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Rainer Breitling

About Rainer Breitling:

I am currently Professor of Systems Biology at the University of Manchester. My research interests focus on the development of innovative computational approaches for post-genomic systems biology, statistical methods for high-throughput biological experimentation and the dynamic modelling of cellular systems. This work is highly interdisciplinary and usually involves close collaboration with experimental biologists and clinicians. A recurrently theme is the study of complex cellular networks at various molecular levels. Recently, a large part of my work has focused on exploiting high-accuracy mass spectrometry for metabolomics systems biology, for example in studies of the metabolic networks of protozoan parasites and the synthetic biology of antibiotic production in actinomycetes.

SEEK ID: https://fairdomhub.org/people/115

Location:  Netherlands

Expertise: Systems Biology, Metabolomics, Transcriptomics

Tools: constraint-based modeling, Computational Systems Biology, Bioinformatics

ORCID: Not specified

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Project positions

SilicoTryp (University of Groningen)

STREAM (University of Groningen)

Related items

STREAM

Global metabolic switching in Streptomyces coelicolor

Antibiotics are made during the second phase of growth when there is a transition in metabolism from primary to secondary metabolism. Primary metabolism is growth related and involves all the normal cellular activities associated with cell growth and division. Whereas secondary metabolism is non-growth linked and is non-essential but many important activities occur during this phase which help the bacterium survive.

Programme: SysMO

Public web page: Not specified

SilicoTryp

The SilicoTryp project aims at the creation of a “Silicon Trypanosome”, a comprehensive, experiment-based, multi-scale mathematical model of trypanosome physiology.
Trypanosomes are blood-stream parasites transmitted by tsetse flies; they cause African sleeping sickness in humans and livestock. Currently available drugs have severe side effects, and the parasites are rapidly developing resistance.
In this project, we collect a wide range of new experimental data on the parasite in its various
...

Programme: SysMO

Public web page: http://silicotryp.ibls.gla.ac.uk/wiki/Main_Page

Metabolism of Streptomyces coelicolor (SysMO STREAM)
STREAM, SYSTERACT

Antibiotics are made during the second phase of growth when there is a transition in metabolism from primary to secondary metabolism. Primary metabolism is growth related and involves all the normal cellular activities associated with cell growth and division. Whereas secondary metabolism is non-growth linked and is non-essential but many important activities occur during this phase which help the bacterium survive.

One of these activities is antibiotic production and is widespread in streptomycetes
...

Snapshots: No snapshots

Timeseries 1
STREAM, SYSTERACT

Genotype: Wildtype (M145E)
Medium: Phosphate-limited (F134)

Person responsible: Jay Moore

Snapshots: No snapshots

Fermentor 199 transcriptomics
STREAM
No description specified

Creators: Jay Moore, Juan-Francisco Martin, Antonio Rodríguez-García, Trond Ellingsen, Øyvind Jakobsen, Per Bruheim, Håvard Sletta, Anders Øverby, Sven Even Borgos, Sunniva Hoel, Alexander Wentzel, Maggie Smith, Louise Thomas, Eriko Takano, Lubbert Dijkhuizen, Rainer Breitling, M. Tauqeer Alam, Anthony Palathingal, R Jansen, Maria Elena Merlo, Morris Swertz, Preben Krabben, Kay Nieselt, Wolfgang Wohlleben, Jens Reuther, David Hodgson, David Rand, David Wild, Elizabeth Wellington, Gregory Challis, Nigel Burroughs, Walid Omara, William Gaze, Brent Kiernan, Roxane Legaie

Contributor: Jay Moore

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Model of Trypanosoma brucei glycolysis as published in Achcar et al. (2012).
SilicoTryp

SBML file supplementary material of the publication.

Creators: Fiona Achcar, Barbara Bakker, Mike Barrett, Rainer Breitling, Eduard Kerkhoven

Contributor: Fiona Achcar

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The silicon trypanosome: a test case of iterative model extension in systems biology
SilicoTryp

Abstract (Expand)

The African trypanosome, Trypanosoma brucei, is a unicellular parasite causing African Trypanosomiasis (sleeping sickness in humans and nagana in animals). Due to some of its unique properties, it has … emerged as a popular model organism in systems biology. A predictive quantitative model of glycolysis in the bloodstream form of the parasite has been constructed and updated several times. The Silicon Trypanosome is a project that brings together modellers and experimentalists to improve and extend this core model with new pathways and additional levels of regulation. These new extensions and analyses use computational methods that explicitly take different levels of uncertainty into account. During this project, numerous tools and techniques have been developed for this purpose, which can now be used for a wide range of different studies in systems biology.

Authors: Fiona Achcar, Abeer Fadda, Jurgen Haanstra, Eduard Kerkhoven, Dong-Hyun Kim, Alejandro Leroux, T. Papamarkou, Federico Rojas, Barbara Bakker, Mike Barrett, Christine Clayton, Mark Girolami, Luise Krauth-Siegel, Keith Matthews, Rainer Breitling

Date Published: 7th May 2014

Journal: Adv Microb Physiol

Handling uncertainty in dynamic models: the pentose phosphate pathway in Trypanosoma brucei
SilicoTryp

Abstract (Expand)

Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, … Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP) of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate "leak" must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i) including additional enzymatic reactions in the glycosome, or (ii) adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally.

Authors: Eduard Kerkhoven, Fiona Achcar, V. P. Alibu, R. J. Burchmore, I. H. Gilbert, M. Trybilo, N. N. Driessen, D. Gilbert, Rainer Breitling, Barbara Bakker, Mike Barrett

Date Published: 5th Dec 2013

Journal: PLoS Comput Biol

Dynamic Modelling under Uncertainty: The Case of Trypanosoma brucei Energy Metabolism
SilicoTryp

Abstract (Expand)

Kinetic models of metabolism require detailed knowledge of kinetic parameters. However, due to measurement errors or lack of data this knowledge is often uncertain. The model of glycolysis in the … parasitic protozoan Trypanosoma brucei is a particularly well analysed example of a quantitative metabolic model, but so far it has been studied with a fixed set of parameters only. Here we evaluate the effect of parameter uncertainty. In order to define probability distributions for each parameter, information about the experimental sources and confidence intervals for all parameters were collected. We created a wiki-based website dedicated to the detailed documentation of this information: the SilicoTryp wiki (http://silicotryp.ibls.gla.ac.uk/wiki/Gl​ycolysis). Using information collected in the wiki, we then assigned probability distributions to all parameters of the model. This allowed us to sample sets of alternative models, accurately representing our degree of uncertainty. Some properties of the model, such as the repartition of the glycolytic flux between the glycerol and pyruvate producing branches, are robust to these uncertainties. However, our analysis also allowed us to identify fragilities of the model leading to the accumulation of 3-phosphoglycerate and/or pyruvate. The analysis of the control coefficients revealed the importance of taking into account the uncertainties about the parameters, as the ranking of the reactions can be greatly affected. This work will now form the basis for a comprehensive Bayesian analysis and extension of the model considering alternative topologies.

Authors: None

Date Published: 19th Jan 2012

Journal: PLoS Comput Biol

The silicon trypanosome
SilicoTryp

Abstract (Expand)

African trypanosomes have emerged as promising unicellular model organisms for the next generation of systems biology. They offer unique advantages, due to their relative simplicity, the availability … of all standard genomics techniques and a long history of quantitative research. Reproducible cultivation methods exist for morphologically and physiologically distinct life-cycle stages. The genome has been sequenced, and microarrays, RNA-interference and high-accuracy metabolomics are available. Furthermore, the availability of extensive kinetic data on all glycolytic enzymes has led to the early development of a complete, experiment-based dynamic model of an important biochemical pathway. Here we describe the achievements of trypanosome systems biology so far and outline the necessary steps towards the ambitious aim of creating a 'Silicon Trypanosome', a comprehensive, experiment-based, multi-scale mathematical model of trypanosome physiology. We expect that, in the long run, the quantitative modelling enabled by the Silicon Trypanosome will play a key role in selecting the most suitable targets for developing new anti-parasite drugs.

Authors: Barbara Bakker, Luise Krauth-Siegel, Christine Clayton, Keith Matthews, Mark Girolami, Hans Westerhoff, Paul A M Michels, Rainer Breitling, Mike Barrett

Date Published: 6th May 2010

Journal: Parasitology

Metabolomic systems biology of trypanosomes
SilicoTryp

Abstract (Expand)

Metabolomics analysis, which aims at the systematic identification and quantification of all metabolites in biological systems, is emerging as a powerful new tool to identify biomarkers of disease, … report on cellular responses to environmental perturbation, and to identify the targets of drugs. Here we discuss recent developments in metabolomic analysis, from the perspective of trypanosome research, highlighting remaining challenges and the most promising areas for future research.

Authors: None

Date Published: 17th Feb 2010

Journal: Parasitology

Metabolic modeling and analysis of the metabolic switch in Streptomyces coelicolor
STREAM

Abstract (Expand)

Background The transition from exponential to stationary phase in Streptomyces coelicolor is accompanied by a major metabolic switch and results in a strong activation of secondary metabolism. Here we … have explored the underlying reorganization of the metabolome by combining computational predictions based on constraint-based modeling and detailed transcriptomics time course observations. Results We reconstructed the stoichiometric matrix of S. coelicolor, including the major antibiotic biosynthesis pathways, and performed flux balance analysis to predict flux changes that occur when the cell switches from biomass to antibiotic production. We defined the model input based on observed fermenter culture data and used a dynamically varying objective function to represent the metabolic switch. The predicted fluxes of many genes show highly significant correlation to the time series of the corresponding gene expression data. Individual mispredictions identify novel links between antibiotic production and primary metabolism. Conclusion Our results show the usefulness of constraint-based modeling for providing a detailed interpretation of time course gene expression data. Other Sections▼

Authors: M. Tauqeer Alam, Maria Elena Merlo, The STREAM Consortium (stream), David Hodgson, Elizabeth Wellington, Eriko Takano, Rainer Breitling

Date Published: 2010

Journal: BMC Genomics

The dynamic architecture of the metabolic switch in Streptomyces coelicolor
STREAM

Abstract (Expand)

BACKGROUND: During the lifetime of a fermenter culture, the soil bacterium S. coelicolor undergoes a major metabolic switch from exponential growth to antibiotic production. We have studied gene … expression patterns during this switch, using a specifically designed Affymetrix genechip and a high-resolution time-series of fermenter-grown samples. RESULTS: Surprisingly, we find that the metabolic switch actually consists of multiple finely orchestrated switching events. Strongly coherent clusters of genes show drastic changes in gene expression already many hours before the classically defined transition phase where the switch from primary to secondary metabolism was expected. The main switch in gene expression takes only 2 hours, and changes in antibiotic biosynthesis genes are delayed relative to the metabolic rearrangements. Furthermore, global variation in morphogenesis genes indicates an involvement of cell differentiation pathways in the decision phase leading up to the commitment to antibiotic biosynthesis. CONCLUSIONS: Our study provides the first detailed insights into the complex sequence of early regulatory events during and preceding the major metabolic switch in S. coelicolor, which will form the starting point for future attempts at engineering antibiotic production in a biotechnological setting.

Authors: Kay Nieselt, Florian Battke, Alexander Herbig, Per Bruheim, Alexander Wentzel, Øyvind Jakobsen, Håvard Sletta, M. Tauqeer Alam, Maria Elena Merlo, Jay Moore, Walid Omara, Edward R Morrissey, Miguel A Juarez-Hermosillo, Antonio Rodríguez-García, Merle Nentwich, Louise Thomas, Mudassar Iqbal, Roxane Legaie, William Gaze, Gregory Challis, R Jansen, Lubbert Dijkhuizen, David Rand, David Wild, Michael Bonin, Jens Reuther, Wolfgang Wohlleben, Maggie Smith, Nigel Burroughs, Juan-Francisco Martin, David Hodgson, Eriko Takano, Rainer Breitling, Trond Ellingsen, Elizabeth Wellington

Date Published: 28th May 2009

Journal: BMC Genomics

Probabilistic assignment of formulas to mass peaks in metabolomics experiments
STREAM

Abstract (Expand)

MOTIVATION: High-accuracy mass spectrometry is a popular technology for high-throughput measurements of cellular metabolites (metabolomics). One of the major challenges is the correct identification … of the observed mass peaks, including the assignment of their empirical formula, based on the measured mass. RESULTS: We propose a novel probabilistic method for the assignment of empirical formulas to mass peaks in high-throughput metabolomics mass spectrometry measurements. The method incorporates information about possible biochemical transformations between the empirical formulas to assign higher probability to formulas that could be created from other metabolites in the sample. In a series of experiments, we show that the method performs well and provides greater insight than assignments based on mass alone. In addition, we extend the model to incorporate isotope information to achieve even more reliable formula identification. AVAILABILITY: A supplementary document, Matlab code, data and further information are available from http://www.dcs.gla.ac.uk/inference/metsamp.

Authors: Simon Rogers, Richard A Scheltema, Mark Girolami, Rainer Breitling

Date Published: 18th Dec 2008

Journal: Bioinformatics

Increasing the mass accuracy of high-resolution LC-MS data using background ions: a case study on the LTQ-Orbitrap
STREAM

Abstract (Expand)

With the advent of a new generation of high-resolution mass spectrometers, the fields of proteomics and metabolomics have gained powerful new tools. In this paper, we demonstrate a novel computational … method that improves the mass accuracy of the LTQ-Orbitrap mass spectrometer from an initial +/- 1-2 ppm, obtained by the standard software, to an absolute median of 0.21 ppm (SD 0.21 ppm). With the increased mass accuracy it becomes much easier to match mass chromatograms in replicates and different sample types, even if compounds are detected at very low intensities. The proposed method exploits the ubiquitous presence of background ions in LC-MS profiles for accurate alignment and internal mass calibration, making it applicable for all types of MS equipment. The accuracy of this approach will facilitate many downstream systems biology applications, including mass-based molecule identification, ab initio metabolic network reconstruction, and untargeted metabolomics in general.

Authors: Richard A Scheltema, Anas Kamleh, David Wildridge, Charles Ebikeme, David G Watson, Michael P Barrett, R Jansen, Rainer Breitling

Date Published: 22nd Oct 2008

Journal: Proteomics

New surveyor tools for charting microbial metabolic maps
STREAM

Abstract (Expand)

The computational reconstruction and analysis of cellular models of microbial metabolism is one of the great success stories of systems biology. The extent and quality of metabolic network reconstructions … is, however, limited by the current state of biochemical knowledge. Can experimental high-throughput data be used to improve and expand network reconstructions to include unexplored areas of metabolism? Recent advances in experimental technology and analytical methods bring this aim an important step closer to realization. Data integration will play a particularly important part in exploiting the new experimental opportunities.

Authors: Rainer Breitling, Dennis Vitkup, Michael P Barrett

Date Published: 21st Nov 2007

Journal: Nat. Rev. Microbiol.

MetaNetter: inference and visualization of high-resolution metabolomic networks
STREAM

Abstract (Expand)

SUMMARY: We present a Cytoscape plugin for the inference and visualization of networks from high-resolution mass spectrometry metabolomic data. The software also provides access to basic topological … analysis. This open source, multi-platform software has been successfully used to interpret metabolomic experiments and will enable others using filtered, high mass accuracy mass spectrometric data sets to build and analyse networks. AVAILABILITY: http://compbio.dcs.gla.ac.uk/fabien/abinitio/abinitio.html

Authors: Fabien Jourdan, Rainer Breitling, Michael P Barrett, David Gilbert

Date Published: 14th Nov 2007

Journal: Bioinformatics

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