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Dentistry in the Age of Genomics
The Answer Lies in the Genome
- Dr. Harold C. Slavkin


Harold C. Slavkin, DDS
Professor of Dentistry
Herman Ostrow School of Dentistry
Center for Craniofacial Molecular Biology
University of Southern California












The biological revolution dividends continue to arrive! They are being delivered from universities, government laboratories, foundations, hospitals, and clinics, and from a growing number of biotechnology industries. These dividends are international, not restricted by national boundary conditions. They impact our language, how we think, how we diagnose, how we plan and implement clinical procedures, how we consider therapeutics that are gene-based, and even how we design and fabricate biomaterials for cell, tissue, and organ regeneration. It's been and remains thrilling for all of us!

My personal exposure to the biological revolution started in high school, when I first heard about Watson and Crick and their discovery of the structure and possible biological functions of deoxyribonucleic acid (DNA) from my chemistry teacher, Miss Nellie Rogers. That was 1953. Later, as I was completing my dental studies, Francis Crick proclaimed, "We are living in a biological revolution," as he received the Nobel Prize in 1964 along with James Watson and Maurice Wilkins. I heard more about this 'revolution' from Marshall Urist as he shared with me his discovery of bone morphogenetic 'factor' during my seven years of private practice; we both practiced one day a week in the same building, and Marshall (an orthopedic surgeon and clinical scholar) became a close friend and my patient.

My awareness grew during my postdoctoral education and training, though I never would have imagined that I would attend the Asilomar Conference held in Monterey, California, in 1975, when recombinant DNA guidelines were crafted. Imagine being present at the inception of the rules and procedures for the human gene for insulin to be inserted into the genome of a bacteria, yeast, plant, or animal, and that organism producing recombinant human insulin protein for the treatment of diabetes and other important human therapeutics (growth factors, hormones, antibodies, anti-microbial therapeutics, and a large array of other pharmaceuticals). In fact, Robert Swanson and Herbert Boyer founded Genentech—the first biotech company in the United States—in 1976 in South San Francisco. At that time, they reported cloning the gene encoding EGFR (epidermal growth factor receptor, HER1) used in studies of cancer and cancer therapy.

Across the Bay, Bill Rutter and his research team founded Chiron in Emeryville, California, and enabled many advances, including recombinant insulin, a number of gene-based diagnostic tests for blood elements, and the Hepatitis B vaccine. Today, the United States is the largest market and leading consumer of biotechnology products in the world, and now home of more than 1,300 firms involved in achieving the goals of the biological revolution. Of the 5.5 million scientists and engineers in the United States, approximately 1.3 million are involved in the biological sciences and related industries. Biotechnology-derived pharmaceuticals were valued at $67 billion in 2010.

After production of antibodies to detect the major protein found in enamel (amelogenin), and identification of the messenger RNAs (mRNAs) for amelogenin in the late 1970s, my laboratory, including Mal Snead, Maggie Zeichner-David, and Alan Fincham, in collaboration with Savio Wu (then at Baylor), would, in 1983, be the first to clone the mouse gene for amelogenin, the major protein found in the bioceramics identified as enamel. Along the way, several postdoctoral fellows in our research group, Ed Lau and James Simmer (now at the University of Michigan), discovered that the amelogenin gene produces multiple and different mRNA transcripts by a process termed 'alternative splicing,' and thereby produces multiple translation products or protein isoforms of varying molecular weights that enlarge the proteome. Alternative splicing is a common mechanism for the generation of multiple isoforms. Many genes are alternatively spliced in tissue-specific, developmentally regulated, and hormone-responsive manners. The central dogma of years ago that "one gene produces one messenger RNA that produces one protein" is no longer true. The total number of possible proteins from the genome can far exceed the number of genes.

The unexpected has always dominated my career. By the late 1980s, we had identified and mapped the human amelogenin gene to both the X as well as Y chromosomes (AMELX and AMELY). This was an unexpected discovery—a variant of a functional gene encoded in two different chromosomes. Thereafter, several investigators used our discoveries for sex determination by genetic typing of amelogenin gene- and chromosome-specific fragments. Amelogenin genes also had utility in forensics.

We explored the molecular explanation of X-linked amelogenesis imperfecta (AI) localized to Xp22.1-p22.3. 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?" In short order, we learned from genomic studies that there are multiple modes of inheritance for AI. There are five responsible gene mutations for AI, including amelogenin, ameloblastin, enamelin, enamelysin, and the transcription factor distal-less homeobox 3 gene.

Independently, Mary MacDougall (at that time a graduate student working with Maggie Zeichner-David and me) isolated and characterized the major non-collagenous protein found in dentin. She cloned the gene and eventually mapped the gene to the chromosomal location responsible for dentinogenesis imperfecta (DI), chromosome 4q21. From genomic studies we learned that genetic mutations in osteopontin, bone sialoprotein, matrix extracellular phosphoglycoprotein, dentin matrix protein 1, and dentin sialophosphoprotein are associated with an array of dentin genetic diseases and disorders.

In the mid-1990s, I was invited by Don Chambers to celebrate the 40th anniversary of the discovery of DNA by James Watson and Francis Crick. The celebration was held in Chicago at the University of Illinois and included the work of Rosalind Franklin, Norman Simmons—a dentist who, as a postdoctoral fellow, prepared the DNA used by Franklin for her X-ray diffraction studies—and Maurice Wilkins.

I spoke of emerging opportunities in oral medicine to utilize the revolution's fruits for applications to diagnostics, treatments, therapeutics, and biomaterials. 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. It was further evident to me at that time, just over 17 years ago, that genomics would also include microbial genomics and viral, bacterial, and yeast microbes ("the Microbiome"). These applications have become reality.

The Human Genome Survey Map is Completed

On June 26, 2000, after five wonderful years (1995–2000) working within Harold Varmus's leadership team at the National Institutes of Health (NIH) as director of the National Institute for Dental and Craniofacial Research (NIDCR), I was standing in the East Room of the White House as President Bill Clinton spoke about and celebrated the first survey map of the Human Genome. I was enormously proud of Francis Collins, who led the Human Genome Project and of our NIH efforts coordinated with other federal agencies (Department of Energy, National Science Foundation), and with scientists from a number of nations, to explore 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 both teams published their work—roughly 95 percent completion of the human genome; Francis's team published in Nature, and Venter's team in Science. Then, in October 2004, the entire Human Genome was completed. Imagine, 100 percent completion by 2004 —the 6.2 billion nucleotides or bases, annotated within 21,000 genes encoded within and mapped to specific locations in the 23 pairs of human chromosomes, were identified. We had entered "the Post-Genomic Era". Essentially, a "parts list of life" was now available online or in hardcopy. It was thrilling!

The Short-Term Dividends from the Human Genome

Francis Collins is now director of the entire NIH enterprise. 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
  • Access to genetic medicine will remain inequitable, especially in the developing world.

Importantly, all six of Francis's 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 research and development, technology, and clinical practice. Sometimes translational research that ultimately yields a clinical trial or material requires one or two decades and many millions of dollars. For over a century, scientific discoveries have been translated into technology that enables diagnostics, treatments and procedures, therapeutics, and biomaterials that have revolutionized the oral health professions.

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 clinical 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 advances in clinical dentistry, medicine, pharmacy, and nursing.

Genomics 101

Following fertilization, the single cell nucleus contains the entire human genome, 21,000 functional genes and 19,000 non-expressed pseudogenes, packaged within 23 pairs of chromosomes. In addition, a few dozen genes are inherited directly from our mothers via their transmission of the mitochondrial organelles within their ova. The mitochondria contains DNA (deoxyribonucleic acid) called 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 are encoded within the nuclear DNA and the mitochondrial DNA within cells and represent "the parts list of life."

Beyond the fertilized ovum, following a series of cell divisions, we eventually become mature adults consisting of 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 six feet. The DNA is formed from 6.2 billion nucleotides or bases (T, thymidine; A, adenosine; G, guanosine; and C, cytosine).

The language of genetics is the sequence and patterns created from Ts, As, Gs, and Cs. The genetic code is the representation for the various amino acids within triplets or codons (e.g., TCG, GCT, etc.). Each codon within DNA encodes for a specific amino acid (e.g. alanine, methionine, proline, arginine, tryptophan, etc.). The sequence of amino acids therefore provides the information and bioactivity of a specific protein (enzyme, co-factor, hormone, growth factor, a structural building block of bone or dentin, neurotransmitter, etc.). Only two percent of the entire length of DNA encodes the information for functional genes. The remaining DNA contains highly repetitive sequences that do not encode genetic information. 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".

Each functional gene has an anatomy that consists of a promoter region, an enhancer region, and a series of exons that contain the encoded information, and interspersed introns that do not contain informative base sequences. At the end of each gene is a stop codon (AAA). In summary, the DNA in our cells contains chains of A, C, T, and G. More than six billion of these chemical bases, strung together in 23 pairs of chromosomes, exist in every single somatic cell in our body. Along this enormous sequence of chemical bases, one in every 1,200 bases, on average, will differ. This difference is a source of genetic variance among people, known as single nucleotide polymorphisms or SNPs. From the investment in the Human Genome Project, we now have 10 million SNPs known to occur in the human genome and these have become "tools" for analyzing human genetic variance around the world now annotated and assembled in the International HapMap Project (see http://snp.cshl.org/whatishapmap.html)."

"The investment in genomics has provided the mechanisms for tissue-specific, developmentally appropriate, and hormone-responsive gene regulation throughout the human lifespan. We are now on the verge of "the $1,000 genome" that can enable the detection of subtle variants, mutations, or misspellings that reveal human disease, disorders, resistance or susceptibility, and even a sense of our ancestral histories. High throughput genotyping, the availability of millions of SNPs, and bioinformatics have enabled "personalized medicine and dentistry."

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
epigenomics
transcriptomics
proteomics
metabolomics
diseasomics
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.

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.

Epigenomics is the study of all of the chemical modifications (methylation, acetylation, etc.), beyond the inherited genetic information, that can modify or regulate many features of the human condition, such as metabolism.

Transcriptomics describes the total number 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 100,000 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 macro-environments, 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 are 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 of data sets 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 that 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 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. Rapid advances reveal that 20 percent of human diseases are now known to be inherited as Mendelian single gene mutations, whereas 80 percent are complex and reflect multiple gene and multiple environmental interactions.

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 oral professionals for the future, a future that offers the promise of gene therapies, increased cell, tissue, and organ regeneration, integration between digital and biological ways of knowing, and so much more? Are we prepared to utilize biology and gene-based therapeutics in the diagnosis and treatment of oral diseases and disorders? Are we ready to employ saliva as an informative fluid from which we can diagnose diseases and monitor the efficacy of treatments? Are we prepared to employ growth factors and other biological ingredients in the repair and regeneration of craniofacial, oral, and dental tissues? Are we prepared to use the principles and data gained from the $1,000 genome, from personalized medicine, in the oral health professions? Are we ready?"



References

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