Executive Sponsor: Sponsoring Publication: Cell Press World Scientific

Plenary Session Metabolic Profiling and Engineering: The Road Ahead Systems Biology of Metabonomics for Drug Discovery Modular Organization of Cellular Systems Genome-Scale Models for Prospective Metabolic Engineering Computer Applications for Comprehensive Metabolite Analysis Metabolic Profiling and Molecular Network Analysis

Sunday, December 1

5:00-6:30pm Early Registration and Poster and Setup Exhibit

Monday, December 2

7:45am Registration, Poster and Exhibit Viewing, and Light Continental Breakfast

Plenary Session

8:45 Welcome by Session Chairperson Dr. John Connelly, Imperial College and Metabometrix 8:55 Metabolic Profiling and Engineering: The Road Ahead Dr. Tom Colatsky, Vice President of Healthcare Research, Paradigm Genetics, Inc. Advanced metabolic studies include profiling for analysis of human health issues and engineering for improved production of biomanufactured products. Industrial and pharmaceutical industries alike are coming to realize the value of analysis of cellular metabolism, although increased attention has revealed the significant challenges that remain to capturing the promise of these studies. Cross-functional communication and collaboration will be critical towards achieving the blend of biology and informatics, research, and commercialization needed to move these related fields forward. 9:25 Metabonomics and Systems Biology: Potential Impacts on Drug Discovery and Development Dr. John Connelly Metabonomics, or metabolite profiling, measures the real outcome of the potential changes suggested by genomics and proteomics. It describes the integrated biochemical status, dynamics, interactions, and regulation of whole systems or organisms at a molecular level. Systems biology approaches present a different and broader perspective from the discrete, relatively static measurements of the past. As such, they offer new understanding of disease processes and targets and of the beneficial and adverse effects of drugs, but they also bring new challenges. Exploitation of patterns rather than single indicators, and the dynamic nature of metabonomics end-points, suggest a dose-response continuum and perhaps challenge both industry and regulators with the obsolescence of the crude no-effect dose/effect dose concept. Characterization of individual amenability to therapy and susceptibility to toxicity ("pharmacometabonomics") has economic and ethical implications. These opportunities and challenges will be explored in the context of the present and future roles of metabonomics in drug development. 9:55 Modular Organization of Cellular Systems Dr. Timothy Galitski, Assistant Professor, Institute for Systems Biology Cellular systems are organized into networks of modules. A network-clustering method was developed to show this emergent level of biological organization. Abstraction of modular network-structure identifies network elements occupying important positions within and between modules. The functions of these elements suggest that they are important for module function and intermodule communication. 10:25 Poster and Exhibit Viewing, Refreshment Break 11:00 Genome-Scale Models for Prospective Metabolic Engineering Dr. Bernhard O. Palsson, University of California, San Diego; and Genomatica, Inc. Genome-scale metabolic networks can now be constructed and described by constraints-based models. These models have been successfully used to predict the phenotypic function of wild-type stains. In particular, the consequences of gene knock-outs, quantitative growth and secretion pattern, outcome of adaptive evolution, and strain substrate preferences are predicted with fairly high success rates. This capability forms the basis for the prospective design of metabolic functions. 11:30 Computer Applications for Comprehensive Metabolite Analysis Dr. Masanori Arita, Researcher, Computational Biology Research Center, AIST; and PRESTO, JST Three tools for comprehensive metabolite analysis are introduced. First is a database for metabolites that can suggest structurally similar compounds for a given input. Second is a graphical viewer of enzymatic reactions in which structural correspondence among reactants is shown in colors. The last is a simulator of tracer experiment, with which all logically possible pathways as well as those with putative metabolites (i.e., predictions) are graphically shown. Metabolic data for Bacillus subtilis are prepared and used for analysis. 12:00 Metabolic Profiling and Molecular Network Analysis Dr. Alison Borrajo, Business Development, Molecular Mining Corporation Modern, high-throughput assay technologies will enable metabolic profiling at much higher resolution and scale than possible so far. Similar to developments in RNA and protein expression profiling, computational data mining and functional inference are required to extract the valuable information contained in these data and integrate them into predictive models. In particular, such large-scale data can provide sample numbers that statistically support the complex, combinatorial, and nonlinear interactions that our most advanced association mining methods now uncover (e.g., GeneLinker™ Platinum). The resulting molecular network models (ideally integrating metabolic, RNA, and protein profiling data) can then be explored in simulations for the identification of key control processes (Drug Discovery Today, 2001, 6:1267). 12:30 Panel Discussion with All Plenary Speakers 1:00 Lunch (on your own)

 

 

ANALYTICAL STRATEGIES

2:15 Comments by Session Chairperson
Dr. John Connelly

2:25 Metabolomic Application of NMR and MS: Linkage to Proteomics and Functional Genomics
Dr. Teresa W.-M. Fan, Department of Land, Air and Water Resources, University of California, Davis
Progress in bioanalytical techniques including NMR spectroscopy and hyphenated mass spectrometry has made metabolite profiling feasible directly in crude biological extracts. Such a broad-screen approach will be most valuable by coupling with bioinformatics, including metabolic databases and computational prediction, to facilitate functional genomic understanding. (Coauthors: Richard M. Higashi, University of California, Davis, and Andrew N. Lane, University of Louisville)

2:55 Metabolic Profiling: Why and How the Comprehensive Analysis of Small Molecules (Metabolites) in Biological Systems Can Put the "Function" Back in "Functional Genomics"
Dr. Dayan B. Goodenowe, President and Chief Executive Officer, Phenomenome Discoveries, Inc.
We have developed a comprehensive, nontargeted, metabolome analysis technology that can be used side-by-side with gene expression arrays in functional genomics research. Our Metabolic Network Analysis Tools and Met-Array software are used to integrate and correlate the gene, protein, and metabolite expression changes in an organism due to developmental changes, mutations, environment (pests/pesticides, nutrient deficiency, temperature, etc.), and disease. Examples of our research in these areas will be presented.

3:25 Metabolic Activity Profiling: Merging Dynamic Flux Analysis and Metabolomics
Dr. Albert A. de Graaf, Chief Scientific Officer, Metabolic Explorer
In this presentation, we discuss a technique by which the labeling state as well as the intracellular concentrations of metabolic intermediates are determined in a single measurement, using NMR or mass spectroscopy, after fast sampling, quenching, and subsequent cellular extraction. This approach, termed Metabolic Activity Profiling, directly correlates flux analysis with metabolomic aspects.

3:55 Poster and Exhibit Viewing, Refreshment Break

4:30 Use of 13C Mass Isotopomer Distribution Analysis (MIDA) to Characterize the Metabolomic Phenotype for a Given Genotype
Dr. Irwin Kurland, Assistant Professor of Medicine, University of California, Los Angeles
Phenotypic characterization by large-scale transcriptosome or proteome analysis can be criticized as a "fishing expedition" in the sense that the analysis is done in the hopes that a phenotypic pattern will emerge worthy of further examination. It will be demonstrated how to use 13C MIDA methodology to define a metabolomic locus key to the understanding of a given genotype, even those genotypes thought to have "silent" metabolic phenotypes. A paradigm will be presented for using a 13C MIDA metabolomic approach to initially focus phenotypic research investigations, which could then be followed up by high-sensitivity transcriptosome or proteome analysis.

5:00 Phenotype Microarrays: Better Information, Better Decisions
Dr. Barry Bochner, Vice President, Research &Development, Biolog
Biolog's Phenotype Microarray technology analyzes, in vitro, a 2,000 phenotypic response of a cell to a drug, or gene's influence. It does this using a rapid, high-throughput system of assays, automated cell incubation and monitoring, and software. PMs provide snapshots of cell growth under thousands of different conditions simultaneously. This capability of measuring the system-response of a complete living cell is an important complement to the data obtained from molecular methods such as DNA microarrays and proteomics analyses. Biolog's PM technology is currently being used in the study of infectious diseases. The company is now expanding its product line to mammalian cell assays. Microbial PM assays are already in use and providing insight into gene function and mechanisms of drug activity. Cellular assay data will be presented demonstrating the technology's use in target identification and validation by determining gene function and in high-throughput cellular lead optimization and validation.

5:30 Panel Discussion with All Afternoon Speakers

 

6:00-7:15pm  NETWORKING RECEPTION

Tuesday, December 3

8:00am Poster and Exhibit Viewing and Light Continental Breakfast

 

APPLICATIONS FOR DISEASE BIOLOGY

8:30 Comments by Session Chairperson
Dr. John W. Davis, II, Senior Scientist, Genetic and Molecular Toxicology, Schering Plough Research Institute

8:40 Metabonomics at the FDA
Dr. Richard Beger, Division of Chemistry, National Center for Toxicological Research, U.S. Food and Drug Administration
This presentation will discuss how metabonomics can be used for risk assessment, drug safety, and other possible regulatory issues for the FDA.

9:10 Metabonomics in Understanding and Development of Disease Models
Dr. John Connelly
The use of metabonomics in exploring disease models will be explored with examples, pitfalls will be identified, and future directions suggested. Practical application of metabonomics to efficacy in drug development will also be considered in that it is a new technology (like genomics and especially proteomics) likely to identify biological changes that are not always simple to explain. While drug discovery and development urgently demand novel approaches, there is a need for regulatory agencies also to participate in the process and to understand the implications of the new paradigm.

9:40 Metabolic Profiling in a Systems Biology Analysis of Atherosclerosis Disease
Dr. Matej Oresic, Head, Computational Biology and Modeling, Beyond Genomics, Inc.
Metabolite profiling in systems biology is a new and rapidly developing approach to studying biology and disease. In order to place measured metabolite components in a proper context, we present an approach that unites metabolic, proteomic, genetic, cellular, and pathway events that are in flux and interdependent. We have developed an integrated analytical platform consisting of high-throughput biochemical analyses and advanced informatics to correlate metabolic profiles with disease states and relevant affected pathways. As a case study, we demonstrate the application of this approach to a mammalian atherosclerosis disease model, the apolipoprotein E3-Leiden transgenic mouse.

10:10 Poster and Exhibit Viewing, Refreshment Break

10:45 Metabolic Profiling and Signatures in Neurodegenerative Disorders: ALS as a Model System
Dr. Rima Kaddurah-Daouk, Metabolon, Inc. and Dana Farber Cancer Institute
We have established metabolic profiles and small molecule databases from ALS patients' plasma using liquid chromatography electrochemical array systems (LCECA). A comparison of these profiles with those established from unaffected controls results in unique signatures for the disease. Our analysis suggests that the profiles contain both known and unknown compounds that are significantly associated with ALS or control samples. The chemical identification of these small molecules will highlight disease-related biochemical and signaling events, potential therapeutic lead molecules, and diagnostic markers for the disease. A comparative analysis with other neurodegenerative disorders is under way to determine common pathways in neuronal cell death and those that are unique for ALS. (Coauthors: M. Flint Beal, Mikhail Bogdanov, Robert H. Brown Jr., Merit E. Cudkowicz, Bruce Kristall, Wayne R. Matson, Steve Rozen, and Karen Vigneau-Callahan)

11:15 Metabolic Profiling for Development of New Diabetes Therapies
Dr. Christopher B. Newgard, Director, Sarah Stedman Center for Nutritional Studies and Duke Program in Diabetes Research, and Professor, Department of Pharmacology and Cancer Biology, Duke University Medical Center
There is a growing appreciation for the complexity of the pathways involved in glucose-stimulated insulin secretion (GSIS) from pancreatic islet b-cells. In our laboratory, this has stimulated the development of an interdisciplinary approach to the problem. This presentation will summarize studies combining the tools of recombinant adenovirus for gene delivery, the development of novel cell lines that exhibit either robust or weak GSIS, and nuclear magnetic resonance for metabolic fingerprinting of glucose-stimulated cells. Using these tools, we demonstrate an important role for pyruvate carboxylase-mediated pyruvate cycling pathways in control of GSIS and discuss potential coupling factors produced by such pathways. We also provide evidence that the pyruvate cycling pathway may be a target for enhancing islet performance in obesity and type 2 diabetes.

11:45 High-Throughput Metabolomic Profiling for Biomarker Discovery
Dr. Haihong Zhou, Research Scientist, SurroMed, Inc.
Metabolites are the products of cellular regulatory processes, and the changes in their production levels can provide indications for disease progression or therapeutic intervention. In this presentation, we will report on technologies we have developed based on nano-flow LC/MS and GC/MS for high-throughput, robust, sensitive, and comprehensive measurements of metabolic products from human bodily fluids or tissues. This metabolomic profiling effort at SurroMed is combined with similarly broad-based proteomic profiling. Examples will be shown comparing metabolic patterns from patients with inflammatory diseases (e.g., asthma), leading to new diagnostic markers. (Coauthors: Christopher Becker and Gary Frenzel)

12:15 Panel Discussion with All Morning Speakers 12:45 Luncheon

 

APPLICATIONS FOR DRUG DEVELOPMENT

2:00 Comments by Session Chairperson
Dr. Susan Sumner, Staff Scientist, Paradigm Genetics, Inc.

2:05 Redirecting Microbial Physiology with Metabolite Profiling for Lead Development and Metabolic Engineering
Dr. Edward Driggers, Senior Scientist, Microbia, Inc.
Metabolite profiling is a powerful tool for both metabolic engineering and drug development efforts. Data will be presented on redirecting the physiology of pathogenic fungi as part of Microbia's Anti-Invasin™ program. These studies include profiling of pathogenic fungi to ascertain spectrum of action, and in animal models of infection to simultaneously correlate pharmacology with fungal metabolism. Data will also be presented on redirecting the secondary metabolism of Aspergillus terreus. Metabolite and transcriptional profiling data were collected on engineered strains, and integrated in a process we refer to as association analysis. Integrating these data types has allowed us to rapidly engineer increased titers of desirable metabolites, as well as decreased titers of contaminant metabolites. Co-Authors: M. Askenazi, T. Norman, J. Royer, P. Blomquist, J. Trueheart, M. Mayorga, and K. Madden.

2:35 Predicting the Mechanisms of Action of Drug Compounds Using Pathway Databases and Structural Homology
Dr. Toby Segaran, Vice President, Research and Development, Incellico, Inc.
Incellico proposes a novel process of integrating bio- and chem-informatics that uses gene expression analysis combined with chemical substructure comparison to predict drug sensitivity and to reveal potential mechanisms of action for such sensitivity. Using the CELL™ ontological database, we search for functional pathways that appear to be more or less active based on the gene expression profiles. In addition, we compared the structure of a given drug with those of the endogenous molecules involved in these pathways. Our results suggest that the abundance of structurally similar endogenous molecules may predispose the effectiveness of a given drug.

3:05 Quantitative Lipid Metabolite Profiling in Discovery and Development:
Insight into the Relationships among Lipids, Drugs and Disease
Dr. Steven M. Watkins, President, Lipomics Technologies, Inc.
In contrast to broad screening approaches, focused and quantitative assessments of subsets of the metabolome provide in-depth information about pathway activity and individual metabolic status. The lipid metabolome is a particularly valuable subset of the overall metabolome because of the broad range of diseases linked to the dysregulation of lipid metabolism, and because many common side effect of drug therapies relate directly to lipids. This work presents the results of a study where the lipid metabolome-wide effects of a PPAR-g agonist and a b3 adrenergic receptor agonist were compared. The results demonstrate the utility of focused, quantitative assessments of metabolism in comparing the effects of drug compounds, identifying early markers of their efficacy and safety and in determining the relevance of animal models for compound evaluation.

3:35 Poster and Exhibit Viewing, Refreshment Break

4:00 Metabonomics: The Use of Electrospray Mass Spectrometry Coupled to Liquid Chromatography Shows Potential for the Screening of Rat Urine in Drug Development
Dr. Chris Stumpf, Senior Chemist, Life Sciences R & D, Waters Corporation
To date the majority of metabonomics applications has centered around the use of proton NMR with much success. This work explores the potential of LC/MS for metabonomics and the subsequent identification of biomarkers. In this presentation we will present both the strengths and limitations of LC/MS and the benefits of using the LC/MS data alone and combining it with proton NMR data for metabonomics. Data will be presented from the analysis of a safety assessment study in rats. We will show how the PCA data is generated and how the biomarkers were identified.

4:30 Measuring Metabolic Responses of Hepatocytes to Drug Treatment using FTMS
Dr. Fei He, Analytical Chemist, Esperion Therapeutics Inc.
The metabolic response of cultured primary hepatocytes treated with lovastatin and other drugs was measured by FTMS methods. The high mass resolving power of FTMS permits the observation and identification of ~1000 metabolites in a single experiment, without chromatographic separation. Statistically significant dose-dependent responses in the metabolic profile are observed, and can be correlated to know biological activities. Conventional wisdom in drug discovery mandates reduction to the study of specific target protein, with pleiotropic activities and validation issues addressed indirectly. Comparison of metabolic profile changes observed during treatment in cells, perfused organs, or whole animals can suggest the appropriate molecular targets for desired physiological responses.

5:00 Panel Discussion with All Afternoon Speakers 5:15 Close of Conference

Metabolic Profiling Conference Summary:
The completion of draft sequences for the human genome has focused attention on the tremendous effort still required to understand the function of expressed genes and the way in which genes and the proteins they encode interact within cells and organisms. Metabolomics, or the analysis of all cellular metabolites, provides a powerful new tool for gaining insight into functional biology. Snapshots of the levels of numerous small molecules within a cell, and how those levels change under different conditions, are very complementary to gene expression and proteomic studies and are actively being applied to studies of infectious diseases and production and model organisms, as well as human cells and plants. This pioneering conference will explore developments in tools for acquisition of profiling data and computational approaches for analysis and modeling based on such data, as well as practical applications of metabolic profiling. Researchers active in any of these areas should consider submitting proposals for poster presentations and make plans to attend the meeting.

HOTEL INFORMATION
Sheraton Imperial Hotel & Convention Center, Research Triangle Park
4700 Emperor Boulevard
Durham, NC 27703
T: 919-941-5050
F: 919-941-5156
Room Rates: $95/single • $105/double
Cut-off Date: November 7, 2002

Please call the hotel directly to make your room reservation. Identify yourself as a Cambridge Healthtech Institute conference attendee to receive the reduced room rate. Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space-and-rate-availability basis. Rooms are limited, so please book early.

TRAVEL INFORMATION
Special Zone and Discount Fares have been established for this conference with United Airlines. Please call United Airlines Meeting Reservation Desk at 800-521-4041 and reference ID #579YS.

CALL FOR SPONSORS AND EXHIBITORS
The Cambridge Healthtech Institute offers an array of sponsorship packages and exhibit space for you to reach this select audience. Make a lasting impression as a thought leader by taking advantage of these marketing tools.

For additional information, please contact Angela Parsons at 781-972-5467 or email at her at aparsons@healthtech.com.

CALL FOR POSTERS
Cambridge Healthtech Institute encourages attendees to gain further exposure by presenting their work in the poster sessions. Please fill out the registration form, with the poster title and primary author. To ensure inclusion in the conference binder, a one-page abstract must be submitted and registration must be paid in full by November 1, 2002.     Click here for poster instructions