Biomedical and behavioral research provides knowledge to support the ever evolving practice of health care. This scientific base requires a broad array of research strategies to help us understand the fundamental causes of diseases and to transform that knowledge into a lifetime of better health for people everywhere. Most dental, oral, and craniofacial conditions arise from complex interactions of biological, behavioral, environmental, and higher system-level factors. Thus, NIDCR-supported research must involve a breadth of approaches including biological mechanistic and interventional studies, behavioral and social sciences, public health research, population-health studies, clinical trials, and community-based studies.
Enable basic research to advance knowledge of dental, oral, and craniofacial health.
The diverse and interactive group of cells and tissues that make up the dental, oral, and craniofacial complex provides a powerful system for discovery research. Recent advances in technology offer exciting opportunities to examine these cells and tissues, in vitro and in vivo, and to develop precise clinical tools for risk assessment, screening, prevention, diagnosis, and treatment of various oral diseases. Several areas of research poised for rapid growth are mentioned below. However, NIDCR remains committed to supporting all areas of science relevant to its broad mission through its intramural and extramural research investments.
The complexity of the oral and craniofacial regions presents special opportunities to investigate basic mechanisms of cell biology such as growth and development, differentiation, stem-cell function, and regeneration. NIDCR investments will focus on defining the molecules and pathways that contribute to development, maintenance, and remodeling of dental, oral, and craniofacial tissues. The goal of these efforts is to develop predictable materials, factors, and delivery systems to sustain and restore tissues and organs of the dental, oral, and craniofacial complex. Two emerging areas of great promise include the study and application of epigenetics and tissue engineering.
NIDCR will continue to support fundamental oropharyngeal cancer research that will enable risk assessment, prevention, early identification, and treatment of this disease that currently takes a life every hour in the United States and is a serious problem worldwide. In addition to basic studies of the biology of oral cancer and of tumor immunology, NIDCR will encourage research building on its support of the Oral Cancer Genome Project, with the goal of guiding the shift toward precise diagnosis and individualized disease management. One area of special focus will be human papillomavirus (HPV)-associated oropharyngeal cancer, the incidence of which is on the rise.4,5
NIDCR invests in rigorously designed biomedical and behavioral research studies that drive science forward. NIDCR will serve a leadership role by promoting the use of common quality standards so that basic, translational, and clinical investigators achieve sufficient sample sizes and use consistent measures and data sets. Resonant with comparable trans-NIH efforts, the Institute will collaborate further with the scientific community and other stakeholders on efforts to ensure scientific rigor and the reproducibility of research results.
NIDCR will support novel basic, clinical, and translational research projects on the many infectious conditions affecting the oral cavity, ranging from caries to HIV/AIDS and HPV. The Institute will continue research on oral mucosal and innate immunity toward the development of a prophylactic HIV vaccine delivered through the oral mucosa. Other areas of research interest related to HIV/AIDS include the role and formation of viral reservoirs in oral cells and tissues, improved animal or cellular models to study host-virus interactions in the oral cavity, and identification of targets for point-of-care diagnostics and new therapies to treat HIV/AIDS and associated oral opportunistic infections and malignancies. Engaging in research with people living with HIV may offer new insights into identifying risk factors and for prevention and treatment of AIDS co-morbidities.
The Institute’s continued investment in salivary gland research will extend general understanding of secretory organs as well as specific knowledge regarding health problems such as dry mouth and its oral complications, and salivary gland cancers. Knowledge gained through this research will be used to prevent and treat salivary gland dysfunction resulting from Sjögren’s syndrome or irradiation-induced salivary gland damage from head and neck cancer treatment. Encouraging research toward the identification and validation of predictive biomarkers in saliva for a variety of oral and systemic diseases will benefit disease screening and monitoring since, as a diagnostic fluid, saliva has many advantages over blood.6,7
NIDCR will be a leader in supporting the development of specialized tools for advancing knowledge about dental, oral, and craniofacial health, including, but not limited to, single-cell methods, stem-cell systems, multiscale imaging modalities, and disease models that accurately represent human biology. Examples of current technologies resulting from NIDCR investment include lab-on-a-chip devices, point-of-care oral health applications, and intravital microscopy.8,9 The Institute will continue to fund the Federal Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Programs10 to support research on products and devices ready for clinical testing and commercialization.
For example, an NIDCR-funded STTR grant enabled the development of a new disinfecting system for polyurethane tubing used in dental water lines. The project involves attaching selenium to the inside of the tubing, which blocks bacterial attachment. Currently, the investigator is developing a selenium-coating process that can be used commercially and will then test the product in dental-practice settings. If successful, the system could be used to address problematic waterline contamination. This STTR investment also has led to a new line of products with antimicrobial properties.
Promote development and use of comprehensive, interoperable databases and informatics resources to advance prevention, diagnosis, and treatment of dental, oral, and craniofacial diseases.
Modern biomedicine is, to a large extent, an information science. Rapid advances in both computing and communications have enabled the collection, storage, and retrieval of massive amounts of biomedical data and knowledge. In turn, large-scale analyses of interactions among genes, proteins, and many other biomolecules, often referred to as ’omics approaches, have become not only feasible, but commonplace. Further development of data management, mining, and integration tools and enhanced access to and use of comprehensive, semantically interoperable databases and resources will facilitate future biomedical research and improve clinical practice and health-science education. The Institute recognizes a particular need for development of adequately sized databases containing oral phenotypes; these resources can help strengthen understanding of gene-environment interactions as well as tease apart subtypes of disease. NIDCR is committed to contributing to and exploiting the depth and breadth of 21st-century ’omics investigations as well as to effectively and efficiently mining the rich datasets, often termed Big Data, that these methods produce.
The NIH Common Fund18 was established as an incubator for catalyzing transformative research relevant to all NIH Institute and Center missions, but specific to none. NIDCR will take advantage of the resources and opportunities available through the NIH Common Fund’s Big Data to Knowledge initiative.19 This important initiative involves all NIH Institutes and Centers and aims to make Big Data and data science more prominent components of all biomedical research. To build on the success of another Common Fund ‘omics initiative, the trans-NIH Human Microbiome Project,20 NIDCR will build on the knowledge resulting from the Human Oral Microbiome Database that is allowing scientists to better understand the interplay among host, microorganisms, health, and disease (see “The Unexplored Microbial Universe in Our Mouths”).23 The Institute will encourage research that defines both overlapping and unique roles of the oral microbiota, not only in oral-related illnesses such as dental caries and periodontal diseases, but also as mechanistic contributors to immune function and other disorders.
By funding genomic research, such as genome-wide association studies (GWAS) and DNA-sequencing studies, NIDCR underscores the utility of systems approaches for interrogating oral health biology. Previous GWAS of dental caries identified genetic variants associated with dental caries history and suggested interplay between genes, home fluoride exposure levels, and in some cases, taste.24 Other results from NIDCR-funded genomic research have identified genetic risk factors for cleft lip with and without cleft palate in Asian and European ancestry populations, pointing to new research, prevention, and treatment avenues.25,26 The Institute encourages genomic research that will enrich these findings as well as identify risk factors for other dental, oral, and craniofacial disorders and other complex disorders such as Sjögren’s syndrome, chronic pain, oral cancer, and others.
NIDCR will sustain the national FaceBase Consortium27 that is designed to provide resources to the craniofacial research community to better understand the genetic instructions controlling development of the middle region of the human face. NIDCR promotes the scientific community’s collaboration across geographic and disciplinary lines in this national network that collects, integrates, and disseminates data on craniofacial development and disorders. NIDCR will broaden and deepen its support of the FaceBase resource by generating and disseminating datasets not covered in the launch phase of the consortium. These may include data describing additional areas of the developing face or skull; novel informatics methods for integrating, visualizing, and analyzing FaceBase data; and face-related research tools arising from studies in model organisms.
Conduct translational and clinical investigations to improve dental, oral, and craniofacial health.
NIDCR will maintain its support of clinical research that advances knowledge and leads to better patient care outcomes. In partnership with the scientific, clinical, and patient advocacy communities, NIDCR will continue to develop and refine the Institute’s clinical research agenda that focuses on the most pressing public health needs that would benefit from new prevention, early detection, and improved treatment approaches (see “NIDCR-Funded Clinical Studies” for current examples of NIDCR-funded clinical research).
NIDCR will support an array of study designs to resolve clinical questions, including, but not limited to, randomized controlled trials, qualitative and mixed-methods research, community-based participatory research, cohort studies, secondary data analyses, and comparative effectiveness research. The Institute will encourage research on technologies for clinical risk assessment and diagnosis. It will also partner with other Federal agencies and public and private organizations to adopt comprehensive electronic health-record, history, and treatment information models as clinical research tools.
NIDCR will encourage the use of large health datasets developed and maintained by both government30 and non-government organizations and it will leverage existing clinical research infrastructure supported by other NIH Institutes and Centers. One important resource is the NIH Clinical and Translational Science Award (CTSA) program, which aims to accelerate translation of laboratory discoveries into treatments for patients, to engage communities in clinical research studies, and to train a new generation of clinical and translational researchers.31 Expanding current CTSA oral health collaborations to others in the oral health research community will enrich this national health research program. Academic health centers, where CTSAs are housed, offer many resources that can augment the training of dental researchers and those from fields such as nursing, behavioral and social sciences, biostatistics, and epidemiology — moving toward a more translational research orientation and facilitating multidisciplinary and interdisciplinary research interactions. The NIH Clinical Center has also extended the availability of clinical research resources to NIH-funded extramural grantees.32
Maintain the role of NIDCR as a trusted source of information and evidence related to dental, oral, and craniofacial health.
An essential companion effort to supporting the highest-quality dental, oral, and craniofacial basic, translational, and clinical research is maintaining and sharing the knowledge this research builds. The oral health evidence base constructed through NIDCR’s biomedical and behavioral research provides important information for the nation’s practice community. Working with professional organizations and societies, especially dental groups, NIDCR will increase efforts to raise awareness of the importance of evidence-based decision-making in clinical dental practice as well as the importance of empowering patients in managing their own care. This will be accomplished in part through the National Dental Practice-Based Research Network33 (see Goal 4, Objective 2), as well as through dynamic modes of communication including social media.
Enhancing oral health surveillance capability in the United States is a cornerstone of enabling evidence-based decision-making in clinical practice. In partnership with organizations including NIH Institutes and Centers, the Centers for Disease Control and Prevention (CDC), and other Federal agencies, NIDCR will continue to support collection, analysis, and dissemination of oral health data to be used for surveillance and population-based research, as well as to inform public health practice and the development of public policy.
The Institute will encourage development and validation of self-reported and real-time data collection and new methods to measure and document oral diseases, disorders, and conditions. Working with stakeholders including public and private sector organizations, NIDCR will encourage the systematic study of practice patterns, professional trends, and other factors that can stimulate research aimed at improving oral health care quality, access, and delivery.
Although national surveys are good sources of population health data, they do not always reflect the diversity of the U.S. population.34 NIDCR has partnered with NIH’s National Heart, Lung, and Blood Institute and six other NIH components to sponsor a multicenter epidemiologic study in Hispanic/Latino populations. The Hispanic Community Health Study/Study of Latinos,35 the largest study of Hispanics ever undertaken by NIH36, will determine the prevalence of specific chronic conditions in four urban-dwelling Hispanic populations, associated risk factors for certain diseases, and the role of acculturation on Hispanic/Latino health. Importantly, the study includes Hispanics of different origins, providing the first opportunity since the 1980s to comprehensively examine the oral health of Latino sub-groups. NIDCR will continue to develop opportunities to support the collection of oral health data within large epidemiologic studies of groups whose health needs and epidemiologic profiles are not well captured in nationally representative data. Studies and analyses of groups within groups will likely shed important light on causes and consequences of disparities related to culture and other factors.
NIDCR Intramural Scientists Explore Taste, Smell, and Itch
For many years, NIDCR-funded research has made formative contributions to the field of sensory biology, in particular taste and smell. These two chemical senses play a significant role in perceiving the external world, and they are also important control points for feeding behavior that affects a huge array of oral and other health conditions.
As a senior investigator in NIDCR’s intramural research program, Nicholas Ryba, Ph.D., has spent more than two decades untangling the fundamental underpinnings of taste and smell. Throughout this period, Ryba has maintained a model collaborative spirit through longstanding scientific relationships with academic partners as well as with other researchers on the NIH campus. In particular, Ryba and Charles Zuker, Ph.D., of Columbia University in New York have worked together to define how the sense of taste detects and distinguishes specific qualities. In wide-ranging studies, they have mapped the pathways responsible for sweet, bitter, salty, sour, and savory taste — from the surface of the tongue to the depths of the brain.1 Their work has revealed that “good” and “bad” tastes are largely innate and genetically specified to influence eating and other behaviors
Our sense of smell is of course intimately linked to taste and plays an even more important role in food-choice than the sense of taste itself. But studying the sense of smell may also help us understand brain disorders. For example, Ryba’s group recently generated genetically altered mice with such a heightened ability to perceive specific odors that these smells triggered powerful seizures.2 The results add to our knowledge of how smell is sensed as well as provide new avenues for studying epilepsy.
Recent findings from NIDCR-supported intramural scientists also shed new light on itch and pain. By examining neuropeptides, transmitters that convey information between nerve cells, Mark Hoon, Ph.D., discovered that one of these molecules is required for the sensation of itch and that another molecule is responsible for sensing certain types of pain.3 Hoon and his team found that genetically altered mice in which the itch-related molecule had been removed could not sense all of the itch-inducing agents the researchers tested. In another surprise, the scientists found that, unlike previously thought, the itch pathway is independent of other sensations, such as temperature, pain, and touch. Hoon is now looking to see if the human nervous system communicates the perception of itch the same way as the mouse nervous system does. If such similarities exist, they provide a promising target for drugs to provide relief to the millions of people with chronic itch conditions, such as eczema and psoriasis. Studies are also ongoing to understand more about the mechanism by which pain signals are detected.
New Opportunities to Track Oropharyngeal Cancer
Human papillomavirus (HPV) infects human cells in mucous membranes, and distinct viral strains cause cervical cancer or oropharyngeal cancer.11,12 Most people exposed to HPV never develop cancer, but a subset of those exposed develop a persistent infection that leads to cancer. Current reports state that the incidence of HPV-associated oropharyngeal cancer more than tripled from 1988 to 2004,13 calling for continued research to understand why this increase occurred and to develop effective methods to stem the rise through population-health approaches. Because of underlying immunosuppression, a higher risk of HPV-associated oropharyngeal cancer is present in people infected with HIV.14
HPV-associated oropharyngeal cancers differ markedly from non-HPV oropharyngeal cancers. Survival rates for the two types are dramatically different: people with HPV-associated oropharyngeal cancer have far better survival rates than people with non-HPV oropharyngeal cancer. The two cancers are also different at the molecular level and respond differently to treatments, indicating that they are by most accounts completely separate diseases. But scientists need to learn much more about HPV-associated oropharyngeal cancer, and NIDCR-supported research is actively pursuing questions related to incidence, risk factors, and disease progression. Researchers have identified a sex-based difference in the prevalence of oropharyngeal HPV infection, with three-fold higher infection rates in men compared to women.15 Smoking is also an independent risk factor for oropharyngeal HPV infection — potentially due to mutagenic or immunosuppressive effects.
Many questions remain, but the FDA-approved HPV vaccine Gardasil16 is effective against infection with the particular strains of HPV implicated in oropharyngeal cancers. A recently published National Cancer Institute-funded clinical trial of 5,840 women demonstrated that another HPV vaccine, Cervarix, was highly effective at preventing oral HPV infection in women with or without HPV cervical infections.17 While it has not been established that currently approved HPV vaccines can prevent oral cancer, NIDCR remains vigilant to this public health opportunity for cancer prevention and will encourage research to fill gaps in understanding.
Salivary Gland Tumor Biorepository
Salivary gland cancers are rare, with only a few thousand new cases in the United States each year.21 They also are often fatal. Research progress has been slowed by the fact that the rarity of this cancer type means that there are few tumor samples available for researchers to study. To address this need, and to encourage salivary gland cancer investigation by more scientists from other disciplines, NIDCR supported a centralized salivary gland tumor biorepository in 2009 through a contract to the University of Texas MD Anderson Cancer Center.22 This effort was driven by a series of workshops co-sponsored by NIDCR and the Adenoid Cystic Carcinoma Research Foundation (ACCRF), which highlighted the need for centralized and accessible biological samples, including authentic cell lines.
This project has relied on expertise and materials from many sources, in particular the input of the ACCRF. Leading the biorepository effort today is MD Anderson Cancer Center’s Adel El-Naggar, M.D., Ph.D., a nationally and internationally recognized expert in salivary gland cancer biology and among the most prominent head-and-neck pathologists in the world. Other contributing centers include Johns Hopkins Medical Institution, Rhode Island Hospital, the University of Virginia, the University of Pittsburgh Medical Center, and the University of Mississippi Medical Center.
In addition to facilitating resource sharing, the effort has another important goal: data standardization. By carefully monitoring and controlling collection of tumor samples and related clinical information, the biorepository can minimize variability among research groups. The resource serves the needs of clinical researchers as well as basic scientists by generating cell lines from primary tumor tissues and cataloging and storing cells, biofluids, and tissues in a centralized facility. A robust database is a central feature of the biorepository. It tracks collection, storage, distribution, and usage of biospecimens and cell lines.
The Unexplored Microbial Universe in Our Mouths
Not unlike early astronomers exploring the heavens, biomedical scientists are increasingly astounded by the vastness and complexity of microbial life in the human body. By the numbers, we are more bacterial than human, and by a long shot — about 10 bacteria to every one human cell — although single-cell microorganisms are much, much smaller than our own. Understanding more about the bacteria that call us “home,” the human microbiota, is a matter of intense interest in the scientific community, since many health conditions have been directly or indirectly linked to specific bacterial types as well as bacterial neighborhoods that vary substantially from person to person, and within the same individual under different conditions and physiological circumstances.
Exploring and characterizing the human oral microbiota is at once a huge opportunity and an immense challenge. We know that host oral tissues and fluids have remarkable protective roles that are also affected by the particular population of resident bacterial species in the host. We also know from NIDCR-supported research that about 600 unique microbial species populate the oral cavity. Less than half of these species can be cultivated using conventional laboratory conditions.28
The NIDCR-supported open access Human Oral Microbiome Database aims to break open this complexity by promoting distribution of genetic, phenotypic, clinical, and bibliographic data for unnamed and uncultivated members of the oral microbiota.29 This resource, along with new methods to study uncultivable oral microbiota, will accelerate translation of basic discoveries to tomorrow’s clinical breakthroughs.
What types of practical applications might benefit the most? Complex infectious oral diseases, such as early childhood caries and destructive periodontal diseases, could serve as models of polymicrobial disease. More broadly, this research will extend the foundation of existing microbiome research to explore and map an exciting new frontier in oral microbiology. The goal of the Human Oral Microbiome Database is to provide the research community with direct access to DNA-sequence information for the hundreds of species of organisms that are present in the human oral microbiota, many of which were previously uncultivable, enabling a deeper understanding of the role of bacteria, viruses, and fungi in immune function. Importantly, NIDCR believes that this research investment will yield novel approaches to study the function of the uncultivable oral microbiota, fostering hypothesis-driven basic research, and supporting the translation of new discoveries to targeted and improved prevention, diagnosis and early treatment.