Friday, August 02, 2002
Brush your teeth after every meal. Floss regularly. And be sure to keep your teeth nicely coated with a film of genetically engineered bacteria.
That’s the advice dentists might offer if scientists achieve their goal of enlisting custom-designed bacteria in the war against tooth decay. The aim is to use an army of gene-altered microbes to rid the mouth of bacteria that cause cavities, effectively shifting the balance of power in the bug-eat-bug world of oral ecology.
“Our strain can be just brushed onto the tooth surface or squirted into someone’s mouth, and it will elbow out any other strain” of cavity-causing bacteria, said Jeffrey Hillman of the University of Florida College of Dentistry. Hillman is one of several researchers to have engineered tooth-friendly versions of the bacteria that cause tooth decay.
Scientists in this field say their work has therapeutic potential beyond dental hygiene. Chronic low-grade bacterial infections cause or contribute to many ailments, such as ulcers and heart attacks. If those harmful bacteria could be displaced by others engineered to be benign, the need for antibiotics and other drugs might be greatly reduced.
The strategy carries risks, however. Ecological disruption — even on the microscopic scale — often results in unexpected consequences.
And then there is the public relations problem that could arise if consumers were to perceive an unsavory alliance between dentistry (“This won’t hurt a bit!”) and genetic engineering.
“You don’t need me to tell you that you’re likely to run into some opposition, when you see statements out of Europe calling genetically modified food ‘Frankenfood,’ ” said William H. Bowen of the University of Rochester Medical Center, who has helped develop designer bacteria against cavities.
Bowen says he’s not yet convinced that tooth decay is a disease serious enough to justify coating people’s teeth with gene-altered bacteria.
But, he said, the work is sure to deepen scientists’ understanding of biofilms — thin but complex communities of protein, carbohydrates and bacteria. Research indicates that many bacteria that are benign on their own can cause medical problems when they become part of a biofilm, and scientists want to understand how bacteria in these environments interact with each other and with the body.
“Dental plaque is a beautiful biofilm model,” Bowen said. “It’s a wonderful research tool that can help us understand other bacterial diseases.”
The human mouth is home to billions of bacteria belonging to more than 300 species, but one species is the major cause of tooth decay. The culprit is Streptococcus mutans, a spherical bacterium that thrives on the organic film that coats tooth surfaces and makes an enzyme called lactate dehydrogenase (LDH). That enzyme converts food sugars into lactic acid, a corrosive chemical that gradually dissolves the protective enamel coating on teeth.
Microbial gene jockeys are experimenting with at least three methods for blocking this biochemical ticket to the dentist’s chair. In one approach, researchers in England and Sweden have created gene-altered versions of a harmless bacterium called Lactobacillus zeae, a relative of the bacterium found in yogurt.
The team put into those bacteria a new gene that allows the microbes to make monoclonal antibodies — biochemical entities specifically designed to attach themselves to the surface of S. mutans.
The antibodies grabbed free-floating S. mutans bacteria in saliva and gave them “a kiss of death,” said lead researcher Lennart Hammarstrom of the Karolinska Institute’s Center for Oral Biology in Huddinge, Sweden.
In laboratory research published in the July issue of Nature Biotechnology, rats that had the altered Lactobacilli swabbed on their teeth every other day for three weeks and were fed a diet of very sweet drinks developed about 40 percent fewer early cavities than those that had a control solution swabbed on their teeth and were fed the same diet.
“If this actually works in people, then there would be a large number of potential applications,” Hammarstrom said, in which Lactobacillus would be engineered to make antibodies against other targets.
Taking a different approach, Hillman of Florida has created a strain of S. mutans that lacks the LDH gene and is incapable of producing lactic acid. Hillman’s strain also secretes a natural antibiotic that kills conventional S. mutans without harming other oral bacteria, ensuring that it will dominate its disease-causing cousins. Experiments showed a significant reduction in cavities in rats whose mouths were colonized with the bacteria.
Hillman said he has recently improved the strain to reduce the chances that it would regain the ability to make lactic acid — or worse, develop an enhanced ability to do so. In an effort to gain Food and Drug Administration permission to conduct the first tests in people, he has added a gene that makes his bacteria dependent on a synthetic nutrient that is not normally in the human diet.
Study subjects would have to rinse their mouths periodically with a solution containing the nutrient or the engineered bacteria would die — an extra level of assurance for those who fear the consequences of releasing gene-altered bacteria into the environment. Hillman said he expects that the extra precaution will be unnecessary after initial safety studies are complete.
Many questions will have to be answered before such biological warriors are unleashed in large-scale tests. How long do engineered bacteria survive in the mouth? Some evidence suggests that a dose in early childhood could last a lifetime. What would be their impact on other oral bacteria?
Lawrence Tabak, director of the National Institute of Dental and Craniofacial Research, said the European team’s plan to use bacterially made antibodies to kill S. mutans in the mouth could open a niche into which even worse bacteria might move. He would rather replace harmful S. mutans with a species engineered to be friendly — perhaps even one that would enhance the body’s methods for rebuilding tooth surfaces.
“Some microorganisms produce acids, but others produce bases, and these bases provide a milieu that favors remineralization,” a natural buildup of tooth enamel, Tabak said. “The processes of tooth decay and remineralization are very dynamic processes, and we now have a whole host of tools to look at this in real time.”
Robert Burne of the University of Florida has pioneered just such an approach. Burne has developed strains of S. mutans that have been endowed with a gene to increase production of an enzyme called urease. That enzyme converts urea into ammonia, a base, creating conditions conducive to making enamel. Rats whose mouths were colonized with Burne’s bacteria strains got fewer cavities.
Of course, that doesn’t mean it will work in people. And even if it does, it might not sell. Getting people to gargle with microbial mouthwash might be like pulling teeth.