Global Metabolite Profiling

Global Metabolite Profiling

Friday, February 11, 2011

The New York Academy of Sciences

Presented By

 

We now know all predicted open reading frames (ORFs) from a multitude of genomes—a next great hurdle in biomedical science will be to define the function of all encoded proteins, as well as the consequences of gene variants and mutations. This meeting will address how this challenge of functional genomics is being met by emerging strategies for untargeted metabolite profiling. Notably, many predicted ORFs encode "hypothetical proteins", meaning that their products are a complete black box in terms of function. Even for functionally annotated gene proteins, annotation is often incomplete or incorrect. Conversely, despite the common view that metabolism is well understood, 30-40% of metabolic activities in most organisms are still without known enzymes. Pioneering research will be presented by investigators who are using untargeted metabolomics in attempt to define the activities of ill-defined and undefined enzymes. Beyond providing global insights into metabolism, an important translation of this new knowledge will be discovery of new therapeutic targets and diagnostic approaches that fuel drug development for decades to come.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City, where possible.

Silver Sponsors

Grant Support

Supported by an educational grant from Celgene Corporation

For a complete list of sponsors, please click the Sponsor tab.

Networking reception to follow.

Agenda

*Presentation times are subject to change.


9:00 AM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Steven S. Gross, PhD, Weill Cornell Medical College

9:25 AM

Metabolomics: The Link Between Genotypes and Phenotypes
Oliver Fiehn, PhD, University of California, Davis

10:15 AM

Global (Unbiased) Metabolomics as a Unique Biochemical Approach to Therapeutic Discovery
Gary Siuzdak, PhD, The Scripps Research Institute, California

11:00 AM

Coffee Break

11:45 AM

Elucidation of Endogenous Substrates for Human P450 Enzymes using Metabolic and Isotope Labeling Approaches
F. Peter Guengerich, PhD, Vanderbilt University School of Medicine

12:30 PM

Lunch

1:45 PM

Deep Phenotyping of Genomes by High-Throughput Metabolomics
Nicola Zamboni, PhD, Institute of Molecular Systems Biology, ETH Zurich

2:45 PM

Global Metabolite Profiling for Assignment of Endogenous Substrates to Enzymes and to Chart New Biological Space
Alan Saghatelian, PhD, Harvard University

3:30 PM

Coffee Break

4:00 PM

Panel Discussion: The Challenge of Discovering Functions for All Proteins
All Speakers

5:00 PM

Networking Reception

Organizers

Steven Gross, PhD

Weill Cornell Medical College

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Oliver Fiehn, PhD

University of California, Davis

Dr Oliver Fiehn is a Professor at the University of California, Davis in the Genome Center. After obtaining his PhD from the Technical University of Berlin, Germany in Analytical Toxicology, he joined the Max-Planck Institute of Molecular Plant Physiology in 1998 to starting the field of metabolomics. He accepted an offer to join UC Davis in 2004 and has since focused on metabolomics in human diseases, analytical techniques and databases. He has published more than 100 papers in peer-reviewed journals and is a member of the board of the directors of the Metabolomics Society, and member of the editorial boards of several journals, among them the Journal of Biological Chemistry. Dr Fiehn’s main research field is the mass spectrometry and its use for metabolite analysis, in conjunction with bioinformatics approaches to utilize metabolic data for plant and animal research

Steven Gross, PhD

Weill Cornell Medical College

Steven S. Gross is Professor of Pharmacology, Director of the Mass Spectrometry Core Facility. Dr Gross' expertise is in pharmacology, and cell and structural biology, particularly in relation to the role of nitric oxide (NO) as a signaling molecule. In the late 1980s, Dr Gross and colleagues made the initial identification of L-arginine as the precursor of NO in blood vessels. They were also first to establish that NOS inhibition elevates blood pressure in animals, demonstrating that NO plays a physiological role in controlling blood pressure and vascular tone. Since then, research efforts have predominantly focused on elucidating the enzymes and mechanisms that regulate NO synthesis in cells. Results of these basic studies have provided fundamental insights into the therapeutic control of NO synthesis, resulting in core technologies for the creation of ArgiNOx Inc., a biotech start-up that is developing novel NO-based drugs. Dr Gross has authored or coauthored more than 90 research publications and 40 book chapters, review articles and books in the area of NO biology. He is an active member of NIH Study Sections and is a founder and Board Director of the Nitric Oxide Society, a group that organizes the major annual international meetings on the subject of NO and publishes a peer-reviewed scientific journal with novel reports on NO biology and chemistry. Dr Gross received his PhD in Biomedical Science from the Mount Sinai School of Medicine in New York City.

F. Peter Guengerich, PhD

Vanderbilt University School of Medicine

Dr. F. Peter Guengerich is a Professor of Biochemistry at Vanderbilt University School of Medicine. He received his B.S. from the University of Illinois in 1970 and then did his graduate work at Vanderbilt University, receiving his Ph.D. in Biochemistry in 1973. After two years as a research fellow at the University of Michigan, he was hired as Assistant Professor of Biochemistry at Vanderbilt in 1975 and has been on faculty since then, having attained the rank of Professor in 1983. Prof. Guengerich has been Director of the Center in Molecular Toxicology, an interdepartmental program at Vanderbilt, since 1981. In 2010 he assumed the position of Interim Chair of the Department of Biochemistry.

His own research laboratory deals with the chemical and biological mechanisms by which drugs and cancer-causing chemicals are processed and the relevance to drug development, toxicity, and disease. A major area of interest is the enzymology of cytochrome P450 enzymes, which are the major catalysts involved in the metabolism of drugs. Studies with the recombinant human P450 enzymes involve the molecular basis for substrate and reaction discrimination, utilizing steady-state and pre-steady-state kinetics, binding analyses, and both site-directed and random mutagenesis approaches. Other work involves mechanisms of chemical reactivity with DNA and miscoding by DNA polymerases. He is an author or co-author of 603 original research articles and 176 invited reviews. He is an associate editor of The Journal of Biological Chemistry and Chemical Research in Toxicology. In 2009 he received the third annual AACR Award for Outstanding Achievement in Chemistry in Cancer Research and was also a member of the first class of ACS Fellows selected by the American Chemical Society. In 2010 he received the R. T. Williams Distinguished Achievement Award from ISSX, and in 2011 he will receive the Founders’ Award of the ACS Division of Chemical Toxicology. More than 130 graduate students, research fellows, and visiting scientists from throughout the world have trained with him.

Alan Saghatelian, PhD

Harvard University

Alan Saghatelian grew up in southern California and attended UCLA as an undergrad where he graduated with a degree in chemistry. He got his first taste of research working with professor Craig Merlic in the area of organometallic chemistry and synthetic chemistry. For graduate school, Alan attended The Scripps Research Institute in La Jolla where he moved into biochemical problems such as the molecular mechanisms that spawned life and allosteric regulation of enzymes through protein engineering. It was at TSRI that Alan became more interested in biomedical research and he remained at TSRI for a postdoc with Professor Benjamin Cravatt where he developed (with Gary Siuzdak's help) methods for global metabolite profiling of lipids to identify novel mammalian lipids and substrates for enzymes. In 2006, Alan started in the chemistry department at Harvard where he has continued to extend the utility of these methods to biology. Alan is currently an Associate Professor of Chemistry and Chemical Biology.

Gary Siuzdak, PhD

The Scripps Research Institute, California

Gary Siuzdak is Director of the Scripps Center for Metabolomics and Professor of Chemistry and 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 unbiased metabolomics, the development of nanostructure-based platforms for mass spectrometry imaging, novel approaches to virus characterization and inhibition, and mass-based inhibitor-enzyme screening. He has over 170 peer-reviewed publications and two books, the latest being The Expanding Role of Mass Spectrometry in Biotechnology, 2nd Edition 2006.

Nicola Zamboni, PhD

Institute of Molecular Systems Biology, ETH Zurich

Nicola Zamboni is a principal investigator at the Institute of Molecular Systems Biology of ETH Zurich since 2005. He graduated in group of Jay Bailey at the Institute of Biotechnology of ETH Zurich, where he also received his Ph.D. degree in 2003 in the field of Metabolic Engineering. In 2004, he moved to Stanford University to devise metabolomics-derived approaches for unraveling causes of intracellular metabolic changes. This activity continues currently at ETH Zurich building upon metabolomics, 13C flux analysis, and computational biology.
Research in his group ultimately aims at identifying interaction networks involving metabolism in complex systems, spanning from microorganisms in natural environments to pathogens and higher cells.


Sponsors

For sponsorship opportunities please contact Cristine Barreto at cbarreto@nyas.org or 212.298.8652.

Silver Sponsors

Grant Support

Supported by an educational grant from Celgene Corporation

Abstracts

Metabolomics: The link between Genotypes and Phenotypes

Oliver Fiehn, PhD, University of California, Davis

Metabolite analysis has been boosted in the past 10 years by use of computational resources and mass spectrometry (MS) based instrumentation. Studies now extend from targeted analysis of classic single-hypothesis-driven biological studies towards integrating unbiased and broad metabolite assays. In clinical newborn screening, hundreds of thousands MS analyses are performed yearly, diagnosing over 50 inborn errors of metabolism from dried blood spots. Can this prime example of linking genetic errors to disease phenotypes be repeated for complex diseases, for early diagnosis of cancer or coupled to genome-wide association studies?

Which platforms to be used? The chemical complexity of metabolites demands that no single instrumentation can cover the metabolome in a truly comprehensive way. Instead, instrumentation, methods of extraction, and methods of data processing and interpretation need to be driven by the biological question. Are volatiles relevant, e.g. in breath analysis? Certainly, no FT-ICR MS or NMR can give answers here. Are complex lipids important to understand a biological phenomenon? If yes, gas chromatography-based methods will be useless. As example, databases and metabolomic platforms used at the UC Davis Metabolomics Facility will be demonstrated that have been applied to over 28,000 samples in over 420 studies.

What has been achieved so far? Metabolomics is collaborative in nature and requires biological and chemical validations of hypotheses that are generated. Results from a range of preclinical and clinical studies will be presented on blood, urine and tissue analyses targeting insulin resistance and cancer research. The discussion will highlight the impact that metabolomics has already made in diagnostics and mechanistic understanding of diseases, and which challenges and prospects lie ahead

Global (Unbiased) Metabolomics as a Unique Biochemical Approach to Therapeutic Discovery

Gary Siuzdak, PhD, The Scripps Research Institute, California

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 represent upstream biochemical events, the metabolites correlate with the most downstream biochemistry and therefore most closely represent the phenotype. This has been proven by the broad success of metabolite analysis in clinical diagnostics. The experimental aim in our studies is to obtain a comprehensive quantitative view of the metabolome to expand our understanding of what pathways are altered in specific diseases. We have developed 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, to address this problem. These platforms will be presented in the context of its application to discovering new disease therapies/pathways.

Elucidation of Endogenous Substrates for Human P450 Enzymes using Metabolic and Isotope Labeling Approaches

F. Peter Guengerich, PhD, Vanderbilt University School of Medicine

Some cytochrome P450 oxygenases (P450s) have not been extensively studied and are termed “orphans”. With regard to elucidation of any physiological functions of the orphan P450s, it is clear that simple trial-and-error approaches with individual substrate candidates will not be very productive in addressing questions about function. A series of LC-MS/informatics approaches will be discussed, with some successes with both human and bacterial P450s. Current information on what are still considered “orphan” P450s will be presented, along with the potential for application of some of these approaches to other enzyme systems.

Deep phenotyping of Genomes by High-Throughput Metabolomics

Nicola Zamboni, PhD, Institute of Molecular Systems Biology, ETH Zurich

Metabolomics affords exclusive insights for functional annotation of genes in vivo. Holistic studies, however, call for large scale studies with either thousands of strains or conditions to exhaustively map gene-environment interactions. To meet the need of analysing tens of thousands of sample, we established a metabolomics pipeline capable of handling > 1’000 samples/day and yet provide a broad coverage of metabolism. We completed a genome-wide analysis of single-knockout mutants of Escherichia coli with ca. 35’000 analyses within 6 weeks. Exemplary cases for the information content of such screens and the unprecedented potential of this platform will be discussed.

Chemical Profiling for Biological Discovery

Alan Saghatelian, PhD, Harvard University

Advances in analytical methods enable us to detect and quantify chemicals (metabolites) on a global scale. We develop and apply these methods to discover bioactive lipids and investigate the regulation of transcription factors. These tools provide unique insights into the molecular biology of physiological systems that can impact our understanding of physiological regulation and enable these processes to be modulated for therapeutic gain.


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