Date: September 20, 2016
Place: Conference Room 6
National Institutes of Health
The 213th meeting of the National Advisory Dental and Craniofacial Research Council (NADCRC) was convened on September 20, 2016, at 8:30 a.m., in Building 31, Conference Room 6, National Institutes of Health (NIH), Bethesda, Maryland. The meeting was open to the public from 8:30 a.m. to 12:45 p.m.; it was followed by the closed session for Council business and consideration of grant applications from 1:45 p.m. until adjournment at 2:20 p.m. Dr. Martha Somerman presided as Chair.
Dr. Patricia E. Arola (ex officio)
Dr. Shenda M. Baker
Dr. Yang Chai (via telephone)
Dr. Richard Peters Darveau
Ms. Tracy Hart
Dr. Yvonne L. Kapila
Dr. Daniel Malamud
Dr. Phillip B. Messersmith
Dr. Anne Louise Oaklander
Dr. Sanjay Shete
Dr. Anne C. R. Tanner
Dr. Jane A. Weintraub
Dr. Benjamin Alexander White, Jr.
Dr. Terrence S. Batliner
Dr. Nisha J. D’Silva
Dr. Daniel W. McNeil
Members of the Public
Dr. Seun Ajiboye, Senior Policy Analyst, International Association for Dental Research (IADR) and American Association for Dental Research (AADR), Alexandria, VA
Dr. John Bartlett, Professor, Johns Hopkins University School of Medicine, and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Dr. Robert J. Burns, Manager, Legislative and Regulatory Policy, American Dental Association (ADA), Washington, D.C.
Ms. Jean Calvo, American Dental Education Association (ADEA)/Sunstar Americas, Inc./Jack Bresch Student Legislative
Internship, and dental student, University of California at San Francisco School of Dentistry, CA
Dr. Umesh S. Deshmukh, Associate Member, Oklahoma Medical Research Foundation, and Professor of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
Dr. Gypsyamber D’Souza, Associate Professor of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Ms. Jennifer Garvin, Washington Editor and Government Affairs, ADA, Washington, D.C.
Dr. Linda Kaste, AADR Scholar in Residence, and Associate Professor of Pediatric Dentistry, University of Illinois at Chicago College of Dentistry, Chicago, IL
Mr. B. Timothy Leeth, Senior Director for Federal Relations, ADEA Policy Center - Advocacy and Governmental Relations, ADEA, Washington, D.C.
Dr. Britta E. Magnuson, ADEA/Sunstar Americas, Inc./Harry W. Bruce, Jr., Legislative Fellow, ADEA, Washington, D.C., and Assistant Professor, Tufts University School of Dental Medicine, Boston, MA
Dr. Jeffrey S. Mogil, Professor, Department of Psychology, and Head, Centre for Research on Pain, McGill University, Montreal, Quebec, Canada
Mrs. Carolyn Mullen, Director of Government Affairs, IADR and AADR, Alexandria, VA
Dr. Scott R. Schricker, Assistant Dean for Student Research and Associate Professor, The Ohio State University College of Dentistry, Columbus, OH
Federal Employees Present
National Institute of Dental and Craniofacial Research
Dr. Martha J. Somerman, Director
Dr. Alicia Dombroski, Executive Secretary, and Director, Division of Extramural Activities (DEA)
Dr. Lillian Shum, Director, Division of Extramural Research (DER)
Dr. Robert Angerer, Scientific Director, Division of Intramural Research (DIR)
Dr. John W. Kusiak, Office of the Director (OD), Acting Deputy Director
Dr. Matthew P. Hoffman, Deputy Scientific Director, DIR, and Chief, Matrix and Morphogenesis Section (MMS), Laboratory of Cell and Developmental Biology (LCDB), DIR
Dr. Margo Adesanya, OD, Office of Science Policy and Analysis (OSPA)
Dr. Israel Agaku, OD, OSPA, Dental Public Health Resident
Dr. Jane Atkinson, DER, Center for Clinical Research (CCR)
Dr. Monisha Billings, OD, OSPA, Dental Public Health Resident
Dr. Karina Boehm, OD, Office of Communications and Health Education (OCHE)
Dr. Preethi Chander, DER, Integrative Biology and Infectious Diseases Branch (IBIDB)
Ms. Patricia Chestnut, Office of Administrative Management (OAM)
Ms. Mary A. Cutting, DER, CCR
Mr. Bret Dean, OAM, Financial Management Branch (FMB)
Dr. Bruce Dye, OD, OSPA
Dr. Olga Epifano, DEA
Dr. Dena Fischer, DER, CCR
Dr. Leslie Frieden, DEA, Research Training and Career Development Branch (RTCDB)
Dr. Crina Frincu, DEA, Scientific Review Branch (SRB)
Dr. Gallya Gannot, DER, CCR
Dr. Nicole Garcia-Quijano, OD, OCHE, Health Information and Public Liaison Branch (HIPLB)
Mr. Joel Guzman, DER, Translational Genomics Research Branch (TGRB)
Dr. Sue Hamann, OD, OSPA
Dr. Emily Harris, DER, TGRB
Ms. Jeannine Helm, DER
Mr. Gabriel Hidalgo, DEA, Grants Management Branch (GMB)
Dr. Laura Hsu, DER, CCR
Dr. Alexander Richard Kailembo, OD, OSPA, Dental Public Health Resident
Dr. Lynn King, DEA, RTCDB
Dr. Wendy Knosp, OD, OSPA
Ms. Carol Loose, OAM, FMB
Dr. Orlando Lopez, DER, IBIDB
Dr. Nadya Lumelsky, DER, IBIDB
Dr. R. Dwayne Lunsford, DER, IBIDB
Ms. Jayne Lura-Brown, DER
Dr. Amanda Melillo, DER, IBIDB
Dr. Marilyn Moore-Hoon, DEA, SRB
Dr. Dawn Morales, DER, Behavioral and Social Sciences Research Branch (BSSRB)
Ms. Anna Nicholson, OD, Office of Clinical Trials Operations and Management (OCTOM)
Mr. Michael David North, OAM
Dr. Morgan O’Hayre, OD
Dr. Deborah Philp, DIR, Office of Education (OE)
Ms. Ann Poritzky, OD, OCHE, Science Communication and Digital Outreach Branch (SCDOB)
Mr. John Prue, OD, Office of Information Technology (OIT)
Dr. Melissa Riddle, DER, BSSRB
Ms. Delores Robinson, DEA
Ms. Diana Rutberg, DEA, GMB
Dr. Steven Scholnick, DER, TGRB
Dr. Yasaman Shirazi, DEA, SRB
Dr. Kathryn Stein, DER, TGRB
Ms. Kathleen Stephan, OD
Dr. Jennifer Symonds, DIR, LCDB
Dr. Yolanda Vallejo-Estrada, DER, IBIDB
Dr. Sundar Venkatachalam, DER, IBIDB
Dr. Jason Wan, DER, IBIDB
Ms. Delores Wells, OD, OSPA
Dr. Gary Zhang, DEA, SRB
Dr. Lois K. Cohen, Consultant
Dr. Iddil Bekirov, Program Analyst, Common Fund Programs, Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes, Digestive, and Kidney Diseases, NIH
Dr. Janine Austin Clayton, NIH Associate Director for Research on Women’s Health, and Director, Office of Research on Women’s Health, NIH
Dr. Tom Hart, Senior Director, ADA Foundation, Dr. Anthony Volpe Research Center, National Institute of Standards and Technology (NIST), U.S. Department of Commerce (DOC), Gaithersburg, MD
Dr. Jeffrey J. Kim, Project Leader, Clinical Research, ADA Foundation, Dr. Anthony Volpe Research Center, NIST, DOC, Gaithersburg, MD
I. WELCOME AND INTRODUCTIONS
Dr. Martha Somerman, Director, NIDCR, called the 213th meeting of the Council to order. She welcomed everyone, including Council members, guests, and participants attending via the NIH videocast (http://videocast.nih.gov). She noted that two Council members are rotating off the Council, as their terms expire. She thanked Dr. Yvonne L. Kapila and Dr. Benjamin Alexander White, Jr. and gave each a certificate of appreciation and a small gift of an NIDCR mug. Dr. Alicia Dombroski, Executive Secretary, NADCRC, thanked Dr. Kapila and Dr. White for their selfless service to the Council.
Dr. Somerman introduced three individuals attending the meeting in an ad hoc capacity pursuant to their official designation as Council members. The ad hoc members are Dr. Terrence S. Batliner, Dr. Nisha J. D’Silva, and Dr. Daniel W. McNeil. [See Attachment I, Roster of Council Members.]
Dr. Somerman introduced Dr. Morgan O’Hayre, who joined the NIDCR in November 2015 as Special Assistant to the Director and Deputy Director, NIDCR. Dr. Robert Angerer, Scientific Director, Division of Intramural Research (DIR), introduced Dr. Matthew P. Hoffman as NIDCR’s new Deputy Scientific Director, who will also continue to serve as chief of the Matrix and Morphogenesis Section in DIR’s Laboratory of Cell and Developmental Biology. Dr. Nadya Lumelsky, chief of the Integrative Biology and Infectious Diseases Branch (IBIDB) in the Division of Extramural Research (DER), introduced Dr. Orlando Lopez, the new director of IBIDB’s Dental and Biomaterials Research Program. Dr. Bruce Dye, director of the NIDCR Dental Public Health Residency Program, Office of Science Policy and Analysis (OSPA), Office of the Director (OD), introduced three Dental Public Health Residents—a full-time resident, Dr. Alexander Richard Kailembo, and two part-time residents, Dr. Monisha Billings and Dr. Israel Agaku.
Dr. Dombroski invited all guests to introduce themselves and welcomed everyone viewing the meeting via the NIH videocast.
II. FUTURE MEETING DATES
January 24, 2017
May 23, 2017
September 15, 2017
January 31, 2018
May 25, 2018
September 13, 2018
III. APPROVAL OF MINUTES FROM PREVIOUS MEETING
Dr. Alicia Dombroski invited the Council to consider and approve the minutes of the May 24, 2016, Council meeting. The Council unanimously approved the minutes.
IV. REPORT OF THE DIRECTOR, NIDCR
Dr. Somerman reported on “NIDCR: A Vision for 2030.” She summarized “where we started and where we are now” with regard to the NIDCR portfolio in Fiscal Year (FY) 2015, and she enumerated four broad visionary goals for the NIDCR. Following her report, Dr. Morgan O’Hayre outlined steps that the NIDCR will take to prepare the draft plan, “NIDCR 2030: a Vision for the Future.” Dr. Somerman’s written Director’s Report to the Council: September 2016 was provided to the Council members and is available on the NIDCR website (http://www.nidcr.nih.gov).
Where We Started and Where We Are Now
Dr. Somerman noted that the NIDCR was founded in 1948 as the National Institute of Dental Research, with a charge to address the nation’s crisis in dental caries, and that today, the NIDCR provides the majority of dental research funding in the country and supports nearly all research training. She noted that with an operating budget of $413 million in FY 2016, the NIDCR continues to seek to improve dental, oral, and craniofacial research through research, research training, and dissemination of information. The NIDCR allocates approximately 85 percent of its budget to extramural research and supports more than 90 percent of career development and training in U.S. dental schools.
Dr. Somerman noted that while the NIDCR begins to plan for 2030, it will continue to attend to the current NIDCR Strategic Plan: 2014‒2019. The four strategic goals of this plan are to support the best science, enable precise and personalized oral health care through research, apply rigorous multidisciplinary research approaches to overcome disparities in health, and ensure that a strong research workforce is dedicated to improving dental, oral, and craniofacial health. She specifically noted for the Council that because of the success of the NIDCR Small Grant Program for New Investigators (R03), in enabling young investigators to move on to individual investigator-initiated research grants (R01s) and other NIH-supported research awards, the NIDCR will increase support for the R03 program from $150,000 to $200,000 per year for up to 2 years.
Dr. Somerman presented a schematic conveying the breadth and extent of NIDCR support. She noted that the Institute supports the full continuum of research, from basic to translational, clinical, and community research. The research, which may be investigator-initiated (85%) or stimulated by NIDCR initiatives and programs (15%), covers a broad array of disciplines and all diseases and conditions pertinent to dental, oral, and craniofacial health. The NIDCR also provides support for areas underpinning this research—workforce development, tools and technologies, data science and “’omics,” and health disparities. She noted that in FY 2015 alone, the NIDCR funded more than 750 grants and more than 350 training and career development awards at more than 200 institutions or small businesses in 43 states. This support was extended to more than 6,500 oral health researchers and approximately 190,000 practicing dentists.
Dr. Somerman stated that looking toward 2030 the NIDCR envisions the oral cavity as a window for assessing oral health and overall health for all people. The specific NIDCR vision is to be a catalyst for driving breakthrough discoveries, transforming research to knowledge, and enhancing oral health for all people. She set forth the following four bold visionary goals to ensure the NIDCR’s research endeavors: Embrace integrated oral, total body approaches to address research questions; promote evidence-based, cost-effective health care and prevention strategies; overcome health disparities and facilitate a diverse workforce; and enhance engagement and partnerships with existing stakeholders and with broader communities.
Dr. Somerman noted that the NIDCR will be soliciting public input on “how to get there” by engaging broad communities at different career stages, consulting with the Council, and utilizing the Web-based tool, IdeaScale. The expected outcomes of the planning effort include building on existing programs and capitalizing on new discoveries; holding workshops to consider and refine top, unique ideas; inviting selected individuals with ideas to participate in workshops; developing several high-risk, high-reward initiatives; and stimulating high-quality proposals in new areas.
How to Get to 2030
Dr. O’Hayre elaborated on the IdeaScale product. She noted that it has been used in the Federal Government and by several NIH institutes and centers (ICs) and is a useful tool for engaging communities and soliciting public input. She also noted that it can be customized for a website and includes review and management tools with which to analyze responses and address questions. She described the experience of the National Cancer Institute (NCI) in using IdeaScale to invite public input on the Cancer Moonshot project, to review the ideas and comments submitted, and then to convey NCI’s research priorities and receive feedback on them. Similarly, the National Heart, Lung, and Blood Institute recently used IdeaScale to obtain input on compelling questions and critical challenges to address in its strategic visioning process.
Dr. O’Hayre suggested that the NIDCR could use the IdeaScale product to engage the public on how to reach the four strategic goals set forth by Dr. Somerman and, specifically, to identify innovations and technologies that would leverage hurdles, gaps, and needs. That is, which tools/technologies and basic/translational/clinical research would result in novel initiatives to direct precision health for all people? Dr. O’Hayre outlined the timeline for preparing the draft NIDCR 2030 plan, which begins with Council’s discussion at the present meeting and culminates with issuance of Funding Opportunity Announcements (FOAs) in 2018‒2019. Intermediate steps include design of the IdeaScale site by January 2017, launch of the site for public comment in March 2017, analysis of feedback and planning of workshops in May‒July 2017, and the convening of workshops and refinement of ideas in fall 2017. Throughout the process, the NIDCR could invite public comment and feedback, as needed, using the site.
In closing, Dr. O’Hayre emphasized that future oral health advances will come at the crossroads of disciplines and communities and that the NIDCR role as a catalyst is critical. Dr. Somerman noted that the NIDCR is very excited about this strategic visioning effort.
V. CONCEPT CLEARANCES
Dr. Dombroski stated that the NIDCR is required to present the purpose, scope, and objectives of staff-developed concepts for NIDCR initiatives in a public forum for the Council’s discussion, review, and approval. Staff presented four concepts for the Council’s review, and designated Council members led the discussion of each.
Oral HIV Vaccine-Induced Humoral Immunity and HIV Specific B Cell Ontogeny
Dr. Sundar Venkatachalam, program director of the Oral and Salivary Cancer Biology Program, IBIDB, DER, presented a proposed initiative on behalf of Dr. Isaac Rodriguez-Chavez, who formerly led NIDCR’s AIDS and Immunosuppression Program in the IBIDB and is no longer with the NIDCR. Dr. Venkatachalam reported that the goal of the initiative would be to support research aimed at developing novel approaches and vaccine designs for inducing oral humoral immune responses against human immunodeficiency virus (HIV) infection. He noted that despite 30 years of research in the field, there are many gaps and opportunities to explore. A protective HIV vaccine has yet to be developed, and only one vaccine has shown limited efficacy in a human clinical trial. He noted, however, that induction of partially protective anti-HIV antibodies upon HIV immunization raises hope for development of an effective vaccine. And, preclinical data in non-human primates show that sublingual and tonsillar immunizations trigger immune responses to simian immunodeficiency virus (SIV) infection in the animals’ oral mucosa and other body sites.
Dr. Venkatachalam highlighted five specific areas of interest in which the NIDCR would encourage research. Two of these would be to test new SIV immunogens and immunization strategies in non-human primates, to induce oral neutralizing antibodies, and to elucidate genetic and immune mechanisms that govern induction of oral anti-HIV immunoglobulins. Three more would be to determine the impact of B cell ontogeny on HIV vaccine-induced oral humoral immunity, to determine the effects of oral innate and cellular immunity on anti-HIV immunoglobulins upon vaccination, and to use single cell analyses and ‘omics approaches to assess oral innate and adaptive immunity after oral HIV vaccination.
The Council’s lead discussants, Dr. Richard Darveau and Dr. Anne Tanner, supported the concept. Dr. Darveau noted that continued research is needed in this area, exciting preliminary data have been obtained, and knowledge of the mucosal environment, including the oral cavity, is limited. Dr. Tanner suggested that implementation of the concept as an NIDCR initiative would stimulate research on HIV prevention. In discussion, Dr. Venkatachalam commented on the failure of HIV vaccine clinical trials. He noted that investigators have not studied the oral route of immunization against HIV infection and that recent studies indicate that the oral route may be a better way to vaccinate against HIV infection.
The Council unanimously approved the concept. [Per the Council’s consideration of the next concept, summarized below, the Council unanimously recommended that the NIDCR consider combining the two concepts into one concept. See below.]
Oral HIV Pathogenesis, Mucosal Immunity, and Prophylactic Vaccines Modulation by the Oral Microbiota
Dr. R. Dwayne Lunsford, program director of the Microbiology Program, IBIDB, DER, presented a related concept, also on behalf of Dr. Rodriguez-Chavez. The goal of this concept would be to encourage research projects that examine the role of and the mechanism by which oral microbiota influence oral HIV pathogenesis, mucosal immunity, immune cell homeostasis, and the immunogenicity and efficacy of prophylactic HIV vaccines.
Dr. Lunsford said that the NIDCR would seek to encourage researchers to define oral microbiota perturbations that may exacerbate oral HIV pathogenesis and associated oral diseases and to examine how HIV infection may disrupt the composition of oral microbiota. The NIDCR also would encourage research to delineate mechanisms for microbiota‒immune system interactions that maintain homeostasis or trigger immune dysfunction and oral diseases and to determine the mechanisms that govern the possible adjuvant effect of oral microbiota in oral HIV vaccine-induced immune responses, as well as mechanisms by which it may interfere with the efficacy of an oral prophylactic HIV vaccine in non-human primate models. In addition, the NIDCR would support studies that examine mechanisms by which maternal vaginal microbiota in HIV-infected mothers exert an impact on offspring’s oral microbiota and HIV-associated oral disease.
The Council’s lead discussants, Dr. Tanner and Dr. Darveau, supported the scope of the concept and elaborated on the evidence for interactions among HIV infection and treatment, diversity of oral microbiota, immune function, and dysbiosis and disease. They noted the importance of research on how immune homeostasis is maintained in individuals with HIV infection. In discussion, the Council agreed with their comments and suggested that research on the oral microbiota before and after HIV infection would be informative and could be conducted in non-human primates and among patients whose status of HIV infection is being followed clinically, to assess disease progression, and in those who are long-term non-progressors.
Dr. Somerman thanked the Council members for their comments and asked whether the NIDCR should consider combining the two, HIV-related concepts into one concept. The Council members discussed this possibility and agreed that the two concepts could be combined into a single, broader concept.
The Council unanimously approved the concept, as presented, and recommended that the NIDCR consider combining the two concepts into a single, broader concept.
Neuroskeletal Biology of the Dental and Craniofacial Skeletal System
Dr. Jason Wan, program director of the Mineralized Tissue Physiology Program, IBIDB, DER, presented a proposed concept to identify and utilize novel regulators of neural processes to optimize normal homeostasis and to repair or regenerate mineralized tissues of the dental and craniofacial skeletal systems (DCS). He noted that research in neuroskeletal biology has been focused mainly on appendicular bones and that extrapolation of this research to the DCS is limited because of the differences between the two skeletal systems’ embryological origin, forces experienced, and microenvironment. Further, although there has been much research on the morphogenesis of the DCS, there are few data on the role of the nervous system in postnatal maintenance and regeneration of the DCS.
Dr. Wan noted that these gaps suggest opportunities for studies that elucidate the neuroskeletal biology of the DCS, drawing on advances made in understanding that of the appendicular skeleton; that take advantage of new technologies for tracing, imaging, and manipulating neuronal cells; and that encourage productive multidisciplinary collaborations in this research area. Specific areas of interest would include the identification and characterization of cellular and molecular mediators and pathways involved in crosstalk between the nervous system and the DCS and the elucidation of functional effects of the nervous system on tooth tissues (dentin, enamel, cementum) and alveolar and craniofacial bone. Three other areas would be the development of strategies to modulate and control the effects of the nervous system on the DCS, the amelioration of DCS disease and enhancement of regenerative functions of DCS tissues, and the development of models to investigate neural‒DCS interfaces and cross-talk.
The Council’s lead discussants, Dr. Yang Chai (via telephone), Dr. Anne Louise Oaklander, and Ms. Tracy Hart, expressed enthusiasm and full support for the proposed concept. Dr. Chai elaborated on the importance of this research and said that the concept is timely, would advance craniofacial research and tissue engineering, and is a good fit for the NIDCR’s mission. Dr. Oaklander noted that the research proposed is truly novel and applicable to the treatment of pain and regeneration of tissues. Ms. Hart commented, as a patient advocate, that the research could benefit patients’ quality of life.
The Council unanimously approved the concept.
NIDCR Dental Specialty‒Ph.D. Program (DSPP)
Dr. Lynn Mertens King, chief of the Research Training and Career Development Branch, DEA, presented a proposed initiative to support a combined Dental Specialty and Ph.D. Program (DSPP) for early-career-stage dentist and other clinician scientists (i.e., individuals who have recently completed their clinical doctoral degree), to prepare them for research careers as highly skilled investigators and leaders in the full scope of dental, oral, and craniofacial research. She noted that the NIDCR currently has no structured, institutional career development programs for early-career-stage dentists who wish to pursue both research training toward a Ph.D. degree and training in an advanced dental specialty, so as to prepare them for academic research careers. Dr. King noted the proposed initiative would fulfill an opportunity to sponsor a flexible and integrated institutional research career development program for dentist scientists who are seeking advanced clinical knowledge in a dental specialty and mentored research training leading to a Ph.D. in biomedical or behavioral science.
Dr. King highlighted four characteristics of the proposed program. The DSPP would support an integrated research and clinical specialty training program that leads to a Ph.D. and a certificate and/or master’s degree in a dental specialty recognized by the American Dental Association. The phasing and integration of the Ph.D. and dental specialty work would be determined by the participating graduate school and specialty program(s). The total length of the combined program should be less than if a dental specialty and Ph.D. training were pursued separately. The NIDCR would support up to 5 years of an individual’s Ph.D. research training program, and a separate institution or other source would be required to support, independently from the NIDCR, a well-mapped dental specialty program.
The Council’s lead discussants, Dr. Yvonne Kapila and Dr. Jane Weintraub, enthusiastically supported the concept. Dr. Kapila noted concerns about the state of dental research in dental schools, the “aging out” of dental faculty, and other obstacles affecting the state of dental science, such as graduating dentists’ need to pay off dental school debts and dental schools’ lack of emphasis on providing or fostering research experiences for their students. She suggested that the NIDCR identify potential partners (e.g., American Association for Dental Research, American Dental Education Association) for this effort and highlight the possibility of loan repayment options. Dr. Weintraub remarked that the concept is timely, greatly needed, well-defined, and broadly inclusive and that it provides for flexibility—all of which would make for a strong training program.
In discussion, the Council said that such a program is desperately needed and deserves additional support. Dr. King clarified that the design of the clinical specialty programs is up to each university or dental school, not the NIDCR, and that NIDCR support (e.g., for salaries and research during the research phase) and the options for loan repayment would accord with NIH policy.
The Council unanimously approved the concept.
VI. SPECIAL SESSION ON FACTORS UNDERLYING DIFFERENCES IN FEMALE AND MALE PRESENTATION OF SPECIFIC DISEASES AND CONDITIONS
Dr. Somerman welcomed and introduced Dr. Janine Austin Clayton, NIH Associate Director for Research on Women’s Health, and Director, Office of Research on Women’s Health (ORWH), NIH. She noted that Dr. Clayton, who has led the ORWH since 2012, is a strong partner on women’s and gender issues in health and research for all of the NIH, including the NIDCR. Dr. Clayton is the second director of the ORWH, succeeding Dr. Vivian Pinn.
Dr. Clayton opened the special session with a presentation entitled “Setting the Stage: Sex as a Biological Variable (SABV) in Action.” She described the evolution of NIH’s focus on women’s health, NIH’s policy and action on SABV, and ORWH’s partnership with the NIDCR. Dr. Clayton noted that the ORWH is celebrating a quarter century of women’s health research at the NIH. Established in 1990, the ORWH launched the Women’s Health Initiative a year later and this was followed in 1993 with the NIH mandate (in the NIH Revitalization Act) to include women and minority groups in NIH-funded clinical research. She noted that the ORWH is today the NIH focal point for research on sex/gender influences on health and on the health of women, for the benefit of girls, women, boys, and men. The ORWH’s mission is to (a) examine sex and gender influences on health and disease; (b) strengthen and enhance research related to diseases, disorders, and conditions that affect women; and (c) develop opportunities and support for recruitment, retention, reentry, and the sustained advancement of women in biomedical careers.
Dr. Clayton said that just over half of NIH-funded clinical research participants are women and that much more is being learned about the role of sex and gender in medicine. For example, sex differences in drug effects are already well-known for some drugs (e.g., Ambien, aspirin), though not yet for others. The NIH, in 2016, is moving beyond just inclusion of women to studying all aspects of sex/gender influences on health and disease. Dr. Clayton noted that the ORWH is actualizing its mission, in partnership with the ICs, to include sex/gender influences in all research, from basic, preclinical studies to translational research and Phase I‒IV clinical trials. This broader effort includes cell and animal studies, education initiatives, sex-specific data analyses and reporting, health care, and health policy.
Dr. Clayton reported that the new policies for preclinical research were announced by herself and Dr. Francis S. Collins, Director, NIH, in 2014 (“NIH to balance sex in cell and animal studies,” Nature, May 14) and that in 2015, she authored a follow-up article (“Studying both sexes: a guiding principle for biomedicine,” The FASEB Journal online, October 29), in which she emphasized that “understanding scientific findings in the context of sex…is crucial for correctly applying research-derived knowledge toward achieving our ultimate objectives.” The NIH’s SABV policy, which became effective January 25, 2016, can be summarized as: “The NIH expects that sex as a biological variable will be factored into research designs, analyses, and reporting in vertebrate animal and human studies. “ Dr. Clayton noted that SABV in preclinical research will help to build the knowledge base for delivering more effective and mistake-proof personalized care. Of 10 recent drug recalls, for example, 8 had more adverse effects in women than in men. Dr. Clayton also said that NIH’s SABV policy is part of the NIH-wide Enhancing Reproducibility Initiative, which was announced by Dr. Collins and Dr. Lawrence A. Tabak, Principal Deputy Director, NIH, in “NIH plans to enhance reproducibility” (Nature, January 30, 2014).
Dr. Clayton called the NIDCR a true partner to the ORWH. Among the key issues for which the ORWH and NIDCR are providing research support are burning mouth syndrome (BMS), sex differences in pain sensation (e.g., the roles of prolactin and myelin basic protein) and pain conditions [temporomandibular joint disorder (TMD)], and sex differences in opioid addiction and treatment (risk of abuse, deaths from overdose, effectiveness in relieving pain). The ORWH also is supplementing NIDCR-supported research on sex differences in autoimmune disorders, human papillomavirus (HPV) associated with oral cancer, and osteoporosis.
In closing, Dr. Clayton emphasized “4 C’s” of studying sex to strengthen science. These are consider (design studies that take sex into account or explain why not), collect (tabulate sex-based data), characterize (analyze sex-based data), and communicate (report and publish sex-based data. She invited Council members to connect with the ORWH through www.NIH.gov/women, Twitter (@NIH_ORWH) or @JanineClaytonMD), and Facebook (NIHORWH).
In discussion, Dr. Clayton clarified the distinction between sex and gender. She noted that sex is a biological variable determined by chromosomal complement, whereas gender is a social construct that incorporates expectations of behavior, norms, standards, identity, and role. When unknown, the terms sex/gender, or sex or gender, are used. Pain is one instance in which sex and gender are interwoven. She noted also that the NIH has built in flexibility for appropriately accounting for sex and gender in existing research programs, which includes the funding of administrative supplements by the ORWH and ICs.
VII. NIDCR RELATED TOPICS IN RESEARCH ON SEX DIFFERENCES
Dr. Amanda A. Melillo, program director, Salivary Biology and Immunology Program, IBIDB, DER, summarized NIDCR’s support of research on dental, oral, and craniofacial diseases and conditions that affect women and men differently. She noted that there can be substantial sex differences in incidence, presentation, severity, and long-term progression of these diseases and conditions, and in response to treatment, and that there are critical scientific gaps in understanding the underlying mechanisms of these differences. She highlighted four conditions—autoimmune diseases, specifically Sjögren’s syndrome; TMD and other orofacial pain; salivary gland tumors; and HPV-associated oropharyngeal cancers—and noted that sex differences are also reported in dental caries.
Dr. Melillo noted that 75 percent of Americans living with autoimmune diseases are women. And, even though 9 out of 10 people who have Sjögren’s syndrome are women, the data on differences in disease severity between men and women are limited and genome-wide association studies (GWAS) focus on just the presence or absence of Sjögren’s syndrome established by clinical diagnosis. Further, although sex hormones, as well as genetics, environmental factors, aging, and infections have been reported to play a role in autoimmune diseases, including Sjögren’s syndrome, the mechanism of sex-based differences is not understood.
Dr. Melillo noted that TMD primarily affects women of childbearing age and its incidence declines sharply with advancing middle age. Evidence from the NIDCR-supported Orofacial Pain Prospective Evaluation and Risk Assessment (OPPERA) indicates that while women have significantly greater odds of developing chronic TMD, the incident rate of first-onset TMD in women is only marginally greater than in men, thereby suggesting the possibility of sex-based differences in pain hypersensitivity responses. Dr. Melillo remarked that other orofacial and overlapping pain conditions are also more common in women than in men and that for BMS specifically, which is highly associated with women and advancing age, the etiology and mechanisms are largely unknown.
Dr. Melillo noted that the incidence rate for cancers of the oral cavity and salivary glands is disproportionately higher for men than for women. Men have a 51 percent higher combined rate for the major salivary gland carcinomas, though the rate varies among tumor subtypes. Women have a 25 percent to 38 percent higher incidence rate than men for adenoid cystic, acinic cell, and muco-epidermoid carcinomas, whereas men have a 122 percent higher rate for squamous cell carcinomas of the salivary gland. She noted that HPV-associated oropharyngeal cancers are threefold to fivefold more common in men than in women, a rate that correlates only partially with behavioral risk factors, and recent studies indicate that men have lower seroconversion rates upon HPV infection than do females. Further research is therefore needed to elucidate the molecular basis of sex-based differences in oral cancers.
Dr. Melillo reported that in FY 2016, the NIDCR issued an FOA for research on factors underlying differences in female and male presentation for dental, oral, and craniofacial diseases and conditions. The FOA offered support through two Program Announcements to stimulate, respectively, R01s and exploratory/developmental grants (R21s). She noted that the FOA highlights the need for studies aimed at understanding immune reactivity, genetic and environmental triggers, and hormonal changes as they relate to sex-based differences, in anticipation of identifying new therapeutic targets leading to development of precision-medicine-based therapies. And, as noted above by Dr. Clayton, the ORWH and NIDCR are funding administrative supplements for research on sex/gender differences. Over the past 4 years, NIDCR-supported researchers have received supplements to add the opposite sex to their studies, increase their sample sizes, and conduct new comparative analyses in research on bone quality, early childhood caries, Sjögren’s syndrome, and pain.
Following her overview, Dr. Melillo introduced three NIDCR grantees who presented their respective research on sex/gender differences in autoimmune disorders, the oral HPV continuum (from infection to cancer), and cellular mediation of pain. Their presentations are summarized below.
VIII. FEMALE PREPONDERANT AUTOIMMUNE DISORDERS: MORE THAN JUST A MATTER OF IMMUNITY
Dr. Umesh S. Deshmukh, Associate Member, Oklahoma Medical Research Foundation (OMRF), and Professor of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, described his research to understand why Sjögren’s syndrome (SS) is preponderant in females. He acknowledged the contributions of his research team at the OMRF’s Arthritis and Clinical Immunology Program and the Oklahoma Sjögren’s Syndrome Center of Research Translation, and he thanked the NIH for funding this research along with the Oklahoma Center for Advancement of Science and Technology and the OMRF. He particularly thanked the NIDCR for stimulating his research on sex/gender as a variable and for providing an administrative supplement.
Dr. Deshmukh noted that among autoimmune disorders known to be female-preponderant, four disorders are 7 to 10 times more likely to arise in females than in men (SS, systemic lupus erythematosus, Graves’ disease, Hashimoto’s thyroiditis) and three disorders are 2 to 3 times more preponderant in females (multiple sclerosis, rheumatoid arthritis, and scleroderma). Influencing this preponderance are hormonal factors (e.g., estrogen versus testosterone) and incomplete X-chromosome inactivation, resulting in enhanced immune responsiveness at T and B cell levels and heightened innate immune responses. Dr. Deshmukh suggested, however, that the preponderance among women is not just a matter of immunity, but also of end-organ susceptibility versus resistance to immune injury.
Dr. Deshmukh described his research on the hypothesis that higher susceptibility of female end organs (in this case, salivary glands) for immune-mediated injury is a major reason for female preponderance of primary SS (pSS). He said the research team analyzed clinical presentations of disease in female and male pSS patients and developed experimental models to obtain insights into the mechanisms of end-organ susceptibility versus resistance in SS. Dr. Deshmukh described the design of the clinical study, the demographics of the patient cohort, and the comparative data obtained (on autoantibody positivity, objective measures of dry mouth and dry eye, and salivary gland inflammatory cell infiltration). He reported that they found no conclusive evidence for a higher severity of multiple clinical parameters in female pSS patients than in male pSS patients and that pSS appeared to affect older individuals. Additional research on changes in the severity of various disease parameters with age showed that female pSS patients clearly had an age-dependent decrease in exocrine gland function (saliva and tear volume), whereas lymphocytic infiltration in the salivary glands did not increase with age.
To address the mechanisms of end-organ susceptibility, the research team developed experimental animal models of 10- to 12- week-old female NZM2758 mice that were immunized subcutaneously with the autoantibody Ro52-myelin basic protein (MBP) in alum (Ro52 has the highest prevalence, 66.7 percent, in sera of pSS patients. They then analyzed the mouse sera for antibody reactivity, cytokines, and chemokines; pilocarpine-induced saliva production; and immunohistochemistry. The data showed that immunization induced anti-Ro52 antibody response and salivary gland dysfunction (decreased saliva production and volume), that immunoglobulin G deposits in the submandibular glands of the immunized mice were localized on the basal side of the ductal epithelium, and that passive transfer of immune sera induced salivary gland dysfunction only if the mice were pretreated with alum.
With an administrative supplement from the ORWH, the team utilized passive transfer of rabbit anti-Ro52 serum at day 14 to assess whether female NZM2758 mice pretreated with alum at days 0 and 10 were more susceptible to autoantibody-mediated glandular dysfunction. The data showed an approximately 50 percent drop in saliva production among the pretreated female mice at day 15, while lupus-prone female mice (NZM2328) were resistant and NZM2758 males were completely resistant. The researchers found that at day 14, deposition of salivary gland antibody was significantly higher in female mice than in male mice, whereas innate immune responses (increased interleukin-1α) were similar for both females and males.
Dr. Deshmukh said the team is studying the effects of age, as old (low-estrogen) female mice have higher antibody deposits and autoantibodies than do young (high-estrogen) females. He noted that SS is generally studied in young mice, but is a disease that affects older women and thus should be studied in old mice. He emphasized that an animal’s age can be a critical variable in constructing experimental models for investigating pSS and other autoimmune diseases (a mouse at age 10‒14 months is “middle-aged” and equivalent to a human of 38‒47 years, and a mouse at age 18‒24 months is “old” and equivalent to a human of 56‒69 years).
IX. DIFFERENCES BY SEX AND RACE IN THE ORAL HPV CONTINUUM
(INFECTION TO CANCER)
Dr. Gypsyamber D’Souza, Associate Professor of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, presented data on the prevalence, incidence, and risk factors for oral HPV and on the association of HPV with oropharynx squamous cell cancer (OPSCC), oropharynx cancer (OPC), and head and neck squamous cell cancer (HNSCC). She described trends and differences by gender/sex, race, behavior, age, and tumor site.
Dr. D’Souza noted that humans are the only known host of HPV, a DNA virus that infects basal cells in squamous epithelium, and though there are more than 100 different types of HPV, only a few relate to cancer, and one in particular, HPV16, is responsible for more than 90 percent of HPV-related head and neck cancer. The burden of HPV-related cancer in the United States is significant, and the oropharynx accounts for approximately 78.2 percent and 11.6 percent of this burden in men and women, respectively.
Dr. D’Souza said that with NIDCR support [R01 and R56 (High-priority Short-Term Project) awards], she and her colleagues were able to address the natural history of oral HPV infection. Their research shows that oral HPV16 is 6 times more common among men than among women, but the difference is not explained by differences in oral sex. Rather, two other risk factors—tobacco use and HIV infection—affect oral HPV prevalence, and the effect increases as tobacco use rises and HIV status declines. Dr. D’Souza noted that the incidence of oral HPV infection is lower than that of genital HPV infection and that most infections clear within 1‒2 years, but not all do. While many people likely are exposed to oral HPV infection over their lifetime, women are less likely to be exposed (to HPV16) than are men (1‒8 percent of women, versus 5‒30 percent of men), and men have higher acquisition and lower clearance rates, neither of which is fully explained by behavior (number of oral sex partners).
Dr. D’Souza reported that the incidence of OPSCC in the United States is much higher in men of all races than in women and that the risk of OPSCC worldwide has increased in many age groups over the past 20 years and dramatically so among middle-aged white men (55- to 74-years-old). U.S. trends show that HPV-OPC is increasing among men and also women. Dr. D’Souza noted that she and her colleagues are exploring why these cancers are increasing and why especially among white men. Their research indicates that behavior (oral sex, number of sex partners) does not explain disparities in risk of HPV-OPC by gender (men and women), race (white and black men), or age. Dr. D’Souza noted that the current thinking is that exposure to HPV via genital sex prior to oral sex may guard against development of OPC from HPV acquired orally.
Dr. D’Souza reported that with additional support from the NIDCR, under a P50 center award, her research team explored the role of HPV in HNSCC, by sex, race, and tumor site, through a retrospective analysis of data from the PROVE study. From this multi-institutional study of U.S. cases diagnosed in 1995‒2012, the researchers oversampled for minorities and females and tested tumors centrally for P16 and HPV16 with in situ hybridization DNA and high-risk mRNA. The research findings show the following: the majority of OPSCC among men and women in 2010‒2012 was HPV-related; the prevalence of HPV-related OPSCC is increasing among whites and non-whites, with an approximately twofold increase from 1995‒1999 to 2012‒2012 among blacks, Hispanics, and Asians; and the proportion of HPV-associated cases outside the oral pharynx is low and did not increase between 1995 and 2012. Overall, improved survival rates were seen among cases of HPV- and P16-related OPSCC, but not among cases of non-oral pharyngeal HSNCC; of those with OPSCC, women had a substantially better survival rate than did men, even when controlling for HPV status. The full findings will be published in JAMA Oncology in 2016.
In closing, Dr. D’Souza thanked her research collaborators and the NIDCR for its support. She noted that the research would not have been possible without support from the NIDCR, Merck, and the Oral Cancer Foundation; her research collaborators; and the study participants.
X. SEX DIFFERENCES IN THE CELLULAR MEDIATION OF PAIN
Dr. Jeffrey S. Mogil, Professor, Department of Psychology, and Head, Centre for Research on Pain, McGill University, Montreal, Quebec, Canada, described epidemiological, clinical, and laboratory data on sex differences in the mediation of pain. He also discussed the implications of the research findings for development of analgesics.
Dr. Mogil noted that research interest in sexual differences in pain arose from a 1997 report that categorized the prevalence of pain disorders by sex and estimated that approximately 70 percent of pain patients are women. Following this, a number of epidemiological survey studies have documented, in women, an excess prevalence of chronic pain states, such as back pain, migraine, musculoskeletal, neuropathic, oral, osteoarthritis, and widespread pain. Dr. Mogil suggested two possible explanations for these findings—that women have more pain, or that they are more susceptible to conditions that are painful. He noted that these possibilities are being explored in laboratory experiments and that his research team has shown, for example, that women are more sensitive to pain of various types (e.g., electrical, pressure, and temperature) and at different levels (e.g., pain threshold, tolerance, and intensity).
Dr. Mogil emphasized the need to address the “bigger picture” of how research on pain is conducted. That is, while the clinical problem of pain predominates among middle-aged women, research experiments are largely conducted using young male rats. He noted that he has documented the overwhelming use of male rodents in basic research on pain (79 percent of studies used only male rats) and continues to argue for inclusion of female rodents in pain research. Dr. Mogil noted, however, that this “scandal” persists even in the face of data which show that the variance in results between normally cycling female rodents is no greater than in male rodents, or in men and women, and therefore is not a valid reason to exclude female rodents in research studies.
Dr. Mogil elaborated on the implications of using only male rodents in pain research. He noted specifically that important qualitative differences between males and females in the mediation of pain may be missed, clinical trials of analgesics that do not address sex differences may be deemed failures when no effects are demonstrated, and sex-specific effects of pain receptors in innate immunity and immune responses to injury may be missed. Dr. Mogil gave as examples the potentiated effect of morphine in combination with dextromethorphan that is only observed in men and not women, the clinical trial of Morphidex® which did not address sex differences and was deemed a “failure,” and the documented sex-specific effect of toll-like receptor 4 dysfunction on neuropathic mechanical allodynia (reversal of pain).
Dr. Mogil emphasized that these examples are only “the tip of the iceberg,” as the processing of pain signals is significantly different between males and females. He noted in particular that although microglia and astrocytes have important roles in the spinal cord, evidence indicates that microglia have no role in the processing of pain in women; nevertheless, laboratory researchers continue to study microglia and pain mostly in male rodents. He described research conducted at McGill which shows that reversal of pain by glial inhibitors is male-specific and may be testosterone-dependent, whereas T cell infiltration in the spinal cord after injury occurs in females and not in males. In these studies, the McGill researchers have determined that female mice have more T cells in the blood at baseline and in the spinal cord after injury and that use of the T-cell system is dependent on the interferon-γ receptor. The researchers are continuing to explore the T-cell action and effects.
In closing, Dr. Mogil noted that the research demonstrates that the etiology of pain is, in part, sexually dimorphic and that, therefore, different drugs will be needed to treat pain in women and in men. He noted specifically that drugs based on microglia will not be effective in women and that those based on T cells will not be effective in men. In closing, he commented that other researchers are “catching on” and are exploring, for example, sex differences in the pharmacology of hyperalgesic priming and in facial hypersensitivity.
XI. QUESTIONS AND DISCUSSION
Dr. Dombroski moderated the Council’s discussion. In response to questions, the presenters commented on differences in species’ responses and the translation of results to humans, measurement of pain in animals and humans, and caretakers’ effects on animals’ responses. Dr. Mogil noted that his research mostly uses only two rodent species (rats and mice) and that computerized tomography scans would be needed to confirm results in humans. Dr. Deshmukh said that he relies on two strains of rats to study genes which predispose or regulate autoimmune disorders and that the genes involved in spontaneous models of disease (e.g., lupus) in humans are being investigated in disease-induced animal models. Dr. Mogil noted that progress is being made in the measurement of pain in both animal models and humans and that although it may not be possible to develop truly objective measures of pain, additional new approaches are being explored.
The presenters said there is evidence for rodents’ responses to their caretakers. Dr. Mogil noted research which indicates that the olfaction of experimenters may affect animals’ stress and pain. Dr. Deshmukh noted that animals’ sensing physiology may complicate pain studies and that little is known about these effects, although researchers have observed, for example, that mouse behaviors and breeding patterns change in response to earthquakes.
Dr. Somerman thanked the presenters, Council members, participants, and staff for their contributions to the meeting.
XII. ADJOURNMENT OF OPEN SESSION
Dr. Somerman adjourned the open session of the Council meeting at 12:45 p.m.
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).
XIII. REVIEW OF APPLICATIONS
The Council considered 331 applications requesting $83,041,595 in total costs. The Council recommended 208 applications for a total cost of $51,551,701 (see Attachment II).
The meeting was adjourned at 2:20 p.m. on September 20, 2016.
I hereby certify that the foregoing minutes are accurate and complete.
Dr. Martha J. Somerman Dr. Alicia Dombroski
Chairperson Executive Secretary
National Advisory Dental and National Advisory Dental and
Craniofacial Research Council Craniofacial Research Council