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.
