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Systems Biology
November 30 - December 4
Armindo Salvador

PDBEB Course on
Systems Biology
The field of systems biology embodies an ongoing paradigm shift in biology. Namely, it emphasizes understanding how phenotype emerges from the integrated action of the molecular components of living organisms and finding theoretically-understood principles of biological organization, rather than just identification of components and bottom-up reconstruction of pathways. The proposed course seeks to familiarize the students with fundamental concepts and ongoing developments in the field. Given the predictably poor mathematical background of the students and short duration (4 days) of the course, we will not try to train the students on mathematical modeling and will avoid mathematical details. Nevertheless, there will be opportunity for the students to get some hands-on experience with simulators and database tools.
The course will cover the following three complementary topics in systems biology:
  • Design principles of biochemical networks. By design principles we refer to widely obeyed rules associating design (e. g., patterns of regulatory interactions or relationships between kinetic parameters of enzymes and effector concentrations) of biochemical networks to their function. The search for such rules and the understanding of their underpinnings is a core research program in systems biology, as it may provide a much-needed predictive theoretical foundation for molecular biology. The course will cover recent work on design principles in metabolic and gene regulatory networks.
  • Gene expression variability and collective behavior of cell populations. Owing to molecular noise affecting gene expression the concentrations of most proteins is subject to large variability both over time and across cell populations. From a single-cell perspective, these fluctuations might be mostly deleterious. However, the fitness of multicellular organisms and of clonal unicellular organisms is largely determined by the collective behavior of cell populations, and from a cell-population perspective that variability may actually be advantageous. The exploration of the implications of these realizations for the design and operation of biological systems is a very promising research area, which is contributing key insights. We will introduce the basic concepts about noise in gene expression and cover some recent developments in the field.
  • Data integration platforms. Access to and integration of very disparate and widely dispersed information about biological processes is a key issue in systems biology research. This problem is has been addressed by relational databases of biochemical information. More recently, informatics platforms are being developed that automatically retrieve data from disparate databases, perform automated literature mining and automatically generate draft models of biochemical networks. We will introduce the students to the main databases and to one of these powerful data-integration tools.

  • The lecturers
    Jorge Carneiro’s (Instituto Gulbenkian de Ciência) main research interests are in molecular variability and collective behavior of cell populations, especially in the context of the immune system, and in morphogenesis. He currently leads the Quantitative Biology Group at IGC and is Director of the Ph. D. Program in Computational Biology. He was a Ph.D. student at Institut Pasteur of Paris (France) and a post-doctoral fellow at the Group of Theoretical Biology and Bioinformatics of the University of Utrecht (The Netherlands).
    Representative references:
    J. Carneiro, T. Paixão, D. Milutinovic, J. Sousa, K. Leon, R. Gardner, and J. Faro (2005). “Immunological self-tolerance: Lessons from mathematical modeling” J. Comput. Appl. Math. 184:77-100.
    N. Sepulveda, L. Boucontet, P. Pereira, and J. Carneiro (2005). “Stochastic modeling of T cell receptor gamma gene rearrangement” J.Theor.Biol. 234:153-165.
    Armindo Salvador’s (CNC) main research interests are design principles of biochemical networks, and mathematical/computational methods for modelling and analysis of biochemical processes. He currently leads the Molecular Systems Biology Group at CNC. Before that he was a post-doctoral fellow at the University of Coimbra, at the University of Michigan and at the Institute for Chemical and Biological Technology. He obtained his Ph.D. in Theoretical Biochemistry from the University of Lisbon in 1997.
    Representative references:
    Savageau MA, Coelho PMBM, Fasani RA, Tolla DA, Salvador A (2009) "Phenotypes and tolerances in the design space of biochemical systems". Proc. Natl. Acad. Sci. USA 106:-
    Salvador A, Savageau MA (2006) "Evolution of enzymes in a series is driven by dissimilar functional demands". Proc. Natl. Acad. Sci. USA 103:2226-2231
    Alves R, Antunes F, Salvador A (2006) "Tools for kinetic modeling of biochemical networks". Nat. Biotechnol. 24:667-672
    Guy Shinar’s (Weizmann Institute of Science, Israel) main research interests are the robustness and design principles of biochemical networks. He is currently a post-doctoral fellow in Uri Alon’s laboratory in the Weizmann Institute of Science, after a getting a Ph. D. in the same group.
    Representative references:
    Shinar, G., E. Dekel, et al. (2006). "Rules for biological regulation based on error minimization." Proc. Natl. Acad. Sci. USA 103: 3999-4004.
    Shinar, G., R. Milo, et al. (2007). "Input-output robustness in simple bacterial signaling systems." Proc. Natl. Acad. Sci. USA 104: 19931-19935.
    Shinar, G., J. D. Rabinowitz, et al. (2009). "Robustness in glyoxylate bypass regulation." PLoS Comput Biol 5(3).
    Isabel Rocha’s (Universidade do Minho) research interests include metabolic engineering and biochemical data integration. Her group is developing a powerful platform for data integration bringing together information about structure and regulation of full-scale metabolic networks of microorganisms. Currently, she is Associate Professor at the Department of BioEngineering of the University of Minho. Before that, she has been a post-doctoral fellow at the Technical University of Denmark. She obtained her Ph.D. in Biotechnology from the University of Minho in 2003.
    Representative references:
    Rocha, M., P. Maia, et al. (2008). "Natural computation meta-heuristics for the in silico optimization of microbial strains." BMC Bioinformatics 9: 499.
    Mendes R, Lourenço A, Carneiro S, Ferreira EC, Rocha I, Rocha M (2008) "A Framework for the Integrated Analysis of Metabolic and Regulatory Networks". In: 8th IEEE International Conference on Bioinformatics and BioEngineering (BIBE 2008). Athens, Greece


    (Armindo Salvador)
    (Jorge Carneiro)
    (Isabel Rocha)
    (Guy Shinar)
    Design principles of metabolic circuits
    Molecular variability and collective behavior of cell populations
    Reconstruction of biochemical pathways
    Design principles in metabolic and gene regulatory networks
    Preparation of paper discussions
    Paper discussions
    Hands-on practice
    Paper discussions
    Paper discussions
    Friday seminar
    Social program
    Social program
    Social program
    Social program


    Paper discussions for Monday
    5 groups of ~4 students, each group will be given a paper and will prepare a 15 min presentation. Each presentation will be followed by 5-10 min. discussion. Five students will be randomly picked before the session to act as chairpersons (one for each presentation). Chairpersons are supposed to keep the session running on time (shutting the speakers down if they exceed the allotted time, and regulating the time for discussions) and to have a couple of relevant questions ready to steer up the discussion.
    All students are supposed to have read the papers by Monday. One hour before the session will be devoted for groups to coordinate and prepare their presentations.
    The articles online (below)  are for the Monday presentation. Until Friday, 27th November  the students must go to
    http://spreadsheets.google.com/viewform?formkey=dHJDSnJnYTU4QXI5TjRjNFUzMjdaTHc6MA  and indicate your choice of paper to present.
    Detailed program for Thursday
    - Introduction
    - Data Sources – Metabolic and Regulatory Databases
    - Data Integration
    - Other steps of Metabolic and Regulatory Reconstruction – Compartmentation, Thermodynamic and Physiological data
    - Simulation Tools
    Paper discussions: 5 groups of ~4 students, each group will be given a paper and will prepare a 10 min presentation
    Friday seminar
    Structural sources of robustness in biochemical reaction networks
    Guy Shinar* and Martin Feinberg
    *Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
    William G. Lowrie Department of Chemical & Biomolecular Engineering and Department of Mathematics, Ohio State University, 125 Koffolt Laboratories, 140 W. 19th Avenue, Columbus, OH 43210.
    In consideration of biological design principles, it is now generally recognized that a central role must be played by system robustness — that is, by the capacity for sustained and precise function even in the presence of environmental disruption. Lacking, however, is a clear picture of common network features that otherwise-different biochemical modules might incorporate to ensure the robustness required. Our general interest is in what we call absolute concentration-robustness (ACR): A biochemical system is said to exhibit ACR relative to an active molecular species if the concentration of that species is identical in every positive steady-state the system might admit. In this way, the function of an ACR-possessing system can be protected even against large changes in the overall supply of the system’s components — changes that might arise from cell-to-cell variability or from variations in the same cell over time. Here, mathematics and chemistry come together to identify quite subtle structural attributes that will impart ACR to any mass action network possessing them. For example, these core network features provide a common source for the strong concentration robustness observed experimentally in the markedly-different E. coli EnvZ/OmpR osmoregulation and IDHKP/IDH glyoxylate-bypass-control systems. We believe that the same structural foundation will undergird a large variety of biochemical networks for which strong concentration robustness is essential.

    Network motifs in the transcriptional regulation network of  Escherichia coli

    Quantifying Global Tolerance of Biochemical Systems: Design Implications for Moiety-Transfer Cycles

    Quantitative evolutionary design of glucose 6-phosphate dehydrogenase expression in human erythrocytes

    Wednesday files


    Thursday PDFs



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