Projects under the Systems Biotechnology group are exploring the Systems Biology of industrially important microorganisms with a view to optimize their performance. Among the Gram-positive model organisms these are Lactococcus lactis and Lactobacillus plantarum, as well as the important production organism Bacillus subtilis. These bacteria are all GRAS organisms (generally regarded as safe). Among the Gram-negative bacteria is Escherichia coli and Salmonella typhimurium. We also study a range of yeasts, including Saccharomyces and several non-conventional yeasts.

Systems Biology within the Systems Biotechnology group involves a multi-disciplinary approach with integration of genetic engineering, physiology, gene regulation and protein modification. Global techniques such as transcriptomics, proteomics, phospho-proteomics, flux analysis and metabolomics are implemented in the analyses.

In the Systems Biology approach of the Systems Biotechnology group we aim at a quantitative description of metabolic pathways and cellular networks, using molecular genetic tools to tune gene function and performing quantitative measurements of physiological responses. We use bio-mathematical tools such as MCA, mathematical modeling and other systems biology related approaches to integrate experimental biological data to integrate the effects of gene regulation and protein modification on cell physiology.

Read more about our experimental and theoretical analysis of biological networks here.

Research projects

	Integrative Analysis of Biological Networks   Collaboration of several metabolic networks is essential for the growth and successful exploitation of microbial cell factories. In most scientific analysis, the metabolic networks are seen as separate entities. It is however becoming increasingly clear that this fragmented view can have severe shortcomings. In our analysis of L. lactis we find that its energy metabolism is highly integrated with its nucleotide metabolism, and it has been found that a specific multi stress resistance mechanism is deeply integrated into the nucleotide metabolism. Interactions between temperate bacteriophages and their bacterial host, is another important area where an integrative approach may reveal the finer details in the decision between lysis and lysogeny.   Nucleotide metabolism is viewed and analysed from many angles. Genetic regulation of the purine biosynthesis, uptake and interconversion reactions that offers the bacteria a robust means of NTP homeostasis is of highest priority. Other currently investigated issues are the specificity of the reactions for uptake and interconversion, and the regulatory basis for nucleotide controlled multiple stress resistance. Nucleic acid synthesis is deeply integrated with the nucleotide metabolism, and the turnover of mRNA is a natural part of the nucleotide metabolism. We have initiated a characterization of the L. lactis Replication control to integrate this important consumer of nucleotides in the network   Glycolysis and energy metabolism   Bacteiophage-host interactions   Major research topics Nucleotide metabolism and its control in lactic acid bacteria (projects: PurR is the global regulator of genes involved in purine metabolism, The salvage of nucleosides and nucleobases, Transporters in nucleotide metabolism, NTP homeostasis, Control of DNA synthesis) Glycolysis and energy metabolism in L. lactis Bacteriophage-host interactions

	Elucidation and comparison of flux regulation across bacterial species   Metabolic fluxes constitute a significant aspect of cellular phenotype. Despite a very long history of research, our understanding of the control and regulation of metabolic fluxes is still scant. Indeed, engineering of metabolic fluxes is often frustrated by regulatory responses that counteract the effects of genetic interventions. There are, however, some clear patches in the perplexities of flux regulation. Fluxes are determined by the properties of enzyme-catalyzed reactions. One of these properties, the displacement from chemical equilibrium, has clear pertinence to the regulation of fluxes. The rate of near-equilibrium reactions is insensitive to changes in the activity of the enzyme catalyzing it. Hence, neither the cell, nor the experimenter, can effect flux changes by modulating the activities of enzymes catalyzing near-equilibrium reactions. We therefore propose to focus our attention on those enzymes catalyzing reactions far away from equilibrium. Central to our strategy is the fact that enzyme activities can be modulated in two different ways: by gene expression, and through inhibition or activation by regulatory metabolites. That enzymes activities can be modulated in different ways, suggest that different organisms may have evolved to regulate their fluxes using different strategies. Our proposal, in a nutshell, is to elucidate and compare flux regulation across species to shed light on the drives and constraints governing metabolic regulation.   (Participants: Sergio Rossell, Tore Ibsen Dehli, Christian Solem, Kelli Doherty, Peter Ruhdal Jensen)   Detailed description

 

	Towards new antibiotics using Salmonella as a model pathogen: Metabolic modelling, high throughput genetics and phages   Antibiotics have been discovered about 60 years ago and led to a revolution in medicine finally allowing to control bacterial infections. Unfortunately, bacteria have soon developped resistance mechanisms which are now so widespread that many types of infection are not clinically treatable. There is therefore an urgent need to develop new antibiotics but the classical approach based on identification and inactivation of single essential targets within the cell has proved its limit and did not provide any significant results for the best part of the last 20 years. In this project we are adressing the feasability of concomitantly targetting redundant instead of essential functions. We are pursuing several lines in this search. First a metabolic model of a model organism, Salmonella, will be established and used in the identification of redundant metabolic pathways relevant to the infection process. The second approach is the establishement of a high throuput multiple mutant generation system which could then be screened for infection relevant functions. The last one uses resident viruses (prophages) to eliminate the bacterium.   (Principal investigator: Sébastien Lemire. With: John Elmerdal Olsen’s group (KU), David Fell’s group (Oxford Brooke University), Hellen Andrews-Polymenis’ group (Texas A&M Health Science Center), Michael McClelland’s group (Vaccine Research Institute of San Diego), Peter Ruhdal Jensen, Mogens Kilstrup, Hassan Hartman, Bjarne Albrektsen, Carmen Pérez de Nanclares Fernández)   Detailed description

 

 

	Optimization of the fermentation process for lysine production Lysine is an essential amino acid for animals and it is used as a food supply for pigs and poultry. The world marked for lysine is around 1,000,000 tons of lysine per year and the production of lysine is done by a fermentation process with Corynebacterium glutamicum. In this new project we cooperate with the Danish company VitaLys A/S, a lysine manufacturer and the goal of the project is to increase the efficiency of C. Glutamicum to lysine production. (Contributors: Jakob Vang Rytter, Christian Solem, Søren Helmark, Peter Ruhdal Jensen, VitaLys I/S)   Detailed description

	Bacteriophages and bi-stable switches   Bacteriophages (phages) have played and are still playing an important role in molecular biology and for mankind. Many gene regulatory mechanisms have first been discovered in phages. Of particular interest are the genetic networks regulating the choice between lysis and lysogeny in temperate phages (the genetic switch). They provide excellent examples of mechanisms for decisive developmental choices. At CSM we are studying a unique example of a bi-stable genetic switch from a lactococcal phage using both computer modelling and system biological methods.   Phages are also known as a potential danger for bacterial starter cultures. Phage therapy is another important usage of phages for combat of antibiotic resistant pathogenic bacteria. Therefore knowledge of phages is useful for both basic and applied science. The knowledge on phages established in CSM is important for all of this. (Contributors: Karin Hammer, Mogens Kilstrup)   Detailed description

	GLYFINERY project Sustainable and integrated production of liquid biofuels, green chemicals and bioenergy from glycerol in biorefineries (Participants: Peter Ruhdal Jensen, Mhairi McIntyre Workman, Brian Jensen Købmann, Christian Solem, Anders Koefoed Holm, Xiaoying Liu, Biogasol ApS (Ballerup, Denmark), A&A Biotechnology (Gdynia, Poland), The Institute for Energy and Environmental research (IFEU, Heidelberg, Germany), Meroco (Leopoldov, Slovakia), Prochimia Surfaces (Sopot, Poland))   Detailed description

Other projects

• Control Analysis and Metabolic Engineering
• Mechanisms in gene regulation
• Growth and stress physiology
• Protein modification and interactions
• Bacteriophage - host interactions