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University of Birmingham School of Biosciences

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Prof M Viant Prof J Colbourne Prof J B Brown No more applications being accepted

Birmingham United Kingdom

About the Project

The University of Birmingham (UoB) is an international leader in OMICS TECHNOLOGIES and SYSTEMS TOXICOLOGY, achieved by pooling its expertise and capacity in omics and bioinformatics with specialists in toxicology, systems biology and chemical regulation. Our mission statement commits to offering leadership in the development and application of omics- and bioinformatics-based solutions, enabling evidence-based chemical safety science to safeguard both human and environmental health.

The BBSRC recognise in their “Food, nutrition and health” priority area that in order to ensure food safety, including “issues around microbial and chemical contamination”, a mechanistic understanding of the relevant cellular processes is required upon which science-based risk assessment can be based. The overall aim of this PhD proposal is to develop and optimise a strategy for utilising metabolomics and computational modelling to derive metabolic measurements with immediate utility in the current risk assessment practices for pesticides in food products. The PhD will focus on the application of mass spectrometry metabolomics – that is, the use of mass spectrometry to measure the low molecular weight chemicals that drive the body’s metabolic biochemistry – to discover the metabolic effects of pesticides on cells in vitro, deriving both a deeper mechanistic understanding of these biochemical effects as well as dose-response data for quantitative risk assessment. Physiologically based pharmacokinetic (PBPK) modelling will enable translation of the findings from in vitro to in vivo and thereby to human risk assessments of the pesticides.

The specific objectives of the PhD proposal are:

1. Develop, conduct and subsequently optimise the experimental design and metabolomics approaches required to generate in vitro metabolomics data describing the mechanistic responses of cells, focusing on pesticides in the food chain that are of human concern. The studies will be designed with the central purpose of deriving ‘benchmark doses’, i.e. the pesticide doses corresponding to low, but measurable metabolic perturbations that precede higher order cellular damage. This builds on a speciality of the University of Birmingham team, to develop experimental strategies to evaluate the metabolic responses of cells to stressors, with on-going studies funded by NERC, the EU and Unilever. The student will use world-class mass spectrometry metabolomics facilities at Birmingham. An interest and some experience in bioanalytical chemistry is therefore needed for this project.

2. Investigate and subsequently optimise the computational strategies for extracting the relevant information from the metabolomics dose-response datasets to derive robust ‘points of departure’ for each chemical. This builds upon related work recently published using transcriptomics data. We will explore data and information derived at a range of levels, from individual metabolites to metabolic pathways. We therefore strongly recommend that applicants have an interest and some experience in data analysis and bioinformatics.

3. Apply biologically-based mathematical models, such as PBPK models, that can be used to extrapolate from the quantitative in vitro data derived above to in vivo, for the purposes of human risk assessment for food-borne pesticides. Specifically, we will seek to incorporate mechanistic biology into the PBPK models to provide quantitative, biologically-based chemical risk assessment, for example using, RVis, a free to use, open access PBPK modelling software package. Again, an interest in data analysis and modelling is strongly recommended.

This PhD involves a collaboration between metabolomics experts at the University of Birmingham (led by Professor Mark Viant) and the head of the Computational Modelling section within the Health & Biohazards Team, Health and Safety Laboratory (Dr. George Loizou), which forms part of the Science Division of the UK Health & Safety Executive. Further translation of this work to Europe will be achieved through collaboration with Dr Jean-Lou Dorne, European Food Safety Authority (EFSA).

Scientific excellence of the University:

The School of Biosciences achieved an impressive performance in the Research Excellence Framework 2014, rising up to 6th place for the quality of its research within the elite, research-focused Russell Group of UK universities.

Are you the right person for this PhD?

We seek an excellent, highly motivated candidate with a high quality undergraduate or Masters degree (can be pending) in fields such as (bio)analytical chemistry, pharmacology, forensics or toxicology, who has a passion to apply and then translate state-of-the-art metabolomics and PBPK modelling approaches to 21st century challenges in food safety and human toxicology.

Funding Notes

This BBSRC studentship is for 4 years. In addition to the payment of tuition fees, the award provides an annual stipend and funds for the laboratory studies. The Health and Safety Executive are providing further funding for this PhD.

NOTE that this PhD funding is for UK HOME STUDENTS ONLY, meaning it is open to UK citizens, or to EU citizens who have lived in the UK for the LAST THREE YEARS.

References

Bartels, M., Rick, D., Lowe, E., Loizou, G., Price, P., Spendiff, M., et al. (2012). Development of PK- and PBPK-based modeling tools for derivation of biomonitoring guidance values. Comput Methods Programs Biomed 108(2), 773-88.

Davidson, R.L., R. J. M. Weber, H. Liu, A. Sharma-Oates, M. R Viant, Galaxy-M: A galaxy workflow for processing and analysing direct infusion and liquid chromatography mass spectrometry-based metabolomics data. GigaScience 5:10 (2016).

Loizou, G. D. (2016). Animal-Free Chemical Safety Assessment. Frontiers in Pharmacology 7, 10.3389/fphar.2016.00218.

Loizou, G. D. and Hogg, A. (2011). MEGen: A Physiologically Based Pharmacokinetic Model Generator. Frontiers in Pharmacology: Predictive Toxicity 2 Article 56, 1-14, 10.3389/fphar.2011.00056.

McNally, K., Cotton, R., Hogg, A., and Loizou, G. (2014). PopGen: A virtual human population generator. Toxicology 315, 70-85.

Southam, A.D., R. J. M. Weber, J. Engel, M. R. Jones, M. R. Viant, A complete workflow for high-resolution spectral-stitching nanoelectrospray direct infusion mass spectrometry-based metabolomics and lipidomics. Nature Protocols 12, 310-328 (2017).

Zhang, J., M. A. Abdallah. T. D. Williams. S. Harrad. J. K. Chipman. M. R. Viant, Gene expression and metabolic responses of HepG2/C3A cells exposed to flame retardants and dust extracts at concentrations relevant to indoor environmental exposures. Chemosphere 144, 1996-2003 (2016).

How good is research at University of Birmingham in Biological Sciences?

Research output data provided by the Research Excellence Framework (REF)

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Where will I study?

University of Birmingham

For more than a century, the University of Birmingham has been pursuing and sharing knowledge through outstanding teaching and research. As a founding Russell Group member and the original ‘redbrick’ university, our high-quality teaching will help you take your career to the next level. We are of the country’s most consistently sought-after universities by the UK’s top graduate employers, and have been for the last decade. With a wealth of opportunities to choose from across study and research, Birmingham has one of the most extensive postgraduate course portfolios in the UK. Hosting an international community of more than 8000 staff and 38,000 students, you’ll work alongside world-leading academics in a diverse community.

Career overview

Professor Mark Viant completed a BSc in Chemistry in 1991 and a PhD in Chemical Physics in 1994, both at the University of Southampton. Following his studies, he spent nearly ten years in the USA, starting as a Royal Commission for the Exhibition of 1851 Postdoctoral Researcher at the University of California (UC) Berkeley, where he focused on chemistry. He then became a postdoctoral researcher and later an independent faculty member at UC Davis, specialising in environmental toxicology. During his time at UC Davis, he pioneered the application of metabolomics to address environmental health issues in aquatic organisms. In 2003, Professor Viant relocated to the University of Birmingham as a NERC Advanced Fellow, tasked with advancing metabolomics in environmental toxicology. With support from various funding bodies, including NERC, BBSRC, MRC, Wellcome Trust, and the EU, he established a significant research group dedicated to environmental metabolomics. He was appointed Reader in Metabolomics in 2008, became the Director of the NERC Biomolecular Analysis Facility for Metabolomics in 2009, and secured his current Chair in Metabolomics in 2010. His leadership in the field was recognised when he served as President of the international Metabolomics Society from 2012 to 2014 and was awarded Lifetime Honorary Fellowship in 2015. In 2013, he received the Joseph Chamberlain Award for Academic Advancement from the University of Birmingham for his contributions to metabolomics research.

Research interests

Professor Mark Viant''s research focuses on metabolomics and its application in environmental toxicology. His work includes method development in analytical chemistry and bioinformatics, as well as the discovery of toxicity pathways for chemicals, drugs, and nanomaterials. He aims to accelerate the creation of Adverse Outcome Pathways (AOPs) through the validation of metabolic Key Events. His laboratory also develops analytical and bioinformatics methods to enhance metabolomics research, including automating sample preparation and improving mass spectrometry techniques. A significant project under his supervision is the Deep Metabolome Annotation (DMA), which seeks to characterise the metabolome of *Daphnia magna*, a model organism for ecotoxicology. Additionally, he is involved in standardising metabolomics practices for regulatory toxicology, collaborating with various organisations to establish best practices and reporting standards.

Metabolomics Environmental Toxicology Analytical Chemistry Bioinformatics Toxicity Pathways Adverse Outcome Pathways Untargeted Toxicokinetics Method Development High Resolution Mass Spectrometry Sample Preparation Automation Galaxy Workflows Deep Metabolome Annotation Regulatory Toxicology Metabolomics Standardisation Environmental Health Aquatic Organisms Toxicogenomics Chemical Grouping Metabolite Identification Mass Spectrometry Data Processing.

View Professor Mark Viant's profile

Career overview

Professor John Kenneth Colbourne joined the faculty of the University of Birmingham in 2012, where he holds the inaugural Chair of Environmental Genomics. He obtained his PhD in evolutionary biology from the University of Guelph in 1999. Following his doctoral studies, he was awarded a NSERC Postdoctoral Fellowship, which allowed him to begin genomics research first at the University of Oregon and then at the University of Indiana. At the University of Indiana, he served as the Genomics Director of the Centre for Genomics and Bioinformatics from 2005 until 2012. During this period, he was instrumental in pioneering the application of genomics in the study of evolutionary ecology and toxicology, primarily using the freshwater crustacean *Daphnia* as a model system to explore gene-environment interactions. This research contributed to *Daphnia* being designated as a model species for biomedical research by the US National Institutes of Health. In addition to his academic role, Professor Colbourne is an Adjunct Professor at the Mount Desert Island Biological Laboratory and a founding member of several consortia, including the *Daphnia* Genomics Consortium and the Shanghai Consortium for Environmental Genomics and Toxicology. He serves as Section Editor for BMC Genomics and is the founding Editor of the journal Ecological and Environmental Genomics, which is set to launch in 2013. His work has involved collaboration with industry and advising government agencies to enhance environmental monitoring and protection practices through high-throughput molecular biology methods. In recognition of his contributions to the field, he co-chaired the Gordon Research Conference on Ecological and Evolutionary Genomics in 2012-13 and received the Royal Society Wolfson Research Merit Award.

Research interests

Professor Colbourne''s research encompasses evolutionary ecology, high-throughput biology, environmental and functional genomics. His work focuses on connecting gene expression and genome structure with individual fitness and population-level responses to environmental challenges. He aims to develop *Daphnia* into a super-model organism to advance Environmental Genomics, which uses interdisciplinary approaches to understand the genetic mechanisms underlying physiological and adaptive responses of organisms to their environment. His group''s investigations include the functional mechanisms of phenotypic plasticity, the genetic basis of evolutionary adaptation within natural populations, and the potential of aquatic organisms to counter chemical threats in the environment. Professor Colbourne has pioneered the application of genomics for the study of evolutionary ecology and toxicology, primarily using *Daphnia* as a model system to study gene-environment interactions. His research also involves high-throughput molecular biology methods to transform practices in monitoring and protecting the environment.

Evolutionary Ecology High-Throughput Biology Environmental Genomics Functional Genomics Gene Expression Genome Structure Individual Fitness Population-Level Responses Developmental Plasticity Environmental Health Protection Population Genomics Molecular Responses Adaptive Tolerance QTL Analysis Gene Networks Chemical Threats Aquatic Organisms Phenotypic Plasticity Environmental Sex Determination Cyclomorphosis Genomics Research Toxicology Model Organisms Daphnia Genomics Interdisciplinary Approaches Fitness Consequences Genetic Variation Analysis.

View Professor John Kenneth Colbourne's profile