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Roy C. Page: Leader in Collaborative and Multidisciplinary Research in Periodontology
1 Department of Periodontics, School of Dentistry, and Correspondence: * corresponding author, bordin{at}u.washington.edu Martin Taubman, Editor
Key Words: periodontology • oral biology • periodontal connective tissue • matrix • clinical trials In a career spanning four decades thus far, Dr. Roy Page has made unique and transforming research contributions to the understanding of the pathogenesis and clinical management of the periodontal diseases. Along the way, Dr. Page became an avid enthusiast of classical opera. In Roy’s view, the strength of any opera performance was less a function of an individual conductor or soloist or cast member, but rather the creative collaboration that brought out the best in all members of a multidisciplinary ensemble. Such a collaborative and multidisciplinary approach to research and clinical excellence is reflected in a career that includes six textbooks and monographs, and more than 300 journal publications and book chapters. Approximately 90% of Page’s journal publications are authored by an average of four other investigators. A review of the co-authors of his publications and abstracts identifies more than 800 unique collaborators with diverse disciplines and institutional affiliations, the majority of whom serve as first author of the publications. The National Institutes of Health records place him above the 95th percentile of extramural grants, obtained primarily through collaborative Center and Institute initiatives funded during the past 25 years. We are among many others who have been profoundly and positively influenced by Roy Page’s intellectual insight, nurturing support, extraordinarily high standards of excellence, and solid friendship. We have discussed Roy Page’s journey of discovery with a broad range of his colleagues and friends. We take great pleasure in reflecting their views of his fundamental contributions to oral biology and clinical periodontology. Page established a distinguished record of undergraduate scholarship at Berea College in Kentucky and graduated Summa Cum Laude from the University of Maryland School of Dentistry. He entered the Experimental Pathology PhD program, led by Dr. Earl Benditt, and Periodontics specialty training with Dr. Saul Schluger at the University of Washington in 1961. He completed this formative period with Dr. Anthony C. Allison at the Medical Research Council Laboratory in London. The resulting convergence of disciplines and internationally respected mentors was remarkable. Dr. Page formed a group that included Dr. Sampath Narayanan and a host of graduate students to describe the localization and distribution of the various collagens and proteoglycans that comprise the healthy and diseased periodontium (Narayanan and Page, 1976). Their laboratory was the first to demonstrate that collagen turnover in the periodontium is far more rapid than in other normal connective tissues. Dr. Sandra Bordin joined them to provide evidence that multiple genetically stable varieties of fibroblasts exist in normal gingiva and gingival granulation tissue (Bordin et al., 1984). A unique fibroblast phenotype was isolated and characterized based on ligand binding to the high-affinity C1q complement receptor. Research with dental students identified a component of root cementum that communicated with and regulated fibroblasts in their vicinity. Dr. Page suggested that a repertoire of fibroblasts may exist in small numbers in all normal connective tissues, and that the cell type that becomes dominant in a tissue is determined by normally occurring mediators that stimulate proliferation of a specific subpopulation, or by drugs such as diphenylhydantoin. A series of early clinical studies in periodontitis patients concluded that prostaglandins and several cytokines were critical inflammatory mediators in the pathogenesis of periodontitis. Related observations also showed that specific serum antibodies to antigens of pathogenic bacteria could block prostaglandin production by mononuclear cells. Dr. Page also suggested a potential role for specific antibody suppression by immunization in controlling alveolar bone loss. The early 1970s marked the beginning of what colleagues smilingly term "Roy’s white linen suit period", owing to multiple copies of the same tailored suit worn at all meetings. He began to focus on relationships among the oral microbiota, the inflammatory infiltrate, and destruction of the connective tissue matrix in multiple forms of periodontitis. His collaborative group expanded to include national and international investigators, and his laboratory became filled with basic and clinician scientists, residents, post-doctoral fellows, and dental, medical, and graduate students. Conversations with those involved with Dr. Page’s group at the time universally remember Roy as a warm and genial host, a connoisseur of fine food and wine, a rigorous debater long into the evening, and an intellectually fearsome critic. His office was unpretentious at best, filled to overflowing with boxes of reprints and manuscripts, unstable furniture, a single line phone with all the numbers worn from the keypad, and an electric typewriter for which replacement parts were no longer available. It was a place for students, faculty, and distant visitors to feel welcome while engaging in spirited discussions on new approaches to research mixed with deliberations on the proper age of wine, the proper care of tomato plants, or a recent opera performance. The result of his collaborative efforts to understand the biology and clinical management of the periodontal diseases were summarized in what has become a citations classic (Page and Schroeder, 1976) and a subsequent monograph on periodontitis in humans and other animals (Page and Schroeder, 1982). These concepts were broadened and updated in a subsequent monograph on the pathogenesis of periodontitis (Page and Kornman, 1997). In what reads like vigorous conversations between colleagues, these works postulated that periodontitis reflected the sum total of interactions among highly organized oral bacteria, the periodontal tissues, and a broad variety of host defense systems. The work further argued that periodontitis was neither linear nor an automatic consequence of gingivitis, and could assume numerous clinical presentations depending on the nature and effective radius of the infecting bacteria, periodontal anatomy, genetic predisposition, and expression of the host inflammatory response. Critical variables also included the size, location, and composition of the biofilm, the frequency and duration of epithelial ulceration, the everyday habits of the host, and the regularity of oral care. Dr. Page proposed a family of different but related clinical forms of periodontitis, including prepubertal and rapidly progressing forms, having features in common but being distinctly different entities in terms of etiology, pathogenesis, progression, natural history, and response to treatment. Later deliberations focused on the iterative nature of the bacterial challenge and host cellular response in periodontitis, a process postulated to be highly regulated and in constant adjustment. The discussion substantially influenced classification schemes subsequently adopted by the American Academy of Periodontology. At the same time, Dr. Page held that periodontal classifications were temporal, and must invite scientific inquiry and necessarily evolve to reflect new research findings. He recently added to the classification evolution by describing case definitions for periodontal diseases that are to be used by the Centers for Disease Control for population surveillance of periodontitis (Page and Eke, 2007).
Beginning in the early 1990s, Dr. Page and his co-workers saw development of a vaccine for human periodontitis as a realistic goal. They identified and partially characterized the predominant antigens of periodontal pathogens and assessed antigenic variation and cross-reactivity among isolates of these species. They characterized the humoral immune responses of normal subjects and periodontitis patients to these same bacterial species, including serum antibody titers, avidity and other functional characteristics, IgG subclass distribution, opsonic activity, and the effects of periodontal therapy on immune responses. Based on these studies, Page and his colleagues developed and began testing a vaccine for human periodontitis using ligature-induced periodontitis in Macaca fascicularis as a model. Repeated trials showed that immunization reduced alveolar bone loss about 50% relative to controls. Total bacterial load, levels of putative bacteria in the subgingival flora, and levels of PGE2 in gingival fluid were significantly reduced. Page and his co-workers concluded that the dramatic results in this animal model were related to antibody-mediated phagocytosis and killing of key pathogens, with concurrent suppression of cytokines mediating connective tissue and alveolar bone destruction. More importantly, the series of studies in non-human primates firmly established a possibility of immunization for human periodontitis. Dr. Paul Robertson arrived as dean at the University of Washington in 1991. Page was establishing a Regional Clinical Dental Research Center with support from the National Institute of Dental and Craniofacial Research. In addition to his international collaborators, Page also involved the majority of faculty in the School of Dentistry and a broadly interdisciplinary group of investigators from departments throughout the university, particularly the Schools of Medicine and Public Health. The Center was engaged in numerous randomized clinical trials on the diagnosis and treatment of periodontal diseases, including the development of techniques to measure disease activity at specific periodontal sites, efficacy and safety of anti-inflammatory agents, and therapeutic utility of antimicrobial therapy. From a dean’s perspective, Page had for years brought great distinction to the university, in general, and to dentistry in particular. He held professorial appointments in Pathology within the School of Medicine, and Periodontics within the School of Dentistry. He had earned independent funding from the public and private sectors for three decades. He had been elected by peers to the presidency of both the American and International Associations for Dental Research. The work of his collaborative group had fundamentally influenced the study and the practice of Periodontics. Thus, it was not surprising for the new dean to learn that Roy was also an outstanding faculty member and a solid University citizen. He taught the major courses on basic and systemic pathology to generations of dental students. Other teaching activities included courses in anatomy, pathology, and human biology for medical, pharmacy, and multidisciplinary graduate students. Students characterized him as an articulate and highly organized instructor with high standards of expectation combined with a clear concern for their educational needs. He willingly brought his extraordinary insight and meticulous preparation to a wide range of dental school and university committees. During the last decade, Page and his colleagues have embarked on projects to improve the quality and design of clinical trials in Periodontics, improve the precision of periodontal diagnosis, and accurately assess risk for periodontal disease. Several clinical trials by his group provide a clear rationale for the local and systemic beneficial effects of surgical, non-surgical, and maintenance periodontal therapy. Most recently, an Oral Health Information Suite was developed as an Internet tool available in the offices of all dental practitioners to assess risk for periodontal diseases, dental caries, and oral cancer. The assessment tool provides a risk score, textual diagnosis, and recommended treatment plan and is currently being evaluated nationally and internationally for its potential to help contain the cost of oral healthcare while significantly improving oral health (Page and Martin, 2007). Dr. Roy Page’s journey of discovery has addressed critical questions about the biology of the periodontium and disease processes that adversely affect periodontal integrity. Roy would have us recognize the efforts of a large number of individuals who worked with or collaborated with him. He would also gratefully acknowledge the generous training and research support provided by the National Institute of Dental and Craniofacial Research over a period of more than 40 years. Taken collectively, collaborative and multidisciplinary research guided by Page has clarified the composition of the periodontal connective tissue matrix, postulated new paradigms to the understanding of periodontal pathogenesis, and fundamentally influenced the diagnosis and clinical management of the periodontal diseases. There will undoubtedly be more to come. He is the recipient of honors and awards from many professional organizations, including the Distinguished Scientist Award from the American Association for Dental Research, the Basic Science Award in Periodontal Research from the International Association for Dental Research, the Gies Award and a Citation of Merit from the American Academy of Periodontology, and the Norton M. Ross Award for Clinical Research from the American Dental Association. In conversations with several directors of these organizations, we were asked to note that Page has a long and positive history of professional service, with an extraordinary ability to bring people together to solve complex administrative as well as scientific problems. We join Roy’s many friends and colleagues in observing that while he is inherently shy, gentle of voice, and intensely private, Dr. Page is most of all a kind, caring, and gentle human being. He applies extraordinarily high expectations of excellence to himself and those around him, but one could have no more steadfast friend. Dr. Roy Page brings great credit to the profession, and the authors join the many colleagues who are far better for his wise counsel, his scientific excellence, and his friendship. Received for publication February 2, 2007. Revision received December 21, 2007. Accepted for publication January 3, 2008. REFERENCES
Journal of Dental Research, Vol. 87, No. 4,
293-295 (2008)
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