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The Metabolome
Wednesday, January 20, 2010
Metabolites are the intermediates and products of cell metabolism. The molecular identity of metabolites cannot be deduced from genetic information and metabolite levels in cells are typically determined by a host of complex inter-dependent kinetic processes that typically include synthesis, degradation, uptake and release from multiple endogenous and exogenous sources, often regulated by undefined biochemical circuits. As the integrated output of the genome, proteome and environment, metabolites define the phenotype of all cells – accordingly, metabolite levels provide the most telling readout of cell function and dysfunction.
Metabolomics, the study of metabolite profiles, hails the lofty goal of establishing the identity and levels of all metabolites in a biological system, under a given set of circumstances. Metabolomic approaches thus offer a powerful tool for discovering the functional status of a cell or tissue and elucidating the broad consequences of genetic and environmental perturbations (i.e., gene mutations, drugs and disease states). Advances in chromatographic separations, mass spectrometry and data analyses have recently come together to empower metabolomics-based approaches. This symposium will highlight the emerging capabilities of untargeted metabolite profiling for realization of the goals of systems biology and as a key platform for biomedical breakthroughs during the next decades.
Networking Reception to Follow.
Sponsorship
This event is part of the Dr. Paul Janssen Memorial Series at the New York Academy of Sciences.
Agenda
| 12:30 PM | Registration |
| 1:00 PM | Opening Remarks |
| 1:05 PM | Untargeted Plasma Metabolite Profiling for Discovery of Molecular Derangements |
| 1:45 PM | Therapeutic Metabolomics Identifies Novel Treatments for Multiple Sclerosis and Chronic Pain |
| 2:25 PM | Metabolite Profiling for Personalized Medicine |
| 3:05 PM | Coffee Break |
| 3:30 PM | Viral Hijacking of Host Cell Metabolism |
| 4:10 PM | Mining the Microbial Metabolome: Metabolomics-based Approaches to Infectious Diseases |
| 4:50 PM | Metabolite Profiling for Discovery of Cancer Biomarkers |
| 5:30 PM | Closing Remarks |
| 5:45 PM | Networking Reception |
Organizers
Steven Gross
Weill Cornell Medical College
Kyu Rhee
Weill Cornell Medical College
Speakers
Chris Beecher
University of Michigan Medical School
Dr. Beecher holds a B.A. in Anthropology (New York University), M.S. Biology (New York University), and a Ph.D. in Pharmaceutical Sciences / Natural products Chemistry (University of Connecticut). He began his research into the high-throughput chemical characterization of complex mixtures while on the faculty of the University of Illinois, College of Pharmacy (1985) where he held the position of Associate Professor. He was the editor of the NAPRALERT database from 1990 to 1998, Editor-in-Chief of the International Journal of Pharmacognosy, and served as a founding member of the Functional Foods Program of the University of Illinois. In 1997 he was invited to continue this research in the laboratories of Bristol-Myers Squibb, and Ancile Pharmaceuticals. His focus shifted from secondary metabolism to primary metabolism with the establishment of the first Metabolomics platform in America at Paradigm Genetics from 2000 to 2002, and in 2003 founded of two Metabolomics-based companies; Metabolon, Inc. (A company that has focused platform technologies on human healthcare.) and Metabolic Analyses, Inc. (A company that has focused on the informatics issues associated with Metabolomics.) Dr. Beecher compiled the first human metabolome in 2002 at Metabolic Analyses, and has been working toward the integration of metabolomic, proteomic, transcriptomic and genomic data. In addition to his primary appointment at the University of Michigan Dr. Beecher serves as an Adjunct Professor at George Mason University, and is an Affiliate of the National Institute of Statistical Sciences. He holds many patents and publications in the areas of Metabolomics and Natural Products chemistry.
Steven Gross
Weill Cornell Medical College
Dr. Steven S. Gross is Professor of Pharmacology at Weill Cornell Medical College (WCMC), Director of the WCMC Mass Spectrometry Facility and Director of Advanced Training in the Pharmacological Sciences. He earned his PhD degree in Pharmacology from the Mount Sinai School of Medicine (NYC) in 1982. With the exception of two years as Senior Lecturer at St. Bartholomew’s Medical College (London, UK; 1991-1993), working with the Nobel Laureate Sir John Vane, Dr. Gross’ entire professional career has been at WCMC. Dr. Gross’ research has been primarily directed toward elucidating the chemistry, biology and therapeutic modulation of nitric oxide (NO), an important cell-signaling molecule that plays diverse and important roles in mammalian physiology. More recently, research interests of the Gross lab have extended to cancer, stem cell biology, metabolism and the development of new mass spectrometry-based tools for proteomic and metabolomic analyses. This basic research has led to over 25 issued US and foreign patents that provided intellectual property for advancement of new drugs into FDA-sponsored clinical trials. Dr. Gross was a Scientific Founder of ArgiNOx Inc., a biotech start-up with the mission of developing new cardiovascular drugs for therapy of critically-ill patients. He served as a past member of the Board of Directors and Executive Committee of the Cornell Research Foundation (the patenting and licensing arm of Cornell University) and currently is an advisor to the Cornell Center for Technology Enterprise and Commercialization.
Rima Kaddurah-Daouk
Duke University Medical Center
Dr. Rima Kaddurah-Daouk is a biochemist who got her initial education at the American University of Beirut and subsequently post graduate training at Johns Hopkins (worked with Nobel Laureate Hamilton Smith) the Harvard Medical School and the Massachusetts Institute of Technology. She is currently Associate Professor at The Duke Medical Center and head of the newly established Pharmacometabolomics Center. She cofounded the Metabolomics Society and served as its founding president and over a period of four years built a metabolomics community with over 500 members attending national and international meetings. She also cofounded a leading biotechnology company devoted to metabolomics and is an inventor on a series of key early patents in the field of metabolomics that sets applications for metabolomics in the medical field. Dr. Kaddurah-Daouk has extensive experience in assembling teams of researchers to work collaboratively on large scientific projects and has lead scientific program (such as creatine kinase) from the bench to clinical trials in over fifty centers. At Duke she has built a major program to map biochemical changes in neuropsychiatric diseases and identified key pathways perturbed in schizophrenia, depression, Alzheimer’s disease and addictive disorders. With major funding from NIH she created the national “Metabolomics Network for Drug Response Phenotype” with the goal of using comprehensive metabolomics tools for Personalized Medicine. Over thirty members are involved in the network and bring a most comprehensive metabolomics capabilities under one virtual roof.
Joshua Rabinowitz
Princeton University
Joshua Rabinowitz grew up in Chapel Hill, North Carolina. In 1994, he earned B.A. degrees in Mathematics and Chemistry from the University of North Carolina. From there, he moved west to Stanford, where he earned his Ph.D. in Biophysics in 1999, followed by his M.D. in 2001. Having finished school, he got a job in the “real world,” co-founding and leading R&D efforts at Alexza Pharmaceuticals, now a public company. In 2004, Joshua returned to academia, joining the faculty of Princeton University. There he began to apply mass spectrometry to study metabolism. His lab focuses on understanding cellular metabolic flux, its normal regulation, and its dysregulation in disease.
Kyu Rhee
Weill Cornell Medical College
Dr. Rhee is an Assistant Professor of Medicine and Microbiology & Immunology and Hearst Clinical Scholar in Microbiology & Infectious Diseases at Weill Cornell Medical College. Dr. Rhee's clinical interests are in the areas of bacterial infection, tuberculosis and antibiotic pharmacology. Major research activities are in the area of drug target discovery against Mycobacterium tuberculosis, the causative agent of TB, and multidrug resistant gram positive bacteria.
Gary Siuzdak
The Scripps Research Institute
Gary Siuzdak, PhD, Dr. Siuzdak is Senior Director of the Scripps Center for Mass Spectrometry and Professor of Molecular Biology at The Scripps Research Institute in La Jolla, California (http://masspec.scripps.edu/). He is also Faculty Guest at Lawrence Berkeley National Laboratory and served as Vice President of the American Society for Mass Spectrometry. His research includes developing novel approaches to metabolomics, the development of nanostructure-initiated desorption/ionization, intact viral analysis, preparative mass spectrometry, and mass-based inhibitor-enzyme screening. He has over 160 peer-reviewed publications and two books, the latest being The Expanding Role of Mass Spectrometry in Biotechnology, 2nd Edition 2006.
Sponsors
For sponsorship opportunities please contact Cristine Barreto at cbarreto@nyas.org or 212.298.8652.
This event is part of the Dr. Paul Janssen Memorial Series at the New York Academy of Sciences.
Presented by
Supported by an educational grant from Talecris Biotherapeutics, Center for Science and Education.
This program is also supported by an educational grant from Celgene Corporation.
Academy Friend
- Agilent Technologies
- Bristol-Myers Squibb R&D
- Umetrics
Abstracts
Untargeted Plasma Metabolite Profiling for Discovery of Molecular Derangements that Result from Gene Mutations and Drug Treatments
Steven Gross, Weill Cornell Medical College
Untargeted metabolite profiling has enormous potential for the diagnosis of conditions that arise from defects in metabolism. Studies will be presented that describe the efficacy of plasma metabolite profiling for discovery of metabolic defects using a mouse model system and analysis of plasma from human babies with rare inborn errors of metabolism. In mice, we evaluated the capability of LC/MS-based metabolite profiling platform to broadly survey the plasma metabolome and discover a defect in purine metabolism that results when xanthine oxidoreductase (XOR) is inactivated, either by gene ablation or pharmacological inhibition with allopurinol. This approach allowed us to confidently survey >3,700 distinct plasma molecules using <5 µl of blood and confidently recognize those which change>2-fold (up or down) when XOR activity is attenuated. Molecular identification of the major differentially-expressed features was established from determinations of accurate mass, isotope ratios, chromatographic retention times and/or fragmentation patterns, relative to standards. Remarkably, knockdown of XOR activity (both genetically and pharmacologically) was associated with the discovery of all predicted major changes in purine metabolism, as well as numerous unanticipated changes. The unanticipated changes highlight unappreciated metabolic links involving XOR. In studies of plasma from several human babies with rare inborn errors of metabolism, untargeted metabolite profiling was similarly able to confidently identify metabolite perturbations and infer responsible gene mutations. These findings affirm the power of untargeted metabolite profiling as an unprecedented tool for diagnosis of pathophysiological conditions that arise from gene defects and drug actions.
Therapeutic Metabolomics Identifies Novel Treatments for Multiple Sclerosis and Chronic Pain
Gary Siuzdak, The Scripps Research Institute
Quantitative global analysis of endogenous metabolites from cells, tissues, fluids or whole organisms - metabolomics, is becoming an integral part of functional genomics efforts as well as a tool for understanding fundamental biochemistry. Where the genome and proteome is largely enabled by the predictable fragmentation pattern of peptides, metabolomics is complicated by the tremendous chemical diversity of metabolites. The experimental aim in our studies is to obtain a comprehensive quantitative with an unbiased quantitative view of the metabolome. We have explored multiple novel mass spectrometry platforms for metabolomics including both solution-based approaches and surface-based mass spectrometry, such as nanostructure-initiator mass spectrometry (NIMS) for tissue imaging. These platforms will also be presented in the context of its application to discovering new disease therapies for chronic pain and multiple sclerosis.
Metabolite Profiling for Personalized Medicine
Rima Kaddurah-Daouk, Duke University Medical Center
The "Metabolomics Network for Drug Response Phenotype" is a national network funded by NIH with a mission to integrate metabolomics in clinical pharmacology and pharmacogenomics research to achieve a deeper understanding of mechanisms implicated in drug-response variation towards a more personalized approach to therapy. We are testing the hypothesis that application of metabolomics analyses and the inclusion of metabolomics data would significantly enhance pharmacogenomic research by providing broad-based, biochemically precise phenotypes capable of supplementing and extending the clinical phenotypes currently used as pharmacogenomic “endpoints”. In addition, metabolomic “signatures” present in patients who do and do not respond to drug therapy, i.e., signatures that reflect the drug response phenotype, could lead to mechanistic hypotheses that would provide insight into the underlying basis for individual variation in drug response. We will exemplify approaches we are taking and early findings from the study of statins and SSRIs classes of therapies.
Viral Hijacking of Host Cell Metabolism
Joshua Rabinowitz, Princeton University
Viruses rely on the metabolic network of their cellular hosts to provide energy and building blocks for viral replication. We used liquid chromatography-mass spectrometry to quantitate metabolite concentration and flux changes induced by viral infections. The flux measurement approach relies on monitoring metabolome labeling kinetics after feeding cells (13)C-labeled forms of glucose and glutamine. For influenza A and herpes simplex virus (HSV), the most profound metabolic alterations occur in pathways that are the targets of current antiviral therapies: neuraminidase for influenza A and thymidine biosynthesis for HSV. In contrast, for human cytomegalovirus (HCMV), flux increases are broad based and include a particularly notable increase in flux through the tricarboxylic acid cycle and its efflux to the fatty acid biosynthesis pathway. Pharmacological inhibition of fatty acid biosynthesis suppresses the replication of HCMV. Intriguingly, it also blocks influenza A replication. These results show that systems-level metabolic flux profiling can identify metabolic targets for antiviral therapy.
Mining the Microbial Metabolome: Metabolomics-based Approaches to Infectious Diseases
Kyu Rhee, Weill Cornell Medical College and New York Presbyterian Hospital
Mtb is the causative agent of tuberculosis (TB), the leading bacterial cause of deaths worldwide. Among bacterial pathogens, Mtb is unique in that it resides in humans as its only known natural host and reservoir. Mtb has thus evolved to survive within a niche committed to its eradication. Prominent among Mtb’s adaptations to its singular niche are those pertaining to central carbon metabolism. Carbon metabolism has thus emerged as a major determinant of Mtb’s pathogenicity. Biochemical knowledge of Mtb carbon metabolism nonetheless remains scant. Here, we present the first metabolomic descriptions of Mtb’s central carbon metabolism and demonstrate the potential for metabolomics-based approaches to expand knowledge of its pathogenicity.
Metabolite Profiling for Discovery of Cancer Biomarkers
Chris Beecher, University of Michigan Medical School
The discovery of biochemical markers for diseases as complex as cancer has been hinted at since 1924 when Warburg discussed the metabolic abnormalities of cancer metabolism, and yet no significant small molecule biomarkers of cancer are currently used as diagnostic biomarkers. In a recent metabolomic investigation of Prostate cancer we have identified the compound sarcosine as both a key mechanistic component in, and significant biomarker for, the progression of cancer to a metastatic state. This Metabolomic study and its biochemical outcomes will be discussed.
Travel & Lodging
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The New York Academy of Sciences
7 World Trade Center
250 Greenwich Street, 40th floor
New York, NY 10007-2157
212.298.8600
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