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Research

METABOLOMICS

Metabolomics Metabolomics is the science and technology of the measurement, identification, and quantification of metabolites in living systems. Metabolites are sensitive to genetics and the environment, and they are closely related to behavioral phenotypes. In a systems biology analysis, metabolomics can provide important data that can improve the understanding and interpretation of other omics such as genomics, transcriptomics, and proteomics.   There are many components of a metabolomics study, including study design, sample collection and preparation, analytical measurements, statistical analysis and data reduction, compound identification, data integration, and pathway mapping. As a result, the required skills in metabolomics studies include statistics, chemistry, biochemistry, computer science, genetics, and more. Clearly, most people don’t have all of these areas of expertise, so metabolomics is a team effort. One of the great challenges in any interdisciplinary science such as metabolomics is to develop a common language and appreciation for disciplines outside of a person’s specific training and education.   The Edison lab is highly collaborative and works with people with expertise in all of the areas necessary for systems biology. Students and postdocs in the Edison lab have different backgrounds, and one of the ongoing themes is to learn as much as possible about all aspects of metabolomics and systems biology.   The video linked with the title of this section is a fun overview of metabolomics. It was made while I was at the University of Florida and was PI of SECIM. It won a contest celebrating the 10th anniversary of the NIH Common Fund and was featured on the NIH Director’s blog.

NMR TECHNOLOGY

High Sensitivity NMR Probe Development NMR is inherently very insensitive but it is one of the most important analytical techniques for metabolomics, natural product discovery and structural biology. To improve the situation, we have worked with engineering groups at the National High Magnetic Field Laboratory and elsewhere in the world to develop new NMR probes that will enhance applications in protein and natural product studies. We previously developed a unique 1-mm high temperature superconducting (HTS) probe with Bruker and the NHMFL (Bill Brey, Rich Withers, and Rob Nast). Although no longer operational, the 1-mm HTS probe is one of the most mass sensitive probes in the world. These probes have coils that are made from thin films of YBCO deposited onto sapphire substrates to achieve very high Q.   We also developed a 1.5-mm HTS probe optimized for direct 13C measurements. This probe has over 2x greater 13C mass sensitivity than the best available commercial 13C probe. It enabled several new studies that would be difficult or impossible without this technology (Wang et al., 2015; Clendinen et al., 2015; Frelin et al., 2015; Clendinen et al., 2014).   We have an NIH R01 project with our collaborators at the NHMFL and Bruker to develop a larger volume 13C-optimized NMR probe at 900 MHz for the system at UGA. This is nearing completion, and we hoping to have a probe with 3-4x greater sensitivity than a corresponding copper wire-based coil.

METABOLOMICS DEVELOPMENT

Unknown Compound Identification Unknown compound identification is a major challenge in metabolomics. Even establishing broad definitions of an “unknown compound” is not straightforward. An unlikely source of clarification (some might say confusion) to our field came from former US Defense Sectretary, Donald Rumsfeld, who once said   Reports that say that something hasn’t happened are always interesting to me, because as we know, there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns—the ones we don’t know we don’t know. And if one looks throughout the history of our country and other free countries, it is the latter category that tends to be the difficult ones.   Following Rumsfeld, a “known known” is a metabolite in a reference database that can be matched with an experimental dataset. A “known unknown” is a metabolite that has been found before but is not in an accessible database. An “unknown unknown” is a metabolite that has not been discovered. The NIH Metabolomics Common Fund has funded 5 centers in the US to improve unknown metabolite identification. Our lab leads one of these centers, and our project is titled Genetics and Quantum Chemistry as Tools for Unknown Metabolite Identification.   We are using the model organism Caenorhabditis elegans and comparing both known mutants and natural isolates with the reference strain PD1074. We collaborate with Erik Anderson on C. elegans and Lauren McIntyre on study design and biostatistics. The conceptual steps that we use in this project are: Use high-resolution LC-MS to compare a mutant with PD1074. We use both Thermo Q-Exactive HF Orbitrap and 12 T Bruker Solerix FT-ICR. We collaborate on this with Facundo Fernandez, Jon Amster, Franklin Leach, and Frank Schroeder. Peaks that change intensity between mutant and PD1074 and do not match databases will be further analyzed. From the accurate m/z values, we can determine the molecular formula From the molecular formula, we will attempt to enumerate as many possible molecules as possible using resources such as chemspider. Each of the possible structures will be computed by high-level quantum mechanical techniques developed by our collaborator, Kennie Merz. We will then compare computed and experimental NMR chemical shifts by adapting an approach called SUMMIT developed by the Bruschweiler lab. The experimental NMR data will be obtained by making a fraction library of C. elegans PD1074 reference material. Each HPLC fraction will be analyzed by both NMR and LC-MS, and we will associate unknown LC-MS peaks with NMR data and their retention time.

METABOLOMICS APPLICATIONS

	Clock Under construction
	Carbon Cycling in the Ocean Under construction
	Cell based therapeutics Under construction
	Stress in Pregnacy Under construction
	Dog Nutrition Under construction