The New Genetics

We are living in an extraordinary time in human history. For the next few minutes as you read this perspective, I invite you to marvel at the sparkling intellectual and technical developments that have recently been achieved at the interface between genomes (the complete gene complement of an organism), biofilms, oral infections, and the oral health professions.

A great deal has been learned from the genomes of humans and of minute living organisms (microbes), like bacteria. Genome databases are being searched to further our understanding of microbial genomes, such as Streptococcus mutans and Candida albicans, which are related to dental caries and oral candidiasis, respectively. Moreover, the intimacy between pathogenic microbes (virus, bacteria, and yeast) and the human host genome is becoming remarkably significant to the diagnosis, treatment, and prognosis of oral and dental diseases. Education, training, research, and clinical practice opportunities are already transforming the curriculum and pedagogy (how we learn/teach/coach/mentor) in undergraduate, predoctoral, residency, and specialty oral health professional programs. In the words of Bob Dylan: “The times they are a changing.”

A Milestone Map

When I was taking chemistry under Ms. Rogers’ tutelage at Hamilton High School in Los Angeles, she exclaimed “A molecule that explains life was just discovered in England!” As a “hormonally challenged” adolescent of the 1950s, I could not fully appreciate at the time what my chemistry teacher was so excited about. James Watson and Francis Crick had published their 1-page scientific paper in the weekly British periodical Nature describing the structure and suggested biological functions of deoxyribonucleic acid (DNA) in April 1953.¹

Forty-seven years later, I was thrilled to hear the President of the United Sates speak while I served as director of the National Institute of Dental and Craniofacial Research (NIDCR). “Without a doubt, this is the most important and most wondrous map ever produced by mankind,” announced President Clinton as he described, at a White House ceremony on June 26, 2000, that scientists had completed the first draft of the human genome—the blueprint of life that guides heredity and the biological processes of our minds and bodies. This accomplishment was made possible by the pioneering discovery of Watson and Crick.¹

Of course, it was only a first draft and much hard work lies ahead, but as a technological achievement and for its health and social implications, this was a profound milestone in the history of mankind. As Francis Collins, MD, PhD, director of the National Human Genome Research Institute, one of the 17 institutes that comprise the National Institutes of Health (NIH), observed at the White House event, “Researchers in just a few years will have trouble imagining how we studied human biology and disease without the genome sequence in front of us.” Around Valentine’s Day 2001, the near-complete human genome was published.^2-3

The rate of discovery has truly been astounding! Almost 10 years ago, I attended a conference entitled “DNA: The Double Helix—40 Years: Perspective and Prospective,” sponsored by the New York Academy of Sciences and the University of Illinois.⁴ Sir Walter Bodmer, who asked the question—where will genome analysis lead us 40 years on—presented one of the last papers of the conference. Sir Bodmer stated, “Well, within the next 40 years, perhaps even within the next 10, essentially all of the human genes (and so effectively all vertebrate genes) will have been found, sequenced, and mapped.”⁴ His prophecy has literally come true.

During my first year as director of NIDCR, the initial publication of a microbial genome was published in 1995—the bacterium Haemophilus influenzae.⁵ Hence, a new era was initiated—the authentic age of genomics.^1-7 Within just a few years, human and microbial genome projects have and continue to revolutionize the practice of biology, dentistry, and medicine.^8-13 The recent completion of the human genome provides “a parts list of life” or approximately 30,000 discrete structural and regulatory genes mapped within 23 pairs of human chromosomes.^2,3,14 Over the past few years, more than 36 microbial genomes have been sequenced to completion and another 120 microbial genomes are as yet in progress.¹⁵ These remarkable advances have increased opportunities to expand the range of potential drug targets.^6,7 Meanwhile, the biggest challenge is no longer to find the genes and identify significant variations in DNA sequence, but to analyze their function.

So, how does this milestone affect the future of the oral health profession? In particular, how will human and microbial genomes and related technology impact education, training, research, and the clinical practice of oral health care? My perspective considers the genomic achievements, the highlights of biofilms, and their implications for oral health professionals such as dental hygienists.

The Human and Microbial Genome Projects

We live in a biosphere with multiple relationships with other living organisms ranging from prions (protein particles that transmit neurodegenerative diseases like mad cow disease) and microbes (virus, bacteria, yeast) at the microscopic level of organization, to insects and plants, animals, and other humans. Common to all of these life forms are the unifying genetic blueprints that serve to guide the genesis of each living creature. DNA is a macromolecule composed of a linear array of deoxyribonucleotides, each nucleotide or base contains a nitrogenous base, a sugar, and a phosphate component.¹ Diseases and disorders can be associated with misspellings or genetic mutations of one or more nucleotides, and these mutations can be caused or induced by infectious microbes, environmental factors such as physical and chemical mutagens, genetic mutations and variations, or (more likely) combinations of these multiple factors (see Figure 1).^2,3

Figure 1. A model of DNA based on x-ray crystallography data.

The haploid genome, which has half the normal somatic number of chromosomes, consists of 3.2 billion nucleotide or base pairs (A, adenosine; T, thymidine; C, cytosine; and G, guanosine) within DNA that are distributed among 23 distinct chromosomes (22 autosomes and one sex chromosome; either X or Y).³ Encoded within the vast array of bases are approximately 30,000 regulatory or structural genes and the necessary elements that control the regulation of genes throughout the life span of the organism.^2,3 In addition to the genomic information found within the nucleus of each human reproductive cell, as well as the trillions of somatic cells (eg, cartilage, bone, periodontal ligament, dental pulp, trigeminal ganglia, salivary glands, oral mucosa), genomic information is also encoded within genes located in the maternally inherited mitochondria termed the mitochondrial genome or mitDNA. Mutations in mitDNA (nine genes) are also associated with a number of human diseases and disorders.
The comparison between bacteria and human genomes is intriguing. Most bacterial genomes contain 1.8 million bases (the summation of all of the A,T,C, and G bases) and these are assembled into 1,740 discrete genes.¹⁶ In contrast, the human genome contains 3.2 billion bases that are assembled into 30,000 discrete genes.^2,3 These human and nonhuman genome sequence databases have evolved essentially over the past 10 years, and now serve as the cornerstone for technological progress in three “wet laboratory” (a comprehensive research laboratory as opposed to a clinical or patient care laboratory) research areas including gene mutagenesis in cells and animal models, nucleic acid hybridization technology, and protein chemistry. These three enabling technologies are promoting rapid progress in functional genomics or proteomics (the study of protein structure and functions). Proteomics is being used to address and solve a number of complex biological problems during development, health, and disease.

Genetic Comparison

How do genes function? How do genes function in combinations? How do gene-gene and gene-environment interactions produce disease? What are the rules for the structure and function of proteins? What are the rules for protein-protein interactions? How do these circuits or networks function within biological systems? What mechanisms resist mutation, and which mechanisms drive mutation in microbial, plant, animal, and human genomes? Integration of functional genomic data from these many types of experimentation will be key to developing a unified understanding of how the information encoded in the genome is interpreted in the clinical oral health community of this new era.

Today, we have the opportunity to compare the human set of genetic instructions with those in microbes, plants, and animals. These comparisons further provide analyses that may result in new models of thought to formulate a broader perspective in biology, diseases, and disorders. These comparisons in this “genome era” allow us to learn about human and nonhuman genomes and their evolution, organization, and rearrangements in health and disease. Moreover, these approaches provide for the development of innovative gene-based diagnostics, treatments and therapeutics, and disclose how individual genetic variance, ie, polymorphisms, are reflected in drug responses and drug metabolism.⁶ The human genome era heralds a call to action to reform dental education for the 21st century.^8-13,16-19

Biofilms, Oral Infection, and Systemic Diseases

The microbial ecology of biofilms found on tooth, mucosal, and implant surfaces offers extraordinary opportunities to investigate the community of pathogens associated with oral infection per se, and oral infections associated with human systemic diseases and disorders.^9-13 Imagine, all possible drug targets for the treatment of human dental diseases and disorders are encoded within the human genome sequence, except for the transmissible infectious diseases attributable to microbial pathogens that present their own genomes. The oral cavity contains 6 billion microbes representing 500 species that reside in the oral cavity; often within biofilms on the surfaces of teeth.¹¹ During the human experience, viruses, bacteria, and yeast are transmitted from caregiver to infant, child to child, spouse to spouse, and caregiver to elderly patient.^12,13 The possible targets for improved diagnosis, therapies, and therapeutics for dental and related systemic infectious diseases are represented by the genomes of both the pathogen(s) and host.

Oral microbial infections are associated with a number of systemic diseases including low-birth weight, premature babies, cardiovascular disease, cerebrovascular disease, osteoarthritis, a number of pulmonary diseases and disorders, and the management of type 1 diabetes.^9-13 Curiously, these often commensal microorganisms (viral, bacterial, and fungal) may become virulent as a consequence of the host environment such as immunodeficiency, nutrition, other medical conditions, medications, and psychosocial stress factors. How commensal microbes become virulent is a critical and, as yet, unanswered question.

Microbial genome analysis provides molecular information into virulence, host adaptation, and evolution.¹⁶ The microbial ecosystem-termed biofilms that reside on various oral, dental, and implant surfaces offer a remarkable opportunity for ambitious studies of differential gene expression; gene polymorphisms and mutation; three-dimensional architecture and physiology of biofilms; community effects of microbes within biofilms under conditions of immune suppression or protein-calories malnutrition; microbial genome plasticity (the capacity to change rapidly); identification and characterization of virulence factors; and drug action mechanisms, drug targets, and new antimicrobial drug development.⁷

Prospectus for Dental Hygiene

The remarkable advances in microbial and human genomics require equally remarkable advances in oral health professional education and clinical practice—what we learn and how we learn. Today we are presented with opportunities for reforms in human genetics, molecular epidemiology, and patient education and counseling based on “the new genetics.” In tandem, we also face the challenges of faculty and staff development and renewal in oral health professional programs around the country.

Dental hygienists will benefit from reviewing the recommendations released by a recently-sponsored Blue Ribbon Panel on the Future of Education and Training in Dental and Craniofacial Sciences.²⁰ Change and revision are the operative terms for the coming decades of the 21st century.

Nested within “change” are variations in demography, patterns of disease, management of health care, access to health care, information technology, quality of life expectations, and innovations and discovery through biomedical research and technology. The recent Surgeon General’s report, Oral Health in America, serves as an excellent primer for “what is” and suggests “what could be.”¹⁷

The study and application of human genetic variance during normal development, diseases, disorders, and responses to treatments and therapeutics introduces a new era in oral health professional education. The potential impact of genomics on the future of education, science, and clinical practice include understanding fundamental basics of diseases and disorders, targeting research to the fundamental root causes of disease processes, risk assessments for preclinical interventions, diagnostics, and tailoring treatment and therapeutics to individual risk and responses. This emerging knowledge base can result in clinical competencies for all health professionals including dental hygienists.

The impact of information technology has revolutionized our lives in many ways as low-cost informatics, computing, and the Internet have become broadly available to health care professionals and patients. These advances have already influenced patient management systems in dental and medical schools, clinics, and hospitals. Likewise, the human and nonhuman genome is leading to unifying theory in the biological sciences and is profoundly impacting oral biology, dental and craniofacial diseases and disorders, dental and medical sciences, education, and clinical practice.^8-13 The rate and magnitude of change in the life sciences cannot be underestimated as we ponder the future.

We are about to experience the completion of the human genome and a number of oral microbial pathogen genomes. We are entering the next phase of progress and are experiencing the transformation from empirical solutions to scientific evidence serving to drive the design and fabrication of the next generation of personalized and more precise therapeutics for oral health care. Tissue engineering, biomaterials, gene-based diagnosis, and gene-mediated therapeutics herald the new century.^18,19 The integration of technology and information from gene-to-patient is the necessary precondition of transcending the limits of current oral health care. Our future is very bright.

References

1. Watson JD, Crick FHC. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature. 1953;171:737-738.
2. Venter JC, Adams MD, Myers EW. The sequence of the human genome. Science. 2001;291:1304-1351.
3. International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature. 2001;409:860-921.
4. Bodmer SW. Where will genome analysis lead us forty years on? In: Chambers D, ed. DNA, The Double Helix: Perspective and Prospective at Forty Years. New York:New York Academy of Sciences; 1995:414-426.
5. Fleischmann RD, Adams MD, White O, et al. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science. 1995;269:496-512.
6. McCarthy JJ, Hilfiker R. The use of single-nucleotide polymorphism maps in pharmacogenomics. Nature Biotechnology. 2000;18:505-508.
7. Bumol TF, Watanabe AM. Genetic information, genomic technologies and the future of drug discovery. JAMA. 2001;285:551-555.
8. Genco RJ, Scannapieco FA, Slavkin HC. Oral reports. The Sciences. 2000;40:25-30.
9. Shum L, Takahashi K, Takahashi I, et al. Embryogenesis and the classification of craniofacial dysmorphogenesis. In: Fonseca R, ed. Oral and Maxillofacial Surgery Vol 6. Philadelphia: WB Saunders Co; 2000:149-194.
10. Slavkin HC, Baum BJ. Relationship of dental and oral pathology to systemic illness. JAMA. 2000;284:1215-1217.
11. Cohen DW, Slavkin HC. Periodontal disease and systemic disease. In: Rose LF, Genco RJ, Cohen DW, Mealey BL, eds. Periodontal Medicine. Ontario, Canada: BC Decker Publishing Co; 2000:1-10.
12. Genco RJ. Risk factors for periodontal diseases. In: Rose LF, Genco RJ, Cohen DW, Mealey BL, eds. Periodontal Medicine. Ontario, Canada: BC Decker Publishing Co; 2000:11-33.
13. Genco RJ, Offenbacker S, Beck J, Rees T. Cardiovascular diseases and oral infections. In: Rose LF, Genco RJ, Cohen DW, Mealey BL, eds. Periodontal Medicine. Ontario, Canada: BC Decker Publishing Co; 2000:63-82.
14. National Center for Biotechnology Information. The human genome: a guide to online information resources. Available at: www.ncbi.nlm.nih.gov/gen ome/guide/human. Accessed December 12, 2002.
15. TIGR Microbial Database. A listing of published microbial genomes and chromosomes and those in progress. Available at: www.tigr.org/tdb/mdb/ mdbcomplete.html. Accessed December 12, 2002.
16. Mahan MJ, Slauch JM, Mekalanous JJ. Selection of bacterial virulence genes that are specifically induced in host tissues. Science. 1993;259:686-688.
17. Oral Health in America: A Report of the Surgeon General. Bethesda, Md : Department of Human Health Services; 2000. NIH Publication No 00-4713.
18. Baum BJ, O’Connell BC. The impact of gene therapy on dentistry. JADA. 1995;126:179-189.
19. Hamilton J. Dental implications of the human genome project. CDA Journal. 2001;29:35-47.
20. Implementation Plan for the NIDCR Blue Ribbon Panel Report. Available at: www.nidr.nih.gov/research/blue ribbon/impPlan_BRP.asp Accessed December 12, 2002.