Dentistry in the Age of Genomics
Dentistry in the Age of Genomics: Q&A with NYUCD Researchers

Vice Dean Louis Terracio

Dr. Daniel Malamud

Dr. Walter Bretz

Dr. Page Caufield

Dr. Brian Schmidt

Dr. Yihong Li

Dr. Steven Engebretson

A group of senior researchers at the NYU College of Dentistry is actively engaged in exploring genomics as a means of advancing knowledge of human genetics, the origins and evolution of human diseases, and the development of therapeutic initiatives to treat disease.

Global Health Nexus recently asked several of these individuals to talk about the future of genomics in dentistry, including individual research projects utilizing genomics. Participants included Dr. Louis Terracio, professor of basic science and craniofacial biology and vice dean for research; Dr. Daniel Malamud, professor of basic science and craniofacial biology and director of the HIV/AIDS Research Program; Dr. Brian Schmidt, professor of oral and maxillofacial surgery and director of the Bluestone Center for Clinical Research; Dr. Walter Bretz, associate professor of cariology and comprehensive care; Dr. Steven Engebretson, associate professor and chair of the Ashman Department of Periodontology and Implant Dentistry; Dr. Page Caufield, professor of cariology and comprehensive care; and Dr. Yihong Li, professor of basic science and craniofacial biology.

Global Health Nexus (GHN): Dr. Terracio, as vice dean for research, could you provide an overview of the prospects for dental research and patient care in the age of genomics?

Dr. Terracio: Genomics is only one of many 'omics that are populating modern science. Proteomics—the large-scale study of proteins—is the other big area that people are looking at. People are using many other forms of evaluation for data collection and any of those that are dominating the research front in medicine are appropriate to dentistry. The head/neck/oral cavity lends itself to all the same sorts of evaluations that one is seeing dominate medicine. So there's no reason why dentistry would do anything but be a major player in genomics research, depending on the disease.

There are folks in this group who are interested in cancer, like Brian, and those who are interested in genomic analysis, like Walter, Yihong, and Page, who are all interested in the microbiome, or the totality of microbes, including their genetic elements and environmental interactions in a defined environment. Dan is involved in multiple investigations using saliva samples collected with a swab from the mouth as a less-invasive and instantaneous alternative to drawing blood and sending samples to the laboratory to determine risk for and onset of disease. Steve is doing research with the ultimate aim of treating diabetes. Page and Yihong are using genetic criteria to conduct research in caries development. It's where we should be.

If there's a reason why dentistry may not in some ways be as active in genomic research as medicine, it's probably because the technology costs a lot of money. If a dental school is not affiliated either with a major medical center or a major research institute, then having access to all the technology to move forward in this field becomes problematic. Luckily for NYUCD, through professional collaborations across the country and around the world, as well as access to analytical methods across the street at the NYU Langone Medical Center, we're able to take advantage of all of the major 'omic technologies, including genomics.

GHN: What role does genomics play in the research that each of you is conducting?

Dr. Malamud: In discussing genomics in dentistry, I think that you can look at this in two ways. First, the oral cavity is a source of DNA that allows you to look for anything in the entire body, and if you do a Pub Med search correctly, you find that 90 percent of the publications refer to the oral cavity as the easiest way to obtain DNA. Second, many people are thinking about using genomics as a tool for studying dental diseases. To Lou's comment about less money available for genomics technology at dental schools as opposed to medical schools, I would add that if a researcher focuses exclusively on oral diseases, there are a smaller number of opportunities compared to systemic diseases. Since there are a limited number of dental diseases, it's not surprising that there is less research in this area.

Dr. Bretz: Despite the low number of dental diseases, what's interesting and attractive is that we can measure these diseases; we can sample people over time; we can be predictive, which is something that you can't do with other diseases, like cardiovascular disease, in which genetic predisposition is very important, but sampling over time is not an option.

From my perspective as a scientist investigating the oral microbial profile, a key opportunity for dentistry in genomic research lies in being able to predict a person's risk for developing dental caries. Certain groups of people, like twins, are especially good population samples for genetic research in caries development.

Scientists seeking to predict a person's risk for developing dental caries by identifying the presence of harmful bacteria have, to date, identified only about 800 of the thousands of microbes residing in the human oral cavity. But now, working collaboratively with the Venter Institute and TIGER (Twins Institute for Genetics Research) in Brazil on a four-year study funded by the National Institute of Dental and Craniofacial Research (NIDCR), NYUCD is utilizing a new genetic sequencing technique to speed the process of identifying the remaining bacteria that play the most important role in tooth decay. The new technique, known as enrichment gene sequencing, will enable us to uncover the existence of many more species than those that have been identified so far with traditional sequencing. The oral microbial profile we develop will enable us to predict which of the twins are likely to develop caries and which will remain healthy. This approach is likely to enhance our understanding of dental caries onset and development and may enable the future development of novel treatment strategies.

This approach is applicable not only to the development of dental diseases, but also to systemic diseases. Two years ago my research team was awarded a grant by the National Institutes of Health (NIH) to look at rheumatoid arthritis (RA) and the potential link to oral and intestinal flora. In fact, we recently had a paper accepted for publication by the journal Rheumatism and Arthritis reporting on the very distinct signatures of the oral microbiome among early-onset, never-treated RA patients and patients with chronic RA.

Dr. Caufield: Potential genetic and environmental risk factors play an important role in the research that my collaborators and I conduct to understand the etiology of early childhood caries (ECC), one of the major public health problems affecting millions of preschool children, especially those in low-income populations both in the United States and around the world. Using such approaches, we were able to characterize a number of risk factors associated with cariogenic bacterial colonization in children with ECC. In a newly funded NIH project, we will look further at the genetic diversity of Lactobacillus populations in children with severe ECC in order to identify a subset of genetic elements that contain "virulence" determinants associated with the development of ECC.

Dr. Li: The question of whether or not there is a significant difference in the microbial species between healthy and diseased conditions, including dental caries and periodontal diseases, is one that my collaborators and I are actively pursuing. We are trying to understand the interaction of oral microbial diversity with other diseases, including HIV infection, oral cancer, gastric precancerous lesions, and infants of preterm/low birth-weight. Other key questions are whether or not changes in the relative abundance of members of the microbial communities are clinically important, and how oral microbes interact with host and immune environmental factors.

Dr. Schmidt: I've always been interested in the incidence and prevalence of oral disease. So compare periodontal disease to heart disease. Probably very similar prevalence, but we do much more in terms of cardiovascular disease. Let's take head and neck cancer as an example. There will be 50,000 cases of head and neck cancer in the US this year. There will be 10,000 brain cancers. The genome project has given us much more information and we've been able to glean clinically useful information for brain cancer, whereas for oral cancer we've not been able to do that, so it's a much more complex challenge.

Oral cancer has what we've termed "capricious clinical behavior." Patient A will have an oral cancer; it can be big and that patient will get treatment and will be alive in five years. Patient B has a much smaller oral cancer. They look exactly the same under the microscope, and that patient doesn't live for two years. If you're diagnosed today with oral cancer, you have a 50 percent chance of being alive in five years, and we don't know which side of that 50 you'll be on. That's been the real challenge.

Just because we understand the genomics, that doesn't mean it's a blueprint for how that cancer's going to behave. So for the last eight to nine years we've been trying to identify a genomic marker that will help us understand which patients will get metastasis. And then the cancers are so good at DNA mutation that they evolve, so cancers recapitulate evolution in nature, and these cancers evolve so the metastasis at a genomic level looks totally different from the oral cavity primary tumor, which just adds another layer of complexity. Within the last year we have developed what's called "massively parallel genome sequencing," which means that you can sequence the entire exons (the parts of the gene that code information for protein synthesis) for very complex genes up to 50 exons in a single gene.

Dr. Engebretson: One of the things we're looking at in the area of periodontal disease is gene expression research using microarray technology, and it's giving us the opportunity to study thousands of genes from a single tissue sample. Even though costs are still high, prices have come down enough to allow us to look at biomarkers in gene expression profiles for patients who have responded well to therapy and for those who have responded less well. As in cancer research, we might someday be able to use a gene expression profile to help with a prognosis for a disease.

The interdisciplinary nature of this type of research is really strong, particularly with regard to bioinformatics, which requires expertise in a number of different disciplines to get any useful information. A lot of different types of problem-solving skills go into this type of research.

Let me give you an example of a program using bioinformatics that we've been using for gene expression profiles. It was developed, I understand, by members of the KGB who defected to the West and somehow wound up in Bethesda, Maryland, where they were put in charge of a project called natural language programming. These people had experience writing algorithms that go out into cyberspace and pick up associations or words that are close together and other words that are far apart in order to interpret information about the ways the spies were passing messages. They decided to look at biology in the same way, using the same process to create software to find associations between molecules or genes and then map them out to see how they interact.

You can always tell how two things interact, but what about the things around them? This program allows you to see what the surrounding interactions are and what their significance is. These biological association networks can then help to identify biological pathways that are relevant to disease study and allow for experimentation to go forward. These programs know nothing about periodontitis or inflammation and they don't care, but they know how to write programs that can help me to find out this information.

GHN: What do you see as the role of genomics in dental education and practice?

Dr. Terracio: A key reason for genomics education for dental health professions is that education is about the future, not the past, and we have entered an era in which genetics and genomics are playing a vital role in oral health research and dental practice. Each new day brings advances in genomics that add to the number of dental conditions whose genetic component is understood. The need for dental professionals to understand, recognize, and utilize genetics and genomics in their daily practice grows commensurately with these scientific advances.

Dentists have long recognized a genetic component to dental health problems, especially in the areas of abnormal tooth formation or physical malformations, such as a cleft lip or palate, resulting from hereditary conditions. But patients now expect more, whether it's their risk for periodontal disease, or the connections between oral and systemic diseases, or the value of utilizing genetic tests to predict risk of disease in individual patients. Our students need to review the scientific literature and be able to evaluate it.

From the standpoint of what the practitioner needs to know, while it might not be imperative to learn to do informatics, practitioners should know how to assess the literature, because biomarkers for oral cancer and periodontics and other oral diseases may turn out to be valid, and practitioners need to know how they can best advise their patients about whether or not they should have this analysis.

Dr. Bretz: We had a large sample of twins and applied whitening procedures to them. Although both groups responded well to the whitening procedures, the identical twins had much less variation in the treatment response than the fraternal twins, suggesting that there might be a genetic component operating. Anecdotally, if you read the literature, many studies have found that some people respond very fast to whitening procedures, whereas others do not. So I think that practitioners will eventually find those kinds of applications especially useful.

Dr. Engebretson: A related area that may turn out to have special interest for the practitioner is pharmacogenetics, the branch of pharmacology that deals with the influence of genetics on a person's response to specific drugs, and with tailoring a drug therapy at a dosage that is most appropriate for an individual patient.

Dr. Schmidt: The reality is that it is difficult to fit all the new information-on genetics and biochemistry and genetics and immunology and pathophysiology and genetics and bioinformatics—into a four-year dental school curriculum and into a dental practitioner's continuing education. But that shouldn't stop us from seeking ways to disseminate this information. We need a biomarker for insatiable curiosity.