Meeting Summary for
September 19, 2000
The NIDDK currently supports a number of large-scale, or trans-NIH, projects in the areas under the purview of this committee. As part of the charge to the committee to explore and define new opportunities, a brief review of several prototypical projects was presented. Each of these projects illustrates the diverse mechanisms available to meet specific needs for the research community at large. Two projects demonstrate what is being done within the DEM Division to meet high priority goals in diabetes research.
The first, the Functional Genomics of Endocrine Pancreas Project, is a consortium of three investigative teams bringing together expertise in pancreatic development, high through-put sequencing, and bioinformatics. The goal is to define all genes expressed in the endocrine pancreas during development and to make bioinformatics tools and reagents available to the research community to support research on pathogenesis and treatment of type 1 diabetes.
The Consortium for Type 2 Diabetes Genetics is also focused on a specialized goal, to identify and characterize genes involved in type 2 diabetes. This project developed from the realization that no one single investigative team is likely to collect enough patients to achieve the power necessary to identify polymorphisms or mutations that are associated with diabetes.
Three trans-NIH programs were also described. The Center for Inherited Disease Research (CIDR) is essentially a contract for genotyping service, which gives access to this technology to NIH-supported clinical studies in which genetic studies are likely to be informative, but where genotyping is not a part of the existing trial support. The Mammalian Gene Collection is again a collective venture of the NIH institutes, but here the focus is on generating data and reagents that are not within the specific purview of any single institute. The goal of this project is to assemble a set of full-length cDNAs representing all genes in the human (and more recently mouse) transcriptome. A third NIH-wide project, the Zebrafish Project, is a comprehensive genetics and genomics project designed to expand the utility of this model system through genome sequencing, mapping, collection of ESTs, and identification of mutations with specific phenotypes. NIDDK has taken a leadership role in this project through Dr. Josie Briggs.
The final example presented was the Biotechnology Initiative that began in 1999. This initiative is designed to disseminate comprehensive gene expression approaches, such as microarray technologies, to NIDDK-supported investigators. This initiative has begun with the establishment of 10 biotechnology centers as well as through small administrative supplements to existing NIDDK grants for application of this technology to a wide range of research projects.
After discussion of these existing programs, the group embarked on a general discussion of the complexity of research problems faced today and the best ways to take advantage of current technology. The group endorsed the principle that new technologies should be disseminated as widely as possible across the breadth of NIDDK programs and the NIDDK should be supportive of technology development through partnerships with the private sector and participation in NIH-wide initiatives.
Genome Anatomy Programs
While the NIDDK has restricted its efforts to date in the development of large scale Genome Anatomy Programs, the group felt that most research areas encompassed in the NIDDK mission could benefit from such approaches. There was considerable discussion about how such programs should be organized and general support for more modest efforts across a wider range of research areas which would include the essential tools and most useful aspects of the larger projects.
The lack of expertise and software for in-depth analysis of the large and diverse amounts of data collected in gene profiling or other microarray experiments was felt to be a major obstacle blocking application of information generated through the Human Genome Project and other related projects to the elucidation of disease pathogenesis and therapeutic development. The group expanded this discussion to include related issues in handling large data sets involving complex phenotyping and genetic data from clinical trials.
The group consensus was that this problem was not restricted to NIDDK, but that NIH as a whole should explore programs to meet this need. However, most members felt that there was an unmet need at the most basic level of providing programmers who could serve as an interface between biomedical researchers and computational systems.
Gene-Gene and Gene-Environment Interactions
The group discussed implications of the anticipated completion of the Human Genome Project, the industry-academic partnership for SNP discovery, and efforts to discover the genetic influences on disease susceptibility, severity, and potential for customized therapies based on genotype. The group discussed the potential for synergy between human linkage or association studies and animal models of disease as genomic sequence becomes available for mouse and other model organisms.
Although this topic was not in the original charge to the working group, there was general consensus that parallel efforts to provide infrastructure bioinformatics support for the collection and annotation of human and animal phenotype data was critical to the research areas supported by NIDDK. The group was advised that several other institutes have embarked on phenotypic screening projects to support large-scale random mutagenesis projects. NIDDK has also issued an initiative for funding in FY2001 to support metabolic phenotyping centers in addition to its support for phenotyping in the zebrafish mutagenesis project.
Goals for the Genetics, Genomics, and Bioinformatics Working Group
The group decided to consider four general areas for discussion and initiative development. Within each area the group should identify any near term opportunities which would have an immediate impact on progress in particular areas of research, as well as anticipate long-term needs and identify potential pathways to fulfill those needs.
Areas for exploration include how to expand the number of natural scientists and computational biologists interested in participating in NIDDK research areas, increasing the availability of mid-level computing expertise, and identifying bioinformatics needs of basic and clinical researchers.
- Disseminate the Genome Anatomy Paradigm
Priorities for large-scale genome anatomy projects as well as cost-effective approaches to developing such projects across a broad range of disease and organ systems are needed. Define the essential elements of the genome anatomy paradigm which can be modeled in more limited programs.
- Infrastructure support for phenotyping
The group felt that maximum value in genetic and genomic studies would only be gained with concomitant development of support structures for phenotyping. Animal model systems methods to support comprehensive assessment of functional status must be developed both to support widespread development of random or targeted mutants. These should have the sophistication required for metabolic phenotype analysis as well as the need for high through-put methods for rapid screening of large numbers of mutants. For human studies, annotation of large clinical data sets, the need for systematic tissue banking, and the need to focus on disease prevention as well as management are priorities for initiative development.
- Expansion/enhancement of genetics consortia
Expansion of collaborative approaches to identify genes involved in disease susceptibility is dependent on the anticipated success of this approach for type 1 and type 2 diabetes. These efforts should serve as pilots to identify best methods to bring investigators together, how best to integrate and manage large data sets, and how to balance consortial approaches with traditional individual-investigator research projects.
The working group considered this to be an ambitious set of goals but felt there were other areas within the area of genetics, genomics, and bioinformatics that should be the focus of future initiative efforts. In particular, technology development and chemical biology were thought to be important development targets.