Studying a relatively large number of molecules through this approach can reveal the interdependence of biochemical processes and pathways and represents the complexity of cellular and tissue activity better than the more traditional approach of looking at only a few molecules. These are the important goals of biomedical research, he adds, and “it is hoped that metabolomics can lead to better diagnostics and the discovery of novel forms of therapy.”
At “metabomeeting,” Dr. Lutz will present some findings from his integrated metabolomic NMR spectroscopy studies. NMR allows the simultaneous determination of the nature and amount of a number of metabolites in intact tissue, cell suspensions, perfused cells, and tissue extracts (the latter giving the highest resolution).
NMR on biopsy samples is a more recent development. Dr Lutz’ studies involve the integration of NMR spectroscopy with findings from other technologies and sources such as MRI, microscopy, enzyme activity measurements, and clinical examination. In the future, metabolomics should, ideally, be combined with genomics and proteomics data to give a more comprehensive picture.
The first of Dr. Lutz’ studies concerns a form of mental retardation called Rett syndrome, for which a transgenic mouse model exists. Here, metabolic fingerprints derived from brain NMR indicated reduced growth and altered activity and volume regulation of brain cells, which have been correlated with diminished brain size and energy uptake. Integrating these findings is now helping elucidate the molecular mechanisms of Rett syndrome.
In the second study, Dr. Lutz and his colleagues uncovered metabolic indicators of resistance to anticancer treatment in thymic lymphoma cells. The resistant cells exhibit altered glucose and glutamine metabolism compared to drug-sensitive cells.
The metabolomic findings were correlated with reduced loss of specific enzymes from mitochondria. Also, the resistant cells had more efficient phospholipid turnover. Animal experiments showed that resistant cells develop tumors more readily than sensitive cells. Therefore, treatment resistance and tendency to develop tumors may be linked through the same metabolic abnormalities.
Martial Piotto, Ph.D., NMR application manager of Bruker Biospin, is also scheduled to speak at the meeting on the metabolic analysis of human brain biopsies in a medical environment using HRMAS (high-resolution magic angle spinning) NMR.
HRMAS can be considered a hybrid between solid-state NMR and classical-solution NMR that is suited to examining complex tissue samples.
The bioinformatics aspect of metabolomics will be presented by Irena Spasic, Ph.D., of the Manchester Centre for Integrative Systems Biology (MCISB) at the University of Manchester. She says that small changes in the activities of individual enzymes can lead to large changes in metabolite concentrations.
This observation is backed by a wealth of experimental and mathematical evidence and means that metabolites are amplified relative to changes in the transcriptome, proteome, or gross phenotype. Therefore, metabolomics, being downstream of transcriptomics and proteomics, lends itself to biological analysis more readily, and the number of metabolites is more tractable. “These facts establish metabolomics as a valuable tool for the purposes of functional genomics, biomarker development, and systems biology,” Dr. Spasic says.