Date: May 23, 2017
Place: Conference Room 10
National Institutes of Health
The 215th meeting of the National Advisory Dental and Craniofacial Research Council (NADCRC) was convened on May 23, 2017, at 8:35 a.m., in Building 31, Conference Room 10, National Institutes of Health (NIH), Bethesda, Maryland. The meeting was open to the public from 8:35 a.m. to 12:35 p.m.; it was followed by the closed session for Council business and consideration of grant applications from 1:30 p.m. until adjournment at 2:02 p.m. Dr. Martha Somerman presided as Chair.
- Dr. Shenda Baker
- Dr. Terence S. Batliner
- Dr. Yang Chai
- Dr. Richard Peters Darveau
- Dr. Nisha J. D'Silva
- Ms. Tracy Haii
- Dr. Daniel Malamud
- Dr. Daniel W. McNeil
- Dr. Phillip B. Messersmith
- Dr. Anne Louise Oaklander
- Dr. Anne C. R. Tanner
- Dr. Jane A. Weintraub
Members of the Public
- Dr. Marcelo W. B. Araujo, Vice President, Science Institute, American Dental Association (ADA), Washington, D.C.
- Dr. Robert J. Burns, Manager, Legislative and Regulatory Policy, ADA, Washington, D.C.
- Dr. Reuben Kim, Associate Professor, Section on Restorative Dentistry, and Director of Collaborative Research
- Programs, Division of Constitutive and Regenerative Sciences, UCLA School of Dentistry, Los Angeles, California
- Dr. Yvonne Knight, Chief Advocacy Officer, Advocacy and Government Relations, American Dental Education Association (ADEA), Washington, D.C.
- Dr. Quynh-Thu Le, Professor and Chair, Department of Radiation Oncology, Stanford University Medical Center, and Co-director, Radiation Biology Program, Stanford Cancer Institute, Palo Alto, California
- Mr. B. Timothy Leeth, Senior Director for Federal Relations, Advocacy and Government Relations, ADEA, Washington, D.C.
- Dr. Ichiro Nishimura, Professor, Weintraub Center for Reconstrnctive Biotechnology, Division of Advanced Prosthodontics, UCLA School of Dentistry, Los Angeles, California
- Dr. Jeffrey Stewart, Senior Director, Institutional Innovation and Development, Leaming Center, ADEA, Washington, D.C.
- Ms. Christina McWilson Thomas, Director for Government Affairs, Advocacy and Government Relations, ADEA, Washington, D.C.
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 oflntramural Research (DIR)
- Dr. John W. Kusiak, Office of the Director (OD), Acting Deputy Director
- Dr. Matthew P. Hoffman, Deputy Scientific Director, DIR
- Ms. Tamera Addison, OD, Office of Administrative Management (OAM)
- Dr. Jane Atkinson, DER, Center for Clinical Research (CCR)
- Dr. Nisan Bhattacharya, DEA, Scientific Review Branch (SRB)
- Dr. Latarsha Juanita Carithers, DEA, SRB
- Dr. Preethi Chander, DER, Integrative Biology and Infectious Diseases Branch (IBIDB)
- Ms. Patty Chestnut, OD, OAM
- Dr. Dave Clark, DER, Behavioral and Social Sciences Reearch Branch (BSSRB)
- Ms. Vicki Contie, Office of Communications and Health Education (OCHE), Science Communication and Digital Outreach Branch (SCDOB)
- Ms. Michelle Cortes, DER IBIDB
- Ms. Mary Daum, OD, OCHE, Health Information and Public Liaison Branch (HIPLB)
- Mr. Bret Dean, OAM, Financial Management Branch (FMB)
- Mr. Jimmy Do, OAM, FMB
- Dr. Olga Epifano, DEA
- Dr. Dena Fischer, DER, CCR
- Dr. Leslie Frieden, DEA, Research Training and Career Development Branch (RTCDB)
- Dr. Crina Frincu, DEA, SRB
- Dr. Gallya Gannot, DER, CCR
- Mr. Joel Guzman, DER, Translational Genomics Research Branch (TGRB)
- Dr. Sue Hamann, OD, OSPA
- Dr. Emily Harris, DER, TGRB
- Ms. April Harrison, DEA, Grants Management Branch (GMB)
- Ms. Jeannine Helm, DER
- Mr. Gabriel Hidalgo, DEA, GMB
- Dr. Jonathan Horsford, OD, Office of Science Policy and Analysis (OSPA)
- Dr. Lynn King, DEA, RTCDB
- Dr. Wendy Knosp, OD, OSPA
- Ms. Carol Loose, OAM, FMB
- Ms. Susan Lowenthal, DEA, GMB
- Dr. Nadya Lumelsky, DER, IBIDB
- Dr. R. Dwayne Lunsford, DER, IBIDB
- Ms. Jayne Lura-Brown, DER
- Ms. Tammy Magid, DEA, GMB
- Ms. Amy Mhatre-Owens, OD, Office of Clinical Trials Operations and Management (OCTOM)
- Ms. Yasamin Moghadam, DER, CCR
- Dr. Marilyn Moore-Hoon, DEA, SRB
- Mr. Paul Newgen, DEA, GMB
- Ms. Anna Nicholson, OD, OCTOM
- Mr. Michael David North, OAM
- Dr. Morgan O'Hayre, OD
- Ms. Debbie Pettit, DEA, GMB
- Ms. Ann Poritzky, OCHE, SCDOB
- Mr. John Prue, OD, Office oflnformation Technology (OIT)
- Ms. Delores Robinson, DEA
- Dr. Steven Scholnick, DER, TGRB
- Dr. Yasaman Shirazi, DEA, SRB
- Dr. Kathryn Stein, DER, TGRB
- Ms. Kathleen Stephan, OD
- Mr. Larry Sutton, OD, OAM
- Mr. Joseph Tiano, OD, OSPA
- Dr. Yolanda Vallejo-Estrada, DER, IBIDB
- Dr. Jessica Walrath, OD, OSPA
- Dr. Jason Wan, DER, IBIDB
- Dr. S. Chiayeng Wang, DER, IBIDB
- Dr. Darien·Weatherspoon, DER, CCR
- Ms. Dolores Wells, OD, OSPA
- Dr. Gary Zhang, DEA, SRB
- Dr. Lois K. Cohen, Consultant
Other Federal Employees
- Dr. Tom Haii, Senior Director, ADA Foundation
- Dr. Anthony Volpe Research Center (VRC), National Institute of Standards and Technology (NIST), U.S. Department of Commerce (DOC), Gaithersburg, MD
- Dr. Jeffrey Kim, Principal Investigator, ADA Foundation, VRC, NIST, DOC, Gaithersburg, MD
I. WELCOME AND INTRODUCTIONS
Dr. Maiiha Somerman, Director, NIDCR, called the 215th meeting of the Council to order. She welcomed everyone, including Council members, guests, and those participating via the NIH videocast (http://videocast.nih.gov). She invited the guests to introduce themselves and then invited the NIDCR staff to introduce new personnel.
Ms. Mary Daum, chief of the Health Information and Public Liaison Branch, Office of Communications and Health Education (OCHE), introduced Ms. Vicki Contie, chief of the Science Communication and Digital Outreach Branch, OCHE.
Dr. Anna Nicholson, director of the NIDCR Office of Clinical Trials Operations and Management (OCTOM), introduced Ms. Amy Mhatre-Owens, clinical research manager, OCTOM.
Dr. Lillian Shum, director of the Division of Extramural Research (DER), introduced Dr. S. Chiayeng Wang, director of the Oral and Salivary Gland Cancer Biology Program, in the Integrative Biology and Infectious Diseases Branch, DER.
Dr. Alicia Dombroski, Executive Secretary, and Director, Division of Extramural Activities (DEA), welcomed the paiiicipants and noted that NIDCR's information technology staff was available for assistance during the meeting.
II. FUTURE MEETING DATES
- September 15, 2017
- January 31, 2018
- May 25, 2018
- September 13, 2018
- January 23, 2019
- May 23, 2019
- September 13, 2019
III. APPROVAL OF MINUTES FROM PREVIOUS MEETING
Dr. Alicia Dombroski invited the Council to consider and approve the minutes of the January, 24, 2017, Council meeting. The Council unanimously approved the minutes.
IV. REPORT OF THE DIRECTOR, NIDCR
Dr. Somerman presented an update on NIDCR/NIH appropriations and reported on NIDCR 2030 and NIDCR/NIH regenerative medicine activities. Before her remarks, she invited attendees to share a moment of silence for those affected by the recent terrorist attack in Manchester, England. Dr. Somerman's written Director's Report to the Council: May 2017 was provided to the Council members and is available on the NIDCR website (http://www.nidcr.nih.gov).
Dr. Somerman reported that the President signed the Consolidated Appropriations Act, 2017, on May 5, which provides funding for the NIH through the end of Fiscal Year (FY) 2017 (ending September 30, 2017). The total FY 2017 appropriations for NIH is $34.3 billion, which includes $425.75 million for the NIDCR. The NIH received a $2 billion, or 6.2 percent, increase in funding over that in FY 2016, and this includes $352 million for the 21st Century Cures initiative. In the appropriations language, the NIH Director was asked to develop policy to promote early independence for new investigators (a Next Generation of Researchers initiative). The President's Budget for FY 2018 was released on May 23, and congressional hearings with the NIH leadership are scheduled for May 17 (in the House of Representatives) and late June (in the Senate). Dr. Somerman noted that the congressional focus on health research is very positive and bipartisan.
NIDCR 2030 Progress
Dr. Somerman reported on development of the NIDCR planning initiative, NIDCR 2030: Envisioning the Future, Together. One year ago, the NIDCR leadership identified the need to continue to plan forward and to take more innovative and bolder steps with the NIDCR portfolio. Looking toward 2030, the NIDCR envisages a world where dental, oral, and craniofacial health and disease are understood in the context of the whole body; research informs strategies to promote health, prevent and treat disease, and overcome disparities in health; and all people have the opportunity to lead healthy lives.
Dr. Somerman noted that the deadline for submission of ideas to the NIDCR Ideascale website created for NIDCR 2030 is June 2 (www.nidcr2030.ideascale.com). Votes and comments are invited in five goal areas: oral health + overall health, precision health, autotherapies, oral biodevices, and workforce diversity. Dr. Somerman reported that, to date, the site has attracted 443 registered users, 83 percent of whom are U.S. residents; participation is well-balanced across communities (e.g., 52 percent of users from academia/research, 15 percent from government, 10 percent from dental practitioners); and 205 ideas have been submitted (the target is 200), with oral health + overall health receiving the most ideas (more than 90).
Next steps include staff review of submissions (to be completed by the end of July), review by the NIDCR leadership, discussions with the NADCRC (at its September 2017 meeting), convening of workshops (in 2018), and development of Funding Opportunity Announcements (FOAs) (in late 2018 and 2019). NIDCR review teams are being organized by Dr. Morgan O'Hayre, NIDCR lead for NIDCR 2030, and Ms. Nakita Kanu, project manager.
NIDCR/NIH Regenerative Medicine
Dr. Somennan reported that regenerative medicine is a very active research area for NIDCR. In FY 2015, NIDCR allocated approximately $40 million, or almost 10 percent of its total funding, to regenerative medicine, making it the second largest funder of this research across the NIH institutes and centers (ICs), which on average allocated approximately 3.4 percent of their budgets to this research. Dr. Somerman noted that about 60 percent of the NIDCR portfolio in regenerative medicine is basic research which spans dental, oral, and craniofacial (DOC) tissues. To help translate this research into products, the NIDCR established the NIDCR Dental, Oral, and Craniofacial Tissue Regeneration Consortium (DOCTR-C). In addition, NIDCR participates in two other initiatives: 21st Century Cures, and the National Academy of Medicine (NAM) Regenerative Medicine Forum.
DOCTR-C. The three aims of DOCTR-C are to develop safe, predictive, and effective clinical strategies for regeneration and reconstruction of functional tissues of the human DOC complex; conduct preclinical studies leading to submission of lnvestigational New Drug (IND)/Investigational Device Exemption (IDE) applications to the U.S. Food and Drug Administration (FDA) for initiation of clinical trials; and take advantage of mature technologies with strong translational promise and to utilize multidisciplinary expertise of biologists, bioengineers, clinicians, regulatory experts, and industrial partners. The consortium has been developed in three stages.
In Stage 1, planning, which began in 2015, the NIDCR funded 10 groups to prepare Stage 2 applications. In Stage 2, development of resource centers (RCs), the NIDCR awarded (in March 2017) two 3-year grants to establish RCs integrating multidisciplinary expertise for technical, administrative, and regulatory support of Integrative Translational Project (ITP) Teams. The two RCs are (i) the Center for Dental, Oral, and Craniofacial Tissue and Organ Regeneration (C-DOCTOR), comprised of six California universities, and (ii) the Michigan Pittsburgh-Wyss Resource Center: Supporting Regenerative Medicine in Dental, Oral, and Craniofacial Technologies (MPWRM TechDOC), comprised of the universities of Michigan and Pittsburgh and the Wyss Institute for Biologically Inspired Engineering at Harvard University. In Stage 3, consortium, the RCs are operationalizing the consortium and accepting applications from ITP Teams (due May 31, 2017) toward fulfilling the goal of developing products for preclinical studies within 7-9 years.
21st Century Cures: Regenerative Medicine. For FY 2017, the Congress set aside $2 million for regenerative medicine in its 21st Century Cures initiative. With this support, the NIH has established the Regenerative Medicine Innovation Project (RMIP). The RMIP is led by the National Heart, Lung, and Blood Institute which has released 12 FOAs for cooperative agreements utilizing various mechanisms, including investigator-initiated research (RO1) and small business awards. The receipt date for grant applications is June 26, and the FDA will contribute to the review process. Dr. Somerman encouraged DOC researchers to access the website and apply.
National Academy of Medicine Forum. The NIDCR serves as co-lead, with the National Institute of Biomedical Imaging and Bioengineering, of the NAM Forum, in which six ICs are participating. The goal is to engage key stakeholders in dialogue on the opportunities and challenges in translating the science and technology of regenerative medicine to the clinic. Dr. Somerman noted that the field is rapidly advancing, as reported in the news, and about 700 clinicians are doing regenerative medicine without specific guidelines. The Forum includes discussion of ethical, legal, and societal issues, in addition to the science. The participants have held two meetings (in June 2016 and March 2017) and convened one workshop (in October 2016), titled "State of the Science in the Field of Regenerative Medicine: Challenges of and Opportunities for Cellular Therapies," the proceedings of which are available at http://www.nationalacademies.org/. A subgroup report, titled Manufacturing Cell Therapies: the Paradigm Shift in Healthcare of this Century, is in review. A second workshop, which will be held June 26, will focus on optimizing cell manufacturing for regenerative medicine. See the National Academies regenerative medicine page for additional information.
In closing, Dr. Somerman encouraged interested parties to go to www.nidcr.nih.gov for NIDCR updates, science news, and information on grants and funding. In addition, the NIDCR is on Twitter, LinkedIn, and YouTube.
V. SPECIAL SESSION ON COMPLICATIONS OF HEAD/NECK CANCER TREATMENT AND SYMPTOM MANAGEMENT
Dr. Dena Fischer, Director, Clinical and Practice-Based Research Program, Center for Clinical Research, DER, introduced the special session. She described the Cancer Moonshots initiative; presented an overview of the NIDCR cancer program and, specifically, its cancer complications/symptom management portfolio; and provided background on the oral complications of head/neck cancer treatment. Later, three extramural grantees separately described their research to improve oral function and manage oral complications after head and neck cancer treatment.
NIDCR Overview/Cancer Moonshot
Cancer Moonshot. Dr. Fischer noted that the 21st Century Cures Act, which the Congress passed in December 2016, authorizes $1.8 billion in funding over 7 years for the Cancer Moonshot. This fast-moving initiative is overseen by the National Cancer Institute (NCI). The mission is to make a decade's worth of advances in cancer prevention, diagnosis, treatment, and care in 5 years. The initiative includes 10 task forces which align with the 10 transformative research areas recommended by an initial Blue Ribbon Panel (www.cancer.gov/brp). The NIDCR participates in the following five task forces: Create a translational science network devoted exclusively to immunotherapy; Minimize cancer treatment's debilitating side effects; Expand use of proven cancer prevention and early detection strategies; Develop a 3-D cancer atlas; and Develop new cancer technologies. More information on the initiative, including FOAs, can be accessed at www.cancer.gov/research/key-initiatives/moonshot-cancer-initiative.
Overview-NIDCR Cancer Program. Dr. Fischer reported that the NIDCR supports oral cancer research in five areas. These are as follows: (i) biology, immunology, stem cell biology, and epidemiology of oral, oropharyngeal, and salivary gland cancers; (ii) role of human papilloma virus (HPV) infections in oropharyngeal cancer (OPC); (iii) genomic analysis and validation of premalignant, diagnostic, and prognostic biomarkers of OPC and salivary gland cancers; (iv) design of effective therapeutic and chemoprevention strategies for OPC and salivary gland cancers; and (v) development of therapies for management of head/neck cancer treatment complications and symptoms. The special session of the present Council meeting addressed the last, fifth area.
Dr. Fischer reported that the majority (51 percent) of intramural and extramural expenditures in the FY 2016 NIDCR portfolio of cancer complications/symptom management research supported research on therapeutics for cancer complications. The other areas of support were pathophysiology of head/neck cancer complications (31 percent), oral health outcomes of head/neck cancer treatment (12 percent), and tools to measure head/neck cancer complications and symptoms (6 percent). By topical areas of cancer treatment, the largest support (40 percent) went to research on salivary hypofunction/radiation-induced xerostomia. The other areas of support were mucositis, graft-versus-host disease (GVHD), and soft tissue healing (23 percent); osteonecrosis of the jaw (ONJ)/osteoradionecrosis (15 percent); diseases of dentition or periodontium (13 percent), and cancer pain (9 percent).
Background- Oral Complications of Head/Neck Cancer Treatment. Dr. Fischer noted the unavoidable toxicities and direct and indirect tissue damage that may occur with standard treatment of malignant disease and supportive care in cancer therapy. Toxicities may adversely affect oral and/or general health and quality oflife. Surgery and/or radiation therapy may cause salivary gland atrophy, soft tissue necrosis, and osteoradionecrosis (ORN). Toxicity from chemotherapy, immunotherapy, and/or targeted molecular therapies may secondarily affect the oral cavity. Both early and late effects are commonly associated with these therapies. And, supportive cancer care may cause late-effect oral complications, such as medication-associated ONJ.
Dr. Fischer elaborated on five complications (oral mucositis, salivary hypofunction, GVHD, oral cancer pain, and ONJ), summarizing their cancer treatment effects and pathogenesis and NIDCR research support. She noted that NIDCR support for research on mucositis, which has a complex pathogenesis, making development of treatments challenging, is robust. The NIDCR funded a prospective, longitudinal, multisite study to validate the Child International Mucositis Evaluation Scale (ChiMES), a mucositis scale for use in children, as well as small business grants for research on therapeutics and prevention. For salivary hypofunction, the NIDCR supports research on prevention and repair of early complications. Researchers in the intramural program have completed a Phase 1 clinical trial on re-engineering of salivary cells with a viral vector expressing human aquaporin-1 (AQP1), a water channel protein, in patients with radiation-induced xerostomia, reporting positive outcomes in 45 percent of patients. A new clinical trial is in progress using an improved vector for longer-term expression of AQP1. Intramural researchers also are analyzing data from a recently completed Phase II clinical trial to better understand the pathogenesis of oral complications of chronic GVHD which affect 40 percent to 83 percent of patients with this condition; the results are pending.
Dr. Fischer noted that NIDCR-supported research shows that the pathobiology of oral cancer pain involves a complex interaction of cells. As reported in 2012, cancer cells produce and secrete pain-inducing mediators (e.g., endothelin-1, proteases, nerve growth factor) that activate primary afferent nociceptors within the cancer microenvironment, and the interaction seems to occur between cancer cells and peripheral neurons and may contribute to perineural invasion in oral cancer. NIDCR research on ORN has clarified the late effects of cancer radiotherapy (RT), which include loss of bone vitality and hypoxia due to reduced vascular supply, and their direct relation to radiation dose, volume, site, and technique. Dr. Fischer said the extent to which newer RT techniques may or may not affect ORN development is unclear. NIDCR-supported ONJ research was addressed later during the session by Dr. Reuben Kim and Dr. Ichiro Nishimura (see sections VIII and IX below).
Dr. Fischer also highlighted a sixth example of NIDCR research-oral health outcomes of cancer treatment. She noted that the NIDCR supports an ongoing longitudinal study of oral health outcomes in patients receiving contemporary treatment for head/neck cancer. This clinical, prospective, multicenter study involves 575 patients from the start of their intensity modulated radiotherapy (IMRT) or proton beam therapy through follow up for 2 years at 6-month intervals. The aim is to assess rates and risk factors for different specific complications of cancer treatment, and the ultimate goal is to improve decision making for management of patients undergoing head/neck cancer treatment.
In discussion, Dr. Marcelo W. B. Araujo, Vice President, Science Institute, American Dental Association (ADA), noted the importance of NIDCR research on HNC and related several ADA initiatives in this area. The ADA published clinical practice guidelines for screening of oropharyngeal cancer, in October 2016, and is engaged in a 2-year project to develop an ADA House Resolution on oral care and treatment of cancer patients prior to radiation and surgery. In addition, the ADA is partnering with The University of Texas MD Anderson Cancer Center to increase HPV vaccination and tobacco cessation and to plan for an Oropharyngeal Cancer Symposium, which will be held on October 18, 2017, preceding the ADA 2017 meeting, in Atlanta, Georgia.
VI. NIH UPDATE
Dr. Lawrence A. Tabak, Principal Deputy Director, NIH, presented an update on NIH efforts to enhance stewardship, in a talk titled "Enhancing Stewardship: New Efforts to Promote a Stronger and More Stable Biomedical Research Workforce." He noted that, through better stewardship, the NIH aims to maximize the impact of its research dollars and to develop and sustain a quality biomedical workforce.
Dr. Tabak noted that there has been much discussion on these issues across the scientific community. A 2014 article, titled "Rescuing U.S. Biomedical Research from Its Systemic Flaws," focused attention on the unsustainability of the hypercompetitiveness of research and the need to rethink the research ecosystem [see B. Alberts, M. W. Kirschner, S. Tilghman, and H. Vamms, Proceedings of the National Academy of Sciences of the USA 111(16):5773-77)]. Dr. Tabak presented data showing that although the number of NIH research grant applications increased from FY 2013 through FY 2016, the number of awardees did not, and he noted that the increasing spread between these numbers is a driver of the hypercompetitiveness in research.
Dr. Tabak highlighted two considerations: the age of investigators funded by the NIH, and the distribution of NIH resources. Multiple analyses show that late-career investigators (i.e., ≥ age 60) are outperforming others [both early-stage investigators (ESIs), ≤ age 45, and mid career investigators (MCIs), age 46 ≤ age 59]. Dr. Tabak commented that late-career investigators have resources to tie themselves over if they are not successful in obtaining a research grant and that the NIH has mechanisms of support for ESIs that were first established in the mid-2000s. With regard to distribution of NIH resources, Dr. Tabak noted that 1 percent of NIH-funded scientists receive 11 percent of the NIH research funds and that 10 percent of NIH funded scientists receive 40 percent of the funds. He commented that although this concentration of resources is partly driven by support of large clinical trials, it is also found among senior investigators. The challenge these data present to the NIH is how to maintain a robust workforce and optimal productivity.
Dr. Tabak said that in taking a closer look at these issues, the NIH considered whether bibliometrics could be used to establish investigators' productivity based on the influence of their publications and the number of their awards. Drawing from the recommendations of three independent analyses of scientific opinion, the NIH elected to use the relative citation ratio (RCR), an article-level- and field-dependent measure of productivity, in combination with the NIH Grant Support Index (GSI) to measure incremental research output. Dr. Tabak reported that analysis of the RCR and GSI for more than 71,000 scientists showed that NIH support of investigators receiving 1-3 investigator-initiated research project grants (R01s) yielded substantial returns, while grantees' productivity diminished after receiving 3 R01s. After 3 R01s, investigators were still productive, but NIH support did not yield the greatest "bang for the buck," marginal returns sloped toward the negative, and NIH's investment had reached a point of diminishing returns. Dr. Tabak noted that the NIH is "rediscovering" what others have published about diminishing returns [see, in particular, "Concentration of Research Funding Leads to Decreasing Marginal Returns" (P. Mongeon, C. Brodeur, C. Beaudry, V. Lariviere, Research Evaluation 25(4):396-404, 2016); "Big Science versus Little Science: How Scientific Impact Scales with Funding" (J.-M. Fortin, D. J. Cuffie, PLoS One 8(6):e65263, 2013); and "Research Groups: How Big Should They Be" (I. Cook, S. Grange, A. Eyre-Walker, Peer J 3:e989, 2015)].
Dr. Tabak summarized the issue as whom to support-investigators receiving their first award, their second award, or their fifth or sixth award? Who will continue to be productive and how can the NIH maximize its resources to sustain the workforce at all career stages? Analysis of the most highly productive investigators (i.e., those with high annual weighted RCRs) showed that most do not have GSIs higher than 21 (each R01 = 7 points) and, for ESIs, there was no correlation with being in a well-funded or less-well-funded research laboratory. Dr. Tabak noted that for the 21st century, the NIH needs to focus on promoting and providing opportunities for new researchers and earlier research independence. The key questions are: How to increase support for early-career scientists? How to stabilize the workforce? How to maximize the impact of NIH funding? That is, how to "bend the curves"? Dr. Tabak highlighted two additional publications: "Strategies from UW-Madison for Rescuing Biomedical Research in the US" (J. Kimble, W. M. Benent, Q. Chang, B. L. Cox, et al., eLife 4:e09305, 2015); and "Sustaining Discovery in Biological and Medical Sciences: A Framework for Discussion" (FASEB, 2015).
Dr. Tabak commented that IC directors have a "suite of approaches" from which to draw for research grant support, but none of them addresses the issue of diminishing returns. For that, a trans-NIH solution is needed. Thus, the NIH is proposing to use the GSI to develop a modified grant count of NIH support for each investigator (PI). Initially, the NIH would focus on research project grants (RPGs), which would be benchmarked as follows: R01/U01 = 7 points; R03/R21 = < 7 points; and R35, TR01, P01/U01 = < 7 points. Each PI would be limited to a GSI of 21 (3 R01s). Those with a GSI of more than 21 would be monitored more closely and asked to develop a plan to keep the NIH commitment to a GSI of ≤ 21. Dr. Tabak emphasized that the proposed plan is a work in progress, is being developed iteratively, and is being presented to each IC Advisory Council for feedback. The aim is to have a trans-NIH policy for monitoring NIH's level of support for each PI. The policy would take effect for RPG applications beginning fall 2017. The NIH anticipates that an estimated 3.1 percent of investigators would be affected (97 percent would not be affected) and that the resources that are released would enable the NIH to fund an estimated 900 new awards over the next several years. An analogous program would be instituted in the intramural program.
Dr. Tabak mentioned the key issues raised thus far in presentations to the IC Advisory Councils. These relate to the initial focus on RPGs, the effect on research teams (i.e., whether co-Pis would have a lower GSI count), special consideration to attract talent into new, emerging fields of science (e.g., in response to a public health emergency), and peer review. Dr. Tabak said the GSI count would be considered by the IC director .and staff after peer review and with or without consultation of the advisory council. Exceptions to the count could be made in cases of truly excellent research.
In closing, Dr. Tabak listed all the NIH personnel involved in this effort and invited the Council members to contact him directly via email at Lawrence.Tabak@nih.gov.
The Council expressed support for implementation of the changes to enhance NIH's stewardship. Members asked about the program's applicability to the breadth of P01 support, non NIH (e.g., foundation) funding, different career stages, and indirect costs. Dr. Tabak noted that redistribution of resources would not be used to fund mediocre science, that the independence of P01s would be up to each IC, and that the GSI count currently does not include non-NIH resources. To build stability and resilience of the workforce, the NIH is targeting redistribution of resources to ESIs and MC1s; will consider both the age and career stage of investigators; and prefers to provide longer-time support (average duration of an R01 is 4.2 years) at an appropriate level of support, rather than higher amounts over less time. Investigators who have ≥ 21 GSI points would have to show an extraordinary need, such as a public health emergency, to be considered for additional research support.
Dr. Tabak noted that the NIH tools for calculating indirect costs are fully accessible online, that all RCR data will be online for investigators to do their own calculations, and that applicants already can access the NIH iCite database of published articles (see https://icite.od.nih.gov/). Asked to comment on the NIH budget, Dr. Tabak said that the NIH is very grateful to Congress for the increased appropriation for FY 2017 and that the President's Budget for FY 2018 was just released and will be discussed in the Congress.
Dr. Somerman thanked Dr. Tabak for his presentation. The Council and staff expressed their appreciation with a round of applause.
VII. TACKLING SALIVARY GLAND STEM CELLS TO IMPROVE FUNCTION AFTER RADIOTHERAPY
Dr. Quynh-Thu Le, Professor and Chair, Department of Radiation Oncology, Stanford University Medical Center, and Co-director, Radiation Biology Program, Stanford Cancer Institute, Palo Alto, California, described her translational research on use of salivary gland stem cells to preserve and improve salivary function in patients receiving RT for HNC. She discussed the incidence and treatment of HNC and current treatment strategies for RT-induced hyposalivation and presented research data on isolation of adult salivary stem/progenitor cells (SSPC) and the role of aldehyde dehydrogenase 3 (ALDH3) activation in preservation of saliva function. Dr. Le's research is supported by the NIDCR and NCI, as well as the private sector.
Dr. Le noted that HNC represents the fifth most common cancer globally and 6.9 percent of all cancer worldwide in 2012 (excluding esophageal cancer). For treatment of HNC, RT is a very effective modality, but has direct effects on salivary function, resulting in hyposalivation and subsequent dvelopment of dental caries, necrosis, and other conditions. Dr. Le said the standard treatment for hyposalivation, IMRT, has been shown to improve salivary function and parotid flow rate. Current approaches to minimize hyposalivation are technical (submandibular gland transfer surgery, and parotid-sparing IMRT) and pharmacological (amifostine administered daily intravenously during RT, and salagen or evoxac after RT to stimulate salivary secretion). Dr. Le said amifostine is the only currently approved drug, is costly, and has many side effects.
In 2008, for the first time, researchers reported identification and isolation of SSPC from submandibular glands in mice and showed that intraglapdular injection of the cells improved salivary secretion up to 120 days after RT and the cells retained their function in vivo. Dr. Le noted that in 2014, her research team outlined a sorting and selection strategy for obtaining adult SSPC in mice submandibular glands and demonstrated that transplantation of adult SSPC improved saliva production and morphology in mice and a subsequent transplantation from the first recipients improved saliva function and acinar number in the second recipients. Analysis of SSPC genes led the team to focus on ALDH, an intracellular enzyme demonstrated to protect stem cells from cytotoxic effects and oxidative insults, and on ALDA3A1, which is selectively expressed in salivary glands. Studies of ALDA3Al in both knockout and wild-type mice showed that loss of ALDH3A1 impairs SSPC function and enhances RT-induced aldehyde load and hyposalivation. The search for a safe, small molecule that could activate ALDH3 ultimately led to identification of four active constituents extracted from traditional medicinal herbs. Alda-341, in particular, was selective for ALDH3A1 and, in RT-treated mice, preserved salivary function, reduced the severity of xerostomia, did not protect the HNC from RT, reduced oxidative stress and aldehyde load, decreased apoptosis, enhanced sphere formation of SSPC, and may enhance differentiation of SSPC.
Dr. Le noted that the phmmokinetics of Alda-341 are well known and that the drug, given orally, is available for use in humans. She and her team have begun a Phase 0 drug distribution study of Alda-341 in salivary glands. They will enroll 15 patients who have salivary gland tumors and elected to undergo surgery and will perform comparative studies in mice. The objectives are to determine the bioavailability of Alda-341 and the change in ALDH3A1 enzymatic activity in salivary gland tissue and saliva.
In closing, Dr. Le noted three conclusions: (i) Adult SSPC can be isolated and can rescue function; (ii) ALDH341 is expressed at higher levels in SSPC, and its activation decreases apoptosis of SSPC and enhances saliva function after RT without protecting the cancer from RT; and (iii) in the future, more knowledge of stem/progenitor cells is needed to help identify novel approaches to mitigation and treatment of late effects of RT.
VIII. THE ROLE OF PRIMARY DENTISTS IN MANAGING MRONJ: LESSONS LEARNED FROM MOLECULAR AND PRECLINICAL STUDIES
Dr. Reuben Kim, Associate Professor, Section on Restorative Dentistry, and Director of Collaborative Research Programs, Division of Constitutive and Regenerative Sciences, UCLA School of Dentistry, Los Angeles, California, discussed the management of medication-related osteonecrosis of the jaw (MRONJ) from the perspective of a primary dentist. He presented an overview of MRONJ and osteomucosal healing, lessons learned from preclinical studies, a proposed model for ONJ development, and the critical roles of primary dentists in managing MRONJ. Dr. Kim thanked the NIDCR for supporting his research.
Dr. Kim noted that MRONJ is defined as exposed or probe-able bone lasting for > 8 weeks. Anti-resorptive or anti-angiogenic agents, such as bisphosphonates (BPs), denosumab (DE), and bevacizumab, are widely used to treat osteoporosis or cancer of the bone and are a leading cause of MRONJ. Dr. Kim noted that more than 90 percent of MRONJ occurs in cancer patients receiving 6- to 10-fold higher doses of BPs than are used to treat osteoporosis. The risk of ONJ is extremely low with oral doses, but is relatively high (1 percent to 2 percent per year) with intravenous doses, and associated risk factors include invasive oral surgery, periodontal and periapical diseases, glucocorticoid use, diabetes, and poor oral hygiene. The agents are known to inhibit bone resorption, but the mechanism of effect (direct or indirect) is not known.
Dr. Kim noted that a current hypothesis is that ONJ is due to defects in osteomucosal wound healing and that tooth extraction has become a model for studying wound healing at the interface of bone and tissue. In preclinical studies in mice, he and his colleagues have shown that tooth extraction can induce osteonecrosis; pre-existing periapical and periodontal inflammatory conditions exacerbate BP-related ONJ lesions; and periodontitis prior to tooth extraction further induces ONJ. He presented two "take-home messages": inflammatory conditions exacerbate ONJ development by BPs, and having inflammatory conditions for a long time further increases ONJ development.
Dr. Kim noted that based on the preclinical studies, he and his colleagues propose a clinical model for MRONJ whereby the probability of ONJ increases over time with use of anti resorptive and anti-angiogenic agents; is further increased in association with pathological inflammatory conditions and, additionally, with defects in soft tissue integrity such as tooth extraction and denture-related trauma; and escalates with bacterial colonization on the bone surface. In this scenario, there are three potential "hits" for thwarting delayed osteomucosal healing and development of ONJ: stop the medications, resolve the inflammatory conditions, and maintain the integrity of soft tissue. With this perspective, and similar to cancer staging, prevention of ONJ development is more manageable early in the process than later in the process when it reaches the bone surface. Dr. Kim suggested that woven bone (occurring during the early stages of wound healing in adults) may play a critical role in mediating soft and hard tissues during osteomucosal healing. After tooth extraction, woven bone can form from existing bone surfaces, or de novo, but BP or DE inhibit the pathway for bone formation and exacerbate other conditions.
Dr. Kirn emphasized that MRONJ should matter to all dental practitioners, and especially general dentists who comprise 79 percent of practicing dentists in the United States. He noted that the condition and its sequelae are preventable, but he stated that education of dentists and patients is needed. He stated that 60 percent of dentists know about ONJ and that 50 percent of them are not cornfo1iable treating ONJ and 65 percent of them will refer their ONJ patients to other providers. Dr. Kirn said the role of dentists in identifying patients at higher risks is critical for early diagnosis, proper management, and prevention of ONJ. Dentists need to know when to manage ONJ and when to refer patients to other providers. The goal for new patients should be to prevent mistakes in doing invasive procedures because of not knowing patients' medical conditions; for ONJ-prone patients, to control pathological inflammatory conditions; and for ONJ patients, to maintain excellent oral hygiene and monitor them for possible referral to oral surgery. He suggested specific guidance in each situation. He also called for education of dentists about the benefit of BPs for osteoporosis, as well as how to prevent and treat BP-related ONJ.
In closing, Dr. Kirn presented three conclusions: (i) MRONJ is preventable, manageable, and possibly treatable in the near future; (ii) the role of dentists in early diagnosis and proper follow ups is critical; and (iii) patient education on proper home care and oral hygiene, is equally important.
IX. MECHANISM OF ORAL BARRIER IMMUNE DYSFUNCTION BY ANTI-RESORPTIVE MEDICATIONS FOR CANCER-INDUCED OSTEOLYSIS
Dr. Ichiro Nishimura, Professor, Weintraub Center for Reconstructive Biotechnology, Division of Advanced Prosthodontics, UCLA School of Dentistry, Los Angeles, California, described his research on the mechanisms of immune dysfunction in oral barrier tissue, specifically in relation to development of ONJ. His research, supported by the NIH and industry, addresses tissue re-engineering and biotechnology and, in particular, wound healing of bone, skin, oral mucosa, and facial nerves, utilizing small animal models and bionanotechnology. The Weintraub Center is supported by the National Center for Research Resources (now the National Center for Advancing Translational Sciences) and philanthropic contributions. Dr. Nishimura, an NIDCR grantee, participates in DOCTR-C.
Dr. Nishimura noted the many health implications of missing teeth. In particular, the associated fluid leakage from oral tissue may result in difficulties in swallowing, silent aspirations, pneumonia, and mild memory loss in older individuals. Two significant problems for everyone with missing teeth are loss of alveolar bone and reduction of the residual ridge (RRR). Longitudinal cephalographic studies conducted in the 1940s and 1950s showed that resorption of alveolar bone after tooth extraction is unidirectional, long-term, and continuous throughout life and that RRR is 4 times greater in the mandible than in the maxilla. Prevention of bone loss is an ultimate goal and would benefit in particular the disproportionate number of individuals who are edentulous in underserved populations.
Dr. Nishimura noted that following tooth loss, osteoclasts interface with oral barrier tissue and are directly associated with loss of alveolar bone. Oral barrier tissue is a functional barrier to protect internal homeostasis, and barrier immunity is specialized as a first line of defense against injury. Though barrier immunity in the intestinal mucosa has been well characterized, barrier immunity in the oral mucosa and at the bone surface has not. Dr. Nishimura noted that research on the intestinal mucosa shows cross talk between barrier immune cells and commensal bacteria (i.e., bacteria may stimulate sentinel intraepithelial lymphocytes, including gamma-delta T cells, as well as the highly inflammatory CD4 and Th17 cells in connective tissue). Interesting recent studies of oral mucosal immunity in mice, conducted by NIDCR intramural investigators, show that oral barrier immunity (specifically, activation of Th17 cells) is not influenced by oral commensal microbiota as much as in the intestinal mucosa and, instead, is activated by mechanical stimuli (e.g., pellet food, cotton swab scratches).
Dr. Nishimura noted that Th17 cells are known inducers of osteoclasts and that T cells in oral barrier tissue, which are likely to be Th17 cells, are responsible for osteoclastogenesis on the external surface of alveolar bone. The thinking is that Th17 cells undergo, in part, osteoimmunology, producing a set of osteoclasts, derived from myeloid cells, on the surface of alveolar bone or in oral barrier tissue. He noted that observations of the immune characteristics of osteoclasts demonstrated that oral barrier tissue uniquely localizes on the jawbone and that osteoclasts on the jawbone surface may be considered an integral part of oral barrier immunity. These observations led him and his research team to propose that oral barrier immunity may initiate osteoimmunology, through activated Th17 cells and abenant osteoclastic bone resorption, and osteoclasts may participate in the regulatory mechanism of oral barrier immunity (i.e., reverse osteoimmunology).
Dr. Kim and his team pursued their hypothesis on osteoimmunology by developing and studying mouse models of ONJ. He reported that mouse ONJ-like lesions induced by tooth extraction were composed of an extensive osteonecrosis area, oral epithelial hyperplasia, and dense, chronic oral barrier inflammation at the oral-microbe interface. The researchers tested different immune components related to ONJ formation in the wild type mouse model, initially focusing on Th17 cells. Because ONJ lesions in mice after tooth extraction did not arise after a long silent period, as in humans, the researchers subsequently developed a humanized mouse model in which human bone marrow, liver, and thymus were grafted on an immune-deficient (targeted lymphocyte knockout) mouse model. Comparison of the two models, wild type and humanized, suggested that osteoclasts contribute to ONJ pathogenesis through two different pathways: lymphocyte deficiency and increased neutrophilia.
Dr. Nishimura said their current working hypothesis on ONJ pathogenesis is that osteoclasts support oral barrier lymphocytes during wound healing, but a deficiency of osteoclasts, which can be caused in different ways (e.g., by injection of BP) results in lymphocyte functional deficiency and lack of support for bone viability; and BP-affected osteoclasts may trigger neutrophilia in the oral barrier, causing tissue damage and extensive ONJ.
Pursuing possible treatment strategies for ONJ, the researchers drew on evidence that BPs such as zoledronate (ZOL) can prevent ONJ in humans with multiple myeloma. They utilized ZOL and other compounds to test the therapeutic effects on ONJ in mice. The team concluded that two treatments would be needed: (a) competitive equilibrium-based displacement of BP by low-activity BP (LABP) during prophylaxis and early stages of treatment, and (b) therapeutic attenuation of discordant myeloid cell plasticity (neutrophilia) by injection of an anti-resorptive agent (e.g., anti-Ly6G). Dr. Nishimura noted that studies in the mouse model showed that intra oral injection of LABP attenuated, if not completed prevented, development of ONJ lesions and that this strategy has been licensed by a start-up company (BioVine LLC) which is developing therapeutic LABP for ONJ treatment.
In closing, Dr. Nishimura said that their mouse models were useful for understanding the pathological mechanisms of ONJ. He noted that the team was the first to demonstrate multiple myeloma in immune-competent mice and that humanized mice have wide utility for research on multiple myeloma. The researchers are continuing to explore therapeutic modalities for ONJ; are actively searching for promising compounds, some of which have shown a curative effect on ONJ; and hope to apply for patent(s) in the future.
X. QUESTIONS AND DISCUSSION
Dr. Dombroski thanked the speakers, and Dr. Somennan thanked everyone for attending the Council meeting.
XI. ADJOURNMENT OF OPEN SESSION
Dr. Dombroski adjourned the open session of the Council meeting at 12:35 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).
XII. REVIEW OF APPLICATIONS
The Council considered 514 applications requesting $138,076,627 in total costs. The Council recommended 307 applications for a total cost of $84,804,669 (see Attachment II).
The meeting was adjourned at 2:02 p.m. on May 23, 2017.
I hereby certify that the foregoing minutes are accurate and complete.
Dr. Martha J. Somerman, Chairperson
Dr. Alicia Dombroski, Executive Secretary
National Advisory Dental and Craniofacial Research Council