Dental Implications of the Human Genome Project

Dr. Marks stared at the new patient sitting in the dental chair. Did she just ask if she could have a genetic test for periodontal disease like one she read about on the Internet?

"Repeat the question please" he asked, carefully adjusting his stool, stalling to think up an intelligent response.

The Human Genome Project, now in its second decade of mapping discoveries, has brought dentistry gifts and curses. With researchers identifying about 300 known dental genes thus far and about 1,000 diseases and disorders with major orodental complications, comes the gift of knowledge. The curses soon follow, however, as dentists realize there is no treatment yet for almost all of the problematic genes. To match the sometimes ominous results of sophisticated genetic screening tests, all dentists have are standard therapies: a scaler, a chip soaked with medicine, a graft.

It is a humbling realization.

Meanwhile, a news story on a study released by the Pew Internet and American Life Project at the end of 2000 found that "more Americans surfing the Internet look for medical information than for sports scores, stock quotes, or online shopping bargains."

In fact, 55 percent of 12,000 people surveyed went online for health information once per month. Dentists, often so bogged down in paperwork they have no time to search the Internet, may be shocked to find that their patients are sometimes better informed on the latest dental discoveries than they are.

The global scientific and health care community’s wonderment continues as genetic discoveries affecting health make the news headlines each week. What the new cloning capabilities mean to medicine and dentistry is that the Human Genome Project is advancing science so rapidly that the production of new biochemical substances, tissues, and entire organs will be taken to new heights.

Xenograft tissue from animals? No problem.

Exograft tissue from a patient’s own body, grown in a dish and reimplanted? No problem.

DNA Diagram. Courtesy of the Human Genome Program, http://www.ornl.gov/hgmis

Disease prevention and delay, diagnosis, and treatment are advancing daily with mapping sequences being added to one of several public gene banks 24 hours a day by genome project international researchers. Investigators continuously tap the gene banks to hunt for genes that will advance their research or lead to a worthy patent.

As genetic discoveries affecting dentistry continue to emerge in the next few years, they will no doubt radically alter some of the basic concepts of disease and its management as taught in dental schools.

This article contains interviews with top government, academic, and industry experts on dental genetics to profile what is known about the science, legal, ethical, insurance, and clinical aspects of genetics in dentistry. Dental school and continuing education, privacy, and future therapeutic issues are addressed with an emphasis on how patients’ genetics are just now beginning to affect the dental practice.

The DNA Panel

If one could peer into a crystal ball, the future dental practice would look quite the same. But some of the tests administered by dentists, and eventually the treatments given, would be markedly different.

Arthur Curley, JD, a San Francisco attorney and an assistant professor at the University of the Pacific School of Dentistry, specializing in medical, health, and dental law, believes that dentists will soon offer blood tests to assess if a disease status is under control. "Instant blood tests for blood sugar levels in diabetics, dilantin levels in epileptics, etc., will become the standard of care; and failure to at least recommend such tests will be malpractice." Then, as DNA testing becomes cheap and easy, Curley said, dentists may start to offer them to take potential-disease inventories. Key among the new tests will be an assay panel that uses cheek swabs, saliva, or crevicular fluid to screen patients for all known genetic dental disease susceptibilities.

Dentists may eventually offer tests for all known medical disease susceptibilities.

Affymetrix, in Santa Clara, Calif., is one of the better-known biotech companies that develops and commercializes systems that enable researchers to create, acquire, analyze, and manage complex genetic information. Affymetrix’ DNA array technology identifies thousands of genes simultaneously using a DNA chip. Its technology is designed to capture the unique gene expression patterns and polymorphic variants of a person’s genome (gene map).

The chip is a DNA affinity test. In simple terms, DNA sequences are combined with a computer chip. The subject’s DNA sample is bathed over the chip. The subject’s complementary DNA binds to the chip, indicating how similar the subject’s DNA is to the chip’s representative mutated and standard DNA sequences. The DNA that binds is identified by software, and the result indicates the subject’s variations from and affinity with standard and mutated DNA. More than 12,000 genes fit on one chip. This information may correlate with specific diseases and therapeutic responses that could be critical knowledge for managing a disease and prescribing the right drugs -- "pharmacogenomics."

With pharmaceutical companies profiting significantly by advertising directly to consumers, they are driving the explosive development of pharmacogenomics. In dental practices, which prescribe mostly antibiotics and pain medications, the benefits will likely come in the package of genetically tailored pain medicines. This is because patients’ genes alter their response to pain. In contrast, resistance to antibiotics is more a function of bacterial genetics, not human genetics. Lawrence Tabak, DDS, PhD, director of the National Institute of Dental and Craniofacial Research, said "Genetic tests will also increasingly be used to identify individual predictors of drug response so that effective therapies can be prescribed sooner, potentially toxic side effects avoided, and diseases more effectively and economically managed."

Affymetrix offers a scanner for electronically recording which gene sequences were found on the DNA chip, along with the software to analyze and manage that information. Mutations, alone and when combined with varied drug regimens, can be analyzed by computer to one day ascertain certain predictable health outcomes -- information physicians, dentists, insurers, employers, and potential spouses may want to know.

But does the individual want to know?

Will Patients Want To Know?

The general public, including dental patients, are divided as to whether they want to know their genetic predisposition for diseases and disorders.

When it comes to a genetic basis for periodontal disease, Interleukin Genetics did some market research and reported more than 90 percent of patients surveyed would want to know the information "if their dentist said it would be useful."

Other sources report that a greater percentage of people are fearful of knowing what invisible diseases silently lurk beneath their skin.

Harold Slavkin, DDS, PhD, former director of the NIDCR and current dean of the University of Southern California School of Dentistry, said that "denial" is an important human mechanism for coping with life, nonetheless "each of us can use denial or choose to live through information and knowledge."

A recent American Medical Association survey and other researchers have found that about half of patients want to know their genetic risk factors. Genes for diseases that cannot yet be cured, such as cancer and Alzheimer’s, may be information in the "I don’t want to know" category.

Tests for genes linked with more cosmetic and controllable diseases may be more amenable to patients’ psyches, and therefore may experience more demand.

Dentistry’s Only Genetic Test

When it comes to dentistry, the only genetic test available is the PST Genetic Susceptibility Test for Periodontal Disease. The company holding the polymorphism’s patent -- and those for several other systemic diseases -- Interleukin Genetics in Waltham, Mass., made the PST test available for dental research and clinical use in 1997, the same year Dolly the sheep was cloned. More than 7,000 PST tests have been processed.

Ken Kornman, DDS, PhD, of Newton, Mass., is one of the early investigators studying the specific interleukin-1 (IL-1) genetic marker associated with periodontal disease for which the test checks. According to Kornman, the chief scientific officer and co-founder of Interleukin Genetics and a professor of microbiology at the University of Texas Health Science Center, the test doesn’t determine whether a patient has periodontal disease but whether he or she has a gene mutation that increases the risk for advanced periodontal disease and the chance of losing teeth. The PST screens for two polymorphisms in the genes for IL-alpha and IL-beta that regulate the activity of the cytokine IL-1. IL-1 is involved in the control of inflammation and immune response in various spots in the body. For PST’s purposes, the focus is on periodontal disease.

The benefits and limitations of finding one’s PST status are subject to debate.

Michael McGuire, DDS, of Houston, is the president of the American Academy of Periodontology. He has performed research for Interleukin Genetics by using the PST test in his periodontal practice. McGuire said the test’s usefulness lies in its capability to identify patients who have a polymorphism that causes their body to over produce IL-1. IL-1, which the body normally produces to help destroy microbes in response to a bacterial challenge, is fine in normal amounts. Overproducers of IL-1, however, have excessive inflammation that appears to result in destruction of bone and connective tissues in the periodontium. Those with IL-1 are almost three times more likely to lose teeth than someone who is IL-1 negative, according to McGuire. Although initially offered as a finger-prick blood test, testing now involves taking a cheek swab and mailing it to a lab. One week later, the results arrive and the patient is given the news: positive or negative status.

The genetic marker for periodontal disease can influence tooth loss.

"If I have the gene for periodontal disease, I want to know because I’m forewarned and forearmed. Perio is preventable so you can take charge," McGuire said.

The "preventable" part indicates that even positive status isn’t a death sentence for patients’ teeth and periodontal health. It just means extra oral care is needed. Tabak is concerned, however, about positive tests leading to exaggerated concern by the patient and being used to support unnecessary interventions by dentists. Likewise, "Inconclusive tests can result in a false sense of security in some patients. Negative results may be interpreted as a reason to bypass needed procedures," Tabak said.

The limits of the PST test lie in its scope: Only 30 percent of diseased patients are PST positive. But the remainder can still get severe periodontal disease, just as those who are positive can remain disease-free for their lifetime.

Another percentage cited comes from a November 2000 study in the Journal of Periodontology by John Gunsolley, DDS, MS, and colleagues on periodontal health and genetic risk in identical and fraternal twins. The investigators found that approximately half of the variance in periodontal disease can be attributed to genetic differences.

Not only is periodontal disease multifactorial, but researchers admit that a number of genes may affect susceptibility -- and all these factors may differ among races and ethnicities.

The genetic marker for perio works in concert with other risk factors.

"Periodontal disease is a lot like heart disease: It depends on risk factors. For heart disease, it’s cholesterol, weight, smoking, exercise, family history. It’s similar in periodontal disease, where bacteria is the cause and two major risk factors are genetics and smoking. Secondary risk factors -- amplifiers -- are stress, systemic diseases, hygiene and care, and medications," McGuire explained.

Researchers of dental disease and genetics have been known to recite: "Like no bug is an island, not every polymorphism is an island." Ken Kornman commented on the saying by connecting bacterial tests for P. Gingivalis and the genetic test for perio: "Many dentists use the PST test (prognostic) together with microbiological testing (diagnostic) to get a more complete picture of the current status and future risk for disease progression."

Meanwhile, there is less genetic research being performed to pursue a "caries gene" than periodontal genes. Caries is often seen in people with certain gene-based disorder’s such as Sjogren’s syndrome. Researchers are debating the role of the host’s gene-related systemic immune response in caries. One rat study showed a 50 percent genetic link to caries. Yet, most scientists believe caries -- more preventable than periodontal disease -- is related more to virulent bacteria than genetic variation in the pathogens and their hosts. Because it is a controllable oral disease perceived by most to have little systemic consequence, the commercialization potential needed to fund the exploration for a genetic link is not as strong as it is for other diseases.

Slavkin has often stated that every disease and condition except trauma or physical accidents has a major genetic component -- although not necessarily a causative component. Everyone interviewed for this article agrees that diseases are multifactorial, and the genetic component is far from being the sole predictive card in the deck.

In McGuire’s opinion, the PST test’s advantage lies in its capability to help clinicians make treatment decisions about whether to maintain or extract a questionable tooth. For general practitioners, the result may tip the scales as to whether to refer a case to a periodontist. In addition, McGuire claims positive PST status can be likened to the "proof" an intraoral camera produces. Not only is it good for case acceptance, it can work as a motivational tool for some patients who reportedly practice extra vigilant hygiene once they learn the "bad news" of their predisposition to gum disease. Yet, some studies find compliance with doctor-prescribed pharmaceuticals for even serious diseases hovers at 50 percent. So, when no one quite understands why an elderly patient won’t consistently take his high blood pressure pills, how can a dentist be sure the PST-positive periodontitis patient will floss?

Skeptics say a patient’s PST status is a moot point, even "information overload," as it doesn’t change the treatment plan, which is often aggressive for all patients with advanced perio disease. To that line of thinking, the test’s proponents counter that they prefer a conservative approach using individualized treatment.

"I’m against overtreatment," McGuire commented.

Michael Lynch, DMD, PhD, from the Council on Scientific Affairs at the American Dental Association, wants dentists to temper their zeal for dentistry’s first genetic test. "It has limited value in that it tells us when a nonsmoker has slightly more risk," Lynch cautioned, adding that dentists should not think of it as a stand-alone tool for predicting periodontal disease.

"A lot of health problems are not the result of one deficiency, but a complex of genes," Lynch said. "There’s a lot of overlap that builds in compensation. Except for the extreme cases of single-gene diseases, one genetic deficiency isn’t going to be enough to create a problem."

NIDCR’s Tabak said he has some concern about premature integration of genetic testing in the dental practice. Before validity and utility are strongly established and providers have adequate knowledge of genetics, there are risks of genetic testing for dental, oral, and craniofacial susceptibilities, just as there are for breast and colon cancer, diabetes, and heart disease. "This can lead to exaggerations about the prognostic and therapeutic implications of testing," Tabak explained.

For a fairly innocuous genetic periodontal disease test, the insurance industry is certainly sitting up and taking notice.

Impact on Insurance and Benefits

A positive genetic test result for significant systemic disease, even in those who are presymptomatic, has the potential to interfere with the ability to obtain or keep health insurance or a job. Tabak agreed: "There are federal laws and laws in some states that provide some protection against genetic discrimination, but no law covers every individual in every situation."

Carriers of the perio genetic marker can face more serious disease progression.

The screening test for the hereditary Huntington’s gene was approved for use in 2000 for assessing risk and setting premiums by British life and health insurers. Standard diagnostic tests for seven diseases -- including Alzheimer’s and breast cancer -- are already used. The Huntington’s ruling, however, paves the way for using genetic tests for insurance consideration -- something Americans fear will eventually be adopted in the states. Especially worrisome is the idea than genetic liabilities may overshadow one’s current health, no matter how robust. U.S. governmental health agencies and insurers are watching the situation overseas closely. Individuals will not be asked to have a genetic test before obtaining insurance, but if they have already been tested, the data that cannot be hidden from insurance companies asking for a health history. There is speculation as to whether this will discourage people from getting tested to learn their genetic susceptibilities, which in turn will prevent them from seeking treatment or changing health habits.

In the United States, the Medical Information Bureau provides information to its members that was provided to them from insurance companies to whom people have availed their medical liabilities. A spokesperson for the bureau said they do not have codes for genetic susceptibilities. They would not, however, indicate if they would refuse receipt of genetic test results or gene-based disease data if acquired indirectly.

The bureau does not collect dental information. In fact, because dental disease isn’t as costly for insurers as, say, diabetes, there may never be a national database of oral health status from which dental patients would need to hide their positive PST test results. No doubt dental insurers are keeping their own files on their members’ claims so it is uncertain what could evolve in the future.

Howard Bailit, DMD, PhD, professor and director of the Health Policy and Primary Care Research Center, School of Medicine, University of Connecticut Health Center, has a lot of experience in this area. He’s also a research associate at the Sloan Managed Care Industry Center at Harvard and a former Aetna Health Plans vice president for medical policies and programs.

Almost all employer-based dental insurance is sold as a group policy without underwriting at the individual member level, according to Bailit. So actuaries wouldn’t access the genetic susceptibility of individuals unless the group being underwritten is small, such as in dental offices where there may be 10 or fewer employees. In that case, as with individual dental insurance policies, "Data on genetic susceptibility could be used to influence rates charged, unless state law prevents the use of this information by insurers," Bailit said.

Because PST positive status does not "strongly link" the patient to periodontal disease susceptibility just yet, according to Bailit, it will not influence rate setting.

Of course, insurance companies always leave open their options for why and when and how much they can raise premiums.

Dental insurers so far are not interested in picking up the $120 tab for the PST test, because employers aren’t interested in higher premiums. A state law mandating coverage of genetic tests would be the only thing to get them interested.

Most people in the dental insurance industry agree than a strong argument can be made for managing (approving/denying) treatments on the basis of a patient’s risk for disease. So far, when it comes to caries, insurers are intrigued by the idea of controls or limits on procedures based on degree of risk. Bailit thinks genetic risk would be even more difficult, "That type of benefit program would be very difficult to market and impossible to administer."

In fact, the dental insurance industry doesn’t know what to make of the new PST test. The test’s manufacturer says PST positive status is correlated with increased risk of future tooth loss, but the insurance industry says this doesn’t mean the PST has "positive predictive value." One insurance group agreed to join the PST’s manufacturer to sponsor a study to gather more data on the PST test.

Michael del Aguila, MS, PhD, is an epidemiologist and director of outcomes assessment for Washington Dental Service, a member of the Delta Dental Plans Association. He is sponsoring the research being performed at the University of Washington School of Dentistry to quantify the relationship between PST genotype status and utilization of dental services by patients in a dental plan. Insurers such as the Washington Dental Service want to target resources appropriately. If the evidence demonstrates that those who are PST positive are more likely to use periodontal dental services, they can receive earlier coverage for services that may slow the progression of the disease. This in turn could minimize more costly complications due to advanced disease (bridges, partials, dentures, implants) and contribute to improved oral quality of life for patients.

"We want to know the total cost and treatment over time of those with PST positive vs. negative status. If it has value in letting dentists know which patients will need care in the future, why not authorize and provide treatment now?" del Aguila asked.

The study began a year ago and has faced challenges recruiting patients. del Aguila didn’t speculate as to the reason behind the reluctance of subjects who declined participation. It may have been inadequate compensation for their level of effort. Or perhaps they did not trust how a dental insurance company would use the information.

The study has currently been reconfigured to take advantages of changes in collection of the PST (cheek swabs vs. fingerprick) that allow patients to perform it in their own homes.

Privacy and Ethical Issues

Seven out of 10 Americans are concerned about their employers or insurance companies accessing their genetic information and using it against them, according to a 1998 American Medical News article.

The National Human Genome Research Institute reports that 90 percent of people it surveyed think employers should be prohibited from obtaining employees’ genetic data, and 60 percent said they won’t take a genetic test if they think employers and insurers can access the results.

Federal employees in 2000 were protected by an Executive Order signed by President Clinton; however, a Patients’ Bill of Rights Act with protection against genetic discrimination is needed. State legislation is pending across the country and has passed in 23 states to enhance patients’ rights and protections. But Americans have a responsibility to keep informed as to how to protect their privacy and voice their concerns about the vulnerability of their medical data to their legislative representatives.

The Human Genome Project itself does not pose ethical dilemmas, but use of its findings will.

Slavkin favors the following analogy: "Like the Periodic Table of Elements from the 19th century, the Human Genome Project is without values per se, but raises profound ethical issues regarding the uses of this knowledge base."

Online Health Histories

In fact, companies are mining the Genome Project’s draft map of a human being for genes and their polymorphic errors or variations as you read this. From it they develop tests using organisms like yeast and lab animals, and sometimes plan to put them through clinical trials on humans.

Dentists one day may offer or even recommend patients take tests that go well beyond dental diseases. Patients may come into the office already having taken such a test at another medical or dental office and know the full spectrum of their health-related susceptibilities.

In 2010, a "Dr. Marks" may see a new 15-year-old dental patient, Sophia, who made her appointment via the Internet. Sophia tells Dr. Marks she has the gene for juvenile onset periodontal disease, not to mention alcoholism, "which means I have to stop at two drinks, or else" she opines, sighing with adolescent drama. Dr. Marks asks if she brought her history on a card or does he need to retrieve it. Sophia, like all Americans, has her certified DNA map stored on an electronically secure site, with portions she can make accessible to her health care providers or potential insurers via a changeable password. However, after reading about full-site hackings using passwords, she decided to bring Dr. Marks her medical and dental history and genetic data on a portable health card with a computer chip. In any case, neither source will allow copying or a printout for security and legal purposes, though reports of bypassing technology surface.

Although a recent survey by the Pew Internet and American Life Project confirmed that in the year 2000, 63 percent of Americans were opposed to keeping their medical records online even with a password-protected site for fear others would see it, expediency will trump public opinion. History is our teacher -- remember when one’s social security number was forbidden to be used as personal identification for any reason except for its express purpose? Today, Americans’ formerly secret social security numbers are used for credit cards, bank account passwords, and appear on most drivers’ licenses, even on personal checks handed to the pizza delivery guy.

Stanley Surabian, DDS, JD, is chief of Dental Services for Community Medical Centers, and Program Director of the General Practice Residency in Dentistry program at University Medical Center in Fresno, Calif. Surabian said he has noticed a trend in a loosening of privacy safeguarding, "Our nation became diverted from the limitation for widespread generalized use of the social security number. Who knows what could happen with genetic data?"

Slavkin has some idea, "The military are advanced in using genotype for identification on microchips," he said.

Attorney Curley has this vision of the future: "A patient will issue their medical record authorization code and the doctor’s computer will access the entire medical history of the patient stored on the Internet. The dentist’s office will have a ‘smart program’ that will filter the information with dental issue priorities and alert the doctor to any significant issues to review, or order up prior test results and digital images -- also stored on the net."

In years to come, dentists will not only request a patient’s full health history, complete with molecular data, but that of the patient’s family members (at least as it applies to oral health). Genetic susceptibilities for conditions such as oral cancer and periodontitis may be information shared among family members. If a sibling knows his brother has the oral cancer gene, he’ll have the opportunity to get tested, quit chewing smokeless tobacco, and pursue individualized gene therapy treatment, which will increasingly be made available for such conditions.

The National Coalition for Health Professional Education in Genetics is developing a tool for eliciting a comprehensive, multigenerational family history. Once it is finished, NIDCR -- a member of the coalition -- may help adapt it and disseminate it to dentists.

A patient’s own and familial oral and general health histories will be integrated information for "disease management" -- a term popping up lately almost as often as "evidence-based dentistry." Disease management involves the coordinated prevention or delay of a particular disease, early and more accurate diagnosis, treatment planning, and outcome prediction to reduce costs and improve outcomes.

More and more, health care providers will be making judgments about genetic test results. Computer programs may even be created that assign weights to risk factors (including genes and home hygiene pattern), disease, treatment, therapy administered, and genetic reception to that therapy. The software will crunch the numbers and output a percentage of the patient’s teeth predicted to be retained at different ages. It should not be surprising if the insurance industry pursues this technology.

Dental Geneticists

Gene therapy is in its infancy -- mostly in animal research -- and is not an established mainline clinical modality.

Lynch of the ADA envisions that gene therapy will be used only when significant morbidity and mortality is involved. "Periodontal disease is not on the radar for that," he theorized. Likewise, he doubts that a dental genetic specialty organization would be able to obtain recognized dental specialty status.

Other dental scientists and researchers disagree.

Tabak admitted that current research on genetic therapy in dentistry is limited to animals. In fact, he said he cannot speculate about when and where the pioneering research of gene therapy for dental disease will occur on humans. He does, however, believe it is just a matter of time.

"The Human Genome Project will identify the players in the complex cascade of gene activation and deactivation involved in tissue repair and that encode proteins that endow cells with key functions," Tabak predicted. He named candidates for periodontal disease thus far as polymorphisms in the IL-1, IL-10, TNF-alpha and cathepsin C gene; and in the cell receptors for IgG and vitamin D and the HLA marker. Genes responsible for defective tooth enamel formation, decreased salivary gland function, and immune dysfunction and others are associated with caries.

After all the players are determined in the next few years, researchers can study how to modulate the cascade to enhance healing in reconstructive surgery, change function, and more.

Tabak, for one, is comfortable using the term "dental geneticists" to describe dental researchers who have received advanced training in genetics and pursue genetic research for dental applications. Likewise, he thinks there may also be geneticists with special knowledge of oral health. "They will conduct basic and epidemiological research on the genetic underpinnings of dental, oral, and craniofacial conditions. In the clinic, they will consult on the dental and oral manifestations of craniofacial conditions or rare systemic diseases that require more specialized genetics expertise than that required of a general dentist."

Tabak noted that although there are craniofacial genetics courses, he is not aware of a set course of study for dental students who wish to become dental geneticists. However, NIDCR has an interest in furthering genetics education in dentistry, so it, as well as other NIH institutions, recently announced their involvement in the Ethical Legal and Social Implications of Human Genetics and Genomic Research Education Grant Program. Applications will be accepted by NIDCR from for-profit and non-profit public or private organizations and agencies. Activities eligible for funding include developing courses, conferences, and curriculum and many other means for improving professional and lay understanding about genetics, related technology, and its ethical, legal and social implications. Schools and organizations interested in applying for a grant can contact the NIDCR’s Office of Training and Career Development, Division of Extramural Research (Dr. James Lipton, assistant director of the office, can be reached at [301] 594-2618 or James_Lipton@nih.gov).

Dental researchers are working at a breakneck pace to study not only genetic susceptibilities, but also pharmacogenetics and tissue engineering/biomimetics in vitro and in vivo. They’ll also study cell cloning, which will one day become commonplace to generate and replace defective or aging organs and tissues. This technology is much like that of physicians in the news recently who soon plan to try repairing weakly pumping hearts in patients who have had congestive heart failure using new muscle and blood vessel fashioned from the patient’s own cells.

Bruce Baum, DMD, PhD, chief of the NIDCR’s Gene Therapy and Therapeutics Branch, said the dentist as gene therapist is not only possible, but will be reality for today’s dental students by the time they reach their "midpractice lifetime." His research in gene transfer technology and the regulation of salivary gland secretion is widely published. It was only natural when he questioned the need for therapeutically injecting genetically engineered proteins (current method) when the same therapy could be less costly and more easily performed using one of the body’s built-in, slow-release pumps: the salivary gland. In his research on laboratory animals, he has proved his theory and already transferred therapeutic genes to salivary glands with good results. He has used this approach to repair irradiation-damaged salivary glands, as well as kill an azole-resistant Candida species using a therapeutic course of gene expression (10 to 14 days). He’s also used this transfer route to deliver genes for therapeutic proteins for endocrine secretion. The glands then can produce and secrete "transgene-encoded proteins" systemically so that they circulate in the bloodstream to treat certain single-protein deficiency diseases such as human growth hormone deficiency or hemophilia. Baum hopes to begin to use his findings in human trials within two years.

If salivary gland gene transfer proves highly efficient and effective, not only for oral disease but also as a modality for therapeutic gene transfer for systemic disease in humans, the possibility of dentists administering gene therapy for health purposes beyond the oral cavity is real.

Slavkin used Baum’s work as an example to explain the mechanics for one method of delivering gene-mediated therapy for local or systemic benefit. Besides injection into the salivary glands, genes can be injected into the mucosa, gingivae, tongue and musculature. They can also be inhaled through oral and nasal mucosa.

Explained Slavkin: "The ‘gene’ is delivered as ‘naked’ DNA or encased in a viral vector (carrier) that has the facility to bind cell surfaces and become engulfed or absorbed or phagocytosized by normal cellular processes. The gene delivery has often been developed to mimic the ways that viruses invade cells; adenoviruses are superb at entering oral and nasal cells."

Safety of Gene Therapy

Genetic researchers have found adenoviruses are the best vectors for testing therapeutic genes, although they pose problems for long-term use. In his work with salivary glands, Baum considers safety concerns the priority.

In 1999, Jesse Gelsinger, an 18-year-old student at the University of Pennsylvania died from a toxic reaction four days after starting experimental gene therapy treatment. His liver had been injected with virus-bearing genes to correct his genetic liver disorder. Ever since gene therapy’s first casualty, safety questions have dogged researchers. The university reported to the Food and Drug Administration that procedural errors were made, but the event could not have been anticipated. Still, the program was temporarily halted, and federal and Congressional scrutiny has begun in the fledgling field. The fact that during adenoviral manufacture contamination with HIV and hepatitis C viruses is a possibility -- albeit rare -- in itself draws attention.

Slavkin sees the accident this way: "In important clinical research, people can die and do die. In the case of the teenager in Pennsylvania, all accounts indicate poor handling of the clinical protocol and the health of the teenager as well as failure to provide informed consent to the parents. This tragedy could have been avoided in the specifics. Meanwhile, adverse effects do appear in clinical trials. and the public needs to understand that clinical trials for life-threatening diseases do have risks."

For now, whatever tinkering is done to therapeutically alter human genes cannot be passed on to our offspring.

Slavkin explained that humans consist of somatic cells and germ cells. "Germ cells are only found in gonads (ovaries and testicles). Everything else is made of somatic cells, and each somatic cell contains the same human genome encased in 23 pairs of chromosomes. Gene-mediated therapy can be performed in germ as well as somatic cells. Modifications to somatic cells are not inherited. The gene-mediation may last for days or weeks, or could last for a lifetime if inserted in to stem cells. Federal guidelines today limit therapy to somatic cells," Slavkin said.

There is comfort in knowing if therapy for a potential problem linked to a polymorphism is botched or if unwanted side effects emerge, the gene therapist should be able to switch off the gene or perform therapy with the opposite effect to reverse course -- even if it was to be a "permanent change" to stem-type somatic cells. But even if it is a permanent change that for some reason cannot fully be undone, at least it will not be passed onto children. Restrictions to prohibit germ cell genetic research exist in every country.

Integrating With Medicine

In the era of biodentistry, the future model of the dental practice is being debated. Parts of dentistry will probably overlap with medicine, as they do now.

DNA variations vary in their effect on the human body.
Courtesy of the Human Genome Program, http://www.ornl.gov/hgmis

For example, a patient calling his doctor’s office to describe a classic blocked salivary gland beneath the tongue is scheduled to see the physician, who then refers to an ear, nose, and throat specialist. Why isn’t the nurse taking the patient’s call instructed to direct the patient to a doctor of dental medicine, who would have more appropriate judgment and could refer to an oral surgeon if need be? These apparent "turf wars" and separate territories will continue if something doesn’t change.

Many think that dental practices that offer genetic testing for a host of systemic diseases beyond oral diseases will be "networked" with genetic counseling and treatment. Perhaps general dentists will still be solo or group practitioners who refer to specialists. Or maybe dentists will become part of a broader group health model -- the multidisciplinary health clinic owned by one health care system that offers a full range of services: medical, nursing, dental, podiatric, ophthalmic, obstetric/embryology, pediatric, audiology, oncology, etc. At such a site, genetic tests for every aspect of human health will be offered with genetic and psychological counseling as well. The idea is to provide a full-spectrum of health care providers within close proximity to more easily treat the patient along a seamless continuum of care.

Dentists are not currently trained to do any genetic counseling, let alone handle counseling patients given test results that they believe lessen their quality of life or shorten their lifespans. In fact, in a 1998 study on providing genetic test results reported in a Journal of the American Medical Association article, only 1 in 5 patients received the appropriate genetic counseling to accompany test results positive for genetic risk of cancer.

If dentistry doesn’t begin carving out a niche in genetics, medicine will claim it.

"The oral health professions, government, and industry need to work together to make this a reality or it will flower in a medical specialty area such at ENT or pediatrics," Slavkin said.

Genetics Curriculum

In a New England Journal of Medicine report a few years ago, physicians had misinterpreted one-third of predictive test results for colon cancer. Physicians need more genetic training and so do dentists.

The first basic genetic course anyone can recall being offered in a dental school was back in the early ’90s. It is a decade later, and not every dental school offers a genetics course. In fact, it is barely mentioned in many dental schools and not at all in most large dental meetings where continuing education courses are held.

Rachel Morrissey, manager of education and institutional surveys at the American Dental Association Survey Center, reported that she collects information from all dental schools on how many clock hours they spend on basic science and clinical science.

"We have a graph with different disciplines within basic science. Twelve categories are represented, and except for ‘other,’ genetics is the least taught of all disciplines, and physiology is the most," Morrissey said.

In the 1997-98 academic year, 42 of 55 dental schools surveyed covered "some genetics." During four years of dental school, the high was 110 clock hours by Harvard School of Dental Medicine, the low was one clock hour by the University of Texas Health Science Center at San Antonio Dental School. The mean average number of clock hours of genetics taught during dental school for all schools is 13.4 hours.

The Survey Center recently surveyed dental schools again. When the results are released later this year, it will be interesting to see if genetics is taught in more schools and covered more thoroughly.

In an encouraging estimate, Slavkin speculated that NIH and industry grant support indicates to him that about one-quarter of dental schools have been involved in some molecular genetic research.

Dental organizations have been publishing genetics research articles but have yet to produce any consensus statements or patient education materials on genetic testing.

Both dental schools and professional societies must play a central role in educating the nation’s dental and oral hygiene professionals on their role in how best to utilize the applications of advancing genetic research and in providing related services, according to Tabak.

"Every attempt needs to be made to train faculty and to reform current curricula and licensure examinations" for the next generation of dental health care professionals. At the same time, current dental professionals need education and updates on "the emerging importance, benefits, and risks for their patients of genetic information and gene-based therapies," Tabak said.

The National Coalition for Health Professional Education in Genetics, formed by the AMA in 1996, will soon issue a set of core competencies in genetics that will outline the minimum knowledge, skills, and attitudes necessary for health professionals, including dentists, to provide high-quality care to patients in this era of genetics. A draft landed in the hands of some dental society board members and leaders charged with modifying educational curriculum. Under way are discussions in some schools as to how they could begin assessing their existing genetic offerings and their faculty’s expertise for teaching genetics. These discussions will help determine needs in formulating just how these competencies could be integrated into their curricula.

Baum from NIDCR has stressed for some time the need to introduce the concept of gene therapy -- not just basic genetics -- into the dental curriculum. Baum believes that practitioners could be using the salivary glands for gene transfer as early as 2010.

Molecular Dentistry in the Average Practice

Leaps in science and technology knowledge mean the finished map of the human genome will be completed ahead of schedule. Originally set for 2005, researchers are now saying 2003 is a real possibility. The compounding understanding from each small discovery is flattening out the learning curve for the Human Genome Project’s researchers. What researchers can sequence in one minute today, took 20 minutes three years ago, and a year or more 20 years ago.

Ten years from now, when general dentists encounter cancer patients with damaged salivary glands from irradiation therapy, they may refer the patients to a dental geneticist, or perhaps an oral surgeon or periodontist with special gene transfer education to restore the glands’ function in moving water. Or, they may just do it themselves if they received the proper continuing education.

By 2010, all dentists will know how to interpret genetic test results and their implications that affect oral health, or refer to someone who does in "complicated cases." "Dentists and dental hygienists will need to make informed decisions about the application of new gene-based drugs and therapies, and to understand the psychological, ethical, legal, and social implications related to the use of genetic information and technologies," Tabak said.

Conclusion

This article discussed the changes and challenges in how oral health will soon be managed in the emerging era of genetic dentistry. We are living in a time when cloning -- not long ago dismissed as "science fiction" -- has become a reality. The principle of genetic manipulation to counter cellular aging is yet another vista for research. Our genome -- a genetic thumbprint -- will provide health professionals with the instructions for everything our cell does, from the time we began dividing into a zygote to the day we die. Nothing akin to this has ever graced science in the history of the world. Indeed the most momentous impact of the Human Genome Project upon humankind will probably unfold in ways we can’t begin to imagine.

Sidebars

The Human Genome Project Facts

* A genome is the complete set of genetic instructions carried within a single cell of an organism. In each cell is DNA, which is composed of chemical bases represented by four letters. Determining the order of those bases is "sequencing." That sequencing results in a person’s genome, which will tell health professionals the instructions for everything a patient’s cell does.

* The Human Genome Project was begun in 1990; by June of 2000, the project’s Public Consortium and Celera Genomics announced a working draft of the sequence of the human genome -- 95 percent of the genetic blueprint for a human being is complete. It is 99.9 percent accurate.

* 20 different human genomes have been used for the basic work, and about 1,000 others have been used for annotations and further detail analyses. The largest difference discovered between two people has been 0.1 percent

* Anyone with Internet access can go to three public databases funded by U.S. National Institutes of Health, U.S. Department of Energy, Wellcome Trust in England, and others, to see each deciphered piece of DNA code. 75,000 people from academia, industry and corporations across the globe search this information daily at no charge.

* More than 1,000 scientists from six countries, including the United States, are sequencing the human genome.

* The sequencing effort is tightly coordinated to minimize duplication of effort.

* Data is deposited by scientists into public databases every day, 24 hours a day.

* To sit down and read the amount of information generated by the Human Genome would take 26 years of round-the-clock reading time.

* $3 billion has been funded for 1990-2005; the tab to produce the working draft is $300 million.

* Preliminary benefits of the working draft sequence: thousands of genes and about a million polymorphisms (mutations). For example, the breast cancer susceptibility gene, as well as genes for several other disorders, most fatal; also a leukemia drug that in preliminary trials, appears positive, and gene therapy for Parkinson’s that appears promising in monkeys.

Gene-Linked Diseases With Oral Component

On NIDCR’s site at nidr.nih.gov/cranio/index.html, many of the diseases/disorders with dental, oral, and craniofacial genetic component are listed. Categories include craniofacial birth defects, severe orthognathic disorder, abnormal tooth size and shape, absence of teeth, periodontal diseases, head and neck cancers, salivary gland disorders, TMJ diseases and disorders, osteoarthritis, osteoporosis, and chronic facial pain.

Fact: Every hour in the United State, a baby is born with a genetic craniofacial defect (1 in 700 live births).

Genetic Web Sites

* The National Human Genome Research Institute: www.nhgri.nih.gov/ (source for how many genes are mapped thus far)

*NICDR: nidr.nih.gov

*GenBank: www.ncbi.nlm.nih.gov/Genbank/GenbankOverview.html

*Links of some useful resources for human genome data searches, Human Genome Central: www.ensembl.org/genome/central

*Interleukin Genetics: ilgenetics.com

*Human Genome news: www.ornl.gov/hgmis

*Ethical, legal, and social implications of genome research on privacy/confidentiality: http://www.ornl.gov/hgmis/elsi/elsi.html

*American Society of Human Genetics: www.faseb.org/genetics

*National Coalition for Health Professional Education in Genetics: www.nchpeg.org