NIDR Supports New Research Pathways

AUTHOR: KAREN YOUNG KREEGER, pp.14 Date: May 16,1994 Arthritis, AIDS, and signal transduction may not be areas of investigation that immediately come to mind when one thinks of dental research. But the National Institute of Dental Research's (NIDR) range of interests and achievement has in recent years broadened well beyond the institute's original 1948 mandate to improve the oral health of the American people. In 1948, a congressional mandate set up the National Institute of Dental Research (NIDR), the third-oldest of the National Institutes of Health, to "address the then deplorable state of oral health in the United States," according to the institute. NIDR, which today covers 19 areas of research--including such diverse investigations as craniofacial disorders and salivary gland physiology, as well as the traditional areas of periodontal disease and tooth decay--funds both intramural and extramural projects. Some current NIDR statistics: NIDR's budget for fiscal year 1994 is $169.5 million, 75 percent of which goes to extramural research. The extramural program supports more than 700 grants and contracts to the scientific community for research and training. Intramural laboratory and clinical research takes place at eight laboratories, a dental clinic, and a pain research unit at NIH headquarters in Bethesda, Md. NIDR employs a staff of about 400 scientists, technicians, trainees, and support personnel. The two main dental research professional societies, headquartered at the same location, are: American Association for Dental Research (AADR) International Association for Dental Research (IADR) 1111 14th St., N.W. Suite 1000 Washington, D.C. 20005 Phone: (202) 898-1050 Fax: (202) 789-1033 John Rugh, president, AADR Barry Sessle, president, IADR John Clarkson, executive director, AADR and IADR E-mail: 72614.3643@compuserve.com Noting NIDR's advances in preventing and understanding the cause of tooth decay and some periodontal diseases over the last 40 years, NIDR director Harald Loe says, "We are [also] moving research in the preventive frontiers into other diseases," such as craniofacial disorders as well as "an array of systemic diseases," including AIDS and diabetes. Other current research areas under NIDR's broad umbrella include osteoporosis, cancers of the mouth, chronic pain disorders, and alternatives to traditional silver amalgams. Lois Cohen, director of the NIDR grants program, describes the current "portfolio" of grantees as covering "disciplines at the very basic molecular-biological level all the way to the applied areas of health promotion and disease prevention" (see accompanying story). Dental researchers say that some in the medical community remain unaware of the extensive implications dental research has for other areas of human health, as well as its intimate connection with molecular biology--for example, the use of common molecular techniques such as cloning as a means of studying the microbes of the mouth. Walter Cohen, chancellor of the Medical College of Pennsylvania and former dean of the University of Pennsylvania School of Dental Medicine, both located in Philadelphia, cites the current curriculum of medical schools as one possible reason for dental research's low profile. "The average physician is given very little information about the oral tissue" in his or her training, Cohen says. According to Harold Slavkin, the George and Mary Lou Boone Professor of Craniofacial Molecular Biology at the University of Southern California, Los Angeles, the situation is changing. Still, he says, "for some people it's counterintuitive to think of dental research being done by molecular biologists. I think they perceive teeth as being dead. There is also a perception that dental research means tooth decay and gum diseases rather than [including] the nuances of taste perception, and craniofacial disorders such as cleft lips and palates." Despite advances in understanding the causes of tooth decay and some periodontal diseases, examining these conditions on a molecular level is a fairly recent development in dental research. About 300 species of bacteria interact in their own ecosystem in the human mouth. To cause disease, these bacteria colonize the surface of teeth and gums, forming networks of interacting species, NIDR scientists explain. Paula Fives-Taylor, a molecular microbiologist at the University of Vermont, Burlington, who is funded through NIDR, has been studying the molecular mechanisms of attachment and invasion by oral microbes--or "bugs," as she calls them--for the last 15 years. To understand the ecological succession of oral bacteria--what species attach first and how they influence the living conditions for later colonizers--Fives-Taylor uses molecular techniques such as cloning and making genome libraries to isolate the gene for hairlike structures called fimbriae that allow bacteria to attach to teeth. Specifically, she is interested in the fimbriae of the bacterium Streptococcus sanguis. One of the areas she is currently studying is "how the fimbria gene is regulated and expressed, with the hopes of eventually understanding how to interfere with colonization" of bacteria. In addition, for the past three years, Fives-Taylor has been looking into the attachment mechanisms of bacteria thought to cause periodontal disease, whose mechanisms are not as clear-cut as those in tooth decay. Her lab has recently cloned genes from a candidate bacterium that attaches to surface, or epithelial, cells of the gums, which "at least confer upon E. coli the ability to attach to oral tissue." Although not the first group to show bacterial invasion of epithelial cells--this has already been shown in the gut by others--her lab is the first to do so for the mouth. The importance of this finding for general medical science, she says, is that invading organisms that get inside cells are immune to host defenses and antibiotics. It is known that, in the gut, epithelium-invading bacteria "fool" the cell into "thinking" that it is a molecule in the signal- transduction pathway of gastrointestinal-tract epithelial cells, thereby gaining entry, she says. "So we're very interested to see if our bug also goes through this. We have some early evidence to suggest that it might." These oral bugs do not stop at wreaking havoc with cellular signal transduction. Sharon Wahl, chief of the cell immunology section at NIDR, explains that many of these oral disease-causing bacteria release "a whole host of antigens, toxins, and cell-wall fragments, which engage the immune system." But the effects of microbes are not limited to oral systems. She notes that her research area extends to inflammation and wound healing, and, more specifically, understanding the regulation of connective tissue metabolism by growth factors and cytokines--hormone-like substances--released by inflammatory cells during an immune response. Using rodents, Wahl studies "what cells are activated in the immune system, what they produce or don't produce, or how these functions might be regulated by growth factors or cytokines." Bacterial cell walls are not digested by the rats, Wahl says, so their persistent presence produces an overactivation of the immune system, "leading to an overproduction of substances such as nitric oxide, or certain cytokines." These, in turn, can eventually cause tissue destruction, damaged DNA, or bone resorption. With nitric oxide-inhibiting chemicals, Wahl's group has shown that they can block the pathology of too much nitric oxide-- inflammation of the joints, liver, and spleen--in rats. Relating these findings to humans, she explains that her group did find increased nitric oxide production in inflamed periodontal tissues. She suggests that if nitric oxide can be blocked, it might be an important future therapy for periodontal disease, as well as for chronic inflammatory diseases like arthritis. Although outside the walls of NIDR the research theme of the Clinical Investigations and Patient Care Branch is not often a subject mentioned in polite conversation, it is an area that many of its intramural researchers drool over. The focus of the branch, according to its chief, Bruce Baum, is salivary gland biology and pathology. Over the last several decades, research at NIDR and here has revealed the myriad functions saliva has for human health. "It's the main protective [medium] in the mouth," says Baum, referring to saliva's antibacterial, antifungal, antiviral, and wound-repair capabilities. In preliminary studies, NIDR researchers have even found that salivary glands secrete a substance that blocks HIV from infecting cells. Two sections of the branch study the physiological mechanisms of ion transport and neurotransmitter signal transduction of the salivary gland. The scientists are trying to understand the molecular chain of events involved in salivation and how this applies to oral and systemic diseases. Knowing the details of these events has allowed the researchers to apply their knowledge of a correctly working system to understanding one that's gone awry. For example, Sjogren's syndrome, an autoimmune disease in which the immune system attacks the body's exocrine glands--such as the salivary gland-- results in decreased or absent production of saliva, tears, and vaginal secretions. Destruction of exocrine glands, resulting in low to no water flow, is also caused by radiation treatment to the head and neck for cancer. "In autoimmune diseases, everyone would like to know what is the switch that suddenly means a tissue is going to be recognized as foreign by our bodies. It's a real tough problem, but what we can deal with is a damage mechanism," Baum says, referring to NIDR work on "a whole host of potential therapeutic implications." Baum, who is also head of the branch's relatively new Gene Transfer Unit, says that the unit's researchers use gene therapy to repair damaged salivary glands. Referring to the biochemical pathway that leads to normal salivation, he says, "we have cloned a gene for a water channel; so, using recombinant adenovirus vectors, we can insert a water-permeability pathway into a water- impermeable cell," such as those damaged by radiation or found in Sjogren's syndrome. According to NIDR, "the variety and severity of oral diseases associated with HIV infection were recognized early by all components of the dental community," thus leading to their increased involvement in AIDS research in the mid- to late 1980s. NIDR-related AIDS research covers basic studies in epidemiology, virology, immunology, and molecular biology. Charles Barr, director of dental medicine at Beth Israel Medical Center, New York, began working on NIDR-sponsored studies of the effect of HIV on saliva and oral tissues about seven years ago. The results of one of his lab's earliest studies--at a time when there was still public concern over transmission of AIDS via saliva--conclusively established that, compared with blood, saliva contained practically no live HIV. In fact, only 1 percent of the homosexual and bisexual male subjects Barr and colleagues studied carried live HIV in their saliva, although 38 percent of them had HIV in their blood. Other aspects of this work dealt more closely with opportunistic oral infections associated with AIDS, such as candidiasis, a fungal infection. In this study, he set out to show that, although not an unequivocal test, "the health of the oral cavity can function as a surrogate marker for relative immunostatus." For example, Barr explains, "if patients have candida in their mouth, their T cells are probably below a certain level, according to our data, and other aspects of their immune-system capabilities may warrant a closer look." Under a grant from NIDR, Barr and colleagues are now extending their HIV-in-saliva-vs.-blood work to the intravenous-drug-using population--a study group that contains 35 percent women. Preliminary data from this study indicate that the same 1 percent as in the homosexual male group studied earlier have live HIV in their saliva. "This is not surprising, because between now and the time that we started the initial study, there have been several reports by NIDR and others that show saliva does have an inhibitory effect on the proliferation of HIV," says Barr. "Identifying this factor is of interest to the scientific community now. It has been published in the AIDS literature, but what's surprising to me is that it hasn't seemed to elicit too much interest on the part of people in other areas." Currently, he explains, "all we know in general is that the factor has an inhibitory effect." However, a preliminary collaborative effort of investigators at Beth Israel and colleagues at Thomas Jefferson University in Philadelphia showed that epithelial cells shed into the saliva contain pro-viral HIV DNA in their nucleus. They hypothesize that if the epithelium does take up HIV and it replicates there, it might do the same in other mucosal tissues, thereby becoming another possible repository for HIV. For information on research grants offered by NIDR, contact Norman Braveman, chief of the Program Development Branch, NIDR, Westwood Building, Room 503, 5333 Westbard Ave., Bethesda, Md., 20892; (301) 594-7648. Fax: (301) 594-9720. E-mail: bravemann@wwpo.nidr.nih.gov

NIDR Supports New Research Pathways

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