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New metabolomics methods by NextGen show promise
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Metabolomics is an emerging research method in life sciences that takes the approach of quantifying and analysing all metabolites in a given sample. Changes as low as one I a few thousand can be detected using this method, utilizing powerful analytic devices and chemometric software. It is rapidly becoming a useful tool used in conjunction with other systems biology methods to provide medically relevant results. The metabolome represents the collection of all metabolites in a biological unit, i.e. a cell, tissue, organ or organism, which represent the end products of cellular processes. Thus, while mRNA gene expression data and proteomic analyses do not provide the whole picture of what might be happening in a cell, metabolic profiling can give an instantaneous picture of the current physiology of that cell. One of the main challenges of systems biology today is to integrate proteomic, transcriptomic, and metabolomic information to give a more complete picture of living organisms.

According to metabolomics researchers, further development of metabolimics platforms and tools will at one point allow for the creation of extremely fast and comprehensive medical tests requiring only a fraction of samples current analytical and diagnostic tools require. Many new ideas and potential uses were discussed at OMICS group’s “Metabolomics and Systems Biology” conference in April.
“Interpretations of metabolomics signatures will make rapid bedside diagnostics possible. In 5–10 years this information will transform our diagnostic capabilities. The meaningful metabolome interpretation will be available to a physician within minutes for a fraction of the cost of today’s analyses.” - said Chris Beecher, Ph.D., CSO, from NextGen Metabolomics.

The company NextGen is contributing to this vision by working on Isotopic Ratio Outlier Analysis (IROA), a mass-spectrometry-based protocol that enables efficient identification of all biological metabolites in a sample and their relative concentration.

This technology is based on a physiochemical phenomenon of naturally occurring C13 atoms. C13 has an extra neutron producing a pattern of additional peaks for each given metabolite in a sample. Because of their relatively low and uncommon natural abundance and the presence of other interfering elemental isotopes, these additional peaks (called M+1, M+2, etc.) are very small and not very informative.
“We simply boosted the C13 concentration by growing cells in a culture media engineered with precise balances of C13-bearing components, when you compare a culture grown with 5% C13 with culture grown in 95% C13, each metabolite will be represented by a symmetrical pattern of C12 and C13 peaks. The parameters of this pattern tell us how many carbons the molecule contains and it’s mass.”, as doctor Beecher explained.

The mirror symmetry of MS peaks in IROA experiments enables fast classification and identification of all peaks as real cell products (those that have have mirror counterparts) or artifacts and contaminants (no enhanced M+1, M+2, etc.). NextGen computer algorithms look for the same symmetry to perform phenotyping experiments.

To identify specific metabolites in tissue biopsies, the tissue cells are mixed and analyzed together with “standard” cells that were isotopicaly labelled with IROA C13 media. The tissue-derived metabolites can be easily identified by their mass and position relative to the standard using this method.

The company’s method has already given a significant proof of principle in the area of toxicology, concerning analysis of drug candidates. The team under Dr. Beecher used IROA to show the effects and response of every metabolite in the cell to flucytosine, a well-characterized inhibitor of DNA synthesis. The data showed clear response in metabolic pathways related to nucleotide biosynthesis, but not in other pathways, confirming the accuracy of the approach.

“We plan to perfect this technology to answer fundamental questions in drug development. What toxicities should we expect? What is the biological reason for this toxicity?”
NextGen plans to set up internal biomarker and toxicology discovery departments based on IROA technology.
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New metabolomics methods by NextGen show promise00