In this month’s Charting Progress, Dr. Rick Valachovic describes the rise of salivary diagnostics and the field’s potential to enhance dentistry’s role in primary care.
Imagine a day when, during a routine dental recall examination, you undergo screening for a variety of oral and systemic diseases. Thanks to point-of-care technologies, before the end of your visit, your dentist shares the results. She is pleased to let you know that your A1C levels are under control and that you are at low risk for periodontitis, but the screening has also detected a biomarker for oral cancer. This is cause for concern, but because the disease has been caught early—before the onset of symptoms—your prognosis is excellent.
Such a scenario may not be far off. Researchers are discovering new biomarkers in saliva every year and clinical trials have already put a number of these to the test. Technological advances are rapidly bringing us closer to the day when screening in the dental office for systemic and oral diseases could become commonplace.
The future I’m describing reflects the promise of the maturing field of salivary diagnostics. Most of us naturally produce a liter of saliva each day, opening the door for clinicians and researchers to obtain a diverse array of biological information in a way that is painless, noninvasive and essentially risk-free. More importantly, the range of biomarkers found in this abundant fluid appears to be every bit as great, if not greater, than the range found in blood. Whether we want to diagnose a disease, engage in screening and early detection, or use saliva to monitor disease progression, patient compliance with treatment or treatment effectiveness, we can achieve these goals by harnessing the potential of saliva.
As early as the 1990s, researchers used saliva to measure cortisol, the hormone whose presence indicates stress. Today, saliva can be tested for many more microscopic components, including:
- Bacteria, including those linked with cariogenic activity.
- Metabolites, a diverse group of chemicals produced by the cells of living organisms.
- Drugs, whether therapeutic or recreational.
- Proteins, including those linked to periodontitis.
- DNA and RNA linked to viruses, bacteria and cancers.
These and other biomarkers have been found for a number of systemic diseases, including HIV, hepatitis, diabetes, Alzheimer’s disease and several cancers.
We have the National Institutes of Health, and specifically the National Institute of Dental and Craniofacial Research (NIDCR), to thank in large part for supporting the researchers responsible for these discoveries. Beginning in 2002, the NIDCR started investing tens of millions of dollars to address two challenges: identifying the salivary proteome and developing new technologies that clinicians could employ to detect salivary biomarkers. This work included cataloging more than 1,100 of the proteins that make up the salivary proteome and identifying the gene transcripts, metabolites, microbes and micro-RNAs that are found in human saliva. In 2010, NIH funded two new studies aimed at identifying salivary biomarkers for early oral cancer detection and proteomic and genomic biomarkers for primary Sjogren’s Syndrome. Today, the NIH continues to fund multiple grants focused on salivary diagnostics.
Among the dental researchers who took part in the initial round of NIDCR research is David Wong, D.M.D., D.M.Sc., Associate Dean of Research at the University of California, Los Angeles (UCLA), School of Dentistry and Director of the UCLA Center for Oral/Head and Neck Oncology. David continues to operate a lab at UCLA that is actively engaged in this research. He and his colleagues have made significant contributions to cataloging the salivary proteome and developing diagnostic technologies. More recently, they have been working on detecting extracellular RNAs—genetic material released by cells and carried throughout the body in blood and saliva—to improve the diagnosis and treatment of a range of disorders.
“When the journey started,” David recalled when we spoke last month, “the scientific understanding was that whatever is in blood is also in saliva. Ten years later, we know that there is also a unique presence of bodily information in saliva that is nowhere else in the body. Our recent discovery that certain non-coding RNAs are uniquely present in saliva, but not in blood, echoes this revelation.”
Despite saliva’s rich diversity of biological information, biomarkers found in saliva exist at lower concentrations than they do in blood. This initially made it difficult to access the information, but the advent of miniaturization technologies and discoveries in other scientific fields have overcome this challenge. Today, a number of extremely sensitive salivary diagnostic tests produce rapid and highly accurate results, and the development of platforms that can screen for dozens of different biomarkers at once is now well underway. These platforms are being incorporated in portable point-of-care devices that could soon find homes well outside the confines of the lab—in community settings, remote areas such as battlefields, and, of course, in dental offices.
David’s latest work centers on the development of saliva- and blood-based liquid biopsies that could determine the genomic fingerprint of a cancer noninvasively. Current research shows that tumor cells shed their genetic information into our bodily fluids in the form of circulating DNA and RNA. The ability to easily tap that information could be tremendously useful in treating diseases that stem from cancer gene mutations.
“What we’re talking about is personalized medicine,” said Jed Jacobson, D.D.S., M.S., M.P.H., Chief Science Officer and Senior Vice President at Delta Dental of Michigan, Ohio, Indiana, and North Carolina. (You can find more on the potential of personalized medicine in my September 2014 Charting Progress).
I called Jed to ask why he has become a public booster of salivary diagnostics, and to get his take on the potential role salivary diagnostics can play in targeting health care dollars where they will have the greatest benefit. In 2013, Jed wrote an article in the Journal of the California Dental Association predicting that one day consumers could benefit from the presence of salivary diagnostics in every dental office in the United States.
When we spoke, Jed used the example of periodontal disease to convey the economic value of salivary diagnostics. “Salivary biomarkers move right into that space where we are looking at the genetic makeup of individuals to see if they are at a greater risk, and if they are, then we would deploy further preventive services in those individuals. Even though it would cost more, we would prevent the disease from happening in the first place, which in the long run is a cost savings.”
Delta Dental has been involved in research exploring salivary biomarkers in dental caries, periodontitis and oral cancer and in pilot projects evaluating the dental office as an opportunistic screening site for chronic medical conditions. He believes that if the use of salivary diagnostics for early screening became routine, the technology could position dental offices as a cornerstone of primary care. After all, 60% of the U.S. population visits the dentist annually, creating major opportunities for dentists to screen for a wide range of diseases. With nearly 90% of respondents to a 2010 national sample survey of U.S. general dentists indicating they would be willing to perform salivary diagnostics in their practices, it’s not hard to imagine the dental office being transformed into a one-stop diagnostic destination.
The utility of salivary diagnostics for a variety of applications seems assured, but their value may be most pronounced in two particular situations. In the first, genetic information allows clinicians to ascertain early the presence of a disease, when it is most amenable to treatment. Because oral cancers are hard to spot clinically in their early stages, diagnosing these diseases from saliva has been a major focus of academic research. Just last month, the Johns Hopkins University School of Medicine announced that its researchers had joined the ranks of those who have identified markers associated with oral and orapharyngeal cancer—in this case, tumor DNA—both in blood and saliva. The two media yielded different results, leading the researchers to conclude that “combining blood and saliva tests may offer the best chance” of finding cancer in the mouth and throat.
Secondly, the value of salivary diagnostics may also be enhanced when genetic information plays a major role in guiding treatment. David Wong gave me the example of EGFR gene mutations, which are associated with 60% of lung cancers in Asia. Drugs that target these mutations have been shown to prolong life up to two years, but determining whether a patient has the mutations currently requires a tumor biopsy, which may not be possible if the patient is frail or living in a remote area of the world.
David’s team studied saliva from 44 people in Taiwan who had been diagnosed with non-small cell lung carcinoma and had these gene mutations. “The concordance of saliva reflecting these mutations in the lungs was almost 100%,” David told me.
The researchers have since validated their findings in a second blinded study in mainland China funded by the National Cancer Institute. David believes the concept can be generalized to all human cancers with a genetic component. If so, salivary diagnostics could radically facilitate and transform clinicians’ ability to better target therapies for their patients.
We are still several years from that reality, despite the remarkable progress made in the last decade. A handful of tests for a very limited number of biomarkers are currently on the market, but none of these tests can be performed at the point-of-care, and researchers question whether they can be relied on to work as advertised.
Spencer Redding, D.D.S., M.Ed., is among those who have expressed concern about commercializing these technologies too soon. The Chair of the Department of Comprehensive Dentistry at the University of Texas Health Science Center at San Antonio School of Dentistry has been involved with salivary diagnostics and the development of point-of-care technologies on the patient recruitment side since 2007. He shares David Wong’s view that review by the U.S. Food and Drug Administration (FDA) is the best way to ensure that salivary diagnostic tests deliver on their promise, and he pointed out several additional hurdles that need to be overcome.
“In the traditional laboratory diagnosis arena,” he reminded me, “there are specific quality control measures employed. With point-of-care testing, you have to come up with another paradigm to make sure that testing is accurate.”
Despite his caution, I heard echoes of David’s and Jed’s enthusiasm when Spencer and I talked. He is following the work of Theranos, a disruptive upstart in the diagnostic market, which is using finger stick blood tests, transparent pricing and direct-to-consumer marketing to test for conditions—including a few cancers—before symptoms appear. As for so-called lab-on-a-chip point-of-care devices, Spencer is convinced that they will one day revolutionize how we diagnose disease. But, he adds, where this will occur and what medium will be used remain to be seen. Saliva, blood and even epithelial cells have all shown their merit. Cells gathered with brush biopsies are the current medium of choice in the research group—led by John McDevitt, Ph.D., Chair of Biomaterials and Biomimetics at New York University College of Dentistry—to which Spencer belongs.
“I think the big question for our profession is, are we going to be involved in this? I hope we are,” Spencer concluded.
I hope so, too, and I’m confident we will be. In just a few years, I expect to see courses on salivary diagnostics become a mainstay of the dental curriculum and to find our students learning to use devices the size of a smart phone to screen their patients for all manner of conditions and disease. The promise of point-of-care diagnostics and their potential to advance personalized medicine is undeniable, and there’s every reason to believe that saliva—and dentistry—will be part of the mix.