NEXUS (winter 2012 issue “Global Health Nexus”)
Genomics in Dentistry
Harold C. Slavkin, Center for Craniofacial Molecular Biology, Herman Ostrow School of
Dentistry, University of Southern California, Los Angeles, California USA
Professor Harold Slavkin
Center for Craniofacial Molecular Biology
Herman Ostrow School of Dentistry
2250 Alcazar Street CSA-103
Los Angeles, California 90033
Telephone (323) 442FAX (323) 442Slavkin@usc.edu
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INTRODUCTION
The 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
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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.
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The Human Genome is Completed by October 2004
And 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 Genome
Francis 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
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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; and
Access 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 Continues
I 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,
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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 101
Following 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.”
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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 Era
How 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
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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.
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Personal Reflections Regarding the Biological Revolution
There 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
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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?
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References
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Pennsylvania.
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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.
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education and the professional community. Advances in Dental Research 23(4): (online at
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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.
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Iwata J, Hosokawa R, Sanchez-Lara PA, Urata M, Slavkin H, Chai Y.(2010)
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). TGFβMediated 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
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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):29-31
Slavkin, 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
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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. 40:2530.
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. 43:795-807
Slavkin HC, Panagis JS, Kousvelari E. (1999) Future Opportunities for Bioengineering Research
at the National Institutes of Health. Clin Orthop. 367:S17-30
Kobayashi 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. 216:299-310
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Xu 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. 208:293-306
Kobayashi 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. 84:153-156
Miettinen 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. 130:413417.
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(13):269-278
Chai 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. 213:500-511
Takahashi 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.
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Slavkin H.C. (1998) Toward Molecularly Based Diagnostics for the Oral Cavity. J. Amer. Dent.
Assoc. 129:1138-1143
Yamane 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. 43:407-416
Slavkin, H.C. (1998) Protecting the Mouth Against Microbial Infections. J. Amer. Dent. Assoc.
129:1025-1030
Slavkin, H.C. (1998) Advice to Coaches of Students in One of the Youngest Sciences. J. Dent.
Education. 62(3):226-229
Takahashi 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. 125:16271635
Chai 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. 42:87-94
Sadler 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):331-337
Yamane 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):161-166
Yamane 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 209:353-366
Slavkin, H.C. (1997) Benefit-to-Risk Ration: The Challenge of Antibiotic Drug Resistance. J.
Amer. Dent. Assoc. 128:1447-1451
Slavkin, H.C. (1997) Sex, Enamel & Forensic Dentistry: A Search for Identity. J. Amer. Dent.
Assoc. 128:1021-1025
Zeichner-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 40:27-38
17
Chai 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 208:526-535
Slavkin, H.C. (1997) Charles Darwin and the Foundation of Clinical Genetics in Dentistry. J.
Amer. Dent. Assoc. 128:241-245
Slavkin, 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. 249-253
Slavkin, H.C. (1996) And the Next Fifty Years? The Future of Recombinant DNA Technology
in Oral Medicine. J. Public Health Dentistry. 278-285
Slavkin, H.C. (1996) Understanding Human Genetics J. Amer. Dent. Assoc. 127:266-267
Slavkin, H.C. (1996) Are We Ready for Clinical Gene Therapy. J. Amer. Dent. Assoc. 127:396297
Slavkin, H.C., Diekwisch, T. (1996) Evolution in Tooth Developmental Biology: Of
Morphology and Molecules. The Anatomical Record 245:131-150
Hu, 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 39:939-945
Slavkin, 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., Zeichner-David, 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.
18
Chai, Y., Mah, A., Crohin, C., Groff, S., Bringas, P., Le, T., Santos, V. and Slavkin, H. C. (1994)
Specific transforming growth factor-beta 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., Zeichner-David, 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, 471-482.
Lau, E.C., Li, Z.-Q., Santos, V. and Slavkin, H.C. (1993) Messenger RNA phenotyping for semiquantitative 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 fusilli-form dysmorphogenesis of Meckel's cartilage during embryonic mouse
mandibular morphogenesis in vitro. Development, 118:903-917.
Slavkin, H.C. (1993) Reigers syndrome revisited: experimental approaches using pharmocologic
and antisense strategies to abrogate EGF and TGF-a functions resulting in dysmorphogenesis
during embryonic mouse craniofacial morphogenesis. Am. J. of Med. Genetics, 47:689-697.
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: 505-516.
Lau, E.C., Simmer, J.P., Bringas, Jr., P., Hsu, D.D.-J., Hu, C.-C., Zeichner-David, 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 1253-1260.
19
MacDougall, M. Slavkin, H.C. and Zeichner-David, M. (1992) Characteristics of Phosphorylated
and non-phosphorylated dentine phosphoprotein. Biochem. J. 287:651-655.
MacDougall, M., Zeichner-David, 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, 50:190-194.
Zeichner-David, M., MacDougall, M., Yen, S., Hall, F., and Slavkin, H.C. (1992) Protein kinases
in dentinogenesis. Proc Finn Dent Soc 88 Suppl. I, 295-303.
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 sex-linked dimorphism. Calcif. Tiss.
Internat. 48:288-290.
Fincham, A.G., Hu, Y., Lau, E.C., Slavkin, H.C. and Snead, M.L. (1991) Amelogenin
post-secretory processing in the postnatal mouse molar tooth. Arch Oral Biol. 36:305-317.
MacDougall, M., Zeichner-David, 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. 50:190-194.
Slavkin, H.C. (1991) Molecular determinants during dental morphogenesis and
cytodifferentiation: a review. J. Craniofac. Genetic & Develop. Biol. 11:338-349.
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. 47:105-111.
Hata, R., Bessem, C., Bringas, Jr., P., Hsu, M-Y. 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):509-519.
Sasano, Y., Kikunaga, S. and Slavkin, H.C. (1990) Development of embryonic mouse mandible
in serumless, chemically-defined organ culture: morphogenesis and growth factors. Tissue
Culture (Japanese) 16(11):424-429.
Slavkin, H.C. (1990). Molecular determinants of tooth development: A review. Crit. Rev. Oral
Biol. Med. (CRC Press) 1(1):1-16.
Slavkin, H.C. (1990). Regulatory issues during early craniofacial development: A summary.
Cleft Palate J. 27(2):121-130.
20
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, chemically-defined medium. Connect.
Tissue Res. 24:41-51.
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
tissue-specific extracellular matrix biomineralization. Differentiation, 41:62-71.
Fincham, A.G., Hu, Y., Pavlova, Z., Slavkin, H.C. and Snead, M.L. (1989). Human
Amelogenins: Sequences of "TRAP" Molecules. Calcif. Tissue Int. 45:243-250.
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. 17:10:26-37.
Slavkin, H.C. (1989). Recombinant DNA Technology and Clinical Dentistry. Int. J.
Prosthodont. 2:80-96.
Slavkin, H.C. (1989). Splice of life: Towards understanding genetic determinants of oral
diseases. Adv. Dent. Res. 3:1:42-57.
Slavkin, H.C., Bessem, C., Fincham, A.G., Bringas, P., Santos, V., Snead, M.L. and
Zeichner-David, M.(1989). Human and Mouse Cementum Proteins Immunologically Related to
Enamel Proteins. Biochim. Biophys. Acta, 991:12-18.
Slavkin, H.C., Bringas, P., Jr., Sasano, Y. and Mayo, M. (1989). Early embryonic mouse
mandibular morphogenesis and cytodifferentiation in serumless, chemically-defined medium: A
model for studies of autocrine and/or paracrine regulatory factors. J. Craniofac. Genet. Dev.
Biol. 9:185-205.
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