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Metabolomics to Provide Biomarkers and Mechanistic Insights RTI International Metabolomics to Provide Biomarkers and Mechanistic Insights Susan Sumner, PhD Director NIH Eastern Regional Comprehensive Metabolomics Resource Core Systems and Translational Sciences Program RTI International [email protected] www.rti.org\rcmrc 919-541-7479 RTI International is a trade name of Research Triangle Institute. www.rti.org RTI International About RTI International . RTI is an independent not-for-profit research institute established in 1958 in Research Triangle Park, NC. RTI’s mission is to improve the human condition by turning knowledge into practice. RTI has 9 offices in the United States, 8 offices worldwide, and has projects in more than 40 countries. RTI is staffed with more than 4,000 employees working in health and pharmaceuticals, laboratory and chemistry services, advanced technology, statistics, international development, energy and the environment, education and training, and surveys. RTI has more than 800,000 square feet (ft2) of laboratory and office facilities in RTP, NC. The metabolomics facility in the Research Triangle Park consists of ~22,000 ft2 laboratory space. RTI International Metabolomics . Metabolomics involves the broad spectrum analysis of the low molecular weight complement of cells, tissues, or biological fluids. Metabolomics makes it feasible to uniquely profile the biochemistry of an individual, or system, apart from, or in addition to, the genome. – Metabon(l)omics is used to determine the pattern of changes (and related metabolites) arising from disease, dysfunction, disorder, or from the therapeutic or adverse effects of xenobiotics; including applications in plant and mammalian studies. This leading-edge method is now coming to the fore to reveal biomarkers for the early detection and diagnosis of disease, to monitor therapeutic treatments, and to provide insights into biological mechanisms. RTI International Why Metabolomics? Specific genes can be identified that define individuals’ at risk for a disease, dysfunction, or disorder, or response to treatments. Some diseases or responses can occur at the level of the proteome; and proteins and metabolites can inform us about the state of a disease, dysfunction or disorder at any given time. 4 RTI International Fluids, Cells, and Tissues Cells / Organ System Released metabolites Serum Urine Saliva Breath Plasma CSF Signatures or Profiles Cytosolic metabolites Discrete peaks Diagnostics 5 RTI International The Metabotype Studies have shown metabolomics signatures (the metabotype) to correlate with gender, race, age, ethnicity, drugs, chemicals, stress, weight status, mental health status, blood pressure, disease state, nutrition, gut microbiome, etc. 6 RTI International Comparing states of wellness and sickness Protein Expression THE NEEDS Pathways More sensitive and early markers for disease detection and staging Metabolite Levels Markers to monitor treatment for • efficacy • adverse response • relapse Traditional Clinical Parameters • transplantation Mechanistic insights from pathway analysis 7 RTI International NIH Common Fund is Investing in Metabolomics NIH Funded Six Regional Comprehensive Metabolomics Resource Cores to – increase our National capacity to provide metabolomics profiling and data analysis services to basic, translational, and clinical investigators – foster collaborative efforts that will advance translational research using metabolomics approaches – facilitate institutional development of pioneering research, metabolomics training, and outreach – establish National standards . RTI (Susan Sumner), UC Davis (Oliver Fiehn) and U Michigan (Chuck Burant), UK (Rick Higashi), UF (Art Edison), Mayo Clinic (Sree Nair) . Metabolomics DRCC (Shankar Subramaniam, PI, UCSD) . Metabolomics Training (Martin Kohlmeier, UNC-CH; Stephen Barnes, UAB) . Metabolite Standards Synthesis Cores (Herb Seltzman, RTI; Mary Tang, 8 SRI) RTI RCMRC RTINIH International Eastern Regional Comprehensive Metabolomics Resource Core at RTI Data Sample Sample Preparation Reduction & Support for Receipt Visualization Discovery Experimental Data Capture & Communicating QC Standards Design Entry into & Storage Pathway Results BSI II Empirical & Mapping Pooled Samples Standards Library Matching B __ R T O A A R D G E S T P E E D C T R U M 9 RTI International NMR Targeted and Broad Spectrum Metabolomics Bruker Avance III 950 MHz (DHMRI) • Equipped with cryogenically cooled triple resonance (1H, 13C, and 15N) probes Bruker Avance III 700 MHz (DHMRI) • Equipped with cryogenically cooled QNP probes (with four nucleus: 1H, 13C, 15N, and 31P) and a Bruker SampleJet autosampler (rack of 480 samples) Bruker Avance III 950 MHz Bruker Avance III 600 MHz (DHMRI) • Equipped with cryogenically cooled probe Varian Unity Innova 500 MHz (RTI) • Inova Performa II pulsed field gradient module • 15N ‐31P with 1H decoupling variable‐ temperature probe • Indirect 1H detection with 15N ‐31P decoupling variable‐temperature probe • 3H ‐1H switchable probe Varian Unity Bruker Avance III 700 MHz NMR data acquisition is performed by using methods cited in Beckonert Innova 500 MHz et al. (2007), Nature Protocols, 2 (11), 2692‐2703, as appropriate. RTI International GC-MS Targeted and Broad Spectrum Metabolomics LECO Pegasus 4D GCxGC TOF‐MS ‐ broad spectrum analysis Agilent 7890A GC + Agilent 5975C MS Agilent 7890‐MS with Agilent 7000B triple quadrupole MS with EI and CI source options Agilent 6890 GC with Agilent 5973 MS Agilent G1530A/5973 MS, GC/MS/ATD Agilent 7890 GC/MS LECO Pegasus 4D GCxGC TOF‐MS RTI International LC-MS Core – Ion Mobility and UPLC-MSn High resolution MS/MSMS platforms available for targeted and broad spectrum metabolomics UPLC-QToF Platform UPLC-Orbitrap Platform __ Acquity UPLC coupled SYNAPT G2 ion mobility QToF HDMS Acquity UPLC coupled Orbitrap (Waters Corporation) Velos with ETD (Thermo Fisher Scientific) 12 RTI International Example Workflow Peak Binned Alignment NMR QC Check Data Fourier NMR Raw NMR Processed NMR Multivariate Sample Transform Phase Statistical data Spectrum Data Pathway Preparation Data and Baseline Analysis Analysis Analysis Acquisition (FID) Correction 1r, cnx, esp, jdx Library Matched Data RTI International Design and Analysis Considerations . Study Design – Gender, race, ethnicity, age, exposures (drugs, chemicals, stress, city, etc..) all contribute to the metabotype . Sample Collection and Storage – Consistency in collection and processing . blood to serum (over ice?), or blood to plasma (anticoagulant?) – Storage consistency (vials, temperature, freeze thaws, etc.) – Selection of chemicals for extraction of samples . Instrument Response and Drift – Consistency in parameters for each sample run – Create phenotypic pools as well pre- and post- run standards . Data Analysis – Data quality, spectral alignment, formatting, etc. 14 – Check the standards and the pooled samples!! RTI International Adolescent Obesity We worked with David Collier, MD, PhD at ECU to understand more about why and how some adolescents lose weight when adopting healthy life styles, while others do not have a positive response. We are collecting psychosocial inventories and biological data to reveal signatures associated with a positive response to treatment that will aid clinicians in providing treatment and care. 15 15 RTI International Predicting Response to Exercise and Nutrition Intervention . Serial urine samples were At baseline the branched-chain amino acids obtained from adolescents (BCAA) valine, leucine, and 2-oxoisocaproate were at lower levels in responders compared participating in a 3 week with non-responders to weight loss. healthy weight camp. Investigators have found high levels of plasma BCAA (valine, isoleucine, phenylalanine, . Metabolomics of urine tyrosine & leucine ) to be predictive of indicated significant changes development of diabetes. in the metabolome over the 3 concentrations_11Nov2010.M3 (OPLS/O2PLS-DA), OPLS-DA All Classed by Response 1 week period. t[Comp. 1]/to[XSide Comp. 1] 2 Colored according to classes in M3 180 160 . Metabolite profiles correlated 140 9 120 100 20 1 80 11 9 2 2 with the responsivity (BMI 60 14 15 7 9 40 11 4 20 116 13 2 0 13 decline, weight loss, to[1] 15 20 -20 3 3 3 4 -40 16 16 11 7 -60 13 psychosocial parameters) to 14 7 -80 17 15 -100 16 -120 treatment. 17 -140 17 -160 -180 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 t[1] Pathmasiri et al., 2012 R2X[1] = 0.0510651 R2X[XSide Comp. 1] = 0.35649 Ellipse: Hotelling T2 (0.95) SIMCA-P+ 12.0.1 - 2010-11-15 11:42:43 (UTC-5) RTI International Predicting Response to Vaccination . Genomic study results* indicate that 3 genes play a significant role in modulating antibody response – MARCO, TNFAIP3, CXCL12 . TNFAIP3 and CXCL12 were significantly associated with increased vibriocidal titers . For the metabolomics analysis, 112 subjects were selected based on their response to the vaccination – Antibody response was based on the bioplex assay – Response = ln (day 28 – day 0) . Only high and low responders were selected . Serum samples were analyzed using the Bruker Avance III 950 MHz NMR spectrometer 17 *Majumder PP, Sarkar-Roy N, Staats H, et al (2012). Genomic correlates of variability in immune response to an oral cholera vaccine. European Journal of Human Genetics doi: 10.1038/ejhg.2012.278. RTI International Biomarkers to Predict Response to Vaccination PopGen_BinningResults_Regions_Removed.01.09.2013.M3 (PLS-DA), Day 0 All Subjects high t[Comp. 1]/t[Comp. 2] low Colored according to classes in M3 Positive 10 9 Response
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