Metabolomics: Is it just another Omics?

The omics
One would not be mistaken for thinking that a new omics word enters our scientific vocabulary every week, from behaviouromics and cytomics to transgenomics and vaccinomics [ref www.genomicglossaries.com/content/omes.asp]. By far the most important and widely established omics terms include genomics - the high throughput analyses of multiple genes including gene sequencing and function; transcriptomics – the study of mRNAs transcribed from a cell’s genome; and proteomics – the determination of the structures and functions of all proteins in a cell or organism. The complete characterisation of cellular processes, whether associated with normal homoeostasis or as a result of disease, toxic insult or genetic manipulation, also requires information on the metabolic status of the cell or organism. Indeed it can be argued that the cellular metabolic status is the most functional measure of the cell’s phenotype (Figure 1). The twenty first century has witnessed the rapid explosion of a new omics science associated with the measurement of metabolites.
What’s in a name?
So what name do we give to the high throughput and comprehensive analysis of metabolites within a cell or organism under a defined physiological state? Metabolomics has emerged as the obvious terminology, although many other variants exist such as metabolic profiling, metabolic fingerprinting and metabonomics. The latter originated from Professor Jeremy Nicholson’s laboratory at Imperial College London, a pioneer of the field, who defines metabonomics as ‘the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification’ (Nicholson, et al. 1999 #3). As with any new research field the definitions continue to evolve, and a formal nomenclature will soon be decided by the new Metabolomics Society.
Applications in the biological and clinical sciences
To date, relatively few metabolomics studies have been published that provide significant new insight into biological processes. Noteworthy papers include the application of metabolomics to the study of drug toxicity (Nicholson, et al. 2002 #2), identification of the phenotype of silent gene mutations (Raamsdonk, et al. 2001 #4), and clinical applications such as the diagnosis of coronary heart disease (Brindle, et al. 2002 #1). Metabolomics has simply had insufficient time to prove itself compared with the more mature omics approaches of genomics and transcriptomics. Indeed, considerable work still remains in developing the bioanalytical and bioinformatic technologies that underpin this science, without which its full potential will never be realised. One of the two primary goals of my research group is exactly that, to develop and optimise metabolomics methodologies at Birmingham, which can then be applied to a range of applications (Figure 2) (Viant, 2003 #5). My group’s other focus is to apply these methods to study the effects of environmental stressors on fish and aquatic invertebrates. To that end I was fortunate to be awarded an NERC Advanced Fellowship, which started in November 2003.
Metabolomics technologies
Birmingham attracted me for several reasons, not least because of it’s new £7.7m nuclear magnetic resonance (NMR) facility named the Henry Wellcome Building for Biomolecular NMR Spectroscopy (HWB•NMR), under the Executive Directorship of Professor Michael Overduin in the School of Medicine. This national facility, which opened officially in November 2004, houses state-of-the-art NMR equipment including the world’s most powerful 900 MHz spectrometer. NMR spectroscopy is currently the most widely used bioanalytical technique for metabolomics, and following recent NERC and BBSRC awards the HWB•NMR is now purchasing additional equipment dedicated to Birmingham’s emerging metabolomics program (Figure 3). Mass spectrometry is an equally important toolset for metabolomics and also proteomics, and the School of Biosciences is currently purchasing an ultra-high mass precision FT ICR mass spectrometer for ‘omics’ research, under the direction of Professor John Heath, Head of School, and Dr Helen Cooper, a newly appointed Wellcome Trust University Technology Fellow. Collectively these instruments and associated expertise have the potential to position Birmingham as an international centre of excellence for metabolomics. In addition, we are well placed to develop the necessary spectral processing tools and bioinformatics for metabolomics studies that are needed to extract the metabolic information from the NMR and mass spectra. This draws upon extensive expertise from across campus and includes Drs. Ulrich Günther and Christian Ludwig (HWB•NMR), Drs. Francesco Falciani and Dov Stekel (School of Biosciences) and Dr. Theo Arvanitis (School of Engineering).
Environmental metabolomics
Metabolomics is ideal for studying the impact of stressors such as pollution and climate change on environmental species, not least because no species-specific DNA sequence information is required. Lactate is lactate whether you are studying a fish, earthworm or human! Current environmental projects at Birmingham, funded by the NERC, include developing a predictive biomarker model for the marine and estuarine environments, based upon metabolomic and bioinformatic methods that use the European flounder and common mussel as sentinel species (Figure 4). This project complements research by Professor Kevin Chipman’s group who are using transcriptomics to characterise the responses of flounder to several classes of toxicants. Recently we have secured a £1.6m NERC Consortium grant, coordinated by Birmingham and in collaboration with a number of UK universities, to identify and define the bases of individual and population susceptibility and adaptation to environmental pollutants in fish using an integrated ‘omic’ approach. Disease processes are also amenable to study. On-going projects include an investigation of withering syndrome in the red abalone, a marine shellfish, in collaboration with the University of California, Davis (Figure 5) (Viant, et al. 2003), and a collaboration with the Centre for Environment, Fisheries and Aquaculture Science at Weymouth in which we are characterising the metabolic consequences of tumour formation in the liver of dab, a marine flatfish.
Birmingham’s Metabolomics Initiative
The application of metabolomics to cancer extends far beyond environmental studies, and not surprisingly this involves the Institute for Cancer Studies in the School of Medicine at Birmingham. In particular, a newly-funded EU project with Dr. Ulrich Günther, Dr. Chris Bunce (School of Biosciences) and me, aims to develop advanced NMR technologies for metabolomics and to use these to investigate the role of specific enzymes in cancer. Other projects include Dr Andrew Peet’s metabolomics studies in paediatric neuro-oncology at the Birmingham Children’s Hospital. Aside from medical studies, metabolomics projects are now starting in several Schools across the campus, including an investigation of acid stress in E. coli by Dr. Pete Lund in Biosciences, and projects by Professor Anton Wagenmakers in Sport and Exercise Sciences and Professor Mohamed Al-Rubeai in Chemical Engineering. In summary, Birmingham is now entering an extremely exciting and productive period of metabolomics research that includes three important components – state of the art equipment and infrastructure, experts in bioanalytical and bioinformatic method development, and world class biological and clinical scientists – and crucial to our success is the highly collaborative environment on which The University of Birmingham thrives.