A Scientific Expert Panel
May 22, 2002
Sponsored by:
The National Institute of Dental and Craniofacial Research
National Institutes of Health
I. Background:
The National Institute of Dental and Craniofacial Research (NIDCR) is the primary sponsor of biomedical and behavioral research and of research training in oral, dental and craniofacial diseases in the United States. The mission of the Institute is to promote and improve health through research. It accomplishes this mission by supporting research and training programs in intramural laboratories and in an extended external community of investigators working in academic institutions and in other research organizations. Support of extramural researchers is provided through the programs and initiatives of the Divisions of Basic and Translational Sciences and of Population and Health Promotion Sciences. Major programs in the first of these Divisions include developmental biology and mammalian genetics, epithelial cell regulation and transformation, oral infectious diseases and immunology, AIDS and oral manifestations of immunosuppression, pain, autoimmune disease and biotechnology and biomaterials. The Division of Population and Health Sciences supports programs in behavioral and social sciences research, population sciences, clinical trials and patient-oriented research and health disparities. The Division of Intramural Research includes laboratories located on the NIH campus in Bethesda, MD. Intramural scientist perform research in Craniofacial and skeletal diseases, Craniofacial development, gene therapy, oral and pharyngeal cancer, oral infection and immunity and pain.
Recognizing the importance of long-term scientific planning to capitalize on the rapid and significant advances that are occurring in biomedical and behavioral research, NIDCR established an internal study group with representatives from all its Divisions to identify broad areas of importance for the Institute's long-range scientific agenda. This group identified three major topics of interests:
- Genomics and Proteomics of Dental, Oral and Craniofacial Diseases
- Repair and Regeneration of Dental, Oral and Craniofacial Tissues
- Clinical Approaches to the Diagnosis, Treatment and Prevention of Dental, Oral and Craniofacial Disorders.
The group also recommended that panels of experts be convened to help the Institute identify and catalogue areas within these major topics where significant scientific opportunity exists for NIDCR to move its research agenda forward. The first of theses panels was convened on May 22, 2002 at the NIH to address the topic of genomics and proteomics. This is a report of its deliberations and recommendations. Seven outside scientists joined NIDCR staff in attendance (see attached roster) in a far-reaching discussion of the topic. The participating experts were asked to do the following:
- Help NIDCR identify the areas of scientific opportunities for the period 2004 - 2009;
- Suggest ways to make these opportunities known to the research community
- Catalogue in general terms, the resources that will be required to successfully address the opportunities identified by the group.
The Institute Director indicated that NIDCR wishes to support the best science and its major goal is to capitalize on science advances to improve dental, oral and craniofacial health. It has to do this in the face of limited resources and of limitations in the basic capacity and infrastructure of its primary constituent institutions to perform cutting-edge research in the rapidly advancing area of genomics and proteomics. A particularly important challenge is how to ensure the appropriate training of individuals so that they can successfully address the challenges and opportunities that exist in this area. NIDCR needs to marshal its resources efficiently and to enter into partnerships in order to leverage these resources and to build the research and training capacity of its client community.
The material provided to the panel members in advance of the meeting was then reviewed. This material included a listing of the projects in the general area of genetics supported by NIDCR in FY 2001; the organization of NIDCR's intramural and extramural programs; the recommendations of a workshop held in 1999 on Genetics and Craniofacial and Dental Anomalies; and copies of recent research initiatives for the years 2001 and 2002.
II. General Issues:
The Panel was asked to first discuss some general issues related to the assessment previously outlined by the Director in terms of available resources and existing research capacity in genomics/proteomics of dental, oral and craniofacial diseases. In particular, the panel focused on two general issues:(1) Identifying the best strategy to jump start a program of research in this area and
(2) Determining how to train the appropriate workforce to perform this research. The Panel made the following comments.
- One way to jumpstart a program of research in the genomics/proteomics, of oral, dental and craniofacial diseases would be to use the approach previously used by other NIH Institutes particularly NCI. This approach contains two elements: (1) establishing strong partnerships between extramural and intramural research groups to focus on the research questions, without regards to the location of the scientists; (2) supporting the creation of extensive, focused databases that can increase the interface between these investigators. These two activities can enhance the integration of the various communities of researchers and are designed to combine their scientific and technical resources, thus meeting more effectively the overall needs of the entire research community. It is necessary to insure that the program directors in both the intramural and extramural divisions work together to achieve the goals of this program of research interaction.
Another approach is to enhance the dialogue between dental researchers supported in this area with those in private organizations. Some of the best and brightest researchers are being lured by industry but some companies are reporting turning down partnerships because they are overextended. However, collaborative undertakings can pool resources and help in dealing with complex and expanded research issues. Another way to help jumpstart the program is to use the approach taken by NCI, which is to increase the use of the contract mechanism to address emerging needs. Resources can be used to target specific contracts in areas of special need without ignoring investigator-initiated projects.
A fourth approach involves the support of efficient, cost effective core facilities, such as those supporting microarray facilities and the Center for Inherited Diseases Research (CIDR) at Johns Hopkins University. The current status of NIDCR-supported facilities was reviewed. NIDCR has awarded funds to 3 microarray facilities in AIDS, 1 in oral cancer and 1 in tissue engineering. NIDCR also contributes to CIDR and there are already NIDCR-supported investigators using this resource. The issue is to make these resources available to the larger community and to entice investigators to make a wider use of them to enhance their individual research capabilities
- With regards to training, the major issues are how to retrofit a skill-set for people who need to get skills up-to-date and how to prepare the next generation of researchers who can work in the lab of the future. Since trainees generally look for mentors who can offer cutting-edge science in a good training environment, an approach is to identify the best labs doing research in genomics and proteomics and offer Lead Mentor Awards to the principal investigators (with salary and other incentives) to recruit and train the most promising candidates with an oral/dental background. A network of lead mentors can be promoted to provide collaborative, flexible training opportunities and to provide collaborative, flexible training opportunities and to design programs to retrain individuals who need to bring their skills up-to-date in relatively short (i.e. 1 - 2 years) periods of time. Supporting regional facilities using the latest technology can also be useful not only in terms of research collaborations but as core resources for training. The lack of trained individuals in bioinformatics is a problem and the community is not taking advantage of existing opportunities. Incentives should be created to train individuals in this and other areas of genomics/proteomics research and to attract more young people into academic-based research. Crafting appropriate RFAs for targeted training programs can influence the behavior of the dental research community. As with research, it is necessary to insure that program directors work together to achieve the goals of the training incentives.
III. Research Opportunities
The Director, NIDCR presented an overview of existing NIDCR programs, highlighting the areas of strength and those that are felt to be important in the long-term research agenda of the Institute. NIDCR has focuses its resources on the following areas of science:
- Oral Infectious Diseases (including the genomics of bacteria and other oral pathogens, host-bacterial interactions, mucosal immunology, biofilms and the oral manifestations of AIDS).
- Repair of hard and soft tissues and biomimetics and tissue engineering
- Craniofacial Anomalies and developmental Biology
- Oral Cancer Research (including disparity issues, issues of access to care, environmental aspects and translational research)
- Pain Research (with emphasis on chronic pain, gender differences, treatment approaches and TMJ)
- Saliva Research (including developmental aspects of salivary glands and the use of saliva and other diagnostic fluids as diagnostic tools given the fact that saliva is more accessible than blood)
- Autoimmune disease, with special focus on Sjögrens Syndrome
NIDCR also devotes resources to the support of population-based and patient-oriented research as well as to behavioral research in most areas of science outlined above and has identified these types of research as priorities in its future research agenda. More recently, NIDCR has started to support stem cell and genomics research in several aspects of its portfolio.
With this information as background, the Panel considered the following as general issues and prospective goals for research in the area of genomics and proteomics of dental, oral and craniofacial diseases.
- Researchers have already realized that the one gene-one protein dogma is wrong and that each gene, by having different combinations of its coding regions converted into what is called an expressed transcript, might specify several proteins. The process of generating multiple transcripts is alternative splicing and a large amount of work needs to be done to identify the full complement of expressed transcripts (i.e. the transcriptome). Already researchers have begun to define the genes that represent the transcript sequence by generating full length, complementary DNAs (cDNAs).
A related issue is that the proteome is highly dynamic with a number of possible variations during normal development, growth and cell division and in response to environmental changes. Most proteins are modified post-translationally and the goal is not only to catalogue the proteins and to define their macromolecular interactions under static conditions but to understand how changes in the proteome contribute to normal and abnormal function (i.e., in disease states).
Based on these considerations, the Panel concurred that the research opportunities during the next few years in the genomics/proteomics of dental, oral and craniofacial diseases involve not only the identification of the genes and the elucidation of protein structure but the unraveling of the links between the genome, the transcriptome and the proteome. The Panel suggested that NIDCR should support studies and projects that address in parallel the genome, the transcriptome and the proteome of dental, oral and craniofacial diseases. For example, in the area of oral infectious diseases, the frontiers of microbial genomics need to be defined and research has to move away from individual microorganism in isolation and look at the defined environments in which the pathogens operate. In this and on all other areas of research, the proteome component of the research agenda should include the support of studies that aim at defining the protein populations that are activated, protein/protein interactions and protein/DNA interactions. In addition, research opportunities exist in the field of cell dynamics and in identifying signaling networks and cell-to-cell signaling processes. A basic diagram of cell localization needs to be developed and focused protein arrays need to be constructed. Most proteins seem to function within complicated cellular pathways interacting with other proteins in pairs or in larger complexes. An understanding of these interactions is needed before we can elucidate how cellular pathways function. An issue is that the number of actual proteins in the various proteomes is much larger than the number of genes in the genome and that structural genomics requires a large number of steps to convert sequence information into three demonstrated structures. This requires a major effort on a scale similar to the genome project and significant support from funding agencies.
- The Panel also felt that given the complexity and variety of functional environments in the oral cavity and the craniofacial complex, the concept of multiple, plastic microenvironments can be used to target specific structures or processes through molecular anatomy type projects. Proteomics research has already provided some insights into normal biology and human disease through, for example, the identification of markers for cancer in body fluids. Initiatives like the recent RFA on the use of oral fluids as diagnostic tools (released by NIDCR in 2002) open up the possibility for research on markers and their correlation with specific environments in the oral cavity.
- The Panel also suggested that to successfully address the multiple research opportunities that will exist in the next few years in the genomics/proteomics area, technology development will be a key part of the future and should be a big part of new grants. Although researchers are using microarrays and cDNA chips to learn when and where genes are turned on, they lack the more sophisticated, automated approaches needed to study all the proteins encoded by those genes. Techniques are needed to monitor and pinpoint multiple protein/protein and protein/gene interaction in living cells. Mass spectrometry will continue to play an important role for proteome approaches and protein arrays (including antibodies) and expressed proteins with affinity tags can be expected to play expanded roles.
Another technology that needs significant development is bioinformatics. This is not necessarily related to computer power but to the lack of methodologies to move large amounts of information around. New algorithms to analyze and interpret the data and ways to visualize and present genomic information to researchers are sorely needed. Initiatives such as the Innovation Molecular Analysis Technology Program (NCI) and the Proteome Centers Initiative (NHLBI) are attempts to support technology development and can be used as models for future NIDCR programs.
Researchers in several countries have begun generating full length complementary DNAs that represent the transcript sequence and NIH has devoted considerable resources to the generation of human cDNAs, while scientists in other countries have produced an extensive collection of mouse cDNAs and are attempting to pinpoint were the proteins specified by those cDNAs work in the cell. Data from these efforts are available to the public and should help researchers in the area of dental, oral and craniofacial diseases. Resources such as transgenic mouse facilities are another resource that needs to be supported.
An issue to keep in mind is the proper mix of big and little science. Some goals in the post-sequencing era might be better met through many labs using a diversity of technologies in an attempt to lower costs.
The Panel thus identifies the following three broad areas of scientific opportunity in the next few years:
- Functional Genomics
- Proteomics
- Bioinformatics
It also highlighted some of the issues NIDCR would face as it expands its research agenda into these areas and suggested some strategies to cope with the tremendous challenges that exist in defining the links between the genome, the transcriptome and the proteome and in cataloging and interpreting the data generated from research in these areas. In addition, the Panel made some additional general suggestion in terms of strategies that may help in developing a research agenda in this area. These included:
- Explore the benefits of supporting conglomerates of small labs that can assist each other with specific expertise. This would help to engage a broader community in genomics/proteomics research of dental, oral and craniofacial diseases.
- Enhance support of core facilities that can provide help with technology with experimental design and with data collection and analysis and inform the investigators of their availability.
- Explore partnerships with other funding agencies, particularly with NIH Institutes, to arrange joint support of programs focused on issues pertaining to oral and Craniofacial diseases but also of interest to the partners.
IV. Engaging the Research Community
The Panel was asked to suggest way for NIDCR to engage the research community at large in genomics/proteomics research and to make that community aware of the opportunities and resources that exist and that are available to researchers. The following suggestions were made:
- Consider supporting workshops for grantees and potential applicants to inform them of short term and longer term opportunities in this area of research and of the laboratory and technical resources (including databases) that can be available to initiate or to expand their research.
- Support the exchange of information on opportunities and resources by electronic means, through extensive listserv and client directories that can be constantly updated and used routinely to disseminate announcements, advances, priorities, etc.
- Support the development and distribution of CDs containing information about current research, recent initiatives, identified opportunities and programs under development. These CDs can be distributed free throughout the research community.
V. Next Steps:
NIDCR will use the suggestions of the Panel as a framework for the development of specific initiatives, programs and program announcements in the period 2004 - 2009. This summary report will be posted on the NIDCR home page as a first step in informing the community of this important area of NIDCR's long-range research agenda.
Panel 1
Genomics and Proteomics of Oral, Dental and Craniofacial Diseases
May 22, 2002
9:00 a.m. to 2:00 p.m.
Claire Fraser
The Institute for Genomic Research (TIGR)
Eric Hoffman
Children's National Medical Center
Robert Strausberg
National Cancer Institute
John Levine
University of California, SF (UCSF)
Jim Melvin
University of Rochester
John Yates
Scripps Research Institute
NIDCR Attendees:
- Dr. Kevin Hardwick
- Dr. Lynn King
- Dr. Dushanka V. Kleinman
- Dr. Eleni Kousvelari
- Dr. Jim Lipton
- Dr. Jack London
- Dr. Dennis Mangan
- Dr. Ricardo Martinez
- Dr. Ann Sandberg
- Dr. Rochelle Small
- Ms. Cheryl Stevens
- Dr. Lawrence Tabak