Panel on Genomics and Proteomics
Of Oral, Dental and Craniofacial Diseases
A Scientific Expert Panel
May 22, 2002
Sponsored by:
The National Institute of Dental and Craniofacial Research
National Institutes of Health
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.
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.
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.
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.
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.
John
Levine
University of California, SF (UCSF)
Claire
Fraser
The Institute for Genomic Research (TIGR)
National Institute of
Dental and Craniofacial Research
National Institutes of Health
Bethesda, MD 20892-2190
e-mail: nidcrinfo@mail.nih.gov
phone: 301/496-4261