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Systems Biology

From genotype to phenotype.

18 September 2019

This course is an introduction to the theoretical tools that are used to understand the emerging behavior of complex biological networks. Systems Biology is a systemic approach to understand the biological phenomena that occurs inside a cell at the molecular level.

A good overview of the subject is available on the following paper. Please read it before the second class.

Albert, Réka. “Network Inference, Analysis, and Modeling in Systems Biology.” The Plant Cell 19, no. 11 (2007): 3327–38.

In this version of the course we are focused on methods used to build a transcription regulation network. In particular we deal with the questions, based on the genomic sequence:

We will focus on the paper @Medina-Rivera2011a.

Slides used in classes

Most classes are done on a whiteboard, so you need to keep your own paper copy. Some of these classes are later transcribed into webpage and published here. When the class used slides, they are published here.

Example Jupyter code


The forum of the course is at You can also participate writing an email to . Feel free to use it to ask any question or give any answer>.


Transcriptional Regulation

  • Which genes code for transcription factors?
  • Which are their binding sites?
  • How do they change gene expression?
    • enhancer
    • repressor

Binding Sites

  • Few experimental results. Expensive
  • How can we generalize them?
    • Probability theory
    • other approaches




  • Marsan, M. “Stochastic Petri Nets: An Elementary Introduction.” Advances in Petri Nets 1989, 1990, 29. <>.

  • Chouikha, M., G. Decknatel, R. Drath, G. Frey, C. Müller, C. Simon, J. Thieme, and K. Wolter. “Petri Net-Based Descriptions for Discrete-Continuous Systems.” At-Automatisierungstechnik 48, no. 9 (2000): 415–25.

  • Kitano, Hiroaki. “Systems Biology: A Brief Overview.” Science (New York, N.Y.) 295, no. 5560 (2002): 1662–64.

  • Albert, Réka, and Albert Laszlo Barabasi. “Statistical Mechanics of Complex Networks.” Reviews of Modern Physics 74, no. 1 (2002): 47–97.

  • Hucka, M, A Finney, B Bornstein, S Keating, B Shapiro, J Matthews, B Kovitz, et al. “Evolving a Lingua Franca and Associated Software Infrastructure for Computational Systems Biology: The Systems Biology Markup Language (SBML) Project.” Systems Biology 1, no. 1 (January 1, 2004): 41.

  • Palsson, B O. “Two-Dimensional Annotation of Genomes.” Nature Biotechnology 22, no. 10 (October 1, 2004): 1218–19.

  • Albert, Réka. “Scale-Free Networks in Cell Biology.” Journal of Cell Science 118, no. 21 (2005): 4947–57.

  • Gilbert, David, and Monika Heiner. “From Petri Nets to Differential Equations – An Integrative Approach for Biochemical Network Analysis.” In Petri Nets and Other Models of Concurrency - ICATPN, edited by S. Donatelli and P.S. Thiagarajan. Springer, Berlin, Heidelberg, 2006.

  • Albert, Réka. “Network Inference, Analysis, and Modeling in Systems Biology.” The Plant Cell 19, no. 11 (2007): 3327–38.

  • Tyson, J J, R Albert, A Goldbeter, P Ruoff, and J Sible. “Biological Switches and Clocks.” Journal of the Royal Society, Interface / the Royal Society 5 Suppl 1 (August 6, 2008): S1-8.

  • Soliman, Sylvain, and Monika Heiner. “A Unique Transformation from Ordinary Differential Equations to Reaction Networks.” PLoS ONE 5, no. 12 (2010): 1–6.

  • Gehlenborg, N, S I O’donoghue, N S Baliga, A Goesmann, M A Hibbs, H Kitano, O Kohlbacher, et al. “Visualization of Omics Data for Systems Biology.” Nature Methods 7, no. 3 Suppl (March 1, 2010): S56-68.

  • Vitali, S, J B Glattfelder, and S Battiston. “The Network of Global Corporate Control.” PLOS ONE 6, no. 10 (January 1, 2011): e25995.

  • Pavlopoulos, G A, M Secrier, C N Moschopoulos, T G Soldatos, S Kossida, J Aerts, R Schneider, and P G Bagos. “Using Graph Theory to Analyze Biological Networks.” BioData Mining 4 (January 1, 2011): 10.

  • Csermely, Peter, Tamás Korcsmáros, Huba J.M. Kiss, Gábor London, and Ruth Nussinov. “Structure and Dynamics of Molecular Networks: A Novel Paradigm of Drug Discovery.” Pharmacology & Therapeutics 138, no. 3 (2013): 333–408.

  • Veloso, Felipe A. “On the Developmental Self-Regulatory Dynamics and Evolution of Individuated Multicellular Organisms.” Journal of Theoretical Biology 417, no. December 2016 (2016): 84–99.


  • Jeong, H, B Tombor, R Albert, Z N Oltvai, and A Barabási. “The Large-Scale Organization of Metabolic Networks.” Nature 407, no. 6804 (2000): 651–54.

  • Wiback, Sharon J., Radhakrishnan Mahadevan, and Bernhard Palsson. “Using Metabolic Flux Data to Further Constrain the Metabolic Solution Space and Predict Internal Flux Patterns: The Escherichia Coli Spectrum.” Biotechnology and Bioengineering 86, no. 3 (2004): 317–31.

  • Almaas, Eivind, Zoltan N. Oltvai, and Albert Lászlo Barabási. “The Activity Reaction Core and Plasticity of Metabolic Networks.” PLoS Computational Biology 1, no. 7 (2005): 0557–63.

  • Becker, S, A Feist, M Mo, G Hannum, B O Palsson, and M J Herrgard. “Quantitative Prediction of Cellular Metabolism with Constraint-Based Models: The COBRA Toolbox.” Nature Protocols 2, no. 3 (January 1, 2007): 727–38.

  • Orth, J D, I Thiele, and B O Palsson. “What Is Flux Balance Analysis?” Nature Biotechnology 28, no. 3 (March 1, 2010): 245–48.

  • Orth, J D, T M Conrad, J Na, J A Lerman, H Nam, A M Feist, and B O Palsson. “A Comprehensive Genome-Scale Reconstruction of Escherichia Coli Metabolism–2011.” Molecular Systems Biology 7 (January 1, 2011): 535.

  • Rolfsson, Óttar, and Bernhard Ø Palsson. “Decoding the Jargon of Bottom-up Metabolic Systems Biology.” BioEssays 37, no. 6 (2015): 588–91.

Transcriptional Regulation

  • Herrgard, M J, M W Covert, and B O Palsson. “Reconciling Gene Expression Data with Known Genome-Scale Regulatory Network Structures.” Genome Research 13, no. 11 (November 1, 2003): 2423–34.

  • Covert, M W, E M Knight, J L Reed, M J Herrgard, and B O Palsson. “Integrating High-Throughput and Computational Data Elucidates Bacterial Networks.” Nature 429, no. 6987 (May 6, 2004): 92–96.

  • Herrgard, M J, M W Covert, and B O Palsson. “Reconstruction of Microbial Transcriptional Regulatory Networks.” Current Opinion in Biotechnology 15, no. 1 (February 1, 2004): 70–77.

  • Markowetz, F, and R Spang. “Inferring Cellular Networks–a Review.” BMC Bioinformatics 8 Suppl 6 (January 1, 2007): S5.

  • Albert, I, J Thakar, S Li, R Zhang, and R Albert. “Boolean Network Simulations for Life Scientists.” Source Code for Biology and Medicine 3 (January 1, 2008): 16.

  • Cho, B, K Zengler, Y Qiu, Y S Park, E M Knight, C L Barrett, Y Gao, and B O Palsson. “The Transcription Unit Architecture of the Escherichia Coli Genome.” Nature Biotechnology 27, no. 11 (November 1, 2009): 1043–49.

  • Thiele, I, N Jamshidi, R M Fleming, and B O Palsson. “Genome-Scale Reconstruction of Escherichia Coli’s Transcriptional and Translational Machinery: A Knowledge Base, Its Mathematical Formulation, and Its Functional Characterization.” PLoS Computational Biology 5, no. 3 (March 1, 2009): e1000312.

  • Markowetz, F. “How to Understand the Cell by Breaking It: Network Analysis of Gene Perturbation Screens.” PLoS Computational Biology 6, no. 2 (February 1, 2010): e1000655.

  • Cho, B, B O Palsson, and K Zengler. “Deciphering the Regulatory Codes in Bacterial Genomes.” Biotechnology Journal 6, no. 9 (September 1, 2011): 1052–63.