Realizing the genetic potential
By Cathy Areu-Jones
With the recent advancements in genetic research-namely
those of the Human Genome Project-the question is being asked: How will all of
this affect dentistry? The answer is, completely.
According to researchers throughout the country,
genetics could entirely change everyday dental practice. One day, for example,
dentists may be able to grow teeth, engineer salivary gland tissues, conduct
genetic testing for periodontal disease susceptibility, and more.
Is this science fiction? No. In fact, some of these
projections are not too far off, and some are already a reality in laboratories.
So, the question dentists must ask is, "When will the recent advancements
in genetic research affect dentistry?"
The Human Genome Project
"The fact is that every human disease, with the
exception of trauma, is caused by a gene-a defect in the gene. Any disease. And
that applies to dental diseases as well," explains Rene D’Souza, DDS,
associate professor in the department of orthodontics at the University of Texas
(UT) Houston Dental Branch. "Everything we deal with has a genetic
basis."
To relate to Dr. D'Sousa's excitement over genetics,
one must go back to basics. The human genome, which is the complete set of
instructions for constructing all living organisms, is estimated to comprise
approximately 50,000 genes-most of which, until now, had not been identified.
Genes are the units of a DNA molecule that contain the organism's code for a
specific function. DNA (deoxyribonucleic acid) carries genetic information
necessary for the replication of cells and for the production of proteins. The
human genetic code is the language in which DNA's instructions are written.
In 1990, the internationally funded Human Genome
Project began to map and sequence the human genetic code. In June 2000, to the
science world's surprise, the international scientific group and a private
biotechnology company, Celera Genomics Inc., Rockville, Maryland, announced that
they had sequenced a rough draft of the entire human genetic code. It marked one
of the biggest advances in genetics.
With the deluge of data and related technologies
generated by the Human Genome Project, scientists can now identify thousands of
genes.
"The Human Genome Project is going to
revolutionize and already has begun to change the shape of medicine," says
Dr. D’Souza.
Genetics and dentistry
The implications of DNA mapping for dentistry are
profound, according to Max Anderson, DDS, co-chairperson of the quality and
outcomes task force for Delta Dental Plans Association and a speaker on the
application of science in the prevention of dental diseases.
"The same technology used to map the human genome
is being used to map the genomes of the major pathogens of human kind," Dr.
Anderson explains. "This includes the mapping of the genome for
Streptococcus mutans-the bacterium that causes dental cavities-and for the major
periodontal pathogens. Mapping these along with the human genome will give us
incredible opportunities to defeat these two diseases in our lifetime."
Dr. D’Souza explains, "If you know the genes
that are necessary for normal development, then you can develop therapies, which
are called designer drug therapies, that are aimed at one area of the gene or
the other." These designer drugs will be safer than today's medicines
because they would only affect the defect in the gene, clearly identified
through genetic research. "You look to see if the gene is abnormal. If it
is, you can do preventive things to avoid it."
Designer drugs for preventing cavities and periodontal
disease-as well as for other oral, dental and craniofacial conditions-may be
available within the next decade. The drugs will be delivered locally and in a
more efficient way.
For now, there is one test, Interleuken 1, commercially
available for testing periodontal susceptibility.
"We're doing some studies right now to determine
whether it's cost effective to cover this test right now," says Dr.
Anderson. "In other words, does the test give the dentist sufficient
information with which to alter a treatment plan so that he can alter the course
of the disease?"
Changing terminologies
Genomic medicine, which is the application of personal
genetic information to medicine bringing about more accurate diagnoses and
treatments, will also help identify a patient's genetic profile and allow the
dentist to prescribe the best available drug therapy from day one. Dentists will
be able to customize treatments according to each patient's genetic
profile-choosing a drug custom-designed to match an individual's needs, and
providing for more accurate dosing based on an individual's metabolism instead
of traditional methods like weight and age.
With the emergence of genomic medicine in everyday
dental practice, Dr. Anderson predicts that dentists may need to practice only
cosmetic- and trauma-related dentistry. After all, dentistry's primary diseases
would be well controlled and treated, allowing new strategies to enter
dentistry.
"Eventually, when you lose a tooth, you'll be able
to regrow one inside your mouth," Dr. Anderson predicts.
Dr. D’Souza anticipates this reality-she has already
begun growing mouse teeth in her lab.
Growing teeth
Through a series of clinical and lab tests, Dr.
D’Souza and a team of scientists from UT-Houston Dental Branch and the Baylor
College of Medicine found PAX9, a master gene critical for tooth development.
Its discovery brings scientists one step closer to understanding the genetic
code to human dentition and sets the path for more discoveries. But the PAX9
discovery would not have been possible without an astute clinician, says Dr.
D’Souza.
The clinician is one of the professor's students,
Monica Goldberg. Ms. Goldberg recognized a unique dental pattern in a Houston
family. Twenty-one out of 43 family members were missing their first and second
molars. After collecting samples of the family's DNA, the scientists discovered
a mutation in the PAX9 gene. By finding that gene, they uncovered one of the
body's essential ingredients for making teeth. Now the possibilities are
endless.
"You can actually grow a mouse tooth in a culture
dish," says Dr. D’Souza.
Scientists remove tooth tissues from a mouse embryo,
add the molecules necessary for tooth development, or PAX9, to the culture dish,
and create mouse dentition.
"The hope is that if we can advance fast enough
with the human genetics that we will be able to bioengineer human teeth for
replacement," says Dr. D’Souza, "the same principal as [tissue
engineering]."
Tissue engineering
Gene therapy is a new approach to treat, cure and
ultimately prevent disease by changing the person's genes. It is done by
introducing a normal-functioning gene into a cell where the gene is defective.
"Gene therapy is gene manipulation," explains
Paul M. Fernhoff, MD, associate professor of pediatrics and medical director of
Emory genetics laboratory, in Atlanta. "It's really learning how to control
a series of genes that are already there making the cell do what you want it to
do. Another approach to gene therapy is actually taking the cells that are
already there and adding new genes."
Although gene therapy is still experimental, Dr.
Fernhoff predicts that in the next 25 to 30 years doctors will be able to use
gene therapy, or gene transfer, with their patients. Currently, researchers are
optimistic about a gene therapy technique most likely to affect dentistry-tissue
engineering, specifically the engineering of salivary gland function. National
Institute of Dental and Craniofacial Research (NIDCR) researchers have found a
way to inject non-saliva producing cells with secretory tissue to turn these
cells into secretory cells.
Engineering salivary gland function is important to
patients who have experienced irreversible salivary gland damage due to
radiation treatment for head and neck cancer. Because the genes that carry out
the process for salivary glands are known, researchers are able to manipulate
the glands and turn them on or off.
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"It's happening in the lab," says Indu
Ambudkar, PhD, chief of the Secretory Physiology Section of the Gene Therapy and
Therapeutics Branch of the NIDCR in Bethesda, Maryland. "We're doing those
sort of experiments in lab animals, for example, mice and rats. The goal would
be ultimately to apply it to humans, to patients."
About two years ago Bruce J. Baum, DMD, and David J.
Mooney, PhD, initiated a pilot program to develop artificial salivary glands to
patients with damaged secretory tissue. They described their program in the
article "The Impact of Tissue Engineering on Dentistry" in the Journal
of the American Dental Association. "We have made substantial initial
progress, proceeding from fairly rudimentary studies using a natural substratum
(denuded trachae) to the use of engineered polymer scaffolds," they wrote.
Dr. Ambudkar believes that the limitation of the
salivary gland gene therapy is at the level of the vector that is currently used
to transfer the genes. The vectors induce immune reactions in the individuals or
they may do other things, so their use is still fairly controversial.
Vectors are the carriers for the genes in gene therapy.
They deliver the genes into the patient's cells. The most common vectors are
viruses, which encapsulate and deliver their genes to human cells in a
pathogenic manner. Scientists have tried to take advantage of virus biology and
manipulate its genome to remove disease-causing genes and insert therapeutic
genes. But, as they have discovered, the body still considers viruses foreign
particles and fights them. Unfortunately, scientists simply do not know how to
turn viruses on and off yet. So alternatives to viruses are being considered,
including complexes of DNA with lipids and proteins. Many researchers currently
are working on vector technology for all types of gene therapy, which will be
more common in medicine soon.
"We believe that there is a realistic opportunity
to develop a first generation artificial salivary gland suitable for initial
clinical testing relatively soon (within 10 years)," write Drs. Baum and
Mooney.
Researchers also are interested in the genetics of
saliva for the prevention of dental caries and periodontal disease. Dr. D'Souza
says scientists now believe certain populations are at higher risk for dental
caries because they are genetically susceptible to the disease. Their saliva is
genetically different. So clinical studies are analyzing saliva, trying to
determine the genes contributing to the risk exposure to these diseases.
Dr. Anderson predicts that, once the genes have been
identified, corrective genes could be delivered to patients passively, perhaps
in food, to enhance their saliva. Current research is already underway to
develop foods to deliver traditional disease vaccines.
"We're talking Franken-food," Dr. Anderson
says. "Where you genetically alter foods. Will the public take those [for
cavity prevention]? Probably not for the next 20 years."
But he says scientists working on altering saliva are
already two years into human trials.
The ethics of genetics
Several fears come to mind when the public thinks about
genetics, including loss of privacy and genetic manipulation, or the altering of
a human's genes to create "designer people." Many agree the
mishandling of genetic information is a valid privacy concern. However, the fear
of a world made up of designer people is still highly unlikely according to
experts. No researcher seems ready for the consequences of those types of
experiments. Nor is research and technology far enough along to perform such
experiments on a routine basis.
To prepare for the influx of patients' genetic
information in their everyday dental practice, Tracy Field, a lawyer from Arnall,
Golden, Gregory, LLP, in Atlanta, warns dentists to learn about the laws
regarding the privacy of patient medical information right away. Indeed, on
December 28, 2000, the Department of Health and Human Services published final
regulations that require health care providers to implement standards to protect
the privacy of certain protected personal health information. Several states
already have stringent privacy laws in effect that practitioners may need to
review. It is important that the dental community be aware of the possible
application of these laws to their practices.
"People are very sensitive about their
privacy," explains Ms. Field, who worked in the area of genetics before
graduating from law school. "So, if I were advising a dentist, anyone who
has confidential health information, you need to consider how you are protecting
that information and how you control access to it. Are you taking what people
would consider reasonable steps to ensure that such private information is
protected?"
Currently, no federal law exists to specifically
address genetic discrimination in insurance and in the workplace. On the
political front, Democrats and Republicans have each proposed legislation to
protect a patient's privacy. Democrats in Congress have their Genetic
Non-Discrimination in Health Insurance and Employment Act and the Republicans
have their Patients' Bill of Rights. Each side says that their bill would
protect the Americans from discrimination based on their health information,
namely their genetic health information. Undoubtedly, the decoding of the human
genome in June has pushed lawmakers into action.
"The concerns related to privacy and ethical uses
of data are legitimate and compelling," says Dr. Anderson. "Our
society will need to answer a series of questions related to this central issue.
For one, the cost of health services can be significantly diminished with the
broad application of genetic information tied to health outcomes data. Society
with limited health care resources will be forced to decide how best to use
these data and protect against their misuse. It's a complex social issue."
"It's hard to tell what will happen," says
Ms. Field. "Genetics is an area that's evolving and people are still
struggling with how to balance legal concerns regarding the field, yet allow for
innovation."
But according to Dr. Anderson, America has an emerging
model to look to-Iceland. The country has hired an independent firm to gather
all the genetic data from its citizens, along with their genealogical and health
data. Iceland, a model for the rest of the world, will face the significant
issues that genetics introduces years before the US.
Cathy Areu-Jones is a freelance writer in Vienna,
Virginia.
AGD IMPACT, April 2001
SIDEBAR
Genetics education
Because of the gap between the actual application of
genetic research and the daily delivery of services to patients, researchers
fear that clinicians are not yet interested in the recent advancement in
genetics.
"Education is an area that we're all worried
about-making sure that both physicians and dentists have a basic understanding
of genetics," says Paul M. Fernhoff, MD, associate professor of pediatrics
and medical director of Emory genetics laboratory, in Atlanta, Georgia.
Rene D’Souza, DDS, associate professor in the
department of orthodontics at the University of Texas (UT)-Houston Dental Branch
shares Dr. Fernhoff fears, saying, "In general clinicians just say, 'Oh
this is too scientific. I don't want to listen to it.' The DDS in me just wishes
that gap would be bridged so that we could educate clinicians and basic
scientists as to what's going on in the clinics."
According to Jordan J. Cohen, MD, president of the
Association of American Medical Colleges (AAMC), only 66 medical schools had a
required course in genetics in 1998, and only 72 in 1999 despite the avalanche
of information from the Human Genome Project. Dr. Cohen acknowledges that other
courses also cover genetics, but medical students want and need more
information. A recent AAMC Graduation Questionnaire revealed that some 44
percent of graduating seniors thought that genetics study time was inadequate.
Realizing the need to educate health care professionals
in all fields, the National Coalition for Health Professional Education in
Genetics (NCHPEG) was founded by the American Medical Association, the American
Nurses Association, and the National Human Genome Research Institute in 1996.
The interdisciplinary group defines itself as "a national effort to promote
health professional education and access to information about advances in human
genetics...comprising leaders from more than 100 diverse health professional
organizations, consumer and voluntary groups, government agencies, private
industries, managed-care organizations, and genetics professional
societies."
In February 2000, NCHPEG endorsed a list of core
competencies in genetics its members considered essential for all health-care
professionals. The core competencies, posted on NCHPEG's Web site,
www.nchpeg.org, currently serve as one of the only guides for genetic education
in dentistry. Other core competencies and curriculum for genetics vary from
dental school to dental school. But that may change.
"I will predict that, as time goes by, there will
be a growing recognition of genetics in dental training," says Dr. Fernhoff.
"But it will be an evolution, not a revolution."
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