Australian Dental Journal
The official journal of the Australian Dental Association
Australian Dental Journal 2014; 59:(1 Suppl): 186–190 doi: 10.1111/adj.12105
The future of research in craniofacial biology and what this will mean for oral health professional education and clinical practice HC Slavkin* *Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, The University of Southern California, California, USA.
ABSTRACT Today, and looking to the future, scientific discoveries from cellular, developmental and molecular biology inform our understanding of cell, tissue and organ morphogenesis as exemplified in skin, bone, cartilage, dentine, enamel, muscle, nerve and many organs such as salivary glands and teeth. Present day biomedical science yields principles for the biomimetic design and fabrication of cells, tissues and organs. Bioengineering has become a strategy that can ‘mimic’ biological processes, and inform clinical procedures for tissue and organ replacements. The future of regenerative craniofacial biology holds enormous promise for the diagnosis and treatment of congenital birth defects, traumatic injuries, degenerative chronic diseases as well as for Mendelian single gene and complex multigene diseases and disorders. The past 50 years have heralded the completion of the human genome and the introduction of ‘personalized medicine and dentistry’, the utilization of stem cell therapy for an array of diseases and disorders, the ‘proof of principle’ to reverse select inherited diseases such as anhidrotic ectodermal dysplasia (ED), and the fruits from interdisciplinary research drawn from the diverse biomedical sciences. Looking to the future, we can readily anticipate as major goals to emphasize the clinician’s role in identifying clinical phenotypes that can lead to differential diagnosis, and rejuvenate missing or damaged tissues by establishing processes for the utilization of gene, cell and/or protein therapies. The future is replete with remarkable opportunities to enhance clinical outcomes for congenital as well as acquired craniofacial malformations. Clinicians play a pivotal role because critical thinking and sound clinical acumen substantially improve diagnostic precision and thereby clinical health outcomes. Keywords: Congenital malformation, acquired craniofacial malformations, genetics, stem cells. Abbreviations and acronyms: ED = ectodermal dysplasia; FGFR2 = fibroblast growth factor receptor 2; iPS = induced pluripotent cell; SNP = single nucleotide polymorphisms.
INTRODUCTION Excellent contributions to this special issue of the Australian Dental Journal repeatedly demonstrate that craniofacial biology is characterized by an elaborate collaboration and often integration between anatomists, anthropologists, audiologists, biochemists, dentists, dental hygienists, nurses, pharmacists, developmental biologists, embryologists, geneticists, immunologists, microbiologists, neurologists, occupational therapists, physical therapists, physicians, physiologists, psychologists, radiologists, social services, speech therapists – all asking important questions and investigating the craniofacial-oral-dental complex. This field has become a trans-professional, multidisciplinary, international coalition working to unravel clinical problems associated with birth defects, head and neck trauma, and a host of chronic degenerative diseases and disorders.1–6 186
As we advance into the 21st century, the future of craniofacial biology – diagnosis, treatment and therapeutics, and outcomes – will continue to herald advances and improvements. A number of indicators further suggest that Australia will continue to provide leadership in patient health care, and to participate in international education programmes designed to improve the clinical competencies needed to provide excellent patient care for congenital as well as acquired facial disfigurements (e.g. Operation Smile Australia, Melbourne Cleft and Craniofacial Unit, Australian Craniofacial Unit).7,8 In tandem, the future of research will consist of uncovering the molecular mechanisms by which organisms recognize and respond to tissue damage. Mechanisms for tissue repair and regeneration are of enormous interest. The yields from these research efforts will herald the emergence of the following: © 2014 Australian Dental Association
Future of craniofacial research gene, cell and protein therapies, tissue engineering, the design and fabrication of scaffolds, digital enhanced imaging, personalized medicine, and regenerative dentistry and medicine. Further, we should anticipate the convergence of bioengineering, molecular biology, nanotechnology, clinical dentistry and medicine, speech therapy, occupational therapy, physical therapy and the behavioural science professions.6 This contribution will focus on a few select examples of future research in craniofacial biology and how these projected advances will influence oral health professional education and clinical practice. The burden of congenital and acquired craniofacial anomalies to society Currently, approximately 1 out of every 10 people in the industrial countries of the world, including the United Kingdom, Australia and the United States present facial disfigurements.7–9 One million people in the United States have severe facial disfigurements resulting from congenital abnormalities such as cleft lip and palate (nationally, 1 in 750 live births out of the 4 million births per year), other craniofacial syndromes, birthmarks and hemangiomas. Some acquired disfigurements result from severe facial burns, facial paralysis, trauma, diseases such as head and neck cancers, hypertrophic scars, and surgery sometimes resulting in a tissue response of producing keloids (the result of an overgrowth of dense fibrous tissue that develops after healing of a skin injury). We understand that the distribution of these conditions often leads to feelings of isolation and lack of support for patient and family in many regions of the United States. In addition, there is a separate group that includes smaller birthmarks, skin conditions such as severe acne scarring and eczema, and facial scars from minor accidents (approximately 10% of the 30 million children with acne develop severe facial scars). Future craniofacial research will also include epidemiology. A few demographic characteristics are useful for comparing Australia with California, my home state, in terms of population and cultural diversity. In 2013, Australia has approximately 22.9 million people and is expected to reach 28 million by 2030.10 California has 38 million people and is expected to reach 50 million by 2030. Immigrants comprise almost 24% of the populations of both Australia and California.10 By design, California currently has 19 cleft and craniofacial teams. Six of these craniofacial teams serve the 12 million people who live in Los Angeles County (e.g. Children’s Hospital of Los Angeles, University of California at Los Angeles, Craniofacial Clinic, The Hemangioma and Vascular Birthmark Center of Los Angeles). Australia also has craniofacial teams and centres proportional to the size of its © 2014 Australian Dental Association
population.7 Craniofacial teams are located essentially in every state of the union. Yet both Australia as well as the United States continue to lack timely surveillance systems for the many forms of facial disfigurement, access to comprehensive quality health care, and critical assessments for psychosocial and economic benefits or outcomes for patients and their families. How can we measure the outcomes from craniofacial teams such as quality of life, gainful employment, and productive lives for patients with severe facial disfigurements? The international challenge is access to comprehensive, quality craniofacial teams for all people along with health literacy and prevention wherever feasible. Examples of current and near future research opportunities in craniofacial biology Presently, throughout the industrial nations there are remarkable discoveries and advancements from the craniofacial behavioural and social sciences, computational and systems biology, bioinformatics, and the complementary mining of databases of clinical phenotypes, animal models, genes, proteins, carbohydrates and teratogens.6 These data sets now extend from prions and microbes to humans – genomes, transcriptomes, proteomes, metabolomes, diseasomes and pharmacogenomics – with complementary imaging data and annotation for storage and retrieval.6 Since World War II, investments in biomedical scientific research have continued to inform health professional education as well as clinical craniofacial-oral-dental health practices and profoundly improve the human condition by reducing the prevalence of disease while enhancing the quality of life.11,12 The following research efforts reflect the future of craniofacial biology and each example provides major opportunities for revision of health professional education in dentistry, medicine, nursing and pharmacy. Further, it is imperative we recall that through integration of modern science into the curricula at university-based health professional schools, the reforms clearly equipped health care professionals (e.g. dentistry, medicine, nursing, occupational therapy, pharmacy, physical therapy) with the knowledge and critical thinking skills that already have contributed to the doubling of the human lifespan by the end of the 20th century. Gene therapy Gene therapy is a technique that utilizes genes as therapeutics to treat or prevent a disease or disorder. This technique provides health professionals the opportunity to treat a disorder by inserting a gene of special interest or value into a patient’s cells rather than using an array of drugs or surgery. Further, this technique 187
HC Slavkin can be used to replace a mutated or defective gene that is the primary cause of the disease with a healthy or normal copy of the same gene. This methodology can also be used to inactivate or ‘knock-out’ a mutated gene that is functioning improperly. The technique can also be used to introduce a new gene into the body to help provide therapeutic benefits for the patient against the disease. The foundation for gene therapy resides in our collective understanding of human, animal, plant and microbial genes, the structure and function of deoxyribonucleic acid, the exquisite processes of gene activation and expression, and more recently the completion of the human genome in October 2004.13 Further, rapid advances in genome-wide sequencing technology, the recent ability to sequence the entire genome of a single human somatic cell, and the enhancing tools termed ‘SNPs’ (single nucleotide polymorphisms) that can diagnose a single mistaken nucleotide amongst 3.5 billion nucleotides.13 These advances have produced the new era of ‘personalized dentistry and medicine’.14 We now know that the human genome in its totality consists of a nuclear genome (total genes in the nucleus of each somatic cell of the body), the epigenome (specific coding regions of all genes) and the mitochondrial genome (a few dozen genes located in the maternally inherited mitochondria found within each of our cells). Humans contain 21 000 genes, 19 000 pseudogenes, and 37 mitochondrial genes.6,13 What we do not as yet know is ‘how’ clusters of genes are expressed in specific tissues and specific times during normal or abnormal development. Which genes in combination are required for morphogenesis of an organ (form) and function (physiology)? How are genes choreographed to regenerate a tissue or organ? Which pathway within a specific cell type is responsible for particular components of development, repair, wound healing and/or regeneration? Cell therapy Cell therapy describes the technique of introducing new or replacement cells into a tissue or organ in order to treat a disease or disorder. The foundation for this technique evolved over the past 200 years and includes blood transfusion, bone marrow transplantation and organ transplantation. A recent and rather formative example of this technology was the transplantation of a human face from cadaver to patient. Other modifications of this technique include embryonic stem cell therapy, mesenchymal stem cell therapy, and induced pluripotent cell (iPS) therapy.15 Collectively, this methodology is becoming a remarkable therapeutic platform technology for regenerative medicine and dentistry. 188
What we do not know as yet is ‘how’ stem cells serve as miniature pharmacies providing nutrients and specific growth factors and immune-modulators during development as well as regeneration? How can we with purpose and predictability harvest and maintain stem cells to be used for regeneration? Can we use mesenchymal stem cells to regenerate human tooth roots for tooth replacement (e.g. a next generation ‘bio-root’ that replaces dental implants)?16 Protein therapy Protein therapy is a technique designed to deliver a therapeutic level of protein that otherwise is absent or of insufficient concentration to support the physiology of the patient with a disease or disorder. The administration of insulin for type 2 diabetic patients is a classical example of protein therapy. Today, and into the future, protein therapies will be applied to antimicrobial therapeutics for the management of microbial diseases (viral, bacterial and yeast), polypeptide hormones for a number of endocrine diseases and disorders, bone morphogenetic proteins for cartilage and bone replacement, and so much more. The search for clinical strategies that improve the body’s endogenous repair mechanisms is based upon a complete understanding of the fundamental biology of development, repair and regeneration. This endeavour will be the ‘cutting edge’ for regenerative medicine and dentistry. An exemplar of gene and protein therapies to treat an inherited craniofacial syndrome (anhidrotic ectodermal dysplasia) Consider for a moment the dividends from discoveries of human genes and their functions during embryonic and fetal development. Once we know and understand how a specific gene-controlled pathway regulates normal development, we are poised to address one or more inherited craniofacial syndromes with therapies designed to reverse the clinical phenotype of the syndrome. Recently, the ‘proof of principle’ for reversal of the clinical phenotype resulting from anhidrotic ectodermal dysplasia has been accomplished in animal models and human clinical trials are now to begin.6,17,18 Future craniofacial biology research in terms of translational and clinical research During the early 1990s, the American Cleft Palate Association became the American Cleft Palate-Craniofacial Association with a complementary change in the name of their journal. This change recognized the increased depth and breadth of the clinical and © 2014 Australian Dental Association
Future of craniofacial research research interests of the growing craniofacial professional membership. Animated and open inquiry and discussions prevailed and several important questions were raised that require translational and clinical trials research. Does lip repair affect mid-facial growth? What is the optimal timing for cleft palate repair with respect to facial growth, development and speech? What are the optimal conditions and biomaterials for osseoconduction and osseoinduction for bone augmentation? These and many other such questions have and continue to inspire inquiry and multidisciplinary translational and clinical research.6,11,12 Our future is even brighter when we consider the emerging research opportunities to be found within phenomics whereby we expand the role of astute clinical evaluations and coordinate with genomics.19,20 Considerable advances in dental phenomics have enhanced both the accuracy and range of measurement of the dentition, advancing genotype to phenotype correlations as critically reviewed in this special issue.21 In order to realize ‘personalized health care’ and the remarkable contributions from high throughput genotyping, we must observe, collect and analyse sensitive and specific phenotype information from large samples of our populations.13,19,20 In this sense, clinicians are crucial to increase study power while decreasing observational or measurement errors. Phenomics is the systematic measurement and analysis of qualitative and quantitative traits, including physical observations, vital signs, blood, urine and saliva chemistries, and biochemical real-time metabolic data that collectively define the phenotype.19,20 Another striking exemplar that illustrates phenomics applied to craniofacial malformations is found in skeletal dysplasias, especially those presenting craniosynostosis.6,22,23 Craniosynostosis, the early fusion of skull sutures, is a serious abnormality of infancy and childhood requiring astute diagnosis and treatment. Because there are many forms of craniosynostosis, both in isolated as well as within syndrome, accurate diagnosis is essential before effective treatment can be implemented.22 During the 1990s, we experienced a profound set of molecular or genetic discoveries that rapidly led to an epiphany of sorts in the diagnosis of a number of clinically different syndromes that each presented craniosynostosis in common and were each variations in genetic point mutations within the fibroblast growth factor receptor 2 (FGFR2).6,22,23 Coordination between clinical phenotype and exquisite genotyping led to the realization that Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome and Beare-Stevenson cutis gyrate syndrome each presented different point mutations all found within the FGF2 gene.6,22,23 © 2014 Australian Dental Association
Prospectus As we progress into the 21st century, major reforms are indicated as to the essential competencies that must become part of health professional education and clinical practice. We recognize that in the previous 100 years, major reforms in medical, dental, nursing and pharmacy professional school education coupled with significant public health measures essentially doubled the human lifespan.24 Science, technology, prenatal care, early childhood development, advances in primary and secondary education, and enhancements in human behaviour together made this possible. In the past 60 years alone, the research and scientific discoveries within the discipline of craniofacial biology, as well as from other tangential fields that have been applied, have led to significant changes and paradigm shifts in terms of health care practices.6,11,12 Much of this has been the result of health promotion, risk assessment, preventive practices, improved diagnostics and treatment planning, procedures and therapeutics, biomaterials, and predictable outcomes. However, despite these productive years, as we look to the future we see glaring gaps and inequities in health that persist in all too many countries. We experience new and re-emerging microbial infections, the challenges from chronic and destructive diseases and disorders, profound advances in gene-based diagnostics, major increases in the ‘ageing’ populations of industrial nations. These, together, present profound challenges to health care and national as well as individual costs. Health professional education has not kept pace with the profound changes in demographics, economics, population migrations and discoveries in the physical, biological, chemical and behavioural sciences.25 This author anticipates an increased emphasis on developing critical thinking, the ability to access and analyse databases relevant to clinical health care, an increase of integration between health professions to address the needs of society (especially the special needs of an ageing society in industrial nations), and skills that enable leadership within trans-professional teams of health professionals. These and other features of education and clinical practice will be informed by science and the needs of societies around the world. I envision oral health being integrated into primary health care and family medicine. For example, the dividends from investments in craniofacial biology research will transform diagnostics, treatment planning, treatments and therapeutics, outcomes and reimbursement standards. Imagine that we will provide routine saliva as an informative fluid for diagnostics for oral-systemic diseases and disorders.26 Imagine that we will utilize gene-based diagnostics and biomimetic approaches for tissue and organ 189
HC Slavkin replacement and/or regeneration.27–31 The future is bright with opportunity. We face the world. Our face ‘makes’ the first impression to others: we are first judged on the basis of our face and only later, after this first impression is indelibly made, are we permitted to make our inner self known to the other, to reveal our secret self, to risk making our true-self known. Ourselves, we have access only to a mirror image of our face. It is a reflection, putting our left on the right, and our right on the left. If this image is not perfect to us, the challenge of becoming known, of being fully human, is orders of magnitude more complex.32 DISCLOSURE The author has no conflicts of interest to declare. REFERENCES 1. Pruzansky S, Slavkin HC. An evaluation and assessment of the state of the science: congenital and acquired craniofacial malformations. Bethesda, Maryland: US Department of Health and Human Services, Public Health Service, National Institutes of Health, 1982. 2. Converse JM, McCarthy JG, Wood-Smith D, eds. Symposium on diagnosis and treatment of craniofacial anomalies. St Louis, Missouri: Mosby, 1979. 3. Grabb WC, Rosenstein SW, Bzoch KR, eds. Cleft lip and palate: surgical, dental and speech aspects. Boston, Massachusetts: Little, Brown & Company, 1971. 4. Tessier P. The definitive plastic surgical treatment of the severe facial deformities of craniofacial dysostosis. Crouzon and Apert’s diseases. Plast Reconstr Surg 1971;48:419–426. 5. Gorlin RJ, Slavkin HC. Embryology of the face. In: Tewfik TL, Der Kaloustian V, eds. Congenital anomalies of the ear, nose and throat. New York: Oxford University Press, 1997:287–296. 6. Slavkin HC. Birth of a discipline: craniofacial biology. Newtown, Pennsylvania, 2012. 7. Craniofacial Australia. URL: ‘http://www.craniofacial.com.au/ aboutus.html’. Accessed 2 May 2013. 8. Australian Institute of Health and Welfare. Oral health and dental care in Australia. URL: ‘http://www.aihw.gov.au/publication-detail/id=10737420710&tab=2’. Accessed 2 May 2013. 9. US Department of Health and Human Services. Oral health in America: a report of the Surgeon General. National Institute of Dental and Craniofacial Research, National Institutes of Health, and US Department of Health and Human Services, Rockville, Maryland, 2000.
15. Han J, Menicanin D, Gronthos S, Bartold PM. Stem cells, tissue engineering and periodontal regeneration. Aust Dent J 2013; doi:10.1111/adj.12100 [Epub ahead of print]. 16. Shi S, Chai Y, Slavkin HC. Emerging opportunities for the next generation of dental implants. Dent Today 2009;28:98–99. 17. Slavkin HC. What the future holds for ectodermal dysplasias: future research and treatment directions. Am J Med Genet A 2009;149A:2071–2074. 18. Gaide O, Schneider P. Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nat Med 2003;9:614–618. 19. Houle D, Govindaraju DR, Omholt S. Phenomics: the next challenge. Nat Rev Genet 2010;11:855–866. 20. Yong R, Ranjitkar S, Townsend GC, et al. Dental phenomics: advancing genotype to phenotype correlations in craniofacial research. Aust Dent J 2014; doi:10.1111/adj.12156. 21. NIFA-NSF Phenomics Workshop Report. Phenomics: genotype to phenotype. National Science Foundation, Washington DC, USA. 2011. 22. Cohen MM Jr, MacLean RE, eds. Craniosynostosis: diagnosis, evaluation and management. 2nd edn. New York: Oxford University Press, 2000. 23. Wilkie AOM. Fgf receptor mutations: bone dysplasia, craniosynostosis, and other syndromes. In: Inborn Errors of Development. Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. 2nd edn. London: Oxford University Press, 2008:461–473. 24. Frenk J, Chen L, Bhutta ZA, et al. Health professionals for a new century: transforming education to strengthen health systems in an interdependent world. Lancet 2010;376:1923–1930. 25. DePaola D, Slavkin HC. Reforming dental health professions education: a white paper. J Dent Educ 2004;48:1139–1150. 26. Slavkin HC, Fox C, Meyer DM. Salivary diagnostics and its impact in dentistry, research, education and the professional community. Adv Dent Res 2011;23:381–386. 27. Slavkin HC. The answer lies in the genome. Global Health Nexus 2012;14:6–15. 28. Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 2011;12:167–178. 29. Slavkin HC. Biotechnology in dentistry. In: Dental Horizons: Essentials of Oral Health. Saini R, Saini S, eds. Hyderabad, India: PARAS Medical Publisher, 2011:276–287. 30. Petersen PE. Global policy for improvement of oral health in the 21st century – implications to oral health research of World Health Assembly 2007, World Health Organization. Community Dent Oral Epidemiol 2009;37:1–8. 31. Cohen MM Jr. Perspectives on the face. London: Oxford University Press, 2006. 32. Preface. Report of the National Institute of Dental and Craniofacial Research Genetics Workgroup. Genetics and Craniofacial and Dental Anomalies. Bethesda, Maryland, USA. 14–16 November 1999.
10. Australian Bureau of Statistics. Demographics of Australia. URL: http://abs.gov.au. Accessed 3 October 2013. 11. Snead ML, Slavkin HC. Science is the fuel for the engine of technology and clinical practice. J Am Dent Assoc 2009;140 (Special Supplement):17–25. 12. Slavkin HC. The evolution of the scientific basis for dentistry: 1936 to now and its impact on dental education. J Dent Educ 2012;76:28–35. 13. Feero WG, Guttmacher AE, Collins FS. Genomic medicine – an updated primer. New Engl J Med 2010;362:2001–2011. 14. Davies K. The $1,000 Genome: the revolution in DNA sequencing and the new era of personalized medicine. New York: Free Press, 2010.
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Address for correspondence: Dr Harold C Slavkin Center for Craniofacial Molecular Biology Ostrow School of Dentistry University of Southern California 2250 Alcazar Street – CSA 103 Los Angeles, California 90033 USA Email: [email protected] © 2014 Australian Dental Association
The official journal of the Australian Dental Association
Australian Dental Journal 2014; 59:(1 Suppl): 186–190 doi: 10.1111/adj.12105
The future of research in craniofacial biology and what this will mean for oral health professional education and clinical practice HC Slavkin* *Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, The University of Southern California, California, USA.
ABSTRACT Today, and looking to the future, scientific discoveries from cellular, developmental and molecular biology inform our understanding of cell, tissue and organ morphogenesis as exemplified in skin, bone, cartilage, dentine, enamel, muscle, nerve and many organs such as salivary glands and teeth. Present day biomedical science yields principles for the biomimetic design and fabrication of cells, tissues and organs. Bioengineering has become a strategy that can ‘mimic’ biological processes, and inform clinical procedures for tissue and organ replacements. The future of regenerative craniofacial biology holds enormous promise for the diagnosis and treatment of congenital birth defects, traumatic injuries, degenerative chronic diseases as well as for Mendelian single gene and complex multigene diseases and disorders. The past 50 years have heralded the completion of the human genome and the introduction of ‘personalized medicine and dentistry’, the utilization of stem cell therapy for an array of diseases and disorders, the ‘proof of principle’ to reverse select inherited diseases such as anhidrotic ectodermal dysplasia (ED), and the fruits from interdisciplinary research drawn from the diverse biomedical sciences. Looking to the future, we can readily anticipate as major goals to emphasize the clinician’s role in identifying clinical phenotypes that can lead to differential diagnosis, and rejuvenate missing or damaged tissues by establishing processes for the utilization of gene, cell and/or protein therapies. The future is replete with remarkable opportunities to enhance clinical outcomes for congenital as well as acquired craniofacial malformations. Clinicians play a pivotal role because critical thinking and sound clinical acumen substantially improve diagnostic precision and thereby clinical health outcomes. Keywords: Congenital malformation, acquired craniofacial malformations, genetics, stem cells. Abbreviations and acronyms: ED = ectodermal dysplasia; FGFR2 = fibroblast growth factor receptor 2; iPS = induced pluripotent cell; SNP = single nucleotide polymorphisms.
INTRODUCTION Excellent contributions to this special issue of the Australian Dental Journal repeatedly demonstrate that craniofacial biology is characterized by an elaborate collaboration and often integration between anatomists, anthropologists, audiologists, biochemists, dentists, dental hygienists, nurses, pharmacists, developmental biologists, embryologists, geneticists, immunologists, microbiologists, neurologists, occupational therapists, physical therapists, physicians, physiologists, psychologists, radiologists, social services, speech therapists – all asking important questions and investigating the craniofacial-oral-dental complex. This field has become a trans-professional, multidisciplinary, international coalition working to unravel clinical problems associated with birth defects, head and neck trauma, and a host of chronic degenerative diseases and disorders.1–6 186
As we advance into the 21st century, the future of craniofacial biology – diagnosis, treatment and therapeutics, and outcomes – will continue to herald advances and improvements. A number of indicators further suggest that Australia will continue to provide leadership in patient health care, and to participate in international education programmes designed to improve the clinical competencies needed to provide excellent patient care for congenital as well as acquired facial disfigurements (e.g. Operation Smile Australia, Melbourne Cleft and Craniofacial Unit, Australian Craniofacial Unit).7,8 In tandem, the future of research will consist of uncovering the molecular mechanisms by which organisms recognize and respond to tissue damage. Mechanisms for tissue repair and regeneration are of enormous interest. The yields from these research efforts will herald the emergence of the following: © 2014 Australian Dental Association
Future of craniofacial research gene, cell and protein therapies, tissue engineering, the design and fabrication of scaffolds, digital enhanced imaging, personalized medicine, and regenerative dentistry and medicine. Further, we should anticipate the convergence of bioengineering, molecular biology, nanotechnology, clinical dentistry and medicine, speech therapy, occupational therapy, physical therapy and the behavioural science professions.6 This contribution will focus on a few select examples of future research in craniofacial biology and how these projected advances will influence oral health professional education and clinical practice. The burden of congenital and acquired craniofacial anomalies to society Currently, approximately 1 out of every 10 people in the industrial countries of the world, including the United Kingdom, Australia and the United States present facial disfigurements.7–9 One million people in the United States have severe facial disfigurements resulting from congenital abnormalities such as cleft lip and palate (nationally, 1 in 750 live births out of the 4 million births per year), other craniofacial syndromes, birthmarks and hemangiomas. Some acquired disfigurements result from severe facial burns, facial paralysis, trauma, diseases such as head and neck cancers, hypertrophic scars, and surgery sometimes resulting in a tissue response of producing keloids (the result of an overgrowth of dense fibrous tissue that develops after healing of a skin injury). We understand that the distribution of these conditions often leads to feelings of isolation and lack of support for patient and family in many regions of the United States. In addition, there is a separate group that includes smaller birthmarks, skin conditions such as severe acne scarring and eczema, and facial scars from minor accidents (approximately 10% of the 30 million children with acne develop severe facial scars). Future craniofacial research will also include epidemiology. A few demographic characteristics are useful for comparing Australia with California, my home state, in terms of population and cultural diversity. In 2013, Australia has approximately 22.9 million people and is expected to reach 28 million by 2030.10 California has 38 million people and is expected to reach 50 million by 2030. Immigrants comprise almost 24% of the populations of both Australia and California.10 By design, California currently has 19 cleft and craniofacial teams. Six of these craniofacial teams serve the 12 million people who live in Los Angeles County (e.g. Children’s Hospital of Los Angeles, University of California at Los Angeles, Craniofacial Clinic, The Hemangioma and Vascular Birthmark Center of Los Angeles). Australia also has craniofacial teams and centres proportional to the size of its © 2014 Australian Dental Association
population.7 Craniofacial teams are located essentially in every state of the union. Yet both Australia as well as the United States continue to lack timely surveillance systems for the many forms of facial disfigurement, access to comprehensive quality health care, and critical assessments for psychosocial and economic benefits or outcomes for patients and their families. How can we measure the outcomes from craniofacial teams such as quality of life, gainful employment, and productive lives for patients with severe facial disfigurements? The international challenge is access to comprehensive, quality craniofacial teams for all people along with health literacy and prevention wherever feasible. Examples of current and near future research opportunities in craniofacial biology Presently, throughout the industrial nations there are remarkable discoveries and advancements from the craniofacial behavioural and social sciences, computational and systems biology, bioinformatics, and the complementary mining of databases of clinical phenotypes, animal models, genes, proteins, carbohydrates and teratogens.6 These data sets now extend from prions and microbes to humans – genomes, transcriptomes, proteomes, metabolomes, diseasomes and pharmacogenomics – with complementary imaging data and annotation for storage and retrieval.6 Since World War II, investments in biomedical scientific research have continued to inform health professional education as well as clinical craniofacial-oral-dental health practices and profoundly improve the human condition by reducing the prevalence of disease while enhancing the quality of life.11,12 The following research efforts reflect the future of craniofacial biology and each example provides major opportunities for revision of health professional education in dentistry, medicine, nursing and pharmacy. Further, it is imperative we recall that through integration of modern science into the curricula at university-based health professional schools, the reforms clearly equipped health care professionals (e.g. dentistry, medicine, nursing, occupational therapy, pharmacy, physical therapy) with the knowledge and critical thinking skills that already have contributed to the doubling of the human lifespan by the end of the 20th century. Gene therapy Gene therapy is a technique that utilizes genes as therapeutics to treat or prevent a disease or disorder. This technique provides health professionals the opportunity to treat a disorder by inserting a gene of special interest or value into a patient’s cells rather than using an array of drugs or surgery. Further, this technique 187
HC Slavkin can be used to replace a mutated or defective gene that is the primary cause of the disease with a healthy or normal copy of the same gene. This methodology can also be used to inactivate or ‘knock-out’ a mutated gene that is functioning improperly. The technique can also be used to introduce a new gene into the body to help provide therapeutic benefits for the patient against the disease. The foundation for gene therapy resides in our collective understanding of human, animal, plant and microbial genes, the structure and function of deoxyribonucleic acid, the exquisite processes of gene activation and expression, and more recently the completion of the human genome in October 2004.13 Further, rapid advances in genome-wide sequencing technology, the recent ability to sequence the entire genome of a single human somatic cell, and the enhancing tools termed ‘SNPs’ (single nucleotide polymorphisms) that can diagnose a single mistaken nucleotide amongst 3.5 billion nucleotides.13 These advances have produced the new era of ‘personalized dentistry and medicine’.14 We now know that the human genome in its totality consists of a nuclear genome (total genes in the nucleus of each somatic cell of the body), the epigenome (specific coding regions of all genes) and the mitochondrial genome (a few dozen genes located in the maternally inherited mitochondria found within each of our cells). Humans contain 21 000 genes, 19 000 pseudogenes, and 37 mitochondrial genes.6,13 What we do not as yet know is ‘how’ clusters of genes are expressed in specific tissues and specific times during normal or abnormal development. Which genes in combination are required for morphogenesis of an organ (form) and function (physiology)? How are genes choreographed to regenerate a tissue or organ? Which pathway within a specific cell type is responsible for particular components of development, repair, wound healing and/or regeneration? Cell therapy Cell therapy describes the technique of introducing new or replacement cells into a tissue or organ in order to treat a disease or disorder. The foundation for this technique evolved over the past 200 years and includes blood transfusion, bone marrow transplantation and organ transplantation. A recent and rather formative example of this technology was the transplantation of a human face from cadaver to patient. Other modifications of this technique include embryonic stem cell therapy, mesenchymal stem cell therapy, and induced pluripotent cell (iPS) therapy.15 Collectively, this methodology is becoming a remarkable therapeutic platform technology for regenerative medicine and dentistry. 188
What we do not know as yet is ‘how’ stem cells serve as miniature pharmacies providing nutrients and specific growth factors and immune-modulators during development as well as regeneration? How can we with purpose and predictability harvest and maintain stem cells to be used for regeneration? Can we use mesenchymal stem cells to regenerate human tooth roots for tooth replacement (e.g. a next generation ‘bio-root’ that replaces dental implants)?16 Protein therapy Protein therapy is a technique designed to deliver a therapeutic level of protein that otherwise is absent or of insufficient concentration to support the physiology of the patient with a disease or disorder. The administration of insulin for type 2 diabetic patients is a classical example of protein therapy. Today, and into the future, protein therapies will be applied to antimicrobial therapeutics for the management of microbial diseases (viral, bacterial and yeast), polypeptide hormones for a number of endocrine diseases and disorders, bone morphogenetic proteins for cartilage and bone replacement, and so much more. The search for clinical strategies that improve the body’s endogenous repair mechanisms is based upon a complete understanding of the fundamental biology of development, repair and regeneration. This endeavour will be the ‘cutting edge’ for regenerative medicine and dentistry. An exemplar of gene and protein therapies to treat an inherited craniofacial syndrome (anhidrotic ectodermal dysplasia) Consider for a moment the dividends from discoveries of human genes and their functions during embryonic and fetal development. Once we know and understand how a specific gene-controlled pathway regulates normal development, we are poised to address one or more inherited craniofacial syndromes with therapies designed to reverse the clinical phenotype of the syndrome. Recently, the ‘proof of principle’ for reversal of the clinical phenotype resulting from anhidrotic ectodermal dysplasia has been accomplished in animal models and human clinical trials are now to begin.6,17,18 Future craniofacial biology research in terms of translational and clinical research During the early 1990s, the American Cleft Palate Association became the American Cleft Palate-Craniofacial Association with a complementary change in the name of their journal. This change recognized the increased depth and breadth of the clinical and © 2014 Australian Dental Association
Future of craniofacial research research interests of the growing craniofacial professional membership. Animated and open inquiry and discussions prevailed and several important questions were raised that require translational and clinical trials research. Does lip repair affect mid-facial growth? What is the optimal timing for cleft palate repair with respect to facial growth, development and speech? What are the optimal conditions and biomaterials for osseoconduction and osseoinduction for bone augmentation? These and many other such questions have and continue to inspire inquiry and multidisciplinary translational and clinical research.6,11,12 Our future is even brighter when we consider the emerging research opportunities to be found within phenomics whereby we expand the role of astute clinical evaluations and coordinate with genomics.19,20 Considerable advances in dental phenomics have enhanced both the accuracy and range of measurement of the dentition, advancing genotype to phenotype correlations as critically reviewed in this special issue.21 In order to realize ‘personalized health care’ and the remarkable contributions from high throughput genotyping, we must observe, collect and analyse sensitive and specific phenotype information from large samples of our populations.13,19,20 In this sense, clinicians are crucial to increase study power while decreasing observational or measurement errors. Phenomics is the systematic measurement and analysis of qualitative and quantitative traits, including physical observations, vital signs, blood, urine and saliva chemistries, and biochemical real-time metabolic data that collectively define the phenotype.19,20 Another striking exemplar that illustrates phenomics applied to craniofacial malformations is found in skeletal dysplasias, especially those presenting craniosynostosis.6,22,23 Craniosynostosis, the early fusion of skull sutures, is a serious abnormality of infancy and childhood requiring astute diagnosis and treatment. Because there are many forms of craniosynostosis, both in isolated as well as within syndrome, accurate diagnosis is essential before effective treatment can be implemented.22 During the 1990s, we experienced a profound set of molecular or genetic discoveries that rapidly led to an epiphany of sorts in the diagnosis of a number of clinically different syndromes that each presented craniosynostosis in common and were each variations in genetic point mutations within the fibroblast growth factor receptor 2 (FGFR2).6,22,23 Coordination between clinical phenotype and exquisite genotyping led to the realization that Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome and Beare-Stevenson cutis gyrate syndrome each presented different point mutations all found within the FGF2 gene.6,22,23 © 2014 Australian Dental Association
Prospectus As we progress into the 21st century, major reforms are indicated as to the essential competencies that must become part of health professional education and clinical practice. We recognize that in the previous 100 years, major reforms in medical, dental, nursing and pharmacy professional school education coupled with significant public health measures essentially doubled the human lifespan.24 Science, technology, prenatal care, early childhood development, advances in primary and secondary education, and enhancements in human behaviour together made this possible. In the past 60 years alone, the research and scientific discoveries within the discipline of craniofacial biology, as well as from other tangential fields that have been applied, have led to significant changes and paradigm shifts in terms of health care practices.6,11,12 Much of this has been the result of health promotion, risk assessment, preventive practices, improved diagnostics and treatment planning, procedures and therapeutics, biomaterials, and predictable outcomes. However, despite these productive years, as we look to the future we see glaring gaps and inequities in health that persist in all too many countries. We experience new and re-emerging microbial infections, the challenges from chronic and destructive diseases and disorders, profound advances in gene-based diagnostics, major increases in the ‘ageing’ populations of industrial nations. These, together, present profound challenges to health care and national as well as individual costs. Health professional education has not kept pace with the profound changes in demographics, economics, population migrations and discoveries in the physical, biological, chemical and behavioural sciences.25 This author anticipates an increased emphasis on developing critical thinking, the ability to access and analyse databases relevant to clinical health care, an increase of integration between health professions to address the needs of society (especially the special needs of an ageing society in industrial nations), and skills that enable leadership within trans-professional teams of health professionals. These and other features of education and clinical practice will be informed by science and the needs of societies around the world. I envision oral health being integrated into primary health care and family medicine. For example, the dividends from investments in craniofacial biology research will transform diagnostics, treatment planning, treatments and therapeutics, outcomes and reimbursement standards. Imagine that we will provide routine saliva as an informative fluid for diagnostics for oral-systemic diseases and disorders.26 Imagine that we will utilize gene-based diagnostics and biomimetic approaches for tissue and organ 189
HC Slavkin replacement and/or regeneration.27–31 The future is bright with opportunity. We face the world. Our face ‘makes’ the first impression to others: we are first judged on the basis of our face and only later, after this first impression is indelibly made, are we permitted to make our inner self known to the other, to reveal our secret self, to risk making our true-self known. Ourselves, we have access only to a mirror image of our face. It is a reflection, putting our left on the right, and our right on the left. If this image is not perfect to us, the challenge of becoming known, of being fully human, is orders of magnitude more complex.32 DISCLOSURE The author has no conflicts of interest to declare. REFERENCES 1. Pruzansky S, Slavkin HC. An evaluation and assessment of the state of the science: congenital and acquired craniofacial malformations. Bethesda, Maryland: US Department of Health and Human Services, Public Health Service, National Institutes of Health, 1982. 2. Converse JM, McCarthy JG, Wood-Smith D, eds. Symposium on diagnosis and treatment of craniofacial anomalies. St Louis, Missouri: Mosby, 1979. 3. Grabb WC, Rosenstein SW, Bzoch KR, eds. Cleft lip and palate: surgical, dental and speech aspects. Boston, Massachusetts: Little, Brown & Company, 1971. 4. Tessier P. The definitive plastic surgical treatment of the severe facial deformities of craniofacial dysostosis. Crouzon and Apert’s diseases. Plast Reconstr Surg 1971;48:419–426. 5. Gorlin RJ, Slavkin HC. Embryology of the face. In: Tewfik TL, Der Kaloustian V, eds. Congenital anomalies of the ear, nose and throat. New York: Oxford University Press, 1997:287–296. 6. Slavkin HC. Birth of a discipline: craniofacial biology. Newtown, Pennsylvania, 2012. 7. Craniofacial Australia. URL: ‘http://www.craniofacial.com.au/ aboutus.html’. Accessed 2 May 2013. 8. Australian Institute of Health and Welfare. Oral health and dental care in Australia. URL: ‘http://www.aihw.gov.au/publication-detail/id=10737420710&tab=2’. Accessed 2 May 2013. 9. US Department of Health and Human Services. Oral health in America: a report of the Surgeon General. National Institute of Dental and Craniofacial Research, National Institutes of Health, and US Department of Health and Human Services, Rockville, Maryland, 2000.
15. Han J, Menicanin D, Gronthos S, Bartold PM. Stem cells, tissue engineering and periodontal regeneration. Aust Dent J 2013; doi:10.1111/adj.12100 [Epub ahead of print]. 16. Shi S, Chai Y, Slavkin HC. Emerging opportunities for the next generation of dental implants. Dent Today 2009;28:98–99. 17. Slavkin HC. What the future holds for ectodermal dysplasias: future research and treatment directions. Am J Med Genet A 2009;149A:2071–2074. 18. Gaide O, Schneider P. Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nat Med 2003;9:614–618. 19. Houle D, Govindaraju DR, Omholt S. Phenomics: the next challenge. Nat Rev Genet 2010;11:855–866. 20. Yong R, Ranjitkar S, Townsend GC, et al. Dental phenomics: advancing genotype to phenotype correlations in craniofacial research. Aust Dent J 2014; doi:10.1111/adj.12156. 21. NIFA-NSF Phenomics Workshop Report. Phenomics: genotype to phenotype. National Science Foundation, Washington DC, USA. 2011. 22. Cohen MM Jr, MacLean RE, eds. Craniosynostosis: diagnosis, evaluation and management. 2nd edn. New York: Oxford University Press, 2000. 23. Wilkie AOM. Fgf receptor mutations: bone dysplasia, craniosynostosis, and other syndromes. In: Inborn Errors of Development. Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. 2nd edn. London: Oxford University Press, 2008:461–473. 24. Frenk J, Chen L, Bhutta ZA, et al. Health professionals for a new century: transforming education to strengthen health systems in an interdependent world. Lancet 2010;376:1923–1930. 25. DePaola D, Slavkin HC. Reforming dental health professions education: a white paper. J Dent Educ 2004;48:1139–1150. 26. Slavkin HC, Fox C, Meyer DM. Salivary diagnostics and its impact in dentistry, research, education and the professional community. Adv Dent Res 2011;23:381–386. 27. Slavkin HC. The answer lies in the genome. Global Health Nexus 2012;14:6–15. 28. Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 2011;12:167–178. 29. Slavkin HC. Biotechnology in dentistry. In: Dental Horizons: Essentials of Oral Health. Saini R, Saini S, eds. Hyderabad, India: PARAS Medical Publisher, 2011:276–287. 30. Petersen PE. Global policy for improvement of oral health in the 21st century – implications to oral health research of World Health Assembly 2007, World Health Organization. Community Dent Oral Epidemiol 2009;37:1–8. 31. Cohen MM Jr. Perspectives on the face. London: Oxford University Press, 2006. 32. Preface. Report of the National Institute of Dental and Craniofacial Research Genetics Workgroup. Genetics and Craniofacial and Dental Anomalies. Bethesda, Maryland, USA. 14–16 November 1999.
10. Australian Bureau of Statistics. Demographics of Australia. URL: http://abs.gov.au. Accessed 3 October 2013. 11. Snead ML, Slavkin HC. Science is the fuel for the engine of technology and clinical practice. J Am Dent Assoc 2009;140 (Special Supplement):17–25. 12. Slavkin HC. The evolution of the scientific basis for dentistry: 1936 to now and its impact on dental education. J Dent Educ 2012;76:28–35. 13. Feero WG, Guttmacher AE, Collins FS. Genomic medicine – an updated primer. New Engl J Med 2010;362:2001–2011. 14. Davies K. The $1,000 Genome: the revolution in DNA sequencing and the new era of personalized medicine. New York: Free Press, 2010.
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Address for correspondence: Dr Harold C Slavkin Center for Craniofacial Molecular Biology Ostrow School of Dentistry University of Southern California 2250 Alcazar Street – CSA 103 Los Angeles, California 90033 USA Email: [email protected] © 2014 Australian Dental Association
