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Ultrahigh sensitivity metabolomics: using mass spectrometry to open a window into discovering novel molecular responses to chemical toxicants (NERC CASE PhD with Thermo Fisher Scientific)


Project Description

METABOLOMICS is a well established technology for discovering the molecular mechanisms of how humans and some other animals respond to chemicals, drugs and disease. However, the mass spectrometry methods used today do not provide sufficient analytical sensitivity to measure metabolites in the very small samples that are often encountered in toxicology and ecotoxicology studies. Nanoscale liquid chromatography-mass spectrometry (nanoLC-MS) is applied extensively in proteomics – offering high sensitivity – but is not yet used in metabolomics due to many technical challenges. In collaboration with our industry partner, Thermo Fisher Scientific, this PhD project will focus on establishing, optimising and then applying novel nanoLC-MS methods to enable transformative investigations in (eco)toxicology.

Examples of the challenging sample sizes encountered in toxicology studies – to be investigated in this PhD – include human cell lines and invertebrate model organisms. CELL LINES form the basis of the massive ‘Toxicology in the 21st Century’ (Tox21) program in the United States that aims to efficiently test whether 10,000 environmental chemicals disrupt processes in the human body and result in toxicity. Using a high-throughput robotic screening system, tiny samples of multiple cell lines are exposed to these chemicals; this is insufficient sample size for current metabolomics methods. DAPHNIA are freshwater invertebrates that play a central role in foodwebs and are widely studied in ecotoxicology. They can form dormant eggs that accumulate in sediments – which can hatch into functional animals many centuries later – allowing reconstruction of responses to past environmental change. This is termed resurrection ecology, and the current record is the resurrection of 700 yr old Daphnia. The biochemical study of dormant eggs in sediment cores therefore offers a unique opportunity to investigate pollutant impacts on animal fitness from well before and throughout the industrial revolution, up to modern timescales of intensive agriculture and high pesticide usage. Yet Daphnia eggs weigh <<1mg, undetectable by current metabolomics technologies.

Mass spectrometry based METABOLOMICS is a transformative technology that measures 1000’s of metabolites in organisms, yielding information rich molecular signatures that describe the responses to chemical compounds. Building on our decade-long track record in metabolomics, we propose to establish and optimise nanoLC-MS metabolomics technologies that are sensitive, reproducible and robust, and then apply these to discover the biochemical responses of human cell lines and Daphnia to chemical toxicants.

Partners and collaboration:
Our CASE PARTNER, Thermo Fisher Scientific, is a world leader in the development of nanoLC-MS and has identified metabolomics as a priority area. In 2013, Thermo Fisher Scientific formed a Technology Alliance Partnership with the University of Birmingham, the first such partnership within Europe. This PhD project builds upon five existing iCASE PhD awards with Thermo as part of their commitment to graduate training.

Training and skills:
Collectively the university and industry teams will provide SPECIALIST TRAINING in nanoLC-MS, including access to the latest instrumentation for metabolomics, as well as in metabolomics, toxicology and more broadly the (bio)analytical sciences. This training will be multi-disciplinary to enrich the student experience. The student will be integrated within pre-existing cohorts of PhD students and researchers, led by a highly experienced supervisor, providing an exceptional TRAINING ENVIRONMENT. This comprises the community of ca. 30 scientists who constitute the analytical and computational metabolomics partnership with Thermo, and the growing Systems Toxicology network at Birmingham.

Scientific excellence of the University:
The School of Biosciences at Birmingham is a world leader in metabolomics and more broadly environmental ‘omics research. The School 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 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 develop bioanalytical approaches and importantly to apply them to a highly relevant 21st century challenge in human and environmental health.

Funding Notes

This studentship is funded for 3.5 years by NERC and Thermo Fisher Scientific. The studentship covers tuition fees and a stipend of ca. £15,296/year for UK and EU nationals (where the EU nationals have lived in the UK for 3+ years). PLEASE NOTE THIS STRICT ELIGIBLITY REQUIREMENT SET BY NERC.

Please apply at: View Website

When applying, include the name of the supervisor (VIANT), state the funding source (NERC iCASE) and the project title above.

Additionally, please contact Professor Mark Viant directly - attaching your CV to the email ()

References

Recent representative papers from Viant’s research team:

A. D. Southam, 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 (accepted, 2016).

M. Clark, U. Sommer, J. Kaur, M. Thorne, S. Morley, M. King, M. R. Viant, L. Peck, Biodiversity in marine invertebrate responses to acute warming revealed by a comparative multi-omics approach. Global Change Biology (accepted, 2016).

J. Zhang, 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).

N. S. Taylor, R. Merrifield, T. D. Williams, J. K. Chipman, J. R. Lead, M. R. Viant, Molecular toxicity of cerium oxide nanoparticles to the freshwater alga Chlamydomonas reinhardtii is associated with supra-environmental exposure concentrations. Nanotoxicology 10, 32-41 (2016).

A. Southam, A. Lange, R. Al-Salhi, E. Hill, C. Tyler, M. R. Viant, Distinguishing between the metabolome and xenobiotic exposome in environmental field samples analysed by direct-infusion mass spectrometry based metabolomics and lipidomics. Metabolomics 10, 1050-1058 (2014).

J. A. Kirwan, R. J. M. Weber, D. I. Broadhurst, M. R. Viant, Direct infusion mass spectrometry metabolomics dataset: a benchmark for data processing and quality control. Nature Publishing Group’s Scientific Data 1, Article 140012 (2014).

K. L. Poulson-Ellestad, C. M. Jones, J. Roy, M. R. Viant, F. M. Fernández, J. Kubanek, B. L. Nunn, Metabolomics and proteomics reveal impacts of chemically mediated competition on marine plankton. Proceedings National Academy Sciences 111, 9009-9014 (2014).

W. B. Dunn, A. Erban, R. J. M. Weber, D. J. Creek, M. Brown, R. Breitling, T. Hankemeier, R. Goodacre, S. Neumann, J. Kopka, M. R. Viant, Mass appeal: metabolite identification in mass spectrometry-focused untargeted metabolomics. Metabolomics 9, S44-66 (2013).

M. R. Viant, and U. Sommer, Mass spectrometry based environmental metabolomics: A primer and review. Metabolomics 9, S144-158 (2013).

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

FTE Category A staff submitted: 42.80

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

Click here to see the results for all UK universities

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