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Testimony on the National Institute of Dental Research's FY 1998 Budget by Dr. Harold C. Slavkin
Director, National Institute of Dental Research
National Institutes of Health

Accompanied by:
Dr. Dushanka V. Kleinman, Deputy Director, NIDR
Ms. Yvonne H. du Buy, Executive Officer, NIDR
Ms. Earlene S. Taylor, Budget Officer, NIDR
Dr. Harold Varmus, Director, NIH
Mr. Dennis P. Williams. Deputy Assistant Secretary, Budget, DHHS
U.S. Department of Health and Human Services

Before the House Appropriations Committee, Subcommittee on Labor, Health and Human Services, Education and Related Agencies
March 4, 1997

NIDR will celebrate its 50th anniversary in 1998. In looking back over this half century we can only marvel at the changes wrought in society--not the least of which reflects progress in research. Fifty years ago the word genome was unknown; today human genes are mapped at the rate of one a day. Fifty years ago the words biotechnology and PC were unheard of. Today biotechnology represents a $83 billion industry in America, while PCS, E-mail and the Internet have become routine modes of communication among scientists--and others--worldwide.

As someone who graduated from dental school in Los Angeles in 1965 I can at test to the dramatic improvements in oral health we have seen, improvements that translate to savings of $4 billion a year in dental care costs in this country (Public Health Report, 109-2). These advances were made possible by the creation of NIDR and its support of men and women who have devoted their lives to understanding the complexities of the craniofacial, oral and dental tissues and the diseases and disorders that plague them.

Among the most tragic are birth defects that disrupt normal development, leading to heartbreaking disfigurement and complications that affect the structures that constitute the face, head and often the nervous system, limbs and internal organs. Over a century ago, Charles Darwin described a family in Schinde, India "in which ten men, in the course of four generations, were furnished, in both jaws taken together, with only four small and weak incisor teeth and with eight posterior molars. The men thus affected have very little hair on their body and become bald early in life. They also suffer much during hot weather from excessive dryness of the skin" though the daughters in the above family are never affected, they transmit the tendency to their sons.

What Darwin so graphically described in 1875 was a condition called anhydrotic ectodermal dysplasia (EDA), one of more than 150 forms of "ectodermal dysplasia," so-called because the tissues affected--teeth, skin, hair and sweat glands--all derive from the ectoderm, one of three tissue layers that form early in embryonic life. The absence of sweat glands alone can lead to dangerous overheating of the body, which can be brain-damaging and life-threatening.

Darwin noted that the disorder was sex-linked, and we now understand why: Affected males inherit a defective X-chromosome from their mothers, but lack a complementary normal gene on the Y-chromosome they inherit from their fathers.

In 1996 an international team of investigators discovered the site of the mutated gene for EDA on the X-chromosome, cloned and sequenced it and then determined the nature of the gene product. The gene codes for a relatively small protein believed to straddle the cell membrane in selected skin, hair follicle, sweat gland and other fetal and adult epithelial tissues. These investigators suggest that this transmembrane protein may serve as a key signaling molecule involved in cell-cell interactions between epithelial and connective tissue layers in the developing embryo.

The role of small molecules in development is even more strikingly illustrated in yet another series of genetic discoveries that have made this a banner year in developmental biology. Investigators have shown that a number of rare craniofacial syndromes, with varying manifestations-- including mental retardation and early death--are linked to mutations in genes that code for a family of proteins called fibroblast growth factor receptors (FGFRs). These transmembrane receptors are found on the surface of many embryonic and adult cells and appear to play a role in cell-cell communications during critical stages of development. What is surprising is that a number of single letter misspellings (called point mutations), in many cases affecting only a small segment of the encoded protein, have been discovered in patients with Crouzon, Apert, Jackson-Weiss, Pfeiffer and Beare-Stevenson syndromes. While these syndromes are characterized by multiple tissue and organ defects, all have in common a small midface and craniosynostosis, a condition in which the skull bones fuse prematurely, deforming the shape of the head and putting pressure on the developing brain.

Studies of the ectodermal dysplasias and the FGFR syndromes are providing the clues to eventually define the master genes and critical events in development that transform a fertilized egg into a healthy baby. We are rapidly moving to a stage of early diagnosis, carrier testing, and the development of interventions to prevent or repair the consequences of mutated genes. When that happens we will have reduced an enormous toll in human suffering and health care costs: One in 33 babies born in 1995 had at least one anatomical birth defect, three-fourths of which affected the head, face and neck. The most common craniofacial defect is cleft lip, with or without cleft palate, which affects one in 500 births. That means that one baby with a cleft is born every hour of every day of the year. Lifetime costs for the repair of clefts and treatment for associated speech, hearing and other problems are estimated to be $100,000 per patient. Costs of treatment for less common, but often more complex syndromes, are even higher.

Development is characterized by cell-cell interactions and processes in which cells migrate, proliferate and differentiate to form the body's organs and systems. Specific command-and- control genes, so-called morphoregulatory genes, determine when and where a cell should divide and when it should stop dividing. It is just such controls that are lost when a cell become malignant. Thus, what we learn about the genes critical to development has applications to the study of cancer. Last year I told the Committee that we needed to look in depth at oral, pharyngeal and laryngeal cancers--cancers which have not benefited from progress in the last 50 years. These cancers affect 42,000 Americans every year and result in an annual toll of 9,000 deaths (Surveillance Epidemiology and End Results, 1997). Mutilating surgery and damaging radio- and chemotherapy have been the standard treatments, while the five-year survival rate stands at a dismal 50 percent. Survival is even worse--only 30 percent--among the group in which these cancers are most prevalent: male African-Americans.

Today I am pleased to report that we were able to fund four new Oral Cancer Research Centers in FY 1996. Among other studies, investigators will explore how the effects of risk factors such as smoking and drinking, alone or in combination with certain viral infections, might trigger mutations in so-called "tumor-suppressor" genes or activate genes that once caused cells to divide in their early stage of development. The next steps will be to develop "smart" therapies; e.g., treatments aimed at reactivating tumor-suppressor genes, eliminating the role of viruses or causing cancerous cells to self-destruct. The four new centers are located at the University of Alabama, Birmingham; University of California, San Francisco; University of Chicago with Northwestern University; and the University of Texas-M.D. Anderson Cancer Center in Houston. Three of these centers are co-funded with the National Cancer Institute (NCI).

Increased collaborations across the NIH, and among intramural and extramural scientists and the private sector, are essential to advance research. We at the NIDR embrace the strategy of leveraging funds and facilitating teamwork to accelerate biomedical research progress. Let me give you a few examples of important collaborations currently under way:

Candida genome and candidiasis. Candida albicans, a normally harmless fungal (yeast) inhabitant of the oral cavity can become virulent, giving rise to candidiasis in immunosuppressed individuals. These include patients undergoing organ transplantation, cancer chemotherapy or radiation, those who have autoimmune conditions such as Sjogren's syndrome and edentulous patients wearing dentures. Candiadasis can interfere with normal oral functions such as eating and swallowing, can predispose to other infectious, and if spread systemically, can be fatal. Increasingly, candida infections are proving to be highly resistant to the treatment of choice-the azole drugs. We are funding a major grant to map the entire Candida albicans genome in collaboration with the Burroughs-Wellcome Trust. The resulting data should yield information on the life cycle of this yeast, its ability to switch to virulent and drug-resistant forms, and facilitate the development of more targeted therapies.

Meanwhile, NIDR staff scientists, working with NCI and Boston University, are developing improved vectors to transport the gene for histatin 3, one of a family of highly effective anti-fungal and antimicrobial proteins secreted in saliva, into rat salivary glands. Their earlier experiments have already demonstrated that the technique works, and they have achieved expression of histatin 3 in the saliva of rats--species that does not normally generate histatins. By FY 1998 they expect to be ready to move to human studies. One potentially very real benefit is that histatin 3 is antimicrobial as well as anticandacidal for both azole-sensitive and azole-resistant strains of candida.

Pain research. NIDR has a proud record of research on pain, an area which has taken on increased importance as the United States, in parallel with other developed countries, is experiencing sharp changes in the demographic profile of the population and in the pattern of diseases. While we have extended the life span and reduced mortality from heart disease, stroke and other major killers, we are seeing increased numbers of people who are living with chronic disabling diseases and disorders. All too often, these patients suffer a severe loss in the quality of life because the disease--and sometimes the disease treatment-- result in chronic pain. Pain specialists estimate that the cost of chronic pain in the United States is $100 billion a year (The Management of Pain, Vol. 1, 1990).

To address the breadth and depth of the problem, NIH Director Dr. Harold Varmus has established a trans-NIH Pain Research Consortium composed of the Directors and key staff of some 20 Institutes and Offices at the NIH and named the Director of the National Institute of Neurological Disorders and Stroke, Dr. Zach Hall, and myself as co-chairs. The purpose of the Consortium is to encourage information sharing, collaborative research efforts and coordination of pain research across all NIH components. This approach should ensure that results of NIH-supported pain research are widely communicated. The Consortium will seek advice from other Federal agencies and from non-Government organizations interested in pain research. A major conference to consider New Directions in Pain Research is planned for early FY 1998.

Biomimetics. The aging of the population is creating increased demands for replacement parts for body tissues such as knee and hip joints, temporomandibular joints, teeth, and heart valves, while there is an ongoing need to develop better treatments for craniofacial and skeletal bone fractures and the clinically complex challenges of trauma and burns. Conferences in 1995 and 1996 involving NH Institutes and the private sector reviewed the state of the science for biomaterials and the new fields of biomimetics and tissue engineering, which exploit the body's own cells and molecules for the repair and regeneration of tissues. Researchers reported on promising works in progress in which analogues of natural body compounds are placed in resorbable carrier materials to test their efficacy in regenerating bone, cartilage, dentin, cementum and skin. Recommendations from these workshops have now led to a collaboration between NIDR and the National Heart, Lung and Blood Institute on a Request for Applications in the field of biomimetics and tissue engineering to address a broad range of scientific opportunities.

In closing I would like to mention that we will be celebrating the Institute's 50th anniversary in the course of FY1998 with a variety of events, conferences and exhibitions that will review and preview the unique contributions to science and the improvements in the health of the nation that have distinguished NIDR over the years and will carry us forward into the future. We have been pioneers in studies of microbial ecology and mucosal immunity--the one dealing with the interactions of microorganisms in the oral cavity; the other dealing with the properties of the body's immune system that involve the mucous membranes that line the mouth, throat, esophagus, lungs, gut and genital tracts. We have studied the unique tissues of the mouth--such as teeth, tongue and taste buds--as well as used the oral tissues as convenient models of bone, cartilage, synovial joint, nerves and muscles common to the rest of the body. In this way, we have contribute to understanding and resolving oral as well as systemic diseases, always emphasizing the intimate connection between oral and general health. The recognition of that symbiotic relationship will continue to inspire our research efforts and drive our mission to improve craniofacial, oral and dental health as we move into the 21st century and our next 50 years.

Mr. Chairman, the FY 1998 request for the National Institute of Dental Research is $190,081,000. I will be happy to answer any questions.

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