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Sponsoring Society:
International Mammalian Genome Society 

16.00-18.00 Early Registration

10.30 Chairperson's Remarks
Dr. Laura Shawver, President and Chief Executive Officer, Phenomix Corp.

10.35 Large-Scale Isolation and Rapid Mapping of Recessive Mouse Mutations
Dr. Monica J. Justice, Assistant Professor, Department of Molecular and Human Genetics, Baylor College of Medicine
The post-sequencing challenge is to define the function of genes, and large-scale high-throughput mouse mutagenesis is one of the best avenues for determining mammalian gene function. A powerful approach for mutagenesis combines gene-based targeting in embryonic stem cells with phenotype-driven ethylnitrosourea (ENU) mutagenesis. The ability to engineer whole chromosome regions using Cre/loxP technologies allows for the creation of genetic reagents such as deletions and balancer chromosomes to isolate, map, and manage the large number of mutations that can be obtained after ENU mutagenesis.

11.05 Phenotype-Driven Mouse Mutagenesis
Dr. Martin Hrabe de Angelis, Director, GSF-Institute of Experimental Genetics
The large-scale mouse-mutagenesis efforts in Germany have been complemented by the German Mouse Clinic (GMC) to characterize mouse models for a wide variety of phenotypes. The projects discovered many genotype-phenotype correlations involved in inherited diseases. The next step will be the dissection of genetic pathways and understanding of genetic networks by sensitized screens and proteomics and bioinformatic tools.

11.35 From Functional Genomics to Systems Biology
Dr. Hans Lehrach, Director, Max-Planck-Institüt für Molekulare Genetik
Biological research is moving rapidly from the focused analysis of single genes and gene products to the systematic analysis of the entire network of biological processes in structural and functional genomics. The deluge of complex, interrelated data will require the development of databases able to link across different types of data and different organisms, as well as the development of quantitative modeling tools able to reproduce the complexity of biological processes in the computer.

12.05 Characterization of Novel Genes
Dr. Claes Wahlestedt, Professor and Chairman, Center for Genomics and Bioinformatics, Karolinska Institute
Over the past several years we have studied the transcriptome, including a large set of well-known drug target family genes as well as novel genes that show orthologs in several species. A number of techniques and approaches have been employed, and these will be described briefly. In the course of this work, we have, e.g., had reason to assess similarities and differences between antisense and RNAi strategies for efficient gene knockdown in vitro and in vivo. Like with antisense oligonucleotides, key issues surrounding optimal in vitro and/or in vivo use of (chemically synthesized) siRNA are/will be (1) delivery, (2) chemistry, and (3) mRNA target site selection.

12.35 Lunch (on your own)

 

14.00 Chairperson's Remarks
Dr. Monica J. Justice

14.05 The Impact of Forward Genetics on Drug Discovery and Development
Dr. Laura Shawver
Genetic manipulations that lead to loss or gain of function for a specific protein are a very powerful method of assessing the impact that protein plays in a particular pathophysiological process. This is exemplified by the numerous mouse models of disease created by targeted disruption and transgenic lines. However, there still remains a considerable gap between the number of genes identified and the amount of phenotype information for these genes. Using a "forward genetics" approach to examine gene function will impact drug discovery and development at several key points. The approach identifies gene alterations causative in disease and, in addition, allows for pathway determination, the ability to generate clusters of disease models, and the application of drug testing in an appropriate pharmacological model. It is also informative about patient selection for clinical trials.

14.35 Mutagenesis and Genomics in the Mouse: Towards a Systematic Analysis of Mammalian Gene Function
Prof. Steve D.M. Brown, Director, MRC Mammalian Genetics Unit and UK Mouse Genome Centre
Systematic approaches to mouse mutagenesis are vital for future studies of gene function. We have undertaken a major ENU mutagenesis program incorporating a large genomewide screen for dominant mutations (Nolan et al., Nature Genetics 25: 440-443). Nearly 30,000 mice have been produced, and around 500 mutants have been recovered from the screening program. We have mapped over 70 mutants to date and confirmed that many of the novel phenotypes represent mutations at previously unidentified loci in the mouse genome. We have also begun to develop gene-driven mutagenesis approaches using ENU (Coghill et al., Nature Genetics 30: 255-256). The approach promises a rapid methodology to recovering an allelic series of point mutations for any gene in the mouse genome enabling a more profound analysis of gene function. The use of both phenotype-driven and gene-driven ENU mutageneses for the generation of a new mutant map of the mouse represents a powerful combination of approaches for gene function studies.

15.05 Deductive Genomics: Industrializing Discovery Biology and Target Validation in the Post-genome Era
Dr. Michael C. Nehls, Chief Executive Officer, Ingenium AG
Until recently, the use of the mouse as a model organism in drug discovery was dominated by reverse genetic approaches. With the advent of ENU mutagenesis in mice, genomewide forward genetics approaches have become feasible. Ingenium Pharmaceuticals has established a screen for recessive mutants relevant for the therapeutic areas of neurobiology, immunology/hematology, metabolic diseases, and cancer biology. An overview of the results of the program, including early-stage drug targets and target validation approaches, will be presented.

15.35 Poster and Exhibit Viewing, Refreshment Break

16.15 Creating New Mouse Models of Cardiovascular Disease Using Random Mutagenesis
Dr. S. Lee Adamson, Director, CMHD Mouse Physiology Lab, Senior Scientist, Samuel Lunenfeld Research Institute, and Professor, Obstetrics & Gynecology, University of Toronto
Toronto's Centre for Modelling Human Disease is creating new mouse models of human disease using random mutagenesis. C57BL/6J male mice are injected with ethylnitrosourea (ENU) to generate mutations in sperm, then bred with normal C3H/HeJ females. G1 offspring are screened for cardiovascular and other physiologic abnormalities. "Outliers" are bred to establish heritability. Dominant mutations responsible for traits are localized using a genome scan. We are screening mice for blood pressure and heart rate abnormalities using a tail cuff system, ascending aortic blood velocity abnormalities using pulsed Doppler while under isoflurane anesthesia, for hematologic abnormalities (hematology analyzer and blood smear) and for abnormal ECGs. The program is always seeking new collaborators and new screening protocols. See www.cmhd.ca for details and a list of the heritable models available.

16.45 Genomic and Genetic Strategies in Cardiac Hypertrophy
Dr. Ketty Schwartz, Director of Research, New Technologies, INSERM
Genetic and genomic studies in hereditary forms of cardiac hypertrophy and of cardiomyopathies showed that at least 20 to 30 different genes are involved in the development of these diseases. The talk will focus on two genes, cardiac myosin-binding protein C and lamin A/C. In both cases, the results of family analysis, of ex vivo cellular models, and of mouse knock-in models will be presented.

17.15 High Throughput Gene Expression in Mammalian Cells: Applications in Target Discovery
Dr. Ulrich Brinkman, Chief Scientific Officer, Xantos Biomedicine AG
We have set up a high-throughput expression screen where single cDNA clones are prepared on a robotics platform. Subsequently, an automated transfection and readout system completes the four robot cascade. This enables genome wide, unbiased screens with 150,000 complete functional assays per month including further analysis. We will discuss the application in the search for targets from phenotypic screens as well as results of a first screen for novel apoptosis inducing genes with new disease associations.

17.45 Networking Reception

19.00 Close of Day One

13.45 Chairperson's Remarks
Dr. Giulio Superti-Furga, Vice President, Biology, Cellzome AG

13.50 Keynote Address Dr. Jan-Anders Karlsson, Executive Vice President, Pharma Research, Bayer AG Leverkusen

14.30 Use of Microarray Technology in the Identification of Drug Targets for CNS Disorders
Dr. Smita Patel, Senior Research Fellow, Department Biochemistry and Molecular Biology, Merck Sharp & Dohme
The beauty of microarray technology is the ability to monitor expression levels of thousands of genes simultaneously in response to different treatments. We are using CNS-focused microarrays to identify key genes and biological pathways of potential importance in neuropsychiatric disorders. Microarray analysis of brain regions from mouse models of schizophrenia revealed significant gene expression variances. Analysis of this data for clusters of functionally related genes and independent confirmation of key gene expression changes by RT-PCR and in situ hybridization may provide insights into the molecular basis of schizophrenia and point to potentially novel therapeutic targets.

15.00 New Lead Compounds via Smart Integrated Proteomics Approaches
Dr. Christoph Hüls, President and Chief Executive Officer, Protagen AG
The post-genomic era left pharmaceutical R&D with a huge number of possible disease-related targets, their respective validation in accepted pharmaceutical in vitro and in vivo models, and the task to design and to develop lead candidates and new chemical entities (NCEs). Until today, proteomics technologies proved to be decisive for target discovery and validation only. Protagen shows that the strategic application of its proprietary integrated proteomics technology (IPT™) platform allows the straightforward design of small molecule lead compounds with significant biological activity. The Protagen strategy is based on the identification of regulatory networks of cellular proteins affected by already marketed drugs in diseased and normal states. The extraction of knowledge from these proteomics studies and its correlation with the basics in cell biology, biochemistry, and pharmacology can be applied to the design of small molecule drugs. In this study, an anti-proliferative and anti-inflammatory drug was used to identify a set of proteins all belonging to the major cellulary energy generating machinery. The comparison of drug structures and natural substrates as well as effectors of these proteins gave guidance for the synthesis of P@G1011. The new lead candidate has been tested in vitro and in animal models and showed efficacy in different cell lines and in a rat cancer model. These data strongly demonstrate the potential of smart designed proteomic studies in delivering superior quality of targets and lead compounds and in speeding up the pharmaceutical R&D process.

15.30 Poster and Exhibit Viewing, Refreshment Break

16.00 Drug Proteomics: Exploiting Tractable Drug and Target Space
Dr. Giulio Superti-Furga
Cellzome AG is an emerging biopharmaceutical company using known drug and target space to exploit the proteome in an efficient and focused approach. Previously unrecognized connections between proteins and protein complexes, drugs, and biological processes are identified with proprietary proteomics technologies. Using this unique perspective, Cellzome has the ability to select druggable targets, choose lead molecules with key features, and reject targets with safety concerns. This can be accomplished very early in the drug discovery process, circumventing future safety concerns and streamlining the process to focus only on the most promising compounds.

16.30 Trying to Find the Best Drug Targets Using Modern Functional Genomics
Dr. Gill Smith, Director of Molecular Biology and Global Head of Molecular and Cell Biology, AstraZeneca R&D Charnwood
The challenges of the post-genomic era for the drug discovery industry is trying to select the best drug targets from the vast array of potential candidates. Genetics and genomics approaches to target discovery often generate a wide range of potential drug targets which need further investigation. I will describe how in AstraZeneca we try to bring a range of functional genomics and target validation techniques together to select the best targets from genetics and genomics target discovery programmes.

17.00 Extreme Phenotype Selection Studies in the Identification of Relevant Genotypes in Cancer Research
Dr. José Luis Pérez Gracia, Clinical Research Physician, European Medical Department, Eli Lilly & Co., Inc.
The investigation of genetic alterations that are potentially related to the prognosis of cancer patients has become a frequently used strategy in recent years, but many times it has led to conflicting results. In contrast, the identification and the study of subjects or families with very characteristic phenotypes have yielded outstanding results in the identification of the genetic characteristics underlying such phenotypes. While on most occasions the individuals selected for these types of studies were characterized by a negative phenotype-for example, an increased risk to develop a determined disease-a few studies have been directed towards individuals with phenotypes of unusual good prognosis-i.e., those presenting a decreased risk of developing determined diseases despite an important exposure to well-known risk factors. Therefore, it seems logical to further develop this strategy as a valid methodology for the study of other diseases such as cancer. The study of individuals with phenotypes of extremely good prognosis, such as long-term survivors of theoretically incurable tumors or of subjects that seem to be protected against certain neoplastic disorders despite possessing a markedly increased risk to develop them, could unveil the genetic alterations that explain such characteristic phenotypes and could provide potentially useful therapeutic targets against this disease.

17.30 Close of Conference

HOTEL INFORMATION
Hilton Munich Park
Am Tucherpark 7
D-80538 Munich, Germany
T: 49-89-3845-0, F: 49-89-3845-2588
Room Rates: Euro 155/S, Euro 175/D
Cut-off Date: April 1, 2003

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.

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 CD, a one-page summary must be submitted and registration must be paid in full by March 21, 2003. Click here for poster instructions

CALL FOR SPONSORS AND EXHIBITORS
Linking Phenotype to Genotype and Proteins to Profits concurrent conferences will provide an excellent venue for companies wishing to network with scientists from the biotechnology and pharmaceutical industries involved in the correlation of phenotype to genotype and/or scientists involved in the technical developments or applications in the fields of Protein and Peptide Arrays and Proteomics. Cambridge Healthtech Institute offers an array of sponsorship packages for you to most successfully reach this select audience. Make a lasting impression as a leader in these areas by taking advantage of these marketing tools. All packages can include an exhibit space or an exhibit space can be purchased alone.