Methods. The author explains the importance of the decoding of the genome and how—based on this now completely depicted molecular structure—genes build, maintain and control all the biological functions of humans and all other living organisms. The potential application of this knowledge to the practice of dentistry is addressed, as well as the ethical, legal and moral challenges to the profession engendered by this new technology.

Conclusion. During the next several decades, many of the current materials and methods will be abandoned in favor of emerging bioengineered technologies, genetically programmed for the prevention and treatment of oral disease as well as for the repair of damaged dental tissues.

Practice Implications. The development and implementation of these innovative dental therapies will require intensive education of current practitioners. Considerable restructuring of dental school curricula will need to take place, and the emergence of a new dental specialty is anticipated.

As more is learned about the workings of genes and how changes in gene structure enhance or damage the usual functions of living organisms, the diagnosis and treatment of disease will become increasingly gene-centered. The American Medical Association has predicted that "over the next several years the practice of medicine will become less acute and episodic in its focus towards more preventive and individualized medicine."³

The implementation of genetic engineering in medicine will have a similar effect on the practice of dentistry. It is likely that young dentists will, during their professional lifetime, control the pathogenicity of dental infectious agents, restore and reconstruct damaged and lost dental tissues through bioengineering methods and build dental structures that are able to resist the destructive elements of dental disease.

	THE GENOME

TOP ABSTRACT THE GENOME THE PROTEOME 21ST-CENTURY DENTISTRY CHALLENGES CONCLUSION REFERENCES

 
Defined as the master blueprint for cellular structures and activities during the lifetime of each and every cell, the genome contains the complete set of instructions for the initiation, construction, operation, maintenance and repair of all living organisms.

The human genome consists of two closely entwined threads of deoxyribonucleic acid, or DNA, which are organized as 23 distinct microscopic units called chromosomes. The DNA extends for the full length of the chromosome, and, according to the Human Genome Project, if unraveled, would stretch out to a distance of 5 feet but only be 50 trillionths of an inch in width.⁴ There are 22 pairs of chromosomes, one from each parent, plus an X or Y chromosome depending on the person’s sex.⁴

DNA nucleotide bases. The DNA molecule, which forms each chromosome, resembles a twisted ladder, with the uprights of the ladder consisting of sugar and phosphate molecules, and the rungs consisting of nitrogen-containing bases called nucleotides, which separate and hold the sides apart. There are four DNA nucleotide bases: adenine (A), cytosine (C), thymine (T) and guanine (G). They are placed two across and called base pairs. These bases are of different size and shape, but because adenine always pairs with thymine (A-T) and cytosine always joins guanine (C-G), units of identical width are constructed. The genome consists of almost three billion base pairs.¹ The order in which the bases are placed along the spiral is called the DNA sequence, and it is this sequence—and this sequence alone—that determines which organism will develop and how it will live and function.¹

During every cell division, the DNA molecule splits up the middle, precisely separating the two bases. Each half then is used as a template to form a completely new molecule, exactly the same as the original.⁵

More than 99.9 percent of deoxyribonucleic acid sequences are exactly the same across the entire human population.

The Human Genome Project defines a gene as a specific sequence of nucleotide bases whose sequences carry the instructions for construction of proteins.¹ These proteins provide the structural components of cells and tissues, as well as enzymes for essential biochemical reactions. Hundreds of genes reside on each chromosome. The complete human genome is estimated to contain about 30,000 genes.^1,2

It is astonishing that more than 99.9 percent of DNA sequences are exactly the same across the entire human population. People differ from one another as the result of DNA variations in only one-tenth of 1 percent of the human genome. However, these small genetic dissimilarities have a major impact on a person’s physical makeup and response to disease, as well as on the effectiveness of therapies instituted¹ (see box, "Online Genome Resources," for more information).

Single-nucleotide polymorphisms. Reporting on the ability to locate and distinguish between these variants, the investigators in the Human Genome Project stated that "methods are being developed to detect different types of variation, particularly the most common type called single-nucleotide polymorphisms, which occur about once every 100 to 300 bases."⁴ Scientists believe that single-nucleotide polymorphism, or SNP, maps will help identify the multiple genes associated with such complex diseases as cancer, diabetes, vascular disease and some forms of mental illness. These associations are difficult to establish with conventional gene-hunting methods, because a single altered gene may make only a small contribution to a specific disease risk.^6–8

Gene sequencing. According to the Human Genome Project, researchers in the consortium also have studied the genomes of other species and have completed the gene sequencing of the bacterium Haemophilus influenzae, the yeast Saccharomyces cerevisiae, the roundworm C. elegans, the fruit fly Drosophila melanogaster and the laboratory mouse Mus musculus.⁹ Geneticists in the Human Genome Project explained that there is a correlation among the genomes of these various species, establishing the commonality of all living things. This authenticates the use of genetic models in these organisms so that researchers can experiment, learn and make use of their genomes for the benefit of humanity.⁹

For example, almost every human gene has a counterpart with similar DNA sequences and basic functions in the mouse genome.¹⁰ Of the estimated 30,000 genes in the human genome, only 300 have no obvious counterpart in the mouse.¹¹ If the 23 pairs of human chromosomes were broken into smaller parts, they could be reassembled to produce a serviceable genetic model of the mouse. By locating corresponding regions on both genomes, researchers can replicate and study human diseases in mice. Of the 289 genes that, when mutated, are known to cause disease in humans, 177 have equivalents in the fruit fly.⁹

	THE PROTEOME

TOP ABSTRACT THE GENOME THE PROTEOME 21ST-CENTURY DENTISTRY CHALLENGES CONCLUSION REFERENCES

 
The primary function of genes is to direct the manufacture of proteins. Wade¹² explained, "Genes contain instructions for the production of proteins. These proteins become the structural components of cells and the enzymes that cause chemical changes in the body." Proteins are the working parts of human cells. Almost every organic molecule in the body is either a protein or the result of a protein’s activity.¹²

Researchers once believed that the assembly of each of these proteins is controlled by its own specific gene, and that the resulting structure of the protein can be predicted from the sequence of the DNA letters in the parent gene. Both the Celera and international consortium researchers reported that human protein coding is more complex. A human gene—acting alone or in concert with other genes—under the influence of on-and-off protein regulators, insulators and editors, has the ability to produce several different proteins by means of the gene’s or genes’ splicing together separate protein components.^1,2 Although many proteins of interest have been studied in great detail, Dr. Francis Collins, the consortium director, described the findings as a "shop manual that contains within it a list of all the parts that we’re made of."⁴

Because the key to effective disease prevention and treatment is an understanding of these proteins, scientific focus now shifts to sequencing the proteins produced by the body, as instructed by its genes. Researchers have begun to determine the structure and shape of these protein molecules. According to Dr. Helen M. Berman, professor of chemistry at Rutgers University and director of the Protein Data Bank, a federally financed database of protein structures, "It’s basically the next step after the Human Genome Project. Instead of a list of letters, we’ll understand biology in a three dimensional way."¹³ In addition, a group of top-level proteomics researchers have launched a global Human Proteome Organization, whose mission is to increase awareness of, and support for, large-scale protein analysis in scientific, political and financial circles.¹⁴

I believe that from this knowledge will come the ability to direct and control the construct and function of humans and all living things. For health professionals, who are constantly interacting with these human functions, the potential for change is prodigious.

Investigators from the Human Genome Project reported that "all diseases have a genetic component, either inherited or resulting from the body’s response to environmental stresses like viruses or toxins."¹⁵ They indicated that the project’s successes will enable researchers to pinpoint the genetic particulars that cause or contribute to disease. "The ultimate goal is to use this information to develop new ways to treat, cure, or even prevent the thousands of diseases that afflict humankind."¹⁵

Discovery of the specific bacterial single-nucleotide polymorphisms and their products that cause dental disease will lead to counter or mitigate their untoward effects.

	21ST-CENTURY DENTISTRY

TOP ABSTRACT THE GENOME THE PROTEOME 21ST-CENTURY DENTISTRY CHALLENGES CONCLUSION REFERENCES

 
The deciphering of the genome, the impending understanding of protein construction and the continuing investigations of cellular function portend momentous changes in the art and practice of the dental sciences. Genetic bioengineering will impact all phases of dental practice. Most significant will be the interaction between dentists and patients as new systems of diagnosis, prevention and treatment are developed.

Control pathogenicity of dental infectious agents. Because the sequencing of bacteria also is progressing rapidly, the first major impact will likely be the modification of bacteria that cause dental disease. The Joint Genome Institute operated by the University of California reported that during October 2000, high-quality draft sequences of 15 bacterial genomes were produced, each in just 1 working days.¹⁶

More significantly, in April 2001, researchers at the University of Oklahoma Health Science Center announced the completion of the sequencing of the pathogen Streptococcus pyogenes, the bacteria responsible for a wide variety of human ailments, including streptococcal sore throat, scarlet fever, acute glomerulonephritis, rheumatic fever, septicemia, toxic shock syndrome and necrotizing fasciitis (flesh-eating disease).¹⁷ The sequencing will broaden our understanding of how the organism causes disease. S. pyogenes contains more than 40 possible virulent genes, half of which were previously unknown.

This ability to determine bacterial genomes speedily will enable dental scientists to better research and understand the cellular function of the organisms responsible for the initiation of caries and periodontal disease. Discovery of the specific bacterial SNPs and their products that cause dental disease will lead to the development of measures to counter or mitigate their untoward effects.

Chronic myeloid leukemia drug. An example of genetic targeting of a disease-producing protein is the drug STI-571, approved in May by the U.S. Food and Drug Administration for marketing as Gleevec (Novartis Pharmaceuticals). In clinical trials, this medication has brought chronic myeloid leukemia into remission in most patients. Gentler and more effective than other available treatments, this drug is generating excitement among cancer specialists and patients.

An abnormal protein produced by an abnormal chromosome causes this form of leukemia. The disease leads to a progressive, and eventually fatal, increase in the number of white blood cells in the body. STI-571 acts to block a signal that the abnormal protein sends out and effectively prevents the growth and production of additional cancerous cells. According to findings presented to the American Society of Hematology,¹⁸ more than 90 percent of patients who were in the first phase of chronic myeloid leukemia experienced a remission within the first six months of therapy.

Similarly, with the isolation and targeting of the specific offending proteins, researchers should be able to modify the bacteria associated with dental disease without disturbing the biological spectrum of the patient or stimulating the emergence of resistant strains. In the future, after careful biomolecular evaluation of the particular flora of a patient, dentists should be able to prescribe a tailored remedy for periodic use by that patient.

Restoration and reconstruction of dental tissues. Within the next few decades, changes in the methods and materials used to treat dental disease will take place. As genetic researchers continue to study the specific genes that control the development and maintenance of teeth and their surrounding structures, implementing proteins will be located, and their tissue-building functions defined. Treating dentists then will be able to apply genetic engineering techniques to stimulate the body to repair itself, rather than place extrinsic materials. For example, during endodontic therapy, dentists will be able to seed genetically developed pulpal tissue into the canal to grow and fill the chamber. A layer of epithelial cells then could be triggered to form dentin and enamel to complete the biological restoration of the tooth.

The ability to stimulate autogenous tissue growth also will enhance the patient’s recovery after periodontal therapy. The dentist, armed with the capacity to stimulate patient-specific regeneration of lost alveolar bone, gingival tissue and cementum (including gingival reattachment in the periodontally compromised patient), will be able to restore an optimal level of periodontal health.

During endodontic therapy, dentists will be able to seed genetically developed pulpal tissue into the canal to grow and fill the chamber.

Current technology. Some of the technology needed to implement such tissue regeneration is currently available. In a report published in The New England Journal of Medicine, Tsai and colleagues¹⁹ presented the results of a study in which they cultured corneal epithelial cells from healthy eyes of patients with severe unilateral corneal disease and subsequently transplanted the cells to the diseased eyes to restore vision. In an editorial about this study, published in the same issue, Schwab and Isseroff²⁰ commented, "The promise of bioengineered replacements for diseased or damaged tissue has become a reality." Bioengineered or cultured tissue products to replace other tissues "indicates that such products are likely to revolutionize the treatment of many epithelial and even visceral diseases."²⁰

Baum and Mooney²¹ explained, "Tissue engineering will have a considerable effect on dental practice during the next 25 years. The greatest effect will likely be related to the repair and replacement of mineralized tissues, the promotion of oral wound healing and the use of gene transfer adjunctively." Researchers at the University of Michigan School of Dentistry reported that they used engineered skin and gingival cells to produce bone with the same spongy interior, hard outer coating and marrow center as naturally developed bone.²²

In a major breakthrough for tissue regeneration, Zuk and colleagues²³ successfully derived stem cells from fat tissue obtained via routine liposuction and were able to grow and differentiate these primitive cells into adipogenic, chondrogenic, myogenic and osteogenic cells in vitro.

Research scientist Robert Freitas explained that nanotechnology, which involves the use of precise, molecular-sized robotic devices to control matter at the atomic and molecular level, could result in the manufacturing of instruments that are able to build and install "a biologically autologous whole-replacement tooth that includes both mineral and cellular components."²⁴

How people differ genetically may explain why a given therapy, such as osseous surgery, is successful with one patient, yet fails to stem the periodontal disease of another. No longer will "one size fits all" be the methodology of patient care. Treatment will be tailored carefully to meet the specific needs of the patient, and adjusted as dictated by his or her genetic profile.

Building disease-resistant dental structures. Further in the future—probably by the middle of the century—lies the specter of human germline alteration, or what is often referred to as "designer babies." Different from interference with the pathogenicity of caries- or periodontal disease–producing organisms, or from genetically engineered tissue replacement, alteration of the germline affects the embryonic formation of the dental complex and creates disease resistance in people, who then pass this immunity on to their children and to all succeeding generations.

As practicing dentists, most of us have noticed that a small minority of patients are completely free of caries. Close examination reveals that the oral hygiene practices and patterns of these patients are no different from those of the majority of patients, who are caries-prone. Moreover, dentists also occasionally observe patients who exhibit the risk factors for advanced periodontal disease, such as massive accumulations of calculus, poor hygiene, heavy smoking and occlusal trauma, but are disease-free.

Evidently, in these unusual cases, some elements are at play that impart inherent resistance to dental disease. In the future, dental geneticists will evaluate and compare the genes of dental disease–resistant patients with those of dental disease–prone patients, which likely will reveal the precise genetic components of these differences. Armed with such knowledge, researchers should be able to identify and replicate the messenger proteins that instruct the dental embryonic tissues to build disease-resistant tissues. Intercession in the dental formative process would become feasible, leading to infants who are free of caries and periodontal disease for a lifetime.

	CHALLENGES

TOP ABSTRACT THE GENOME THE PROTEOME 21ST-CENTURY DENTISTRY CHALLENGES CONCLUSION REFERENCES

 
As dental care becomes increasingly genomic in nature, dentists will find their interaction with patients increasingly "hands off." They will become more involved with the management of dental information systems and, eventually, much of the doctor/patient interaction may take place at the computer.

Need for new skills. I believe that as genetic developments lead to improved therapies, practitioners will adapt easily to these new modalities, and will find their treatments and patient relationships substantially enhanced. However, as genetic engineering becomes more complex, implementation will demand that practitioners be trained in—and skilled in—molecular biology, analytical and physical chemistry, and computer science. Acquiring these skills will require the technical retraining of practicing dentists, and an entirely new dental specialist—such as dental biogeneticist or dental genetic therapist—could emerge. As the ability to genetically alter the dental structures to resist dental disease increases, coupled with the capacity to mitigate the biological effects of oral etiological agents, dentistry as it is currently practiced could cease to exist.

I believe it is likely that by the middle of the 21st century, practitioners responsible for dental care will have available full computer models of all human genes, their proteins and related somatic interactions. As a result, therapy will be gene-based and genetically developed drugs will target, and be effective for, most dental (and most other) diseases. The dental profession then will be able to abandon most of the materials, instruments and techniques currently in use, and patients will enjoy unprecedented levels of dental health. However, despite the far-reaching potential of gene-based therapy, implementation is replete with ethical, legal and moral difficulties that society in general and the dental profession in particular must address.

Privacy and confidentiality. As technological progress makes genetic testing and screening readily available, treating physicians and dentists will obtain, use, store and maintain comprehensive and personal genetic information. Some of these data will be sensitive and ethical questions arise. How must access to this information be controlled? Should a practitioner inform an asymptomatic patient if testing reveals a genetic predisposition to a disease for which there is no treatment? Should the government control personal genetic information and release that information to health professionals only on a need-to-know basis?

Distributive justice. The initial costs associated with genetic engineering could be substantial, but should moderate as technology improves. Nevertheless, personal genetic analysis and treatment always will have associated costs for the patient. Should gene-based care be available only to the wealthy? If cures for such devastating diseases as cancer, heart disease, Alzheimer’s and mental illness become available, how can society deny access on the basis of financial status? Because dental disease usually does not entail such dire consequences, will the development of therapeutic procedures be unnecessarily delayed?

Professional imperatives. To maintain dentistry as a profession, current practitioners will need to make a major effort to acquire new competencies. After faculty members are retrained, dental schools will have to undertake major revisions of both didactic and clinical curricula. This transition will be especially difficult, as instruction in both old and new technologies will be required. What are the consequences of failing to adjust? How soon should the process be initiated?

	CONCLUSION

TOP ABSTRACT THE GENOME THE PROTEOME 21ST-CENTURY DENTISTRY CHALLENGES CONCLUSION REFERENCES

 
Just as harnessing steam in the 19th century fueled industrial growth, and controlling electrical energy heralded the modern world of the 20th century, deciphering and interpreting the genome of humans and all other living organisms is, in my opinion, the seminal event of the 21st century.

Armed with this knowledge, molecular biologists will be able to understand and adjust chromosomal function to create optimal cellular performance. Dentistry will be affected profoundly, as current materials and methods are abandoned in favor of emerging bioengineered technologies for disease prevention, tissue repair and disease resistance. However, the transition will be difficult as ethical, legal and moral issues arise. The dental profession faces the challenge of addressing and resolving these concerns.

View larger version (84K): [in this window] [in a new window]   Dr. Yeager is retired from his general dentistry practice. Address reprint requests to Dr. Yeager, 33 Park Gate Drive, Edison, N.J. 08820, e-mail "alyeager{at}aol.com".