Consortium Member Profiles
Professor Marta Cascante, Barcelona University Biochemistry and Molecular Biology Department, has 20 years of research experience in experimental and theoretical biochemistry with especial focus on modelling of cellular processes. She directs the research group of “integrative biochemistry and cancer therapy” whose main research objective is to understand the mechanisms that result in tumour proliferation. The group is composed of three staff researchers, a visiting professor and ten young researchers engaged in specific projects relevant to the main objective of the group. She has extensive experience of combining biochemistry, molecular and cell biology techniques with tools of systems biology to construct models of biochemical systems and to predict the consequences of genetic, proteomic or metabolic interventions (Cascante et al., 2002). Her group has been a pioneer in contributing to the development of Metabolic Control Analysis (MCT or MCA) and Biochemical Systems Theory (BST) tools in the framework of Systems Biology that have proved very useful for the analysis and understanding of metabolic network regulation. She has also performed studies of enzyme-enzyme interactions, binding between biopolymers and enzymes, and metabolic flux quantification using GC/MS methods in pancreatic and colon cancer cells. She has extensive experience in investigating the mechanisms of action of antitumour drugs at the cellular level. Her current main interest is the understanding of different mechanisms of regulation of metabolic and signal transduction networks. She is presently working experimentally on the evaluation of the consequences at the proteomic and metabolomic level of transfecting NIH3T3 cells with different k-Ras mutants, and constructing a colon cancer model based in the experimental data obtained in her team and available in the literature. Moreover, she and her team iare also working on modelling MAPKs signal transduction network on NIH3T3 cells on the basis of experimental data. She is also involved in a Spanish FBBVA sponsorized project together with Dr. Kholodenko, Dr. Westerhoff and Dr. Fell on modelling MAPKs network. She also participate in the SYMBIONIC System Biology Initiative within the FP6 program of European Comission and is member of the Metabolomics Society and Metabolomics Journal boards.
David Fell is Professor of Biochemistry and Assistant Dean in the School of Biological and Molecular Sciences at Oxford Brookes University . After studying biochemistry at Oxford University , followed by a DPhil on the physical biochemistry of yeast pyruvate kinase, he started lecturing at Oxford Polytechnic, now known as Oxford Brookes University . His research moved from enzymology into computer simulation and theoretical analysis of metabolic control, and he has written the only textbook on metabolic control analysis, Understanding the Control of Metabolism. More recently, he has been analysing the structure of metabolic networks, and extending his computer modelling into signal transduction pathways and the cell cycle. Applications of his work include metabolic engineering and the modelling of drug action. In 2001, he became part-time Scientific Director of the Oxford company Physiomics plc, which is using computer simulation of cellular systems for the development and analysis of therapeutic strategies for the pharmaceutical industry.
David is also a member of the Editorial Board of the Biochemical Journal, a former Editorial Advisor to the European Journal of Biochemistry, a member of the Policy Committee of the Biochemical Society, member of the Engineering and Biological Systems Committee and the Integrated and Systems Biology Strategy Panel of the BBSRC, a member of the Steering Group of the UK Bioinformatics Forum, and a member of the Scientific Advisory Panel for the Center for Modeling Integrated Metabolic Systems at Case Western Reserve University.
E. D. Gilles is Professor at the Institute for System Dynamics and Control Engineering at the University of Stuttgart and the founding director of the Max Planck Institute for Dynamics of Complex Technical Systems . Gilles's systems biology group (distributed between Magdeburg and Stuttgart ) is set up of about 25 people (including PhD students, postdocs, technical assistants and secretaries), mainly with an engineering background.
The analysis of signaling networks in eukaryotes , in particular of Receptor Tyrosine Kinases , is an essential area of investigation in the group. Our first efforts concentrated on the development of a detailed model for the EGF-induced MAPK Cascade [1]. Currently, we are extending the analysis to other RTKs (in particular, c-Met and Insulin Receptor), with special emphasis on the crosstalk mechanisms among them. Furthermore, we are interested in the connection between RTKs signaling and the cell cycle regulation in order to draw a picture of the mechanisms that lead to the decision of proliferation in primary hepatocytes. Our firsts projects were performed experimentally with HeLa cells, while we are now focused on primary hepatocytes. On a different, yet related project, we focus on the interaction between the bacteria Helicobacter pylori and the epithelial cells of the stomach. In particular, we are interested in how H. pylori influences c-Met signaling for its own benefit, using MDCK cells as system.
Our aim is the development of general methods for the analysis of signaling networks, which we test on the particular cases described above. We use different tools which focus on different levels of detail. On one hand, we perform structural analysis based only on qualitative information. On the other hand, we apply a modular approach based on detailed models. We try to decompose the signaling networks in modules unidirectionally connected [2], which we subsequently analyze using system-theory's methods [3]. Rewiring together the modules provides new insights into the whole network. Furthermore, simulation dynamics of the modules can lead to a significant simplification of the models [4].
We also develop modeling tools and methods for the set-up and analysis of mathematical models of signaling networks. Our tool ProMoT (freely available) allows to set up models in a modular and hierarchical manner by means of a visual interface [5]. The models can be exported to Matlab, DIVA (our own simulation tool), and in SBML format. Additionally, we have recently developed a method to cope with the combinatorial complexity of protein complexes [6], which we plan to integrate into ProMoT.
References:
[1] Schoeberl, B., et al., Nat Biotechnol., 20(4):370-5, 2002.
[2] Saez-Rodriguez, et al. Comput. Chem. Eng. , 29(3): 619-629, 2005.
[3] Saez-Rodriguez, J., et al., IEEE CSM, 24(4):35-52, 2004.
[4] Conzelmann, H. et al., Systems Biology, 1(1):159-169, 2004.
[5] Ginkel, M. et al., Bioinformatics, 19(9):1169-76, 2003.
[6] Conzelmann, H. et al., submitted.
Contact person : Julio Saez-Rodriguez email: saezr@mpi-magdeburg.mpg.de
Mariko Hatakeyama is a senior research scientist of Cellular Systems biology Team, Computational and Experimental Systems Biology Group in RIKEN Genomic Sciences Center , Japan . Study topics of our team are model-aided analyses of ErbB signal transduction pathways. Our team has 5-years experiences in Systems Biology-oriented understanding of signal transduction pathways with each team members' long-tem experiences in biochemistry, cell biology, bioinformatics and mechanical engineering. Our current research interest is an allosteric behavior of signal transduction pathway to regulate whole signaling network. We also target integrated understanding of intracellular signaling and gene regulatory networks. For this purpose, we develop several methodologies to understand the signal transduction systems in collaboration with researchers in area of structural biology, physics, artificial intelligent, computer science and statistics. We revealed novel binding patterns of PI3K-ErbB3 receptor interaction and Shc domain motion using molecular dynamics (MD) simulation (1,2), also predicted protein-protein interaction of ErbB receptor-Grb2 proteins using surface plasmon resonance (SPR) assay and MD simulation (3). We developed and analyzed a mathematical model of heregulin-induced ErbB4 signaling pathway (4) and experimentally newly found novel pathways on Shc phosphorylation and B-Raf activation by PP2A in ErbB1-ErbB4 co-expression systems (5,6). Now we are focusing on the integration of signal transduction pathway and gene expression networks. Until now, we have developed new algorithms that infer gene networks from time-series gene expression data (7,8). Those methods are applied to ligand-induced gene expression analysis of signal transduction pathways to predict hub molecules that control gene networks that is critical to cancer development.
1. Suenaga, et al. Novel mechanism of interaction of p85 subunit of PI3K and ErbB3 receptor-derived phosphotyrosyl peptides. J. Biol. Chem., 280, 1321-1326, 2005.
2. Suenaga et al. Tyr317 phosphorylation increases Shc structural rigidity and reduces coupling of domain motions remote from the phosphorylation site as revealed by molecular dynamics simulations. J. Biol. Chem., 279, 4657-4662, 2004.
3. Suenaga, et al. Molecular dynamics, fee Energy and SPR analyses of the interactions between SH2 domain of growth factor receptor binding protein 2 and ErbB phosphotyrosyl peptides. Biochemistry (U.S), 42, 5195-5200, 2003.
4. Hatakeyama, et al. A computational model on the modulation of MAPK and Akt pathways in heregulin induced ErbB signaling. Biochem J., 373, 451-463, 2003.
5. Hatakeyama, et al. Transformation potency of ErbB heterodimer signaling is determined by B-Raf kinase. Oncogene, 23, 5023-5031, 2004.
6. Yumoto, et al. Expression of ErbB4 receptor causes reversal regulation of PP2A in the Shc signal transduction pathway. Submitted.
7. Kimura, et al. Inference of S-system models of genetic networks using a cooperative coevolutionary algorithm. Bioinformatics, 21, 1154-1163, 2005.
8. Kimura, et al. Inference of Neural Network Models of Genetic Networks using a Memetic Algorithm. IEEE Transactions on Systems, Man and Cybernetics, Part B. Submitted.
http://www.gsc.riken.jp/eng/group/system/index.html
Boris N. Kholodenko is Professor and Director of Computational Cell Biology at the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University in Philadelphia . He graduated (with the distinction of Summa Cum Laude) and received Ph. D. in Biophysics from the Moscow Institute of Physics and Technology. Soon he was invited to work in the lab of A. Zhabotinsky, known for his studies of the Belousov-Zhabotinsky reaction. Boris Kholodenko was Professor at the Moscow State University and Free University in Amsterdam , where together with Hans Westerhoff he made crucial contributions to Metabolic Control Analysis, such as the development of the control analysis of cellular systems involving direct enzyme-enzyme interactions, restricted diffusion and information transfer. In 1997, Dr. Kholodenko joined the faculty of Thomas Jefferson University in Philadelphia . His laboratory studies growth factor signaling networks and transcriptional regulatory networks by exploiting Systems Biology techniques and data-driven mathematical models. This emerging synergistic approach generates new knowledge with quantitative and predictive explanatory power. Ultimately, it provides new insight and better tools to control cell-fate decisions, such as proliferation and apoptosis, in normal tissue and malignant tumors. Together with colleagues, Dr. Kholodenko developed the first systems biology model of the epidermal receptor growth factor signaling pathway and showed remarkable dynamic features of protein kinase and phosphates cascades including oscillations, bistability and traveling waves of phosphorylation signals. He published more than 190 publications on spatio-temporal dynamics and control analysis of cellular signaling, metabolic and gene networks. Dr. Kholodenko is a founding chairman of the International Consortium on Systems Biology of Receptor Tyrosine Kinase Regulatory Networks.
Shinya Kuroda is the associate professor at Undergraduate Program for Bioinformatics and Systems Biology, Graduate School of Information Science and Technology, University of Tokyo, Japan since 2002, His laboratory investigates systems analysis of signaling networks including RTK (EGFR, TrkA and Insulin) as well as downstream cascades such as ERK and Ras and Rho GTPases family, that regulate cell fate-determination (cell growth, differentiation and death), cell morphology, and synaptic plasticity. His lab takes advantage of both in vivo dynamics measurements and in silico dynamics using kinetic simulation. His lab has recently found that distinct physical information of growth factors (EGF and NGF), such as increasing rate and concentration of growth factors, are specifically encoded into transient and sustained ERK activation in PC12 cells (Nat. Cell Biol., 7 (4), 365-373, 2005). For detail, visit our website (www.kurodalab.org).
Ulrich Rodeck is Professor at the Kimmel Cancer Center and the Department of Dermatology and Cutaneous Biology at Thomas Jefferson University in Philadelphia , PA , USA . His laboratory investigates regulation of cell survival and cell death by coordinate signaling through RTKs and cell/cell as well as cell/matrix adhesion receptors. Dr. Rodeck's laboratory was the first to demonstrate that EGFR activation in normal and malignant epithelial cells supports expression of Bcl-xL, an anti-apoptotic Bcl-2 family member and, thus, enables cell survival in the anchorage-independent state. Current projects are concerned on signaling events downstream of the EGFR involved in transcriptional and posttranscriptional regulation of apoptosis regulators as they relate to the malignant phenotype. A recent focus has been signal integration, i.e. the coordinate regulation of cell survival through extracellular matrix adhesion receptors and EGFR activation. In addition to cell culture models, Dr. Rodeck's laboratory has recently utilized the tropical fish Danio rerio to determine the role of RTK activation and signaling components in the whole organism.
Dr. Yoshiyuki Sakaki is Director of RIKEN Genomic Sciences Center and Emeritus Professor of the University of Tokyo . He has been the President of HUGO (Human Genome Organization) from 2002 to 2005. He has represented Japan in the international Human Genome Project, and the RIKEN team led by him made significant contributions to the completion of the human genome sequence, particularly playing a major role in completing the sequence of chromosome 21 and 11. Furthermore he has organized an international consortium and successfully completed the chimpanzee genome chromosome 22 sequence. Recently he becomes the chief coordinator of Genome Network Project, a Japanese nation-wide project towards the comprehensive study on the transcriptional regulatory networks of the human genome. In the past, he discovered a gene responsible for familial amyloidotic polyneuropathy (FAP) in 1984, and the human biological clock gene “period” in 1997. As well, in 1986, his group demonstrated for the first time that repetitive sequence L1 is retrotransposon.
He was awarded to "Chevalier" from France Government 2001, in recognition of his contribution to the scientific cooperation between France and Japan, the Award of Japanese Society of Human Genetics (2001), Medal of Purple Ribbon from Japanese Government (2003) and Chu-nichi Culture Award (Chu-nichi Culture Foundation) (2003).
http://www.gsc.riken.jp/eng/group/system/index.html
Joseph Schlessinger has been the William H. Prusoff Professor and Chairman of the Department of Pharmacology of Yale University School of Medicine since 2001. He was the Director of the Skirball Institute for Biomolecular Medicine at New York University (NYU) Medical Center from 1998-2001, and the Milton and Helen Kimmelman Professor and Chairman of the Department of Pharmacology at NYU Medical School from 1990 until 2001. He was a member of the faculty of the Weizmann Institute from 1978 until 1991 and the Ruth and Leonard Simion Professor of Cancer Research in the Department of Immunology from 1985-1991. Joseph Schlessinger was a Research Director for Rorer Biotechnology from 1985 until 1990. He co-founded Sugen, Inc. in 1991, and Plexxikon in 2001. He is currently the Chairman of the Board of Plexxikon and a member of the Scientific Advisory Board of the company.
Joseph Schlessinger received a B.Sc. degree in chemistry and physics in 1968 (Magna cum Laude), and a M.Sc. degree in chemistry (Magna Cum Laude) in 1970 from the Hebrew University in Jerusalem . He obtained a Ph.D. degree in biophysics from the Weizmann Institute of Science in 1974. From 1974 until 1976 he was a postdoctoral fellow in the Departments of Chemistry and Applied Physics at Cornell University and from 1977 until 1978 he was a visiting fellow in the immunology branch of the National Cancer Institute of NIH.
He received the Michael Landau prize in 1973, Sara Leady prize 1980, Hestrin prize 1983, Levinson prize 1984, the Drew-Ciba prize 1995, the Antoine Lacassagne prize 1995 and The Distinguished Service Award of Miami Biotechnology in 1999, Honorary Membership of the Japanese Biochemical Society 1999, the Taylor Prize 2000 and an Honorary Doctor of Philosophy from the University of Haifa, 2002. Joseph Schlessinger is a member of the European Molecular Biology Organization (EMBO), 1982; member of the National Academy of Sciences, 2000; a fellow of the Neuroscience Research Program, 2000 and a member of The American Academy of Arts and Sciences, 2001. He is serving on the editorial boards of many journals, including Cell and Molecular Cell.
Professor Axel Ullrich was trained as a biochemist at the University of Tuebingen ( Germany ) and earned a Ph.D. in Heidelberg in Molecular Genetics in 1975. After a postdoctoral tenure at the University of California , San Francisco , he joined Genentech in 1978. His groundbreaking work in the field of signal transduction research has elucidated major fundamental molecular mechanisms that govern the physiology of normal cells and allowed insights into pathophysiological mechanisms of major human diseases such as Diabetes and Cancer.
Professor Ullrich's efforts to translate basic science discoveries into medical applications led to the development of Humulin (Human Insulin for the treatment of Diabetes;Lilly), the first therapeutic agent to be developed through gene-based technology, Herceptin (Genentech/Roche), the first target-directed, gene-based cancer therapy for the treatment of metastatic breast carcinoma and SU11248 (Pfizer) a multi-targeted drug for the treatment of GIST and Renal Cell Carcinoma.
Since 1988, Professor Ullrich has been Director of the Department of Molecular Biology at the Max-Planck-Institute of Biochemistry in Martinsried and currently he is a visiting scientist in the Centre of Molecular Medicine at the Institute of Molecular and Cell Biology in Singapore and Research Director of the Singapore OncoGenome Project. He is an Honorary Professor of the Second Military Medical University ( Shanghai , China ) and the University of Tuebingen ( Germany ) and elected member of the European Molecular Biology Organization and the German Academy of Natural Scientists “Leopoldina”. Professor Ullrich has been named "International Fellow" of the Garvan Institute of Cancer Research, Sydney , Australia . and in 2005 he was honored by being elected a member of the American Academy of Arts and Sciences.
Professor Ullrich received numerous honors and awards: the Paul Langerhans Medal of the German Diabetes Society (1987), the Berthold Medal of the Germany Society for Endocrinology (1988), the Antoine Lacassagne Prize of the Cancer Society of France (1991), the Gold Medal of the Lorenzini Medical Science Foundation of Italy (1997), the German Cancer Research Prize (1998), the Bruce F. Cain Memorial Award of the American Association of Cancer Research (2000), the Robert Koch Prize (2001), the Robert Virchow Medal of the University of Würzburg, Germany (2002), the King Faisal International Prize for Medicine of the King Faisal Foundation Saudi Arabia (2003)and the Warburg Medal of the German Society for Biochemistry and Molecular Biology (2005).
Because of his major contributions to Science Professor Ullrich was appointed to advisory boards of internationally renowned institutions such as the Wistar Institute (USA), the Biomedicum (Finnland), the Max-Delbrueck-Center for Molecular Medicine ( Germany ) and the International Advisory Council of the EDB ( Singapore ). His scientific work has been published in more than 450 articles in international journals and with over 58000 citations he is one of the ten most cited scientists over the past 25 years worldwide.
Dr. Ullrich has been a leader in international Biotechnology development. He is a founder of three Biotech companies - SUGEN Inc. ( USA ), Axxima Pharmaceuticals AG ( Germany ) and U3 Pharma AG ( Germany ) - and has served on numerous Boards of Directors and Science Advisory Boards of Biotech and Pharmaceutical companies.
Steven Wiley
Dr. H. Steven Wiley joined Pacific Northwest National Laboratory, Richland , WA , USA in 2000 as Director of the Biomolecular Systems Initiative (BSI). The BSI is a multidisciplinary program to understand complex biological systems from a systems perspective. As Director, Dr. Wiley built a program to develop and leverage PNNL's unique capabilities in cell imaging, computational biology, and high-throughput proteomics to understand cell communication. His research interests have focused on understanding mechanisms of cell communication using the epidermal growth factor receptor (EGFR) system as a model. More recently, his work has focused on understanding regulation of growth factor shedding and autocrine signaling as a mechanism by which cells interpret their microenvironment. This work also involves mapping cellular networks connected to ligand shedding and receptor heterodimerization to determine how information is decoded from multiple inputs.
Dr. Wiley pioneered methods for the quantitative analysis of receptor dynamics in mammalian cells and published some of the first computer models of receptor regulation. He has been a major contributor to the field of receptor research, particularly with regard to the control of receptor distribution within cells. Dr. Wiley's work is notable for combining the techniques of molecular and cellular biology with both biochemical and optical assays. The results are then used to build computer models of the underlying cellular processes. He is the author or co-author of more than 100 scientific journal articles, review articles and book chapters. He is also scientific director for the Center for Molecular and Cellular Systems, a joint project with Oak Ridge National Laboratory that is developing high-throughput approaches to mapping the protein-protein interaction networks that underlie cellular functions.
