conference proceedings - Technische Universität Braunschweig

Proceedings of the BRICS forum 2014
Systems Biology for Infection Research and Biotechnology
17 – 18 March, 2014
Helmholtz Centre for Infection Research
Table of Contents
Conference Program
Image-based Systems Biology of Fungal Infections
Superresolving nanodomains and counting molecules on dendritic cells
The effects of aging on viral infection dynamics
Targeting immune cell activations at the systems level
Characterization of pathogenic Pseudomonas aeruginosa biofilms in urinary tract catheters
A proteomics approach to understand physiology and virulence of Staphylococcus aureus
Bi2SoN - A Digital Library for Supporting Biomedical Research
Mathematical models in life science applications
Metabolism and inflammation: What pathway to look at?
Next-Generation Sequencing: novel aspects in personalized medicine
Omics data for optimization of antibody production in Bacillus megaterium
Systems biological bricks for understanding the diversity of cellular metabolism
Analysis of time-resolved omics data
Population genomics – elucidating the evolution of the marine Phaeobacter
Poster Catalogue
BRICS forum ‐ Systems Biology for Infection Research and Biotechnology Monday, 17 March 2014
Hansjörg Hauser
Dieter Jahn
Session 1 ‐ Systems Biology of Infectious Diseases
Session Chair: Michael Meyer‐Hermann
Marc Thilo Figge
Image‐based systems biology of fungal infections
Philip Tinnefeld
Superresolving nanodomains and counting molecules on dendritic cells
Esteban Hernandez‐Vargas
The effects of aging on viral infection dynamics
Poster Session 1
Marco Van Ham
Katrin Dohnt
Susanne Engelmann
Benjamin Köhncke Dirk Langemann
Targeting immune cell activations at the systems level
Characterization of pathogenic Pseudomonas aeruginosa biofilms in urinary tract catheters
A proteomics approach to understand physiology and virulence of Staphylococcus aureus
Bi2SoN ‐ A Digital Library for Supporting Biomedical Research
Mathematical models in life‐science applications
Tuesday, 18 March 2014
Session 2 ‐ From Omics Data to Systems Biology
Session Chair: Dieter Jahn
Karsten Hiller
Metabolism and inflammation: What pathways to look at?
Robert Geffers
Next‐Generation Sequencing: novel aspects in personalized medicine
Rebekka Biedendieck
Omics data for optimization of antibody production in Bacillus megaterium
Poster Session 2
All participants
Conference photo
Jana Tillack
Systems biological bricks for understanding diversity of cellular metabolism
Frank Klawonn
Analysis of time‐resolved omics data
Heike Freese
Population genomics ‐ elucidating the evolution of the marine Phaeobacter
BRICS forum – proceedings
17-18 March, 2014
Image-based Systems Biology of Fungal Infections
Marc Thilo Figge
Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll Institute
Applied Systems Biology
Jena, Germany
During the past two decades the frequency of invasive mycoses due to opportunistic fungal pathogens has
increased significantly. The filamentous fungus Aspergillus fumigatus and the yeast Candida albicans are by far the
most important causes of life-threatening infections in humans. Whereas an invasive infection by the human
commensal C. albicans almost exclusively begins endogenously, starting from a colonisation in particular of the
gastrointestinal tract, infection by A. fumigatus mainly occurs exogenously via inhalation of the fungal spores.
Dynamical, functional and morphological aspects of fungal pathogenicity can be investigated by the image-based
systems biology approach. This approach seeks to take full advantage of the information contained in microscopy
images and establishes an essential connective link between experimental and theoretical examination of
biological processes at a quantitative level. It includes: (i) acquisition and automated analysis of image data for
high-content and high-throughput screening, (ii) quantitative description of biological processes by appropriate
characteristic measures, and (iii) construction of image-derived spatiotemporal models and predictive computer
simulations. In this keynote lecture, we discuss the kinetics of epithelial invasion during C. albicans infection and
demonstrate that invasion outcompetes hypha development. Furthermore, in the context of bloodstream
infections, we quantify innate effector mechanisms and discuss the observation of C. albicans immune escape in
human blood. In order to study the early immune response against inhaled A. fumigatus conidia, we present a
spatio-temporal agent-based model of the human alveolus. A key readout of these in silico experiments is the firstpassage-time of alveolar macrophages for searching the conidium in the alveolus. We test for various migration
modes of alveolar macrophages and predict that these phagocytes most be guided by chemotactic signals in order
to achieve the clearance of in due time before the germination of conidia. On a general note, we encourage that
investigations of biological systems, which are nowadays often routinely accompanied by microscopy experiments,
exploit the valuable information contained in image data by quantitative analyses.
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BRICS forum – proceedings
17-18 March, 2014
Superresolving nanodomains and counting molecules on dendritic cells
Philip Tinnefeld
Technische Universität Braunschweig
Institute for Physical & Theoretical Chemistry and Braunschweig Integrated Centre of Systems Biology (BRICS)
38106 Braunschweig, Germany
Email: [email protected]
Seeing is believing: fluorescence microscopy is the most rapidly emerging imaging technique in biological and
biomedical research. It has experienced a further boost with the recent development of superresolution
techniques that overcome the diffraction limit with conventional far-field optics. We present different
superresolution techniques that are used or even were developed in our department including STED microscopy
and techniques that are based on successive single-molecule localizations 1-4. We will show how these techniques
are tested with the aid of supramolecular DNA structures that have defined numbers of fluorescent dyes in
controlled geometries 5-7.
Superresolution “Blink Microscopy” was then used to resolve nanodomains of C-type lectins on dendritic cells. Not
only could the size of the nanodomains be determined but the number of molecules per nanodomain could be
estimated and colocalization with other C-type lectins was excluded 8.
S. Beater, P. Holzmeister, E. Pibiri et al., PhysChemChemPhys online (2014).
R. Jungmann, C. Steinhauer, M. Scheible et al., Nano Lett 10, 4756 (2010).
J. Vogelsang, T. Cordes, C. Forthmann et al., Proc Natl Acad Sci USA 106 (20), 8107 (2009).
M. Heilemann, S. van de Linde, M. Schuttpelz et al., Angew Chem Int Ed 47 (33), 6172 (2008).
J. J. Schmied, M. Raab, C. Forthmann et al., Nat Protoc, accepted (2014).
J. J. Schmied, C. Forthmann, E. Pibiri et al., Nano Lett 13 (2), 781 (2013).
P. Tinnefeld and T. Cordes, Nat Methods 9 (5), 426 (2012).
M. S. Itano, C. Steinhauer, J. J. Schmied et al., Biophys J 102 (7), 1534 (2012).
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BRICS forum – proceedings
17-18 March, 2014
The effects of aging on viral infection dynamics
Esteban A. Hernandez-Vargas
Helmholtz Centre for Infection Research
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology,
Inhoffenstr.7, 38124 Braunschweig, Germany
The recent outbreaks of H1N1 (swine flu), H5N1 (bird flu), and H7N9 virus infections have underlined the impact of
influenza A virus infections and have shown that influenza A virus is a major threat for human health.
The consequences of influenza virus infection are generally more severe in individuals over 65 years of age (the
elderly). Immunosenescence enhances the susceptibility to viral infections and renders vaccination less effective.
Understanding age-related changes in the immune system is crucial in order to design prophylactic and
immunomodulatory strategies to reduce morbidity and mortality in the elderly.
Here, we use mathematical modelling to describe the course of influenza virus infection using experimental data
from young and aged mice.
Simulation results suggested a central role of CD8+ T cells for adequate viral clearance kinetics in young and aged
mice. Furthermore, our results suggest that the increased levels of IFN-α/β, IFN-γ, and TNF-α (the “inflammaging”
state) promote slower viral growth in aged mice, which consequently limits the stimulation of immune cells and
contributes to the reported impaired responses in the elderly. A quantitative understanding of influenza virus
pathogenesis and its shift in the elderly is the key contribution of this work.
The effects of aging on influenza virus infection dynamics, Journal of Virology, Vol.88, No.8, 2014
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BRICS forum – proceedings
17-18 March, 2014
Targeting immune cell activations at the systems level
Marco van Ham
Helmholtz Centre for Infection Research
Cellular Proteome Research and Braunschweig Integrated Centre of Systems Biology (BRICS)
Inhoffenstr.7, 38124 Braunschweig, Germany
Activities of distinct immune cell subsets in blood and tissues are required to control infections and constitute a
prime target for immune-modulatory drug research. However, functional models that can discriminate between
the activation pathways in related subsets are widely missing, which limits the identification of clinically relevant
drug targets. At this stage, the T cell receptor (TCR) pathway is best characterized in CD4+/Foxp3- conventional T
lymphocytes (Tconv), and effector-responses were studied by Boolean networks. In contrast, TCR engagement in
CD4+/Foxp3+ regulatory T lymphocytes (Treg) induces a unique and suppressive phenotype, but the molecular basis
of the unique TCR signal network properties are merely undefined. Interestingly, all TCR pathway components are
expressed in both T cell subsets. Upon the contact with antigen-presenting cells, signaling is coordinated by posttranslational modified components within a dynamic immunological synapse, which allows speculating about a
different spatial-temporal organization of the molecular networks in Tconv and Treg (see Figure 1).
Figure 1: Subcellular localization of signal components can be
studied systematically by toponomics (coop. Schraven);
individual cell pairs are characterized consecutively for the
distribution of up to 30 different signal components at
individual time points.
In this seminar, we will discuss how TCR-dependent signaling in ex vivo isolated Tconv and Tregs can be studied by
proteomics, phosphoproteomics and toponomics. We will highlight the importance of molecular systems under
the control of phosphorylations, ubiquitinations and microtubule-associated protein transport that unequivocally
results in subset-specific immunological synapse formation. In conclusion, the power of functional models of
immune cell activation will depend on the acquisition & combination of molecular determinants regulating protein
activities and localization. This also underscores the necessity for more interdisciplinary and integrated approaches
to direct systems biology for infection research.
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BRICS forum – proceedings
17-18 March, 2014
Characterization of pathogenic Pseudomonas aeruginosa biofilms in urinary tract catheters
Katrin Dohnt†, Sandra Kerstan†, Antje Berger†, Ann-Kathrin Meyer††, Petra Tielen††, Rainer Krull†
Technische Universität Braunschweig
Institute of Biochemical Engineering and Braunschweig Integrated Centre of Systems Biology (BRICS)
Institute of Microbiology and Braunschweig Integrated Centre of Systems Biology (BRICS)
Gaußstraße 17, Braunschweig, Germany
Over the past years, the "biofilm" relevant research has become an important topic in medicine. Biofilms represent
a sessile form of microbial life embedded in a self-produced extracellular matrix which enables the microorganisms
to survive under sub-optimal growth conditions like dryness or in the presence of antibiotics. Infections, e. g. otitis
media, parodontitis and chronical wound infections, are connected with sessile growing pathogens. The
application of medical devices and implants like urinary tract catheters on which the biofilms settle are linked with
a high risk of infection. 25 % of all nosocomial infections are urinary tract infections which are up to 62 % caused
by the use of catheters. The opportunistic pathogen Pseudomonas aeruginosa is often linked with complicated
catheter associated urinary tract infections. The great amount of virulence factors of P. aeruginosa raises the risk
of an infection and the high intrinsic antibiotic resistance complicates the successful treatment. These facts
demonstrate the importance of investigations concerning the development and avoidance of catheter associated
urinary tract infections.
Different treatment strategies and methods were used to characterize these uropathogenic strains in more detail
and to obtain further informations about the successful prevention. Quantitative analysis of carbon fluxes by using
a comprehensive approach of 13C metabolic flux analysis has been used to detect typical and specific pathways of
17 clinical isolates. The results showed a high variability in the pyruvate metabolism the TCA cycle and the
glyoxylate shunt depending on the origin of the isolate (urinary tract infection versus catheter associated urinary
tract infection).
Another approach was the development of an in vitro urinary tract catheter reactor system with the intention to
simulate the conditions of a catheterized patient. This approach allows the investigation of biofilm growth and the
influence of treatment strategies on the biofilm development. The antibiotic Ciprofloxacin has been tested in the
reactor device and showed a reduced growth behavior of P. aeruginosa biofilms.
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BRICS forum – proceedings
17-18 March, 2014
A proteomics approach to understand physiology and virulence of Staphylococcus aureus
Susanne Engelmann
Technische Universität Braunschweig
Institute of Microbiology, Spielmannstr. 7, Braunschweig, Germany;
Helmholtz Centre for Infection Research
Microbial Proteomics, Inhoffenstr.7, Braunschweig, Germany
S. aureus is a human pathogen with strong clinical significance due to increasing infections with multi-resistant
isolates. To successfully combat the pathogen a better understanding of its physiology and virulence is required.
Under infection conditions S. aureus is confronted with a multitude of signals including growth-limiting factors and
life-threatening host defense mechanisms and, hence, adaptation of bacterial gene expression is a multi-signal
response. Global protein expression profiling is an excellent approach to show the pattern and the level of the
proteins expressed under definite conditions.
S. aureus colonizes the anterior nare of approximately one third of the human population. Nasal carriage of S.
aureus is an important source of nosocomial infections and might be a result of adaptation and selection of certain
S. aureus strains to the nasal environment. We investigated the adaptation of S. aureus to nasal secretions derived
from twelve healthy volunteers. S. aureus isolates derived from the carriers were characterized by MLST and DNAarrays. Moreover, the microbiome, the metabolome and the proteome of the nasal secretions has been analysed.
To profile the protein expression pattern of S. aureus during adaptation to nasal secretions, green fluorescence
protein (GFP) expressing S. aureus Newman cells were incubated with the nasal secretions and isolated via FACS
sorting. The intracellular and surface-associated proteome was analyzed by mass spectrometry and quantified by
isotopic labeling. From these analyses we found evidence that in the nasal secretions, S. aureus copes with various
nutrient limitations. Amino acids and fatty acids were used as carbon and energy source. Enzymes producing
glycine betaine to protect the bacterial cell from osmotic lysis were exclusively synthesized in cells exposed to the
nasal secretions. Moreover, we got evidence that proteins necessary for tissue adhesion and immune evasion are
preferentially expressed in cells grown in nasal secretions whereas toxins and exoenzymes are repressed.
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BRICS forum – proceedings
17-18 March, 2014
Bi2SoN - A Digital Library for Supporting Biomedical Research
Benjamin Köhncke
Technische Universität Braunschweig
Institute for Information Systems, Mühlenpfordtstraße 23, Braunschweig, Germany
In my presentation I will introduce the Bi²SoN Stampede literature search platform. Furthermore, I present insights
from our research regarding contextual search. The problem is that for searches focusing on abstract contexts, a
simple keyword-based Web search may compromise retrieval quality, because query terms may or may not
directly occur in the texts (vocabulary problem). The respective state-of-the-art solution is query expansion leading
to an increase in recall, although it often also leads to a steep decrease of retrieval precision. This decrease
however is a severe problem for digital library providers: in libraries it is vital to ensure high quality retrieval
meeting current standards. In this talk, I present an approach allowing even for abstract context searches
(conceptual queries) with high retrieval quality by using Wikipedia to semantically bridge the gap between query
terms and textual content. In our approach, we do not expand queries, but extract the most important terms from
each text document in a focused Web collection and then enrich them with features gathered from Wikipedia.
These enriched terms are further used to compute the relevance of a document with respect to a conceptual
query. The evaluation shows significant improvements over query expansion approaches: the overall retrieval
quality is increased up to 74.5% in mean average precision.
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BRICS forum – proceedings
17-18 March, 2014
Mathematical models in life science applications
Dirk Langemann
Technische Universität Braunschweig
Institute of Computational Mathematics, AG PDE, Pockelsstr. 14, 38106 Braunschweig
Tel +49 531 391 7403, Email [email protected]
In recent years, mathematical models became more and more important for the understanding of processes in life
science applications. Biological, chemical and medical research benefits from the mathematical formulation and
discussion of problems. The trade-off between complexity and simplicity is characteristic for all modeling
approaches. Usually, complex models result in more accurate simulations after parameter estimation, but simple
models generate more insight into the underlying process.
Here, we present a rather simple model for the discussion of the chronification of liver infections. A predator-prey
system is used to model the time-dependent virus and lymphocyte populations during a liver infection. We can
show mathematically that the resulting reaction-diffusion equation has non-trivial stationary solutions whenever
the underlying domain is sufficiently extended or fissured. Simulations are shown and medical consequences are
discussed. The non-trivial solutions are interpreted as chronic infections. Hence, we have a conceptual framework
to analyze the process of hepatitis chronification. In particular, qualitative differences between acute and chronic
hepatitis infections become dispensable, which has strong implications to medical research.
Finally, we give a short outlook to various occurrences of mathematics in life science applications, e.g.
mathematical optimization in the discussion of large metabolic networks, statistics in parameter and model
identification and ordinary and partial differential equations to model time-dependent processes.
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BRICS forum – proceedings
17-18 March, 2014
Metabolism and inflammation: What pathway to look at?
Karsten Hiller
By studying cellular metabolism of mammalian immune cells during inflammation, we discovered a yet unknown
metabolic pathway for the production of an antimicrobial compound. Having profiled the metabolome of microglial
cells and macrophages with and without LPS treatment, we identified an intracellular and highly abundant
metabolite synthesized only under inflammatory conditions: itaconic acid. This metabolite is used as a precursor for
plastic polymer synthesis and currently biotechnologically produced by the fungus Aspergillus terreus. Applying
stable-isotope labeling experiments, we could demonstrate that this metabolite is produced in the tricarboxylic
acid cycle from cis-aconitate. However, no mammalian enzyme catalyzing the production of itaconic acid has been
described so far. Here, we demonstrate that immune response gene 1 (IRG1) is the mammalian gene coding for the
enzyme catalyzing the decarboxylation of cis-aconitate to produce itaconic acid. We purified mouse and human
IRG1 protein and could show
itaconic acid production in an
enzymatic assay. Although itaconic
acid has not been known to
participate in human metabolism,
an antibiotic function of this
metabolite has been described: it
needed by many bacteria to
confirmed the growth inhibitory
effect of itaconic acid by supplementing different concentrations of the compound to the growth medium of
Mycobacterium tuberculosis and Salmonella typhimurium. To test for the intracellular antimicrobial function of
itaconic acid, we silenced the IRG1 gene in mouse macrophages to decrease the intracellular level of the
metabolite under inflammatory conditions. We could show a decreased killing activity of these impaired
macrophages when infected with S. typhimurium.
In the second part of the talk I will present very recent results of our group about profiling the dynamics of glucose
metabolism in humans. After application of stable-isotope labeled glucose, we determined enrichment patterns of
plasma metabolites to estimate glucose fluxes on a whole organism scale.
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BRICS forum – proceedings
17-18 March, 2014
Next-Generation Sequencing: novel aspects in personalized medicine
Robert Geffers
Helmholtz Centre for Infection Research
Genome Analytics and Braunschweig Integrated Centre of Systems Biology (BRICS)
Inhoffenstr.7, 38124 Braunschweig, Germany
In the past several years, next-generation sequencing (NGS) technologies have greatly revolutionized our
approaches to explore and depict the characteristics and functions of the genomes for various species. The NGS
technologies have been broadly used in diverse fields including genomics (genome sequencing and exome
sequencing), transcriptomics (RNA-Seq) and epigenomics (ChIP-Seq, MeDIP-Seq, BS-Seq). Generally, if the studied
organism does not have available reference genome, one can sequence its DNAs and then construct the genome
using de novo assembly. Furthermore, the genome and exome sequencing enable researchers to identify and
characterize the SNPs (single nucleotide polymorphisms), indels (insertions and deletions), inversions and other
structural variations at single nucleotide resolution to investigate the underlying mechanisms of certain
phenotypes or diseases. Using the whole transcriptome sequencing (RNA-Seq) technology, researchers have the
opportunities to comprehensively inspect the transcriptional events and expression profiles of genes in cells. Many
applications have been carried out with RNA-Seq, such as exon-exon splice junction detection, alternative splicing
identification, gene and isoform expression quantification, gene fusion inference and etc. To study the epigenetic
marks responded to environmental and developmental signals, NGS technologies can also be employed to profile
the histone modifications (ChIP-Seq) and DNA methylations (MeDIP-Seq, BS-Seq) in normal and disease states.
Personalized medicine refers to the right drug for the right person at the right time with right dose. The first step
for realizing personalized medicine is to decipher the disease related and drug sensitive genes and SNPs at multilevels, and then carry out massive genetic screening for identifying those variations on each individual genome.
The presentation will provide an overview of the established NGS techniques in the framework of oncogenomic
profiling for identification of drug sensitizers for the treatment of liver cancer as well as addresses future
challenges for NGS in the determination of genetic risc factors related to complex microbiomes.
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BRICS forum – proceedings
17-18 March, 2014
Omics data for optimization of antibody production in Bacillus megaterium
Rebekka Biedendieck1, Florian David2, David Fröde1, Jessica Willner3, Kathrin Bohle3, Daniela Zühlke4, Christian
Scherling5, Claudia Korneli2, Katharina Riedel4, Christoph Wittmann2, Dieter Jahn1
Technische Universität Braunschweig, Institute of Microbiology and Braunschweig Integrated Centre of Systems
Biology, Braunschweig, Germany
Technische Universität Braunschweig, Institute of Biochemical Engineering and Braunschweig Integrated Centre of
Systems Biology, 38106 Braunschweig, Germany
Fraunhofer Institute for Toxicology and Experimental Medicine, Department of Pharmaceutical Biotechnology,
Braunschweig, Germany
Ernst-Moritz-Arndt Universität Greifswald, Institute of Microbiology, Jahnstr. 15, 17489 Greifswald, Germany
Technische Universität Braunschweig, Department of Bioinformatics & Biochemistry, Langer Kamp 19b, 38106
Braunschweig, Germany
Since many years the Gram-positive microorganism Bacillus megaterium is used for the production and, due to its
missing outer cell membrane, also for the secretion of recombinant proteins. Optimized promoter systems as the
xylose-inducible one, improved strains and adapted cultivation conditions are available resulting in intracellular
protein amounts of more than one g per liter [1]. Also recombinant proteins naturally secreted by their original
host can be found in the g per liter scale in the cell free supernatant [2]. Anyway, when analyzing other target
proteins, they are found to be secreted in less amount indicating bottlenecks somewhere in the secretion process
of recombinant proteins.
A better insight into recombinant protein secretion using B. megaterium was achieved by transcriptome, proteome
and metabolome analyses [3] using the anti-lysozyme antibody fragment D1.3 scFv as a modell [4]. First
bottlenecks could be identified in form of the strongly up- or down-regulated expression of involved genes and
differences in protein levels when comparing recombinant and wild type strains. The expression of certain genes
was found to be more than 200-fold up- (PrsA-like protein) or 70-fold down-regulated (ribosomal protein). Genes,
whose expression was strongly regulated, were individually used as targets for xylose-inducible vector-encoded
coexpression together with the target gene coding for D1.3 scFv. These recombinant coexpression experiments
resulted in an up to 4-fold increased secretion of D1.3 scFv which was established in microtiter plates and shake
flasks cultivation and could be improved in controlled bioreactor approaches. When combining different target
genes in artificial operon structures, the secretion of recombinant antibody fragment could be enhanced even
more than 5-fold.
[1] Stammen, S., Müller, B.K., Korneli, C., Biedendieck, R., Gamer, M., Franco-Lara, E. & Jahn, D. (2010) High yield
intra- and extracellular protein production using Bacillus megaterium. Appl Environ Microbiol 76:4037-4046
[2] Korneli, C., Biedendieck, R., David, F., Jahn, D. & Wittmann, C. (2013) High yield production of extracellular
recombinant levansucrase by Bacillus megaterium. Appl Microbiol Biotechnol 97:3343-3353
[3] Biedendieck, R., Borgmeier, C., Bunk, B., Stammen, S., Scherling, C., Meinhardt, F., Wittmann, C. & Jahn, D.
(2011) Systems biology of recombinant protein production using Bacillus megaterium. Methods Enzymol 500:165195
[4] Jordan, E., Hust, M., Roth, A., Biedendieck, R., Jahn, D., Schirrmann, T. & Duebel, S. (2007) Production of
recombinant antibody fragments in Bacillus megaterium. Microb Cell Fact 6:2
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BRICS forum – proceedings
17-18 March, 2014
Systems biological bricks for understanding the diversity of cellular metabolism
Jana Tillack
Technische Universität Braunschweig, Institute for Biochemistry, Biotechnology and Bioinformatics and
Braunschweig Integrated Centre of Systems Biology (BRICS), Langer Kamp 19b, Braunschweig, Germany
Abstract: Systems biology is a field of study that uses methods from computer science, mathematics, and
engineering to answer biological questions [1]. The large variety of interdisciplinary tasks and methods can be
summarized in four major parts of a cycle describing the synergy of models and experiments in systems biology:
The modeling procedure incorporates knowledge obtained from experiments and stored in databases into a
computational model, which is then analyzed using simulations and statistical methods. As a result of model
analysis, the behavior of an organism is predicted. To verify or reject hypotheses, experiments have to be
performed and the data have to be analyzed using omics techniques. Finally, data analysis leads to new knowledge
and the cycle starts again. In the context of this cycle we introduce methods and tools established and/or applied in
the Bioinformatics and Biochemistry Group of Technische Universität Braunschweig as bricks, i.e. functional units in
a modular approach.
This approach is illustrated using the example of amino acid degradation in Phaeobacter inhibens DSM 17395.
Preliminary studies demonstrate that P. inhibens is adapted to diverse nutrient conditions because it can import
and utilize all common substrate classes in marine environments with a preference for amino acids. Since the
original genome annotation [2] contained gaps regarding amino acid degradation pathways, we focused on this
substrate class. The systems biological approach combines methods from all four parts of the cycle. Applying this
approach sheds light on the catabolic network of cells adapted to different substrates. To increase the quality of
genome annotation, the gene repertoire of P. inhibens DSM 17395 was compared with other complete genomes of
the Roseobacter clade [3].
[1] Kitano, Science (2002).
[2] Thole, S., Kalhöfer, D., Voget, S., Berger, M., Engelhardt, T., Liesegang, H., et al., ISME (2012).
[3]Drüppel, K., Hensler, M., Trautwein, K., Koßmehl, S., Wöhlbrand, L., Schmidt-Hohagen,
Environmental Microbiology (2014).
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BRICS forum – proceedings
17-18 March, 2014
Analysis of time-resolved omics data
Nada Abidi, Frank Klawonn
Helmholtz Centre for Infection Research
Bioinformatics and Statistics, Inhoffenstr.7, Braunschweig, Germany
Modern high-throughput technologies like microarrays, mass spectrometry or next generation sequencing enable
biologists to measure cell products like metabolites, peptides, proteins or mRNA. With the advance of these
technologies it is possible tp carry out more and more experiments that do not only compare the cell products
under two or more specific conditions, but also track them over time. These experiments usually yield timeresolved data for a large number of cell products, but with only a few replicates. In contrast to the setting in
classical time series analysis, the time points are not equidistant and their number is very limited. The noise in the
measurements, but also the often strong biological variation of the replicates makes a coherent analysis of such
data difficult.
Effects like time shift, different speed of metabolism and varying intensity of the reaction demand for an
adjustment of the time-resolved data for an improved and more reliable analysis of the data. Various methods
based on special regression models, correlation measures or generalised dynamic time warping can be used for
this adjustment.
Here we focus mainly on an an application that tries to avoid to avoid the effect of preanalytical variation that can
have a major influence on biological experiments. Especially MS-based proteomics analyses of blood specimens
are seriously affected because of limited protein stability due to the high fundamental proteolytic activity of serum
and plasma. Our aim is to measure the preanalytical quality of a given sample regarding its peptides and proteins.
Therefore, we propose a method for determining the preanalytical quality of serum by monitoring the ex vivo time
dependent decay of endogenous peptides with LC/MS.
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BRICS forum – proceedings
17-18 March, 2014
Population genomics – elucidating the evolution of the marine Phaeobacter
Heike M. Freese
Leibniz Institute DSMZ-German Collection of Micoorganisms and Cell Cultures
Microbial Ecology and Diversity Research and Braunschweig Integrated Centre of Systems Biology (BRICS),
Inhoffenstr.7B, Braunschweig, Germany
Systems Biology is typically understood as the scientific field that explores the system of a biological cell, e.g., the
dynamics of cellular reactions towards various environmental challenges. However, biological systems exist also on
other, higher, levels of biological organization, such as the species level or even at the level of entire communities
of living beings (Zengler and Palsson, Nat Rev Microbiol 2012).
Phaeobacter gallaeciensis and P. inhibens which are supposed to have a substantial role in protecting fishes in
aquaculture against pathogenic Vibrio species are biofilm forming members of the important marine Roseobacter
clade. In out attempt to understand this biological system i.e. its population structure, its metabolic diversification
and the underlying evolutionary forces we study a set of approximately 30 strains with highly similar 16SrRNA by
means of whole genome sequences and substrate utilization patterns. The genome sequences were generated via
a newly developed assembly approach integrating PacBio and Illumina sequence reads. On the level of whole
genome comparison, the strains split in three distinct lineages with a rather large core genome and genetic
radiation limited to the tips of the three main branches. On the chromosomal level, the population was
characterized by a rather low level of recombination; occasional genomic rearrangements and some prophage
diversity added besides SNPs to the chromosomal diversity. In contrast to this rather straightforward clonal mode
of phylogenetic divergence, which is partly corroborated by metabolic phenotypes, the numerous plasmids in the
population evidence a high dynamic of plasmid biology that does not match the chromosomal evolution.
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BRICS forum
Systems Biology for Infection Research and Biotechnology
17 -18 March, 2014
Poster catalogue
Session 1 ‐ Systems Biology of Infectious Diseases
Poster Title
New superresolution capabilities in
Susanne Beater, Mario Raab, Jürgen
Schmied, Birka Lalkens and Philip
Gene regulatory networks in Clostridium
Mareike Berges, Melanie Burghartz,
Martina Jahn, Dieter Jahn
Sebastian Binder, Esteban A.
Towards dynamic modelling of the cytokine
Hernandez Vargas, Michael Meyernetwork in infectious diseases
TU Braunschweig
TU Braunschweig
Development of monoclonal antibodies
Sabine Buchmeier, Thorben
Dammeyer, Philip Tinnefeld
TU Braunschweig
Broad host range plasmid-tools for
expression of proteins with (Twin-) Streptag and engineered, export optimized
yellow fluorescent protein
Thorben Dammeyer, Philip Tinnefeld
TU Braunschweig
Multi-Scale Modeling of Pathogenesis of
Diabetes Mellitus
Gang Zhao, Jaber Dehghany,
Michael Meyer-Hermann
What Derives the Mushroom-Shape in
Biofilms: Competition or Cooperation? An
Agent-Based Perspective
Azadeh Ghanbari, Jaber Dehghany,
Michael Meyer-Hermann
Mathematical modelling of anaerobic
adaptation in fluctuating environments
Steffi Heyber, Louisa Roselius, Dirk
Langemann, Steffi Heyber, Johannes
Müller, Burghard Hense, Dieter Jahn,
Richard Münch
TU Braunschweig
HIV modelling
Johannes Zick, Esteban A. HernandezVargas
Superresolution fluorescence imaging of
nanopatterned DNA-origamis with
semisynthetic fluorescent protein-DNA
Ija Jusuk, Thorben Dammeyer, Carolin
TU Braunschweig
Vietz, Mario Raab, Philip Tinnefeld
BRICS forum
Systems Biology for Infection Research and Biotechnology
17 -18 March, 2014
Poster catalogue
Session 1 ‐ Systems Biology of Infectious Diseases
Poster Title
Biofilm growth conditions of
uropathogenic organisms in an in vitrourinary tract catheter system
Sandra Kerstan, Antje Berger,
Katrin Dohnt, Rainer Krull
TU Braunschweig
A mathematical model of immune
activation with a unified self-nonself
Sahamoddin Khailaie, Fariba
Bahrami, Mahyar Janahmadi, Pedro
Milanez-Almeida, Jochen Huehn,
Michael Meyer-Hermann
Bi²SoN – A Digital Library for Supporting
Biomedical Research
poster and demonstration
Benjamin Köhncke, Wolf-Tilo Balke
TU Braunschweig
Mathematical models in life-science
Dirk Langemann
TU Braunschweig
A model of CD4+ T cell differentiation in
the thymus and periphery
Philippe Robert, Michael MeyerHermann
Mathematical model of T lymphocyte
calcium dynamics
Christine Dorothee Schmeitz,
Esteban Hernandez-Vargas, Ralf
Fliegert, Andreas H. Guse, Michael
Self‐deceleration of mitochondrial fission
Valerii Sukhorukov, Michael MeyerHermann
Cellular and tissue infection models for
understanding Clostridium difficile
Can M. Ünal, Michael Steinert
Modeling of germinal centers interaction
Alexey Uvarovskii, Michael MeyerHermann
TU Braunschweig
BRICS forum
Systems Biology for Infection Research and Biotechnology
17 -18 March, 2014
Poster catalogue
Session 2 ‐ From Omics Data to Systems Biology
Poster Title
Improved secretion of recombinant
antibody fragments using Bacillus
Florian David, David Fröde, Jessica
Willner, Kathrin Bohle, Daniela
Zühlke, Claudia Korneli, Katharina
Riedel, Christoph Wittmann, Dieter
Jahn, Rebekka Biedendieck
TU Braunschweig
Systems biology of Pseudomonas
aeruginosa - Pathway and pathway fluxes
of the human pathogen
Berger, A., Dohnt, K., Wittmann, C.
TU Braunschweig
3rd Generation Sequencing on the PacBio
Boyke Bunk, Cathrin Spröer, Jörg
Systems biology of osmoadaptation in
Bacillus megaterium and its potential
Godard Thibault, Melanie Wall,
Daniela Zühlke, Katharina Riedel,
Dieter Jahn, Rebekka Biedendieck
TU Braunschweig
Engineering a biofilm: A Gellan-Hydrogel as
Jan Hellriegel, Steffi Günther, Ingo
Model Biofilm Simulating Mechanic
Kampen., Arno Kwade, Rainer Krull
TU Braunschweig
Modern Drug Delivery Carriers made by
Applied Biotechnolgy
Christoph Hönnscheidt, Rainer Krull
TU Braunschweig
From planctomycetal ecology to novel
bioactive compounds
Olga Jeske , Marcel Ketteniß, Patrick
Rast, Christian Boedeker, Mareike
Jogler, Marc Stadler, Joachim Wink ,
Christian Jogler
Biodiversity of Acidobacteria in grassland
soils: the onset of community systems
Johannes Sikorski, Vanessa
Baumgartner, Jörg Overmann