeeded in unravelling the organisation principle that enables the directed and effective transport of material via the endocytotic pathway. We term this principle the “cut-out switch”, and it may also play a part in other biological contexts. Our simulations and the detailed investigation of the mechanisms and organisation principles of endocytosis will make a contribution towards aSimulation (mprDPD from BioMIP) of budding vesicles in liver cells. better understanding of this phenomenon. On thisThe model shows the self-organisation of different proteins and mem- basis, it is possible to identify new targets for treat-brane lipids which induce cascades of protein recruitment processes. ing such diseases as Alzheimer’s, asthma, bacterialThe coat protein complexes (green) show the formation of distinct or virus infections such as tuberculosis, HIV anddomains and the budding of new vesicles. flu and even cancer, in which endocytosis plays a decisive part. Rab5 and Rab7 are molecular switches that caneach recruit a specific ensemble of partner effec- authors:tor proteins which undertake different tasks in thesorting, recycling and degradation of transported Dr. Marino Zerial is a director at thematerial up to and including vesicle movement and Max Planck Institute of Molecular Celldeformation. Fluorescence microscopy investiga- Biology and Genetics in Dresden and istions at the Max Planck Institute of Molecular Cell coordinator of the Endocytosis networkBiology and Genetics in Dresden have shown that of HepatoSys.absorbed material of endocytosed cargo destined Phone: +49(0)351-210 2636for degradation is first concentrated in Rab5 endo- zerial@mpi-cbg.desomes and then collected and transferred to a Rab7 www.mpi-cbg.deendosome. In this process, Rab5 appears to playtwo conflicting roles. On the one hand, the protein Prof. Dr. McCaskill is head of the Biomolec-controls the accumulation of cargo by fusing several ular Information Processing researchRab5 vesicles. This requires a sufficiently high Rab5 group at the Ruhr University in Bochum.density on the vesicle membrane which is regulated His research concerns the interplay ofvia a positive feedback mechanism. genetic information and self-organisation With the aid of simulations, we sought an an- in synthetic and biological systems.swer to the question of which organisation principle Phone: +49 (0) 231-9742 6420enables Rab5 to best fulfil its task in accumulating john.mccaskill@biomip.ruhr-uni-bochum.dematerial before the protein is displaced from thesurface of the vesicles. The model analysis supplied Dr. Andreas Deutsch is head of the depart-an astonishing answer. Rab5 does not “defend” itself ment of Innovative Methods for Comput-against its supposed opponent Rab7 but rather actu- ing at the Centre for Information Servicesally activates the Rab7 protein. As a consequence and High Performance Computing,of vesicle fusion, the density of Rab5 increases with Dresden University of Technology. He istime, which initially promotes the accumulation. interested in the organisation principlesHowever, at the same time more Rab7 is also recruit- of biological systems.ed on the membrane – until it displaces its predeces- Phone: + 49(0)351-463 31943sor Rab5 through a negative feed-back mechanism. andreas.deutsch@tu-dresden.de http://rcswww.zih.tu-dresden.de/~imc
  22. 22. 20 hePatoSySIron NetworkSystems analyses of iron metabolism in the liver Ionic iron is an essential trace element butalso a dangerous poison. Ionic iron mediates the leroy hood, President of the Institute ofelectron transfer during cellular respiration, as Systems Biology in Seattlerequired for energy supply to the body. Moreover,it is indispensable for detoxification of foreign “the new era of predictive, preventive and perso-substances by the liver. Above all, however, iron nalised medicine made possible by systems biologyis an important component of hemoglobin, represents a radical change in medicine and willthe red blood pigment, without which oxygen have an impact on many aspects of our lives.”could not be supplied to the body´s organs. Iron depletion - as a result of illness, of unbal-anced diet, or during growth phases and pregnancy,as well as after repeated blood donation - is there- the liver as control centre of iron metabolismfore a serious health problem which afflicts about500 million people world-wide. However, excess Iron metabolism is therefore of central sig-of iron is also problematic, for example in patients nificance. It is controlled by a complex regulatorywho due to certain other diseases depend on regu- system that steers absorption, distribution andlar blood transfusion therapy, or even in the case of excretion of the trace element. The intestinal tract,a certain genetic disease, an iron overload disorder, the liver, the spleen, several kinds of macrophageswhich causes excessive accumulation of iron in the and also the muscular system play a key role in thisliver, and can lead to liver cirrhosis, liver cancer, system. A special coordination task is performedand ultimately even to death. Nowadays, iron can by the small intestine as the organ that absorbsbe flushed out by application of certain drugs but iron, and the liver as the control centre. The liverthen again an iron deficiency must be avoided. has sensors for the iron requirement of the entire organism and sends an appropriate dose of the peptide hormone hepcidin as a signal to the small intestine and macrophages, which fine-tunes absorption and distribution of iron in accordance with the overall requirements of the organism. The “IronLiver” collaborative project com- bines a theoretical working group (Max Delbrück Centre, Berlin) with two experimental working groups (EMBL and University Clinic Heidelberg). Their objective is to study the regulatory processes of the iron metabolism in more detail. We are developing a computer model of iron regulation which reflects the interactions of the liver with other organs of the body in the form of a dynamic network integrating absorption, transport, inter- conversion and excretion of iron-related proteins.The iron storage metabolism is controlled by a complex system. Thefigure shows the flowchart of body iron. The thickness of the arrowsymbolises the conversion rate (small arrow: 1–2 mg iron per day; thickarrow: 20–30 mg iron per day; Hb: haemoglobin, red blood pigment;transferrin: iron-transport protein; ferritin: iron storage protein)
  23. 23. hePatoSyS 21the mouse as model animal We use mice for the physiological studies - thebasis for developing the model. Using geneticmodifications, we selectively inhibit or switch offcertain components in the iron metabolic system.We then analyse the iron content in the variousorgans involved in the network in these animals,for example in the liver and the intestines, as wellas in the blood. In this way, we elucidate the regu-latory roles of the components of the iron system. Liver tissue of a healthy mouse (wild type, left) and of a knock-outThis will allow us to modify, for example, the fer- mouse (right), where the Hfe-gene that is involved in the production ofroportin gene, which codes for the iron transport the iron sensor Hepcidin is switched off. If the gene is absent or dam-protein at the entry port from the intestine into aged, an iron storage disease appears. The iron uptake of the duode-the blood, such that it can no longer react to the num is out of control and a deposit is build in the liver (brown colour).hepcidin signals from the liver. This will result,of course, in iron excess of the body. It is of greatinterest to discover how the iron metabolismsystem and the complete organism of the mousereact to this drastic perturbation of the system. authors: The physiological data acquired from the ex-periments with genetically modified animals are in- Prof. Dr. Jens Georg Reich is head of thecorporated into a flux model. Basis of comparison is working group for bioinformatics ata model of iron content and distribution rate of the the Max Delbrück Centre for Molecularhealthy mouse which we have already developed. Medicine in Berlin-Buch and is a member In parallel to our work on genetically engi- of the German National Ethics Council.neered animals, we also prepare an analogous His research interests are the molecular-model for humans. The basis here is the flux model genetic and systems-biology principles ofof the mouse into which we feed literature data the cholesterol and iron metabolism.on human iron metabolism. The aim is to qualita- Phone: +49(0)30-940 628 33tively and quantitatively simulate the physiological reich@mdc-berlin.dehuman iron turnover, as well as its pathologicaldeviations - on the basis of interactions between the Prof. Dr. Martina Muckenthaler is head oflevels of cellular and organismic system hierarchy. the Department of Molecular Medicine at This type of overall model serves as basis for University Clinic Heidelberg. She studiesa detailed study of iron-related human diseases. the role of iron for health.It is also hoped that it can be used for computer- Phone: +49(0)6221-56 69 23controlled therapy planning in conditions of either martina.muckenthaler@med.uni-heidelberg.deiron deficiency or iron overload. With the aid ofcomputer simulations, it could become possible towash out or replete iron as required – thus avoid- Prof. Dr. Matthias Hentze is head ofing excessive as well as insufficient dosage of iron. the working group “Cytoplasmic gene regulation and molecular medicine” at EMBL in Heidelberg. He focuses on the molecular biology of the iron storage metabolism. Phone: +49(0)6221-38 75 01 hentze@embl.de
  24. 24. 22 hePatoSySCentral Data ManagementThe scientific communications platform of the HepatoSys consortium The main aim of the HepatoSys network is to into practice by Genedata, a company providinguse the methods of systems biology to achieve as computational systems for life sciences research.comprehensive an understanding as possible of the The system is administered by the coordinators forcellular processes in hepatocytes. This requires close central data management within the HepatoSysinterdisciplinary collaborations between scientists consortium at the Max Planck Institute for Dynam-from widely differing disciplines. More than forty ics of Complex Technical Systems in Magdeburg.groups from universities, clinics and other researchinstitutions and industry throughout Germany three components for data managementconduct research within the framework of a largealliance. In order to allow the various teams to A significant function of the central datacollaborate efficiently, a central infrastructure is re- management system is to create a joint com-quired to collect essential research data and allow it munications platform for the partners in theto be exchanged between the groups. This function research network through which they canis fulfilled by the central data management system. exchange data, findings and information on models. To this end, the application was installed on a central server at the Max Planck Institute in Magdeburg. All HepatoSys groups have password-protected access via the Internet. The system is composed of three modules: • the experiment block allows experimental findings obtained within the consortium to be stored centrally. • the component block is used to store information on the genes, mRnas, proteins and signalling pathways under investigation.Design of the central data management system: the data within • In the model block, in silico models of the(1) the experiment block, (2) the component and reaction block, simulation of the dynamics of theand (3) the model block are linked to each other and centrally metabolic and signalling pathways in themanaged and retrieved. liver cells are stored, linked with the individual components and exchanged In the planning phase of HepatoSys, it had between the hepatoSys partners.already become clear that the volumes of data gen- • While the experiment and componenterated in the research network are considerable, blocks are based on software alreadyparticularly as a result of the application of high- available from genedata, the model blockthroughput processes. The central data manage- had to be developed from scratch.ment system therefore had to be designed in such away that it could scale with large volumes of data. data management for the Furthermore, the central storage of the data systems biology research processin a relational database was essential, as was thesystematic structuring and integration of different Systems biology research requires the defini-types of data on the level of the gene, RNA and tion and application of new standards, such asprotein, and also tools in order to biologically standard operating procedures (SOPs) for in vivointerpret the various types of data in the context experiments, the unified processing and nor-of the liver cell. The concept of the central data malisation of data, and the introduction of jointmanagement system was developed by the mem- data formats within the research consortium. Thebers of the HepytoSys consortium and then put central data management system is therefore
  25. 25. hePatoSyS 23 The systems biology investigation into liver cells also requires tools for the analysis and inter- pretation of data within a biological context. This demands a technology-independent data analy- sis, which is also performed by the central data management system. Specialised “cross-omics” analyses were developed for this purpose, which help us to analyse and gain a better understand- ing of signal transduction pathways and the underlying regulation processes in hepatocytes. data management in the future The HepatoSys consortium has taken on a pioneering role in developing and establishing data management software for systems biology research processes in cooperation with Genedata. The central data management system currently supports systems biology investigations into liver cells. The functionalities of the system, however, will also be used to address other challenges in systems biology in the future.Database in use: a screenshot of the user interface shows the geneexpression of hepatocytes stimulated with rifampicin from threepatients (HH26, HH27, HH44). (1) The raw data were loaded, processedand the quality of the data was evaluated. (2) The data were thenanalysed further with the functions of the data management system.The analyses show that the expression of the gene CYP3A4 is much authors:higher after treatment with rifampicin, while the other genes,for example from PXR(NR1I2) and from HNF4a, remain largely Dr. Detlev Bannasch is responsible forunaltered. (The diagrams were provided courtesy of Thomas Reichart, the central data management within theITB, University of Stuttgart). HepatoSys network. He focuses on designing and monitoring the develop-based on established IT Community Standards, ment and administration of the database,such as Systems Biology Markup Language (SBML) user support and cooperations with exter-for the exchange of mathematical models that nal data providers and database providersrepresent molecular biology cellular processes. for HepatoSys. The central data management system also has Phone: +49(0)391-6110 216analysis software for processing systems biology bannasch@mpi-magdeburg.mpg.dedata and for interpreting data. Of critical impor-tance here is the automated, computer-assisted data Dr. Hans Peter Fischer has been headquality and consistency control. Only after quality of Genedata Phylosopher, biology datacontrol and the subsequent steps for normalising management and data analysis,and standardising the data, can the different types since 1999.of biological data be compared to each other. For hans-peter.fischer@genedata.cominstance, this allows an informative comparison of www.genedata.comthe expression of the gene that codes for a particu-lar enzyme with the intrinsic enzyme activity.
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