NEXUS (invitation to submit manuscript)
NEXUS (winter 2012 issue “Global Health Nexus”)Genomics in DentistryHarold C. Slavkin, Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California USAProfessor Harold SlavkinCenter for Craniofacial Molecular BiologyHerman Ostrow School of Dentistry2250 Alcazar Street CSA-103Los Angeles, California 90033Telephone (323) 442-FAX (323) 442-Slavkin@usc.eduINTRODUCTIONThe Biological Revolution has arrived! It’s been and remains thrilling for me! As I was completing my studies to become a dentist, during my seven years of private practice, or even during my years of postdoctoral education and training, I never would have imagined that I would have attended the Asilomar Conference held in Monterey, California, in 1975 when recombinant DNA guidelines were crafted. Imagine, establishing the rules and procedures for the human gene for insulin to be inserted into the genome of a bacteria, yeast, plant, or other animal, and that organism producing recombinant human insulin protein for the treatment of diabetes. Important human therapeutics (growth factors, hormones, antibodies, anti-microbial therapeutics, and a large array of other pharmaceuticals) could be produced from bacteria, yeast, plants and animals using the guidelines for recombinant DNA technology.And my scientific journey continued. After successful production of antibodies to detect the major protein found in enamel, (amelogenin), and after success in identification of the messenger RNAs (mRNAs) for amelogenin, my laboratory, including Mal Snead, Maggie Zeichner-David, and Alan Fincham, and in collaborations with Savio Wu then at Baylor, would be the first to clone the mouse gene for amelogenin, the major protein found in the bioceramics identified as enamel. Along the way we discovered that the amelogenin gene produces multiple and different mRNA transcripts by a process termed ‘alternative splicing,’ and thereby produces multiple translation products or proteins of varying molecular weights.And the unexpected dominated my career. By the late 1980s, we successfully identified and mapped the human amelogenin gene to both the X as well as Y chromosomes. This was an unexpected discovery---a variant of a functional gene encoded in two different chromosomes. We could explore the molecular explanation of X-linked amelogenesis imperfecta. Thereafter, we produced a recombinant amelogenin protein for studies of protein-protein interactions associated with the initiation and control of biomineralization. We asked “How does amelogenin function with respect to the crystal formation and growth associated with enamel?” Independently, Mary MacDougall (at that time a graduate student working with Maggie Zeichner-David and myself) isolated and characterized the major non-collagenous protein found in dentin. She then cloned the gene and eventually mapped the gene to the chromosomal location responsible for dentinogenesis imperfecta. In the mid-1990s, I was invited by Don Chambers to celebrate the discovery of DNA by James Watson and Francis Crick in Chicago (and Rosalind Franklin, a dentist named Norman Simmons who prepared the DNA used by Franklin for her x-ray diffraction studies, and Maurice Wilkins), and I spoke of emerging opportunities in oral medicine to utilize the biological revolution’s fruits for the applications to diagnostics, treatments, therapeutics, and biomaterials (Donald A. Chambers, editor, DNA The Double Helix: Perspective and Prospective at Forty Years. Annals of the New York Academy of Sciences, Volume 758, 1995). At that time, I predicted the delivery of genetic therapeutics for oral fungal infections such as candidiasis, the production of oral mucosal lubricants for xerostomia, the oral delivery of systemic gene-based therapeutics, genetic approaches to the design and fabrication of dental tissues, the production of recombinant proteins such as bone morphogenetic proteins for tissue regeneration, the production of vaccines to manage human papilloma viral infections, and the utilization of gene-based diagnostics to identify craniofacial syndromes.The Human Genome is Completed by October 2004And there I was, after 5 wonderful years working within Harold Varmus’ leadership team at the NIH (1995-2000), my specific role being Director of the NIDCR, standing in the East Room of the White House as President Bill Clinton spoke and celebrated the first survey map of the Human Genome. It was June 26th 2000 and I was enormously proud of Francis Collins who led the Human Genome Project and our NIH coordinated efforts, and other federal agencies (Department of Energy, National Science Foundation), and scientists from a number of nations, for the exploration of the genes that regulate our human condition. That day the limelight was shared with Craig Venter who led the private sector Celera team that provided enormous competition in the race to complete the Human Genome. The following February 2001, around Valentine’s Day, both teams published their work---roughly 95% completion of the human genome; Francis’ team published in Nature and Venter’s team in Science. Then, as of October 2004, the entire Human Genome was completed. Imagine, 100% completion by 2004 - - -the 3.2 billion nucleotides or bases, annotated within 21,000 genes encoded within and mapped to specific locations in the 23 pair of human chromosomes, were identified. We now entered into “the Post-Genomic Era.” Essentially, a “parts list of life” was now available on the world wide web or in hardcopy. It was thrilling!The Short-Term Dividends From the Human GenomeFrancis Collins is now Director of the entire NIH enterprise. Back in 2000, when Francis was serving as Director of the Human Genome Project, he shared his predictions with NIH leadership as to where the biological revolution was going. According to Francis and his PowerPoint presentation of 2000, there will be six major themes delivered as dividends from the completion of the Human Genome:Predictive genetic tests will be available for a dozen conditions;Interventions to reduce risk will be available for several of these disorders;Many primary-care providers will begin to practice genetic medicine;Pre-implantation genetic diagnosis will be widely available, and its limits will be fiercely debated;A ban on genetic discrimination will be in place in the United States; andAccess to genetic medicine will remain inequitable, especially in the developing world.Importantly, all six of Francis’ predictions from the year 2000 have come true! It is also fair to assert that the promise of a biological revolution in human health remains very real. It is further valid that many of us overestimate the short-term impacts of new technologies and underestimate their long-term effects.The Biological Revolution ContinuesI have repeatedly learned that science informs clinical practice! Sometimes the translation of a basic discovery to eventually become a clinical activity or material takes time, lots of time; sometimes one or two decades and many millions of dollars expended for clinical trials. For over a century, scientific discoveries have been translated into diagnostics, treatments and procedures, therapeutics and materials that have revolutionized the oral health professions. Discoveries from physics, chemistry, and biology have been extraordinary over the past 100 years. The discovery of chemicals to achieve anesthesia revolutionized surgery. The discovery of x-rays led to radiology and how we image hard and soft tissue structures. The discovery of antimicrobial therapeutics profoundly changed clinic outcomes associated with acute and chronic infectious diseases – viral, bacterial, and yeast infections. A number of discoveries through adhesive chemistry led to sealants , an array of composite resins, and the bonding of porcelain to enamel. The discovery of fluoride and fluoridated drinking water to reduce the prevalence of tooth decay has been extraordinary. The discoveries from the digital revolution have and will continue to enhance how we see, how we take impressions, and how we design and fabricate restorations for tooth replacement. Science remains the fuel for innovations, applications, and the advances in clinical dentistry, medicine, pharmacy, and nursing.Genomics 101Following fertilization, the single cell contains the entire human genome, 21,000 functional genes and 19,000 psuedogenes, in the nucleus. In addition, a few dozen genes are inherited directly from our mothers via her transmission of the mitochondrial organelles within her ova. The mitochondria contains mitDNA. Genomics is the study of all of these genes and their interactions with one another as well as with the environment. These collective genes encoded within the nuclear DNA and the mitochondrial DNA represent “the parts list of life.”Beyond the fertilized ovum, following a series of cell divisions, we eventually become mature adults consisting of 10,000,000,000,000,000 cells (ten trillion cells), each somatic cell containing the complete human genome. The length of DNA that encodes these genes within each somatic cell is approximately 6 feet in length. The functional genes encoded within the nucleus as well as the mitochondria produce a total of 100,000 different proteins and this is called “the proteome.” Introducing “ –omics” in the Post-Genomic EraHow will we utilize the various “ –omics” in the oral health professions? First, let’s untangle some of the emerging terminology. In the emerging lexicon of “-omics,” we identify genomics, transcriptomics, proteomics, metabolomics, diseasomics, and pharmacogenomics. In these examples, “-omics” is used to modify a term based upon large databases that enable alignment and integration of enormous amounts of information. For example, genomics describes the complete set of genes in organisms in terms of gene structure and function(s) . Comparative genomics is the study of many diverse organisms - - - viral, bacterial, yeast, plant, and animal - - -for analyses in evolution, environmental studies, and/or in health and disease. Transcriptomics describes the total numbers of messenger RNA transcripts derived from genes. In humans, the process of alternative splicing results in multiple and diverse transcripts produced from a single gene. As humans contain 21,000 different functional genes in the nucleus of every somatic cell in the body, the number of transcripts (the transcriptomes) is far greater, likely exceeding 100,000 different mRNAs. Proteomics describes the total number of proteins produced from a particular genome. In humans, our proteome is greater than 200,000 different proteins. Metabolomics describes all the genes associated with metabolism, metabolism of nutrients as well as drugs. Genes encoded within chromosomes in the nucleus of every somatic cell in our body, as well as genes encoded within the mitochondrial DNA in the mitochondria directly inherited from our mothers, cooperatively regulate metabolism. Diseasomics describes diseases and their relationship to genes, micro- and macroenvironments, and social determinants. This field of inquiry incorporates a taxonomy of networks that has the potential to unify various forms of databases. Biomedical researchers are attempting to redefine diseases by clustering or finding patterns and associations between different symptoms, signs, physiology, socioeconomic determinants, genes, protein and so much more. The various databases suggest that diseases often cluster within specific socioeconomic groups that further align with a number of risk factors associated with disease and disorder patterns. For example, analyses between children, poverty, diabetes, obesity, hypoglycemia, and hyper-insulin databases is starting to change nosology or the classification of disease. Pharmacogenomics describes all genes that affect or are affected by pharmaceuticals such as non-steroid anti-inflammatory drugs, analgesics, and psychotropic drugs. These areas of exploration, and the plethora datasets reflecting the yield from the biological revolution of the last 60 years, clearly impact diagnostics, therapeutics, biomaterials, and clinical outcomes throughout the health professions including the oral health professions. I’m imagining the dividends from these quarters will significantly impact how we understand and manage autoimmune disorders, chronic facial pain, and xerostomia.Personal Reflections Regarding the Biological RevolutionThere is a nexus formed by the convergence of clinical medicine, clinical dentistry, and the biological revolution. The dividends from the discovery of DNA, recombinant DNA technology, and the emerging field identified by “ –omics” continue to change the human condition and how we advance as health professions. Fundamental scientific discoveries were augmented by clinical observations that elucidated the inheritance of single-gene, or monogenic disorders, also known as Mendelian disorders since they are transmitted in a manner consonant with Mendel’s laws of inheritance. Today, the National Library of Medicine at the NIH in Bethesda, Maryland, hosts the online compendium known as Mendelian Inheritance in Man (OMIM) that has annotated more than 100 years of documented human genetic disorders. We now have many thousands of disorders and these can be readily accessed on the Internet or in hardcopy.In tandem, a number of guidelines to ensure safety were adopted and offered to governments for the regulation of recombinant DNA technology. A few years later, the first biotechnology company was formed in Emeryville, California, based upon the discoveries of how to produce recombinant protein products such as human recombinant insulin for the treatment of diabetes. Today, the United States has more than 4,000 biotechnology companies utilizing these technologies and producing more than 64 billion dollars each year.As we look to our futures, the future of the oral health professions, I suggest we ask ourselves a simple question. “Are we ready for the dividends from the biological revolution?” Are we allocating resources to educate and train for the future, a future that offers the promise of gene therapies, increased cell, tissue and organ regeneration, an integration between digital and biological ways of knowing, and so much more. Are we ready?ReferencesSlavkin, H.C. (in press) Birth of a Discipline: Craniofacial Biology. Aegis Communications, Newtown, Pennsylvania.Slavkin H.C. (2011) Biotechnology in Dentistry: Advances in Genomics, Biomimetics and Tissue Engineering. In Dental Horizons: Essentials of Oral Health (edited by Rajiv Saini and Santosh Saini), Paras Medical Publisher, New Delhi, India, pp. 276-287.Chai Y, Lee M, Slavkin, HC, Warburton D (2011) Regulation of Embryogenesis. In: Fetal and Neonatal Physiology. Fourth Edition (eds. R. Polin, W. Fox and S. Abman) Philadelphia, PA: WB Saunders Co. Slavkin H.C., Navazesh M, Patel P. (2008) Basic principles of human genetics: a primer for oral medicine. In Burket's Oral Medicine. 11 ed. (eds. Greenberg M, Glick M, Ship J) Hamilton, Ontario: BC Decker Inc. pp 549-568.Slavkin, H.C. (2002). Molecules and Faces: What is on the Horizon? In: Understanding Craniofacial Anomalies (eds. Mooney, M. and Siegel, M.). John Wiley and Sons, New York, pp.549-560Shum L, Takahashi K, Takahashi I, Nagata M, Tanaka O, Semba I, Tan DP, Nuckolls GH, and Slavkin, HC. (2000) Embryogenesis and the Classification of Craniofacial Dysmorphogenesis. In: Oral and Maxillofacial Surgery, Vol. 6. (eds. Baker, SB and Fonseca, RJ). W.B. Saunders Co., pp149-158.Cohen W., Slavkin H.C. (1999) Periodontal Disease and Systemic Disease. In: Periodontal Medicine (eds. Genco R, Mealey B, Cohen W, Rose L). B.C. Decker, Inc. pp. 1-8Slavkin H.C., Shum L, Nuckolls G.H (1998) Ectodermal Dysplasia: A Synthesis Between Evolutionary, Development and Molecular Biology and Human Clinical Genetics. In: Molecular Basis of Epithelial Appendage Morphogenesis. (eds. Chuong C.M.). Landes Science Publishers. pp. 15-37Gorlin, R.J. and Slavkin, H.C. (1997). Embryology of the Face. In: Congenital Anomalies of the Ear, Nose, and Throat. (eds. T.L. Tewfik and V. DerKaloustian) New York: Oxford University Press. Pp. 287-296Slavkin, H.C. (1997) Molecular Determinants of Anodontia. In: Studies in Stomatology & Craniofacial Biology (eds. M. Cohen, Jr., and B. Baum) Canada: IOS Press, pp. 397-405.Slavkin, H. C. (1995) Recombinant DNA technology in the diagnosis and therapeutics of oral medicine. In: DNA, The Double Helix Forty Years: Perspective and Prospective, ed. D. Chambers, Ann. New York Acad. Sci., pp. 314-328.Slavkin, H.C. (1995) Antisense oligonucleotides: an experimental strategy to advance a causal analysis of development. In: Odontogenesis: Embryonic Dentition As A Tool For Developmental Biology, ed. J.V. Ruch, The International Journal of Developmental Biology, 39:123-126.Slavkin, H.C., Chai, Y., Hu, C.C., Millar-Groff, S. and Bringas, Jr., P. (1994). Intrinsic molecular determinants of tooth development from specification to root formation: A review. In: Biological Mechanisms of Tooth Eruption, Resorption and Replacement by Implants. (ed. Z. Davidovitch) EBSCO Media, pp. 263-272. Slavkin, H.C. (in press) The evolution of the scientific basis for dentistry 1936 to now and its impact on dental education. Journal Dental Education.Sakata, T., Takahashi, K., Kiso, H., Huang, B., Tsukamoto, H., Takemoto, M., Hayashi, T., Sugai, M., Nakamura, T., Yokota, Y., Shimizu, A., Slavkin, H.C., Bessho, K. (in press) Id2 controls chrondrogenesis acting downstream of BMP signaling during maxillary morphogenesis. Bone.Slavkin, H.C., Fox, C., Meyer, D.M. (2011) Salivary diagnostics and its impact in dentistry, research, education and the professional community. Advances in Dental Research 23(4): (online at adr.content/23/4.toc).Nagata, M., Nuckolls, G.H., Wang, X., Shum, L., Seki, Y., Kawase, T., Takahashi, K., Nonaka, K., Takahashi, I., Noman, A.A., Suzuki, K., Slavkin, H.C. (2011) The primary site of the acrocephalic feature in Apert syndrome is a dwarf cranial base with accelerated chondrocytic differentiation due to aberrant activation of the FGFR2 signaling. Bone 48(4):847-856.Iwata J, Hosokawa R, Sanchez-Lara PA, Urata M, Slavkin H, Chai Y.(2010) HYPERLINK "" \t "_blank" Transforming growth factor beta regulates basal transcriptional regulatory machinery to control cell proliferation and differentiation in cranial neural crest-derived osteoprogenitor cells.J. Biol. Chem.284:13987-14000.Slayton, RL and Slavkin, HC (2009) Commentary: Scientific investments continue to fuel improvements in oral health (May 2000 – Present). Academic Pediatrics. 9(6):383-385.Huang, X., Bringas, P., Slavkin, H.C., Chai, Y. (2009) Fate of HERS during Tooth Root Development. Developmental Biology. 334 (1):22-30.Slavkin, H.C. (2009) What the Future Holds for Ectodermal Dysplasias: Future Research and Treatment Directions. American Journal of Medical Genetics. 149A:2071-2074.Snead, M.L. and Slavkin, H.C. (2009) Science is the fuel for the engine of technology and clinical practice. Journal American Dental Association. 140 (Special Supplement):17-25.Murashima-Suginami A., Takahashi K., Sakata T., Tsukamoto H., Sugai M., Yanagita M., Shimizu A., Sakurai T., Slavkin H.C., Bessho K. (2008) Enhanced BMP signaling results in supernumerary tooth formation in USAG-1 deficient mouse. Biochem Biophys Res Commun. 369(4):1012-6.Murashima-Suginami A., Takahashi K., Kawabata T., Sakata T., Tsukamoto H., Sugai M., Yanagita M., Shimizu A., Sakurai T., Slavkin H.C., Bessho K. (2007) Rudiment incisors survive and erupt as supernumerary teeth as a result of USAG-1 abrogation. Biochem Biophys Res Commun. 3;359(3):549-55. ?Slavkin, H.C., Bartold, P.M. (2006) Challenges and potential in tissue engineering.Periodontol 2000. 41:9-15.Sasaki, T., Ito, Y., Bringas, P. Jr., Chou, S., Urata, M.M., Slavkin, H.C., Chai, Y. (2005). TGFβ-Mediated FGF Signaling is Crucial for Regulating Cranial Neural Crest Cell Proliferation During Frontal Bone Development. Development. 133.Sasaki, T., Ito, Y., Xu, X., Han, J., Bringas, P. Jr., Maeda, T., Slavkin, H.C., Grosschedl, R., Chai, Y. (2005). LEF1 is a Critical Epithelial Survival Factor During Tooth Morphogenesis. Dev. Biol. 278:130-143.DePaola, D., Slavkin, H.C. (2004). Reforming Dental Health Professions Education: A White Paper. J. Dental Education. 1139-1150.Crowley, W.F. Jr., Sherwood, L., Salber, P., Scheinberg, D., Slavkin, H., Tilson, H., Reece, E.A., Catanese, V., Johnson, S.B., Dobs, A., Genel, M., Korn, A., Reame, N., Bonow, R., Grebb, J., Rimoin, D. (2004). Clinical Research in the United States at a Crossroads: Proposal for a Novel Public –Private Partnership to Establish a National Clinical Research Enterprise. JAMA. 3;291(9):1120-6.Sung N., Crowley W., Genel M., Salber P., Sandy L., Sherwood L., Johnson S., Catanese V., Tilson H., Getz K., Larson E., Scheinberg D., Reece E., Slavkin H., Dobs A., Grebb J., Martinez R., Korn A., and Rimoin D. (2003). Central Challenges Facing the National Clinical Research Enterprise. JAMA. 289:1278-1287.Slavkin, H.C. (2003). Applications of Pharmacogenomics in General Dental Practice. Pharmacogenomics. 4(2):163-170. ?Slavkin, H.C. (2003). Genomes, Biofilms, and Implications for Oral Health Professionals. Dimensions of Dental Hygiene. 1:16-20.Chai, Y, Slavkin, H.C. (2003). Prospects for Tooth Regeneration in the 21st Century: A Perspective. Microscopy Research and Technique (MRT). 60:469-479.Yamane, A., Amano, O., Slavkin, H.C. (2003) Insultin-like growth factors, hepatocyte growth factor and transforming growth factor-alpha in mouse tongue myogenesis. Dev Growth Differentiation 45(1):1-6.Slavkin, H.C. (2002). Distinguishing Mars From Venus: Emergence of Gender Biology Differences in Oral Health and Disease. Compendium. 23(10):29-31Slavkin, H., Rossomando, E.F. (2002). JADA’s Industry Advisory Board. Journal of the American Dental Association. 133(6):696,698.Slavkin, H.C. (2002). Implications of Pharmacogenomics in Oral Health. The Pharmacogenomics Journal. 2:148-151.Slavkin, H.C. et al (2002). YY1 Activates Msx2 Gene Independent of bone morphogenetic Protein Signaling. Nucleic Acid Research. 1;30(5):1213-23.Slavkin, H.C., (2001). Human Genome, Oral Infection/systemic Diseases and the Future of Clinical Dentistry. Annals of Dentistry. 5(1):12, 21. Ayres, J.A., Shum, L., Akarsu, A.N., Dashner, R., Takahashi, K., Ikura, T., Slavkin, H.C., Nuckolls, G.H. (2001). Msx2 is a Repressor of Chondrogenic Differentiation in Migratory Cranial Neural Crest Cells. Developmental Dynamics. 222(2):252-62.Ayres, J.A., Shum, L., Akarsu, N., Dasher, R., Takahashi, K., Ikura, T., Slavkin, H.C., and Nuckolls, G. (2001). DACH: Genomic characterization, evaluation as a candidate for postaxial polydactyly type A2, and developmental expression pattern of the murine homologue. Genomics. 77(1): 18-26.Slavkin, H.C. (2001). Expanding the Boundaries: Enhancing Dentistry’s Contribution to Overall Health and Well-being. J. Dental Education. 65: 1323-1334.Slavkin, H.C. (2001). The Human Genome, Implications for Oral Health and Diseases, and Dental Education. J. Dental Education. 65: 463-479.Genco, R.J., Scannapieco, F.A., and Slavkin, H.C. (2000). Oral Reports. The Sciences. 40:25-30.Slavkin, H.C. (2000). Toward Understanding the Molecular Basis of Craniofacial Growth and Development. Amer. J. of Orthodontics and Dentofacial Orthopedics. 117(5)538-539. Takahashi K, Shum L, Takahashi I, Nonaka K, Nagata M. Ikura T, Nuckolls G.H., and Slavkin, H.C. (2000). Mxs2 is a repressor of chondrogenic differentiation in migratory cranial neural crest cells. Develop. Biol.Semba I, Nonaka K. Takahashi I, Takahashi K, Dashner R, Shum L, Nuckolls G.H., and Slavkin, H.C. (2000). Positionally dependent chondrogenesis induced by MBP4 is co-regulated by Sox9 and MSX2. Develop. Dynamics. 217:401-414.Nuckolls GH, Slavkin HC. (1999) Paths of glorious proteases. Nature Genetics. 23:378-380.Nonaka K, Shum L, Takahashi I, Takahashi K, Ikura T, Dashner R, Nuckolls G.H., Slavkin, H.C. (1999). Convergence of the BMP and EGF Signaling Pathways on Smad1 in the Regulation of Chrondrogenesis. Internat. J. of Develop. Biol. 43:795-807Slavkin HC, Panagis JS, Kousvelari E. (1999) Future Opportunities for Bioengineering Research at the National Institutes of Health. Clin Orthop. 367:S17-30Kobayashi S, Satomura K, Levsky J.M., Sreenath T, Wistow G.J., Semba I, Shum L, Slavkin HC, and Kulkarni A.B. (1999). Expression Pattern of Macrophage Migration Inhibitory Factor During Embryogenesis. Mechanisms of Development 84:153-156.Amano O, Bringas P Jr., Takahashi I, Takahashi K, Yamane A, Chai Y, Nuckolls GH, Shum L and Slavkin HC. (1999). Nerve Growth Factor (NGF) Supports Tooth Morphogenesis in Mouse First Branchial Arch Explants. Developmental Dynamics. 216:299-310Xu X, Li C, Takahashi K, Slavkin HC, Shum L, and Deng CX (1999). Murine Fibroblast Growth Factor Receptor 1α Isoforms Mediate Node Regression and Are Essential for Posterior Mesoderm Development. Developmental Biology. 208:293-306Kobayashi S, Satomura K, Levsky JM, Sreenath T, Wistow GJ, Semba I, Shum L, Slavkin HC, Kulkarni AB. (1999) Expression pattern of macrophage migration inhibitory factor during embryogenesis. Mechanisms of Development. 84:153-156Miettinen PJ, Chin JR, Shum L, Slavkin HC, Shuler C, Derynck R, and Werb Z. (1999). Epidermal Growth Factor Receptor Function is Necessary for Craniofacial Development and Palate Closure. Nature Genetics. 22:69-73.Slavkin H.C. (1999) Entering the Era of Molecular Dentistry. J. Amer. Dent. Assoc. 130:413-417.Nuckolls G.H., Shum L., Slavkin H.C. (1999) Progress Towards Understanding Craniofacial Malformations. The Cleft Palate Craniofacial Journal. 36(1)12-26.Takahashi K, Yamane A, Bringas P, Jr., Caton J , Slavkin, H.C., Zeichner-David M. (1998) Induction of Amelogenin and Ameloblastin by Insulin and Insulin-like Growth Factors (IGF-I and IGF-II) During Embryonic Mouse Tooth Development In Vitro. Connec. Tissue Res. 39(1-3):269-278Chai Y, Bringas P Jr., Shuler CF, Slavkin HC. (1998) PDGF-A and PDGFR-α Regulate Tooth Formation via Autocrine Mechanism During Mandibular Morphogenesis in Vitro. Developmental Dynamics. 213:500-511Takahashi I, Nuckolls GH, Takahashi K, Tanaka O, Semba I, Dashner R, Shum L, and Slavkin HC. (1998) Compressive Force Induces Sox9, Type II Collagen and Aggrecan and Inhibits IL1-β Expression Resulting in Chondrogenesis in Mouse Embryonic Limb Bud Mesenchymal Cells. J. Cell Sci. 111:2067-2076.Yamane A, Bringas P Jr., Mayo ML, Amano O, Takahashi K, Shum L, and Slakin HC. (1998) Transforming Growth Factor Alpha Up-regulates Desmin Expression During Embryonic Tongue Morphogenesis. Developmental Dynamics. 213:71-81.Slavkin H.C. (1998) Toward Molecularly Based Diagnostics for the Oral Cavity. J. Amer. Dent. Assoc. 129:1138-1143Yamane A, Takahashi K, Mayo M, Vo H, Shum L, Zeichner-David M, Slavkin H.C. (1998) Induced Expression of MyoD, Myogenin and Desmin During Myoblast Differentiation in Embryonic Mouse tongue Development. Archives of Oral Biol. 43:407-416Slavkin, H.C. (1998) Protecting the Mouth Against Microbial Infections. J. Amer. Dent. Assoc. 129:1025-1030Slavkin, H.C. (1998) Advice to Coaches of Students in One of the Youngest Sciences. J. Dent. Education. 62(3):226-229Takahashi K, Nuckolls G, Tanaka O, Semba I, Takahashi I, Dashner R, Shum L, Slavkin, H.C. (1998) Adenovirus Mediated Ectopic Expression of Mxs2 in Even-Numbered Rhombomeres Induces Apoptotic elimination of Cranial Neural Crest Cells in Ovo. Development. 125:1627-1635Chai Y, Bringas P, Jr., Shuler C, Devaney E, Grosschedl R, Slavkin, H.C. (1998) A Mouse Mandibular Culture Model Permits the Study of Neural Crest Cell Migration and Tooth Development. Inter. J. Develop. Biol. 42:87-94Sadler TW, Melissa R, Slavkin HC, Lauder J, Maness P, Linney E, Sulik K, Mirkes P (1997) Growth and Differentiation Factors. Reproductive Toxicology 11(2-3):331-337Yamane A, Takahashi K, Bringas P. Jr., Amano O, Slavkin H.C., Zeichner-David M. (1997) Insulin-like Growth Factor-I and II Induce an Increase in the Translational Activity of Amelogenin in the Mouse Embryonic First Molar In Vitro. Int. J of OralBiol. 22(3):161-166Yamane A., Mayo M.L., Bringas P. Jr., Chen L., Huynh M., Thai, K., Shum, L., Slavkin, H.C. (1997) TGF-α, EGF and Their Cognate EGF Receptor Are Co-Expressed with Desmin During Embryonic, Fetal and Neonatal Myogenesis in Mouse Tongue Development. Developmental Dynamics 209:353-366Slavkin, H.C. (1997) Benefit-to-Risk Ration: The Challenge of Antibiotic Drug Resistance. J. Amer. Dent. Assoc. 128:1447-1451Slavkin, H.C. (1997) Sex, Enamel & Forensic Dentistry: A Search for Identity. J. Amer. Dent. Assoc. 128:1021-1025Zeichner-David M, Vo H, Tan H, Diekwisch T, Berman B, Thiemann F, Alocer MD, Hsu P, Wang T, Eyna J, Caton J, Slavkin HC, MacDougall M. (1997) Timing of the Expression of Enamel Gene Products During Mouse Tooth Development. Int. J Dev Biol 40:27-38Chai Y, Sasano Y, Bringas P Jr., Mayo M, Slavkin H.C., Shuler, C. (1997) Characterization of the Fate of Medial Epithelial Cells During the Fusion of Mandibular Prominances in Mice Lacking TGFβ. Developmental Dynamics 208:526-535Slavkin, H.C. (1997) Charles Darwin and the Foundation of Clinical Genetics in Dentistry. J. Amer. Dent. Assoc. 128:241-245Slavkin, H.C. (1996) Basic Science is the Fuel that Drives the Engine of Biotechnology: A Personal Science Transfer Vision for the 21st Century. Tech & Health Care 4. 249-253Slavkin, H.C. (1996) And the Next Fifty Years? The Future of Recombinant DNA Technology in Oral Medicine. J. Public Health Dentistry. 278-285Slavkin, H.C. (1996) Understanding Human Genetics J. Amer. Dent. Assoc. 127:266-267Slavkin, H.C. (1996) Are We Ready for Clinical Gene Therapy. J. Amer. Dent. Assoc. 127:396-297Slavkin, H.C., Diekwisch, T. (1996) Evolution in Tooth Developmental Biology: Of Morphology and Molecules. The Anatomical Record 245:131-150Hu, J.C.C., Zhang, C., Slavkin, H.C. (1995) The Role of Platelet-Derived Growth Factor in the Development of Mouse Molars. Int. J. Dev. Biol 39:939-945Slavkin, H.C. (1995) Molecular biology experimental strategies for craniofacial-oral-dental dysmorphology. Connective Tiss. Res. 32:233-239.Fincham, A.G., Moradian-Oldak, J., Diekwisch, T.G.H., Lyaruu, D.M., Wright, J.T., Brigas, Jr., P. and Slavkin, H.C. (1995) Evidence for amelogenin "nanospheres" as functional components of secretory-stage enamel matrix. J. of Struct. Biol. 115:1-10.Moradian-Oldak, J., Simmer, J.P., Lau, E.C., Diekwisch, T., Slavkin, H.C. and Fincham, A.G. (1995) A review of the aggregation properties of a recombinant amelogenin. Connective Tissue Research, 31, [No. 3]:1-6.Diekwisch, T.G.H., Berman, B.J., Gentner, S. and Slavkin, H.C. (1995) Initial enamel crystals are not spatially associated with mineralized dentine. Cell Tissue Res. 279:149-167.Zeichner-David, M., Diekwisch, T., Fincham, A. Lau, E., MacDougall, M., Moradian-Oldak, J., Simmer, J., Snead, M. and Slavkin, H.C. (1995) Control of ameloblast differentiation. Int. J. Dev. Biol. 39:69-92.MacDougall, M., ZeichnerDavid, M., Crall, M., Yen, S., Vides, J. and Slavkin, H.C. (1994) Presence of dentine phosphoprotein in molars of a patient with dentinogenesis imperfecta type II. J. Craniofac. Genet. Develop. Biol. 14:26-32.Chai, Y., Mah, A., Crohin, C., Groff, S., Bringas, P., Le, T., Santos, V. and Slavkin, H. C. (1994) Specific transforming growth factorbeta subtypes regulate embryonic mouse Meckel's cartilage and tooth development. Develop. Biol. 162:85-103.Simmer, J.P., Hu, C.C., Lau, E.C., Slavkin, H.C. and Fincham, A.G. (1994) Alternative splicing of the mouse amelogenin primary RNA transcript. Calcif. Tiss. Internat. 55:302-310.Fincham, A.G., Moradian-Oldak, J., Simmer, J.P., Sarte, P.E., Lau, E.C., Diekwisch, T. and Slavkin, H.C. (1994) Self-assembly of a recombinant amelogenin protein generates supramolecular aggregates, J. Struct. Biol. 112, 103-109.Simmer, P.J., Lau, E.C., Hu, C., Aoba, T., Lacey, M., Nelson, D., ZeichnerDavid, M., Snead, M.L., Slavkin, H.C. and Fincham, A.G. (1994) Isolation and characterization of a mouse amelogenin expressed in Eschericia coli. Calcif. Tiss. Internat. 54:312-316.Diekwisch, T., David, S., Bringas, P., Santos, V. and Slavkin, H.C. (1993) Antisense inhibition of AMEL demonstrates supramolecular controls for enamel HAP crystal growth during embryonic mouse molar development. Development, 117, 471482.Lau, E.C., Li, Z.-Q., Santos, V. and Slavkin, H.C. (1993) Messenger RNA phenotyping for semi-quantitative comparison of glucocorticoid receptor transcript levels in the developing embryonic mouse palate. J. Steroid Biochem. Mol. Biol. 46:751-758.Lau, E.C., Li, Z.Q. and Slavkin, H.C. (1993) Preparation of denatured plasmid templated for PCR amplification. BioTechniques,14:378.Shum, L., Sakakura, Y., Bringas, Jr., P., Luo, W., Snead, M. L., Mayo, M., Crohin, C., Millar, S., Werb, Z., Buckley, S., Hall, F.L., Warburton, D. and Slavkin, H.C. (1993) EGF abrogation induced fusilliform dysmorphogenesis of Meckel's cartilage during embryonic mouse mandibular morphogenesis in vitro. Development, 118:903917.Slavkin, H.C. (1993) Reigers syndrome revisited: experimental approaches using pharmocologic and antisense strategies to abrogate EGF and TGFa functions resulting in dysmorphogenesis during embryonic mouse craniofacial morphogenesis. Am. J. of Med. Genetics, 47:689697.Hu, C.C., Sakakura, Y., Sasano, Y., Shum, L., Bringas, P., Werb, Z. and Slavkin, H.C. (1992) Endogenous epidermal growth factor regulates the timing and pattern of embryonic mouse molar tooth morphogenesis. Int. J. Dev. Biol. 36: 505516.Lau, E.C., Simmer, J.P., Bringas, Jr., P., Hsu, D.D.J., Hu, C.C., ZeichnerDavid, M., Thiemann, F., Snead, M.L., Slavkin, H.C. and Fincham, A.G. (1992) Alternative splicing of the mouse amelogenin primary RNA transcript contributes to amelogenin heterogeneity. Biochem. Biophys Res. Commun. 188:3 12531260.MacDougall, M. Slavkin, H.C. and ZeichnerDavid, M. (1992) Characteristics of Phosphorylated and nonphosphorylated dentine phosphoprotein. Biochem. J. 287:651655.MacDougall, M., ZeichnerDavid, M., Murray, J., Crall, M., Davis, A. and Slavkin, H.C. (1992) Dentin phosphoprotein gene locus in not associated with dentinogenesis imperfecta Type II and III. Am. J. Human Genetics, 50:190194.ZeichnerDavid, M., MacDougall, M., Yen, S., Hall, F., and Slavkin, H.C. (1992) Protein kinases in dentinogenesis. Proc Finn Dent Soc 88 Suppl. I, 295303.Fincham, A.G., Bessem, C.C., Lau, E.C., Pavlova, Z., Shuler, C.F., Slavkin, H.C. and Snead, M.L. (1991) Human developing enamel proteins exhibit sexlinked dimorphism. Calcif. Tiss. Internat. 48:288290.Fincham, A.G., Hu, Y., Lau, E.C., Slavkin, H.C. and Snead, M.L. (1991) Amelogenin postsecretory processing in the postnatal mouse molar tooth. Arch Oral Biol. 36:305317.MacDougall, M., ZeichnerDavid, M., Murray, J., Crall, M., Davis, A. and Slavkin, H.C. (1991) Dentine phosphoprotein gene locus is not associated with dentinogenesis imperfecta type II and III. Amer J. Med. Genet. 50:190194.Slavkin, H.C. (1991) Molecular determinants during dental morphogenesis and cytodifferentiation: a review. J. Craniofac. Genetic & Develop. Biol. 11:338349.Fincham, A.G., Hu, Y., Lau, E.C., Pavlova, Z., Slavkin, H.C. and Snead, M.L. (1990). Isolation and partial characterization of a human amelogenin from a single fetal dentition using HPLC techniques. Calcif Tissue Int. 47:105111.Hata, R., Bessem, C., Bringas, Jr., P., Hsu, MY. and Slavkin, H.C. (1990). Epidermal growth factor regulates gene expression of both epithelial and mesenchymal cells in mouse molar tooth organs in culture. Cell Biol Int. Rep. 14(6):509519.Sasano, Y., Kikunaga, S. and Slavkin, H.C. (1990) Development of embryonic mouse mandible in serumless, chemicallydefined organ culture: morphogenesis and growth factors. Tissue Culture (Japanese) 16(11):424429.Slavkin, H.C. (1990). Molecular determinants of tooth development: A review. Crit. Rev. Oral Biol. Med. (CRC Press) 1(1):116.Slavkin, H.C. (1990). Regulatory issues during early craniofacial development: A summary. Cleft Palate J. 27(2):121130.Slavkin, H.C., Sasano, Y., Kikunaga, S., Bessem, C., Bringas, P., Jr., Mayo, M., Luo, W., Mak, G., Rall, L. and Snead, M.L. (1990). Cartilage, bone and tooth induction during early embryonic mouse mandibular morphogenesis using serumless, chemicallydefined medium. Connect. Tissue Res. 24:4151.Fincham, A.G., Bessem, C., Bringas, P., Hu, Y., Snead, M.L. and Slavkin, H.C. (1989). Amelogenesis in vitro: a model for studies of epithelial postsecretory processing during tissuespecific extracellular matrix biomineralization. Differentiation, 41:6271.Fincham, A.G., Hu, Y., Pavlova, Z., Slavkin, H.C. and Snead, M.L. (1989). Human Amelogenins: Sequences of "TRAP" Molecules. Calcif. Tissue Int. 45:243250.Lau E.C., Mohandas T.K., Shapiro L.J., Slavkin H.C., Snead M.L. (1989) Human and mouse amelogenin gene loci are on the sex chromosomes. Genomics.4:162-168.Slavkin, H.C. (1989). The Changing Face of Dentistry: Craniofacial growth and development in the 1990's. Calif. Dent. Assoc. J. 17:10:2637.Slavkin, H.C. (1989). Recombinant DNA Technology and Clinical Dentistry. Int. J. Prosthodont. 2:8096.Slavkin, H.C. (1989). Splice of life: Towards understanding genetic determinants of oral diseases. Adv. Dent. Res. 3:1:4257.Slavkin, H.C., Bessem, C., Fincham, A.G., Bringas, P., Santos, V., Snead, M.L. and ZeichnerDavid, M.(1989). Human and Mouse Cementum Proteins Immunologically Related to Enamel Proteins. Biochim. Biophys. Acta, 991:1218.Slavkin, H.C., Bringas, P., Jr., Sasano, Y. and Mayo, M. (1989). Early embryonic mouse mandibular morphogenesis and cytodifferentiation in serumless, chemicallydefined medium: A model for studies of autocrine and/or paracrine regulatory factors. J. Craniofac. Genet. Dev. Biol. 9:185205. ................
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