The 174 th meeting of the National Advisory Dental and Craniofacial Research Council (NADCRC) was convened on January 20, 2004, at 10:55 a.m., in Building 45, Conference Room E1&2, National Institutes of Health (NIH), Bethesda, Maryland. The meeting was open to the public from 10:55 a.m. until adjournment at 4:10 p.m. The meeting was preceded by the closed session, from 8:30 a.m. to 10:30 a.m. , for Council business and consideration of grant applications. Dr. Lawrence A. Tabak presided as Chair.
Members Present:
Dr. Eli I. Capilouto
Dr. Louise T. Chow
Dr. Nereyda P. Clark
Dr. Matthew J. Doyle
Dr. Raymond J. Fonseca
Dr. Linda G. Griffith
Dr. Mark C. Herzberg
Dr. Howard K. Kuramitsu
Dr. Josephine Lai
Dr. Francis L. Macrina
Dr. Brian L. Mealey
Dr. Harold Morris
Dr. Lin da C. Niessen
Dr. Michael J. Reed
Dr. George W. Taylor, Jr.
Members of the Public Present:
Ms. Janet Aker, The Blue Sheet, Chevy Chase, MD
Dr. Aida Chohayeb, Professor, Howard University , Washington , DC
Dr. Robert J. Collins, Deputy Executive Director, American Association for Dental Research, Alexandria, VA
Ms. Alicia Doherty, Masi Max Resources, Inc., Reston, VA
Dr. Ronald Dubner, Chairman, Department of Bio-Medical Sciences, Dental School, University of Maryland, Baltimore, MD
Dr. Christopher Fox, Executive Director, International Association for Dental Research, Alexandria, VA
Ms. Gina G. Luke, Director of Legislative Policy Development, Center for Public Policy and Advocacy, American Dental Education Association (ADEA), Washington, DC
Ms. Monette McKinnon, Director of Grassroots Advocacy & State Issues, Center for Public Policy and Advocacy, ADEA, Washington, DC
Ms. Myla Moss, Director, Congressional Relations, ADEA, Washington, DC
Dr. Jonathan P. Schuermann, Ph.D. Candidate, University of Missouri, Columbia, MO
Mr. Alec Stone, Executive Director, Friends of the NIDCR, Washington, DC
Federal Employees Present:
National Institute of Dental and Craniofacial Research:
Dr. Lawrence A. Tabak, Director, NIDCR
Ms. Carolyn Baum, Committee Management Specialist and Council Secretary, Office of the Director (OD)
Dr. Sangeeta Bhargava, Health Scientist Administrator and Program Director, Immunology and Immunotherapy Program, Division of Basic and Translational Sciences (DBTS)
Dr. Henning Birkedal-Hansen, Acting Deputy Director, NIDCR
Ms. Karina Boehm, Chief, Health Promotion Branch, Office of Communications and Health Education (OCHE)
Dr. Norman S. Braveman, Executive Secretary, NADCRC, and Assistant to the Director, OD
Dr. Patricia S. Bryant, Health Scientist Administrator and Program Director, Behavioral and Social Sciences Research Program, Division of Population and Health Promotion Sciences (DPHPS)
Ms. Sharrell S. Butler, Diversity Program Manager, OD
Ms. María Teresa Canto, Health Scientist Administrator and Program Director, Population Studies Program, DPHPS
Dr. Lois K. Cohen, Associate Director for International Health, NIDCR, and Director, Office of International Health (OIH)
Mr. George J. Coy, Chief, Financial Management Branch, Office of Administrative Management (OAM)
Mr. Kevin Crist, Grants Management Specialist, Division of Extramural Activities (DEA)
Ms. Mary Daley, Chief Grants Management Officer, Grants Management Branch (GMB), DEA
Ms. Yvonne H. du Buy, Associate Director for Management, and Chief, OAM
Dr. Caswell A. Evans, Director, National Oral Health Initiative, Office of the Surgeon General, and NIDCR
Mr. William Foley, Grants Management Specialist, DEA
Dr. Isabel Garcia , Acting Director, Office of Science Policy and Analysis (OSPA), and Co-Director, Residency Program in Dental Public Health at NIDCR, DPHPS
Ms. Christen Geiler , Computer Specialist, Office of Information Technology (OIT), OD
Dr. Sharon Gordon, Special Assistant for Research Training, Career Development, and Education, OD
Dr. Kevin Hardwick, International Health Officer, OIH, and Special Assistant for Research Infrastructure and Curriculum Development, OD
Dr. H. George Hausch, Acting Director, DEA
Dr. Jeffrey Hyman, Epidemiologist, Health Policy, Analysis, and Development Branch (HPAD), DPHPS
Ms. Lorrayne Jackson, Extramural Research Analyst and Outreach Specialist, OD
Ms. Mary Kelly, Scientific Review Specialist, Scientific Review Branch (SRB), DEA
Dr. Lynn King, Scientific Review Administrator, DEA
Dr. Albert Kingman, Chief, Biostatistics Core, DPHPS
Dr. Eleni Kousvelari, Director, Center for Biotechnology and Innovation (CBI), and Chief, Cellular and Molecular Biology, Physiology, and Biotechnology Branch, DBTS
Dr. John W. Kusiak, Health Scientist Administrator and Program Director, Molecular and Cellular Neurobiology Program, DBTS
Ms. Wendy A. Liffers, Associate Director for Policy Integration, OD
Ms. Carol Loose, Budget Analyst, Financial Management Branch, OAM
Ms. Jane Lura-Brown, Program Analyst, DPHPS
Dr. Dennis F. Mangan, Acting Deputy Director, DBTS, and Chief, Infectious Diseases and Immunity Branch, DBTS Ms. Nathalie Morin, Grants Technical Assistant, DPHPS
Dr. Richard L. Mowery, Chief, Clinical, Epidemiology and Behavioral Research Branch, DPHPS
Mr. Christopher Myers, Lead Grants Management Specialist, GMB, DEA
Dr. Mostafa Nokta, Health Scientist Administrator and Program Director, AIDS and Oral Manifestations of Immunosuppression Program, DBTS
Dr. Ruth Nowjack-Raymer, Health Scientist Administrator and Program Director, Health Disparities Research Program, DPHPS
Ms. Sonia Penafiel, Grants Technical Assistant, CBI
Ms. Helen Pham, Grants Management Specialist, GMB, DEA
Dr. Bruce L. Pihlstrom, Acting Director, DPHPS
Ms. Diana Rutberg, Grants Management Specialist, GMB, DEA
Ms. Rebecca Roper, Scientific Review Administrator, DEA
Dr. Ann L. Sandberg, Acting Director, DBTS
Dr. Robert H. Selwitz, Chief, HPAD, and Co-Director, Residency Program in Dental Public Health at NIDCR, DPHPS
Ms. Patricia Sheridan, Information Specialist, OCHE
Dr. Yasaman Shirazi, Health Scientist Administrator and Program Director, Epithelial Cell Regulation and Transformation Program, DBTS
Dr. Lillian Shum, Health Scientist Administrator and Program Director, Physiology, Pharmacogenetics, and Injury Program, DBTS
Ms. Traci Walker, Committee Management Assistant, OD
Mr. Robert Tarwater, Grants Management Specialist, GMB, DEA
Ms. Anne Welkener, Financial Analyst, DEA
Ms. Dolores A. Wells, Program Analyst, OSPA, OD
Ms. Mary Ann Williamson, Computer Specialist, OIT, OD
Other Federal Employees:
Dr. Jessica Bell, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH
Dr. Jahid Davies, NIDDK, NIH
Dr. James A. Lipton, Senior Advisor to the Chief Dental Officer, U.S. Public Health Service
OPEN PORTION OF THE MEETING
I. CALL TO ORDER
Dr. Lawrence A. Tabak, Director, NIDCR, called the meeting to order. He reviewed the agenda and invited the Council members to introduce themselves.
II. APPROVAL OF MINUTES
The minutes of the Council's meeting on September 25 & October 2, 2003 , were considered and unanimously approved.
III. OPERATING PROCEDURES
The Council unanimously concurred with the rules governing the Council's operating procedures.
IV. FUTURE COUNCIL MEETING DATES
The following dates for future Council meetings were confirmed:
May 25, 2004
September 28, 2004
January 28, 2005
June 10, 2005
September 23, 2005
V. REPORT OF THE DIRECTOR, NIH
Dr. Elias A. Zerhouni, Director, NIH, discussed the NIH Roadmap – Accelerating Medical Discovery to Improve Health. He began by thanking the Council members for their service and commitment. Dr. Zerhouni noted that, each year, NIH relies on approximately 21,000 individuals who provide advice to the NIH, making it perhaps the most open Federal agency in the world. Much of the NIH success can be attributed to this richness of advice.
Dr. Zerhouni said that NIDCR provides significant leadership at the NIH and that the Council should be proud of the Institute's contributions. He noted that Dr. Tabak continues to have a major role in the NIH Roadmap and that Dr. Dushanka V. Kleinman, Assistant Director for Roadmap Coordination, Chief Dental Officer, U.S. Public Health Service, and former Deputy Director, NIDCR, is on detail to the Office of the Director, NIH, to coordinate NIH Roadmap activities.
Dr. Zerhouni commented on the importance of oral health and oral sciences and the impact of oral diseases on the total burden of disease. He suggested that NIDCR could be at the focal point of several research areas (e.g., proteomics) and that possible synergies exist between NIDCR and other NIH institutes and centers (ICs). One example is NIDCR's vision of interdisciplinary research on the proteomics of salivary glands, which the Office of the Director, NIH, has supported with discretionary funds.
Dr. Zerhouni noted that, by organizing science in a multi- and interdisciplinary way, rather than by disciplines, researchers can approach broader scientific questions that reflect a profound unity among biological systems and the growing convergence among fields of science. This vision for the future cuts across the traditional structures of ICs at the NIH and their research portfolios. This vision is the premise for the NIH undertaking the development of a roadmap to transform medical research.
The NIH Roadmap, announced in September 2003, embraces three thematic areas and includes 28 initiatives. Dr. Zerhouni noted that the three Roadmap areas are integral to NIDCR's mission.
In the first thematic area, New Pathways to Discovery, the aim is to understand complex biological systems, such as the craniofacial complex. In this area, NIH is investing in the development of molecular tools that can provide quantitative information to understand these systems. A specific initiative is to construct molecular libraries of publicly available compounds (i.e., molecular probes) that scientists can use to interrogate complex biological systems.
In a second area, Research Teams of the Future, NIH is offering incentives to encourage the creation of multi- and interdisciplinary research teams that integrate the biological, physical, engineering, and quantitative sciences, including computer sciences. In the third area, Re-engineering the Clinical Research Enterprise, NIH is addressing the need for clinician scientists, use of informatics to improve diagnosis and testing methods for populations, and assessment of clinical outcomes.
Discussion
In response to questions, Dr. Zerhouni said that the core issue for NIH is how to transform the management of research to fit the research. He noted that the Roadmap will “test the boundaries” of the functionally organized structures and research portfolios at NIH. The development of molecular probes is one area in which NIDCR has an opportunity to play a large role. Dr. Zerhouni said that the molecular tools will be user friendly and that NIH will support specialized training in the use of these tools and other aspects of clinical research through the NIH National Clinical Research Associates program. He noted that a main question for NIDCR is how to position dental research to take advantage of these opportunities as medical research becomes progressively more quantitative.
Another initiative is the establishment of an NIH Director's Pioneer Award to fund researchers with innovative ideas. Dr. Zerhouni noted that the aim is to support individual scientists or thinkers with pioneering ideas and approaches to contemporary challenges in biomedical research. He agreed that a major challenge is attracting the best and brightest young students, especially those with quantitative skills, into careers in science. Dr. Zerhouni noted that only about 4 percent of NIH grantees are younger than 35 years old, and he invited Council's suggestions on how NIH could meet this challenge. With the shift in how science is being conducted, NIH is especially interested in individuals who have a combination of skills (e.g., in computer science, engineering, and biology).
In closing, Dr. Zerhouni commented on the close interaction among IC directors. The IC directors meet twice monthly, rotate membership on a scientific committee of 10 IC directors involved in the governing of NIH, and carry on informal dialogue with the Director.
VI. REPORT OF THE DIRECTOR
Dr. Tabak presented an overview of NIDCR activities, advances, and changes since the previous Council meeting, highlighting items from the written Director's Report (see Attachment III).
Activities of the NIDCR Director. Dr. Tabak continues to represent NIDCR on various NIH-wide committees. For example, he co-chairs the NIH Information Technology Working Group. Also, during the past several months, Dr. Tabak spoke at several international meetings, including the Fèdèration Dentaire Internationale Annual World Dental Congress, held in Sydney , Australia (which he addressed via teleconference). He gave presentations at Hebrew University-Hadassah School of Dental Research and Tel Aviv University School of Dental Medicine, Jerusalem , and continued discussions with faculty at U.S. dental schools.
Activities of the Chief Dental Officer. Dr. Tabak noted that Dr. Kleinman is very busy as Chief Dental Officer and as Assistant Director for Roadmap Coordination, in the Office of the Director, NIH. This fall she received the prestigious American Public Health Association's John W. Knutson Distinguished Service Award for Dental Public Health and the Carl A. Schlack Award from the Association of Military Surgeons of the United States .
Dr. James A. Lipton, formerly Special Assistant, Research Infrastructure and Curriculum Development Program, NIDCR, is serving full-time as senior advisor to the Chief Dental Officer, Dr. Kleinman.
Activities of the Deputy Director. Dr. Henning Birkedal-Hansen, the NIDCR Scientific Director for almost 10 years, is serving as Acting Deputy Director, NIDCR.
Budget Update. Dr. Tabak reported that the U.S. Senate is currently meeting on the Omnibus Appropriation for Federal agencies for Fiscal Year (FY) 2004. The conference allowance for NIDCR is approximately $383.2 million. The President's Budget for FY 2005 will not be released publicly until February 1, 2004 .
DHHS/NIH/NIDCR Activities. Dr. Tabak encouraged Council members who are not familiar with the NIH Roadmap or have questions about the roadmap initiatives to contact NIDCR staff. Specific NIDCR, as well as NIH, staff have been designated as contacts for each roadmap initiative. The lead liaison for NIDCR is Ms. Wendy Liffers, Associate Director for Policy Integration. Ms. Liffers presented an update on the NIH Roadmap later during the meeting (see section XI below).
Regarding loan repayments, Dr. Tabak reported that NIH awarded student loan repayment contracts to 1,200 U.S. researchers in FY 2003. This total represents a 66 percent increase over the number awarded in FY 2002, the first year of this NIH program. Dr. Tabak noted that NIDCR funded slightly more than the number targeted for NIDCR and is pleased to provide support in response to applications.
Two individuals have been appointed to NIH positions: Dr. Norka Ruiz Bravo is the new NIH Deputy Director for Extramural Research, and Mr. Richard Turman is the new Associate Director for Budget. Dr. Gerald T. Keusch has stepped down as Director of the Fogarty International Center (FIC) and NIH Associate Director for International Research. Dr. Sharon Hrynkow, formerly Deputy Director, FIC, will serve as Acting Director, FIC.
Dr. Tabak noted that the Friends of the NIDCR organized a wonderful program for its 2003 Gala Annual Awards Dinner, held November 3, 2003 . Dr. Zerhouni was the keynote speaker.
Scientific Advances. Dr. Tabak highlighted three recent advances. (i) As reported in the Journal of Dental Research, NIDCR-supported researchers at the University of Illinois at Chicago created a mandibular condyle from rat adult stem cells that is the precise three-dimensional shape of the human joint. (ii) Researchers in the NIDCR intramural research program collaborated with scientists elsewhere to transfer the gene for human interleukin-10 via an adeno-associated virus into the salivary glands of mice to reduce inflammation of the glands and preserve salivary flow. Dr. Tabak noted that this exciting advance has promise for the use of gene therapy to treat Sjögren's syndrome. (iii) NIDCR-supported researchers completed sequencing of the human genome for Porphyromonas gingivalis strain W83. Researchers can access the database containing the sequence data at http://www.nidcr.nih.gov/Research/ResearchResources.htm.
Dr. Tabak encouraged Council members to contact Dr. Dennis F. Mangan, Acting Deputy Director, Division of Basic and Translational Sciences (DBTS), and Chief, Infectious Diseases and Immunity Branch, DBTS, NIDCR, regarding the status of research on individual microbes. Dr. Mangan also can provide information on the NIH initiative to establish the Molecular Libraries Small Molecule Repository ( http://grants.nih.gov/grants/guide/notice-files/NOT-RM-04-003.html ).
Dr. Tabak noted two significant published reports—on receptors for mammalian sweet and umani taste and on the remodeling of unmineralized cartilage, a critical process in skeletal growth. The written Director's Report provides the citations for these publications.
Meetings and Workshops . For the first time, NIDCR will host a meeting for NIDCR trainees, fellows, and training program directors at NIH on April 19-20, 2004 . Previously, NIDCR hosted these gatherings at annual meetings of the American Association for Dental Research and International Association for Dental Research.
On May 6-7, 2004 , NIDCR will host a workshop on “Methods for Enhancing the Efficiency of Dental/Oral Health Clinical Trials: Current Status, Future Possibilities.” The workshop will be held at NIH and will focus on the state of the science and future research needs related to biomarkers, surrogate endpoints, and technologies for clinical trials in oral diseases. The discussions will include consideration of regulatory concerns involving the Food and Drug Administration.
NIDCR provided support for the newly established Gordon Research Conference on Craniofacial Morphogenesis and Tissue Regeneration. The first meeting was held in Ventura , California , in January 2004, and future meetings will take place every 2 years. Dr. Rochelle Small, Program Director, Developmental Biology and Mammalian Genetics Program, DBTS, is the NIDCR contact.
In October 2003, Dr. Lois K. Cohen, Associate Director for International Health, NIDCR, was an invited guest at a meeting of the advisory board of the Institute of Musculoskeletal Health and Arthritis, Canadian Institutes of Health Research (CIHR), held in London , Ontario . Dr. Tabak noted that the CIHR has a research portfolio similar to the NIH and that joint efforts with CIHR would be beneficial.
Personnel Changes. Dr. Tabak noted the following changes among NIDCR personnel. Dr. Pamela Robey, Chief, Craniofacial and Skeletal Diseases Branch, NIDCR, is serving as Acting Scientific Director, NIDCR. Dr. Kevin Hardwick, International Health Officer, NIDCR, will assume responsibility for the Dental School Infrastructure and Curriculum Development Program, which was previously held by Dr. Lipton.
Dr. Ricardo Martinez, Associate Director for Program Development, NIDCR, retired from government service in November 2003. With his departure, Dr. Norman S. Braveman, Assistant to the Director, assumed responsibility as Executive Secretary for both the NIDCR Board of Scientific Counselors and the NADCRC. Dr. Braveman will also take the lead in coordinating future ad hoc panels that NIDCR will convene to help advise the Institute on scientific directions.
Dr. Jack London, Assistant Scientific Director, NIDCR, recently retired from Federal service. He is remaining in a part-time position to help guide completion of the renovation of the NIDCR laboratories in building 30.
The written Director's Report provides additional detail on NIDCR activities, advances, and changes (see Attachment III).
Discussion
Dr. Richard L. Mowery, Chief, Clinical, Epidemiology and Behavioral Research Branch, Division of Population and Health Promotion Sciences (DPHPS), NIDCR, reported that NIDCR sponsored the “Practice-Based Research Network Technical Assistance Conference” on February 4, 2004. The purpose of the conference, which was broadcast via the NIH Web cast, was to inform potential applicants about the Request for Applications (RFA) for practice-based research networks. Dr. Tabak noted that the RFA has generated tremendous interest, and he encouraged Council members to participate. The NIDCR initiative arose separately from the NIH Roadmap and in consultation with the external dental research community. Information on the initiative is available at http://grants.nih.gov/grants/guide/notice-files/NOT-DE-04-001.html .
VII. BUDGET UPDATE
FY 2003. Dr. Tabak reported that the total NIDCR budget for FY 2003 was $373,630,000. The breakdown was approximately as follows: $292.7 million for extramural programs, $59.1 million for intramural research, and $19.8 million for research management and support. Of the funding for intramural research, only about $36.9 million supported research activities; the remaining funds were allocated to renovations of the NIDCR laboratories (approximately $6.1 million) and central, NIH-wide assessments (e.g., for the Warren Grant Magnuson Clinical Center) ($16.1 million).
Extramural funds supported 810 research grants (at approximately $257.9 million), which included the following: 657 research project grants (at approximately $219.3 million), 12 research centers ($21.1 million), 107 research career awards ($12.3 million), 15 Phase I planning grants for dental school infrastructure ($2.2 million), and 19 other research awards ($2.9 million). NIDCR also was able to support 330 training grants (Kirschstein National Research Service Awards) ($12.0 million) and 14 research and development contracts ($22.8 million).
Seventy-five percent of the extramural funds supported research project grants. The distribution for other mechanisms of support was as follows: 8 percent for contracts, 7 percent for centers, 4 percent for training, 4 percent for research careers, and 2 percent for other research.
Dr. Tabak emphasized that 80 percent of NIDCR funds was already committed in FY 2003, leaving only 20 percent in discretionary funds to support new activities. He also noted that, like all ICs, NIDCR contributes to various central assessments (e.g., management and rent, information technology, program evaluation, research training, study sections). In FY 2003, the NIDCR assessments amounted to approximately $32.1 million.
With the funds available in FY 2003, NIDCR was able to develop and fund a number of new initiatives in three main areas: clinical and translational research; bioengineering, genomics, and proteomics; and HIV/AIDS research. NIDCR emphasized increased clinical and translational research and was able to fund specific initiatives to attract new researchers to studies of the pathobiology of temporomandibular joint disorders and dental practice-based tobacco control interventions. NIDCR also supported establishment of registries for Sjögren's syndrome and 15 planning awards to improve the research infrastructure in U.S. dental schools.
Two specific initiatives to attract new research groups into bioengineering, genomics, and proteomics focused on (a) restoration of orofacial tissues using a biomimetic/tissue engineering approach and (b) gene discovery for craniofacial disorders. In HIV/AIDS research, NIDCR supported research on oral mucosal innate immune factors and the development of oral mucosal vaccines.
FY 2004. The conference allowance for NIDCR in FY 2004 is $383,242,000. For the first time ever, NIDCR expects to have more than $300 million for extramural programs. NIDCR anticipates funding 818 research grants (including 674 research project grants), 321 training awards, and 14 research and development awards. NIDCR would contribute $1,316,000 to the NIH Roadmap. NIH will spend about $128 million for roadmap activities, of which approximately $101 million will be available across the NIH for extramural awards.
In FY 2004, NIDCR plans to increase clinical research; capitalize on advances in bioengineering, genomics, and proteomics; and continue to pursue HIV/AIDS research. Among the initiatives in clinical research are Phase III clinical trials in oral infectious diseases, Phase II awards in the dental school infrastructure program, support of NIDCR exploratory (R21) grants in clinical research, and Phase II awards for implementation and expansion of state models for oral cancer prevention and early detection. Other initiatives would focus on the oral health of special need and older populations, epidemiological and behavioral research in oral health, and clinical genetics of craniofacial and oral diseases.
In bioengineering, genomics, and proteomics, NIDCR plans to support research on microbe–host interactions in periodontal diseases, the molecular anatomy of head and neck cancer, and the salivary proteome (including support for specialized centers of research). In HIV/AIDS research, NIDCR would support research on the oral mucosa and on the use of topical thalidomide for oral lesions.
FY 2005 and Beyond. Dr. Tabak provided a glimpse of NIDCR planning for the future. The initiatives envisaged include a pilot trial to determine whether human salivary glands can be used to test for local bioreactivity, plans for a dental practice-based research network, development of in vitro models of human oral mucosa, application of stem cell biology for regenerative dental medicine and treatment of joint and muscle pain, and multidisciplinary research on the mechanisms of orofacial pain, oral complications of HIV infection, and AIDS-related oral malignancies and tumors. Dr. Tabak noted that the fulfillment of these plans depends on the resources available.
VIII. STRUCTURE OF AN ANTI-DNA Fab COMPLEXED WITH A NON-DNA LIGAND PROVIDES INSIGHTS INTO CROSS-REACTIVITY AND MOLECULAR MIMICRY
Mr. Jonathan P. Schuermann, Ph.D. candidate, University of Missouri , Columbia , described his research studies in crystallography to understand the structure of an anti-DNA antibody complexed with a non-DNA ligand molecule. He conducted this research in collaboration with Dr. John J. Tanner and others in the Departments of Chemistry and Biochemistry, University of Missouri .
Anti-DNA antibodies contribute directly to lupus nephritis, the kidney inflammation associated with systemic lupus erythematosus (SLE), an autoimmune disease characterized by an aberrant immune response involving antibodies. Mr. Schuermann noted that the aim of his research was to elucidate the structural basis of antibody–DNA recognition in order to identify the features of the anti-DNA antibodies responsible for pathogenicity. Only two anti-DNA antibody structures have been characterized: Fab BVO4-1 and Fab DNA-1. Focusing on the latter, he noted its isolation and binding features.
Mr. Schuermann described the procedure used to crystallize proteins—slow, controlled dehydration of an aqueous protein solution. Using high-power x rays (at the National Synchrotron Light Source, Brookhaven National Laboratory, New York ), the researchers were able to visualize the diffraction patterns of the protein crystals and then, through computational analysis, determine their three-dimensional atomic structure.
The team used this process to crystallize and analyze the structure of Fab DNA-1 complexed with two different ligand molecules (HEPES and oligo-thymidine, dT 5 ). Mr. Schuermann depicted the structures of these two complexes (DNA-1+HEPES and DNA-1+dT 5 ) statically and dynamically (in rocking motion). He noted that comparison of the structures showed that the binding of the complexes was similar, but there was a conformational change in the large HCDR3 loop region of the protein.
Mr. Schuermann suggested that the research offers a three-dimensional framework for discussing and studying two fundamental aspects of autoimmunity: cross-reactivity and molecular mimicry. Using this framework, researchers can specifically examine how an anti-DNA antibody recognizes similar features on different molecules. He noted that several studies have reported the binding of non-DNA ligands to anti-DNA antibodies and that cross-reactivity, or the ability to recognize multiple ligands, is a hallmark of anti-DNA antibodies. Mr. Schuermann suggested that, based on the findings of these studies, one would predict that the interactions between the protein and ligands used in his research would be similar, but they were not. Rather, the cross-reactivity reflected a conformational change, or structural plasticity, in the HCDR3 region. This change altered the size and shape of the conforming site to match those of the ligand (cross-reactivity).
Mr. Schuermann noted that, because of the potential effects, researchers should use caution when choosing buffer molecules for biochemical or structural studies. He also noted that his research provides a starting point for designing small molecules that inhibit DNA (with HEPES being the representative component). Such studies would be the first crystal structure-based inhibitory design studies using an anti-DNA antibody as a target protein. They could establish a new paradigm for using the structure-based approach for designing drugs to treat autoimmune disease.
IX. CONCEPT CLEARANCES
NIDCR staff from the Division of Extramural Activities (DEA) presented four concepts for Council's review and approval.
Oral Complications from Cancer Treatment
Dr. María Teresa Canto, Health Scientist Administrator and Program Director, Population Studies, DPHPS, described a proposed initiative to support investigator-initiated research grants (R01s) to stimulate clinical research that will reduce the incidence and severity of oral complications from cancer therapy. The research activities will target oral mucositis and osteonecrosis, improvement in the management of oral infections and salivary gland dysfunction, and ways to minimize the risk of associated chronic oral diseases such as dental caries. In 2002, approximately 1.2 million individuals were diagnosed with cancer. Treatments for cancer are available (e.g., chemotherapy, immunotherapy, radiation), but they are aggressive and may have serious negative impacts on the oral cavity. This Program Announcement (PA) addresses this complication of cancer treatment.
The Council unanimously approved the concept.
NIDCR Small Research Grant for Data Analysis and Statistical Methodology
Dr. Mowery presented an initiative to expand NIDCR's existing small grant (R03) program in the following ways: (a) to provide investigators with the necessary support to conduct secondary data analyses using existing datasets and (b) to help investigators using these datasets develop statistical methodology appropriate for analyzing oral health data. Although many datasets are available from previous NIDCR-supported research studies, as well as the National Health and Nutrition Examination Survey (NHANES), few investigators are exploring these data. The proposed expansion of the small grant program would not be limited to new investigators, as is the current R03 program.
In discussion, the Council suggested that the proposed concept include a stimulus for organizing workshops to help investigators learn how to access and use the datasets. Dr. Mowery noted that the R13 mechanism of support could be used to support workshops. He also noted that the funding and duration of support for the expanded R03 program would be the same as for the current R03 program.
The Council unanimously approved the concept.
Novel Approaches to Study Polymicrobial Diseases
Dr. Mangan presented a proposed PA that would invite applications to develop and utilize innovative approaches for studying the mechanisms by which two or more microorganisms cause infectious diseases. The PA would encourage investigators to think beyond Koch's postulates of one organism for one disease. Periodontal diseases, dental caries, and oral mucositis are examples of conditions caused by many different organisms acting synergistically to maintain a chronic infectious disease. Understanding the mechanisms of their interaction is a new challenge in studying infectious disease. Researchers will need to overcome difficulties in cultivating the organisms and to re-examine the definitions of pathogen and virulence. The proposed PA would foster the organization of interdisciplinary, collaborative research teams; development of better in vitro and in vivo models, as well as improved experimental designs for studies of multiple organisms; and systematic analysis of large datasets. NIDCR has high expectations that the research supported would result in information that would enhance diagnosis, treatment, and prevention of diseases of the oral cavity.
The Council agreed that the proposed concept was strong. The Council suggested that NIDCR revise the concept to encourage investigators to study the interactions of commensal pathogens, as well as using the pathogens to prevent or treat infections. The Council also noted two editorial changes, to correct word usage.
The Council unanimously approved the concept.
Simian Models for the Oral Biology of HIV Infection and AIDS-Related Oral Complications
Dr. Mostafa Nokta, Health Scientist Administrator and Program Director, AIDS and Oral Manifestations of Immunosuppression Program, DBTS, described a concept for a PA to stimulate research on the oral biology of HIV infection and the oral complications associated with AIDS in a nonhuman primate model. These models are especially useful for studying infectious diseases because the immune system in nonhuman primates closely approximates that in humans. Much of the current knowledge about HIV/AIDS has been enhanced by studies of nonhuman primates. NIH supports approximately 90 studies of HIV in simian AIDS models, but only 4 studies are supported by NIDCR. The oral complications of HIV have yet to be characterized in simian AIDS models. Existing animal colonies provide a unique opportunity to explore in depth the oral complications of AIDS and the potential transmission of HIV via the oral mucosa. Under the proposed PA, investigators would be expected to establish collaborations with researchers in ongoing projects involving macaques and to fully utilize state-of-the-art technologies such as genomics, proteomics, bioimaging, and gene silencing. By adding an oral component to existing studies, NIDCR would be able to leverage its planned use of set-aside funds to support the research.
In discussion, the Council emphasized the need to make outreach between oral researchers and simian AIDS researchers a “two-way street.” In addition, the Council noted that primate centers do not have sufficient resources to support adding other organisms and pathogens to ongoing studies, but probably could tag oral components onto these studies, without introducing new pathogens, at minimal cost. The Council suggested that NIDCR pursue the following revisions and actions:
- Encourage existing centers of simian AIDS research to reach out to, and interact with, the oral research community—in addition to encouraging oral researchers to connect with existing centers.
- Foster this interaction, as a first step, by convening a conference that brings together oral researchers and current simian investigators.
- Discuss, with the National Center for Research Resources, ways that NIDCR can leverage its resources as an incentive to add observational studies in oral research onto existing primate studies.
- Compile a database of the approximately 90 simian research protocols currently supported by NIH. Review these research grants and identify those that might be appropriate for adding an oral component.
- State clearly in the PA the NIDCR intent to support research that would be added onto existing, meritorious primate research protocols.
The Council unanimously approved the concept with the modification that wording be added to the PA to restrict studies to existing protocols.
General Discussion
Link between Concepts and NIDCR Planning . The Council asked how the concepts developed by staff fit into the management of the NIDCR extramural and intramural research portfolios. Dr. Tabak noted that the new NIDCR Strategic Plan provides a framework and that staff are developing the follow-up implementation plan that will enable NIDCR to tag the concepts proposed directly to the budget and research portfolio.
Funding of Concepts . The Council noted the need to receive feedback on the funding of concepts that it approves, in order to “connect the dots” and to better advise NIDCR on the management of its portfolio. Dr. Tabak said that the tracking of concepts and identification of research gaps will be part of the implementation plan. He also noted that, as grants are funded, this information is provided to the public domain.
X. UPDATE ON PAIN CONSORTIUM
Dr. Tabak reported on the status and activities of the NIH Pain Consortium. The NIDCR participates in this consortium, and Dr. Tabak serves as co-lead with Dr. Story Landis, Director, National Institute of Neurological Diseases and Stroke, and Dr. Patricia Grady, Director, National Institute of Nursing Research. The three directors had asked Dr. Zerhouni, on his arrival as Director of NIH, to revitalize the Pain Consortium, which had languished because of changes in leadership since first established in the mid-1990s.
In summer 2003, representatives of 18 ICs attended the first meeting of the revitalized Pain Consortium. At this meeting, Dr. Zerhouni charged the consortium to (a) catalog and analyze the portfolio of pain research across the ICs, and (b) do outreach. He noted that chronic pain is a critical national problem and a tremendous burden on the health care system. He also noted that fundamental knowledge about pain is lacking and that pain research fits well with the NIH Roadmap as a multidisciplinary research area that would benefit from the involvement of many disciplines. Dr. Zerhouni urged the Pain Consortium to move forward with action.
Dr. Tabak noted that, after Dr. Zerhouni's remarks, each representative presented a capsule view of its IC's interest in pain research. The group then discussed the organization and goals of the consortium. Three major goals were defined, as follows: (i) to develop a comprehensive agenda of pain research, building on past efforts and moving forward to focus on inter- and multidisciplinary research areas that encourage broad participation by the ICs; (ii) to increase the visibility of pain research intramurally and extramurally, including among patient advocate groups and patients; and (iii) to explore the forging of necessary public–private partnerships to achieve the first two goals.
Since the summer meeting, the Pain Consortium has taken a number of actions in response to Dr. Zerhouni's charge. The IC representatives have held several meetings and have formed a subgroup to catalog NIH pain research. The subgroup has completed the cataloging of activities and a preliminary analysis. The consortium will review the results of the analysis in more detail at its next meeting in order to identify gaps in NIH-supported pain research. With regard to outreach, the consortium plans to re-establish its Web site and is discussing the content of the Web site (e.g., research only, NIH-supported research only, patient and research information). The three co-leads will present to the consortium a final concept for the site. Other outreach efforts will include sponsoring a seminar series and bringing in experts from the extramural research community to advise on the analysis of the NIH portfolio.
Dr. Tabak said that the Pain Consortium aims to be forward thinking and to plan intramural and extramural research activities over the next 3-4 years that will benefit the entire field of pain research. He noted that, although the NIDCR intramural program has one of the most active pain research programs at NIH, the magnitude of pain and pain research far exceeds the capacity of the intramural program and must involve the extramural community.
Discussion
The participants thanked Dr. Tabak for taking an active role in revitalizing the Pain Consortium and encouraged the consortium to seek the broadest contribution possible, including the involvement of professional societies and patient advocate groups addressing pain and pain research.
XI. UPDATE ON ROADMAP
Ms. Wendy A. Liffers, Associate Director for Policy Integration, NIDCR, presented an update on the NIH Roadmap. She highlighted salient points in the roadmap process, areas of emphasis, and implementation activities. The comprehensive NIH Web site for the roadmap can be accessed at http://nihroadmap.nih.gov or via direct links from the NIDCR or NIH Web sites. Ms. Liffers is the designated roadmap liaison for NIDCR.
The Roadmap Process. Ms. Liffers noted that NIH designed the roadmap process to involve all NIH stakeholders in identifying and prioritizing the most pressing problems and issues in biomedical research. The key questions asked of the participants during the process were: What are today's scientific challenges? What are the roadblocks to progress? What do we need to do to overcome roadblocks? What cannot be accomplished by any single institute and is the responsibility of NIH as a whole?
The 18-month development process began in August 2002 with an NIH consultation involving more than 100 leaders in biomedical research. This consultation was followed by a leadership forum of IC directors, in September 2002; formation of 15 working groups involving more than 300 experts, in March 2003; a presentation to the NIH Director's Council of Public Representatives (COPR), in April 2003; development of proposed initiatives and plans by the working groups, by May 2003; an IC director's retreat, on June 20; presentation of the draft roadmap to the Advisory Committee to the Director, on June 30; and public announcement of the NIH Roadmap, on September 30. Implementation of the roadmap is being staged through FY 2004 and beyond.
Areas of Emphasis. The NIH Roadmap embraces three themes, as mentioned by Dr. Zerhouni (see section V above), and nine implementation groups. Under New Pathways to Discovery, five implementation groups are focusing separately on building blocks, pathways, and networks; molecular libraries and imaging; structural biology; bioinformatics and computational biology; and nanomedicine. Under Research Teams of the Future, three implementation groups are focusing on high-risk research; interdisciplinary research; and public–private partnerships. Under Re-engineering the Clinical Research Enterprise, one implementation group is focusing on all aspects of clinical research—translation of basic findings into treatment and prevention strategies, partnerships among patients and researchers and others, standards and regulations, and clinical informatics.
The nine implementation groups are pursuing 28 specific initiatives. The considerations weighed by each group in defining the initiatives are: Is the initiative truly transforming—will it change how or what biomedical research is conducted in the next decade? Would the outcomes be used by and synergize the work of many ICs? Can the NIH afford not to do it? Will be the initiative be compelling to the NIH stakeholders, especially the public? Does the initiative position NIH as unique—doing something that no other entity can or will do?
Interdisciplinary Research Teams of the Future. Ms. Liffers elaborated on the activities of the implementation group addressing interdisciplinary research (IR) teams of the future. This group is co-chaired by Dr. Tabak, Dr. Kenneth Olden, Director, National Institute of Environmental Health Sciences, and Dr. Patricia Grady, Director, National Institute of Nursing Research. The group consists of more than 35 representatives from 22 ICs and offices within the Office of the Director, NIH. The group determined that NIH already is robustly addressing multidisciplinary research—bringing together individuals and teams from different disciplines to focus collectively on complex research issues. It is therefore focusing on initiatives to help catalyze inter disciplinary research—to bring different expertise to the creation and melding of a new discipline. The group has been charged to consider the type of efforts that could lead to new and novel disciplines. Within this framework, multidisciplinary research is viewed as a precursor to interdisciplinary research.
The implementation group has formed the following six subgroups to develop initiatives (implementation plans) for FY 2004-09: interdisciplinary research centers, interdisciplinary research training, removing structural barriers to interdisciplinary research, innovations in interdisciplinary technology and methods, NIH intramural program as a model for interdisciplinary research, and a conference committee charged to consider the interface of life sciences and physical sciences. With regard to the conference committee, Ms. Liffers noted that the Congress has asked NIH to take the lead in organizing an interagency conference to address the interface of the two fields of science.
Implementation. As previously noted, Dr. Kleinman is the NIH's Assistant Director for NIH Roadmap Coordination. Located in the Office of the Director, NIH, she reports to the Deputy Director and the Director, NIH. She is assisted by the NIH Roadmap Implementation Coordination Committee which consists of the chairs of the nine implementation groups, who are responsible for implementation of initiatives, and representatives from offices within the Office of the Director, NIH. Communication with each IC is maintained through lead IC-designated liaisons for the roadmap.
The NIH has budgeted $128 million for implementation of the roadmap in FY 2004; expenditures for FY 2004-09 will total more than $2 billion. The NIH has estimated the annual funding levels for each of the three thematic areas. For FY 2004, NIH would allocate $64 million to New Pathways to Discovery, $27 million to Research Teams of the Future, and $38 million to Re-engineering the Clinical Research Enterprise. The funds will be contributed from the NIH Director's discretionary fund and from each IC, at approximately 0.34 percent of each IC's budget. In FY 2004, $35 million would come from the discretionary fund and $93 million would come from the ICs; NIDCR would contribute $1.3 million.
Ms. Liffers noted that NIH has already announced 14 of the 28 initiatives planned. These include RFAs, Requests for Proposals (RFPs), and Broad Agency Announcements (BAAs). She also noted that the implementation group on IR teams of the future developed 6 of the current 14 announced initiatives. These initiatives, all RFAs, are: Interdisciplinary Health Research Training: Behavior, Environment, and Biology: Short Programs for Interdisciplinary Research Training; Curriculum Development Award in Interdisciplinary Research; Centers for Innovation in Membrane Protein Production, Exploratory Centers (P20s) for Interdisciplinary Research; and Training for a New Interdisciplinary Research Workforce.
Discussion
Dr. Tabak and the Council strongly encouraged dental, oral, and craniofacial researchers to apply for research funds in response to the initiatives of the NIH Roadmap. Dr. Tabak noted that, through the NIH Roadmap, NIDCR will be able to leverage its contribution of $1.3 million in FY 2004 to gain access to $128 million for its research community.
The Council noted the need for a concerted effort to advertise the roadmap in the dental, oral, and craniofacial research community and to encourage research grant applications from this community, especially for the 14 initiatives already announced. Dr. Tabak emphasized that the entire research community must be engaged in the roadmap, and he urged Council members to visit the NIH Web site for detailed information on the implementation plans for each thematic area and the activities of the implementation groups and subgroups. He also encouraged the members to contact Ms. Liffers and the NIDCR designated liaisons for the roadmap areas.
Dr. Tabak commented on the review processes for applications submitted in response to roadmap initiatives. NIDCR staff will participate only in the review of applications received from the dental, oral, and craniofacial research community. Dr. Tabak emphasized that NIH is developing new mechanisms of support and review and that the community and NIDCR should be involved in this process. An NIH committee under the guidance of Dr. Kleinman is addressing this topic.
Dr. Tabak noted that NIDCR has utilized several approaches to advertise the roadmap in the research community. For example, Dr. Tabak wrote an editorial on future research directions, which was published in the Journal of Dental Research , and staff hosted a forum and exhibit booth at the annual meeting of the American Association for Dental Research. An interview with Dr. Tabak conducted by the Inside Scoop is posted on the NIDCR Web site ( www.nidcr.nih.gov ).
CLOSED PORTION OF THE MEETING
This portion of the meeting was closed to the public in accordance with the determination that it was concerned with matters exempt from mandatory disclosure under Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix 2).
There was a discussion of procedures and policies regarding voting and confidentiality of application materials, committee discussions, and recommendations. Members absented themselves from the meeting during discussion of and voting on applications from their own institutions, or other applications in which there was a potential conflict of interest, real or apparent. Members were asked to sign a statement to this effect.
XII. REVIEW OF APPLICATIONS
Grant Review
The Council considered 418 applications requesting $77,564,710 in total costs. The Council recommended 311 applications for a total cost of $58,546,576 (see Attachment II).
ADJOURNMENT
The meeting was adjourned at 4:10 p.m. on January 20, 2004 .
CERTIFICATION
I hereby certify that the foregoing minutes are accurate and complete.
____________________________
Dr. Lawrence A. Tabak
Chairperson
National Advisory Dental and Craniofacial Research Council
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Dr. Norman S. Braveman
Executive Secretary
National Advisory Dental and Craniofacial Research Council
ATTACHMENTS
I. Roster of Council Members
II. Table of Council Actions
III. Director's Report to the NADCRC, January 2004
NOTE: A complete set of open-portion handouts is available from the Executive Secretary.