Will Genetically Modified Bacteria End Dental Cavities?

Want long-lasting cavity protection? A quick squirt of genetically engineered bacteria could do the trick, and might even safeguard your teeth for life.

Streptococcus mutans, a bacterium that inhabits the human mouth, causes cavities by converting sugar into enamel-corroding lactic acid. Dr. Jeffrey D. Hillman of the University of Florida College of Dentistry in Gainesville has developed a genetically modified strain of the bug that doesn't make lactic acid, but is able to shoulder out competing bacteria.

The new bacterium, dubbed BCS3-L1, could theoretically prevent cavities by colonizing the mouth and getting rid of its cavity-causing cousin. Although the experimental treatment has only been tried in animals, clinical trials for cavity prevention could start as early as the beginning of next year.

Hillman described his research on BCS3-L1 Saturday at the American Academy for the Advancement of Science's annual meeting in Boston. He has been working on developing bacterial replacement therapy for cavity prevention for 25 years.

In rats, Hillman noted, mouth colonization with BCS3-L1 provided lifetime prevention. He is "hopeful" that the same could be true for humans, he told Reuters Health in an interview. "At worst, the treatment could be repeated as often as needed without any problems, but it certainly shouldn't be necessary more than every couple of years."

Hillman presented his data on BCS3-L1 to the Food and Drug Administration last year. "In general they quite like the idea," he said. After further investigations to address the FDA's safety concerns are complete, Hillman said, he plans to go back to the regulatory body this fall. Trials of the bacteria in humans could begin early next year.

In the dentist's office, he said, the bacteria would probably be applied after tooth cleaning. "The dentist would simply squirt a suspension of our bacteria, our modified bacteria, onto your tooth surfaces for about 5 minutes, then more than likely the dentist would pat you on the head and tell you to go home and eat sugar."

Sugar, he explained, helps the genetically modified bug stick to tooth surfaces.

The End of Tooth Decay as We Know It
Report and Interview

Within the next four to five years, a new mouth rinse may provide lifetime cavity protection, quite possibly with a single application in infancy.  Dr. Jeffrey Hillman, professor of oral microbiology at the University of Florida at Gainesville, recently announced successful results in laboratory rats, after twenty years of research. The new anti-decay vaccine will undergo a series of clnical trials to determine efficacy and safety, lasting two to three years and involving thousands of human subjects.  The vaccine, involving a genetically altered variant of the normal "tooth decay" bacterium, represents a new technology that may eventually be applied to the treatment of disease and infection without antibiotics.

The naturally occurring tooth-decay germ, Streptococcus mutans, evolved along with humans over hundreds of thousands of years.  Over that span of time, the bacterium came into balance with its host (that's us!) so that it caused no harm.  The introduction of refined sugars into our diet, relatively recent in evolutionary terms, upset that balance.  Streptococcus mutans lives on the sugar residue on people's teeth, and produces lactic acid as a waste product. ? The lactic acid eats away at tooth enamel, causing cavities. (This does suggest that more frequent brushing and fewer sweets could make make visits to the dentist a more unusual event!)

The new mouth rinse treatment contains a genetically modified version of the Streptococcus mutans.  Dr. Hillman's modified bacterium does not produce acid, and so does not cause decay.  Once introduced into the mouth, it will replace the naturally occurring bacterium, greatly reducing the likelihood of decay. ?    According to Dr. Hillman, the treatment will probably cost less than $100 and may last a lifetime, an obviously smart investment.  Dr. Hillman cautions that we will still need to brush and floss to prevent bad breath and gum disease, even if we use the new treatment. 

Dr. Hillman's research, published in the February 2000 issue of the journal Infection and Immunity, has demonstrated the safety and effectiveness of the treatment in laboratory rats. Rats with the modified bacterium had fewer cavities after two months and showed no sign of adverse affects after six months.  (If this seems like a suspiciously short observation time, remember that lab rats have a life span of at most three years, so the observation period is at least the equivalent of twenty years in a human subject.)

According to Dr. Hillman, the naturally occurring, decay-causing bacterium would eventually evolve into a strain similar or identical to his genetically engineered one.  This could take another hundred thousand years or so; the new vaccine accomplishes the same thing right away.

A significant added benefit of this new technology, called "replacement therapy", is the possibility of developing treatments for infectious diseases without the use of antibiotics.  ? A benign variant of a harmful organism could act as a vaccine, by preventing the bad germ from setting up housekeeping in a person; or could be used as an acute treatment, by competing with the closely related strain after an infection had started. The difference between this approach and the method of vaccination as it is now practised is that currrently, a killed or weakened species of harmful bacterium  is introduced to prepare the immune system to fight a future infection by that bacterium.  In the new method, a completely viable, live, but harmless variant is introduced which prevents or halts the infection by the harmful variant. 

This development is of critical importance to public health. The overuse of antibiotics during the past half-century has resulted in many very dangerous germs acquiring a resistance to treatment.  The race between pharmaceutical researchers and bacteria continues non-stop, but scientists are finding their choices increasingly limited. There is the definite possibility that strains of bacteria will develop that are resistant to any sort of antibiotic treatment.  The use of genetically engineered harmless bacteria may turn out to be one answer to this problem.

A patent for the engineered bacterium has been issued to the University of Florida, which has licensed the technology to OraGen, a biotech company founded by, of all people, Dr. Jeffrey Hillman.  (Watch for the IPO, then the buyout by the big pharmaceutical giant.)

One might think that dentists would be hostile to such a new treatment.  After all, if it succeeds, there will be a lot fewer cavities to fill. However, the consensus so far seems to be that any procedure that furthers the cause of healthy teeth will be welcomed by the profession. An example of this kind of support is the endorsement by dentists of the introduction of water fluoridation in the 1950's.  Fluoridation reduced the incidence of cavities, yet there are many more practising dentists now than before the addition of fluoride.

Exclusive interview
After we read the reports of this new discovery, a few questions came to mind.  We contacted Dr. Jeffrey Hillman and he agreed to answer a few questions.

Healthmantra: You say the present (natural) strain produces lactic acid from "refined" sugars, and was thus not harmful to its host until introduction of such sugars into the diet relatively recently. What, actually, is the difference chemically between added sugars, including refined white sugar, but also those found in honey or maple syrup, and naturally occurring simple sugars in fruit or any other foodstuff? They are all monomer sugars, right? 
Dr. Hillman: Monomeric sugars actually are preferable from a health and tooth decay standpoint. While they can be metabolized to lactic acid, many of them, such as galactose, are slowly metabolized and also yield other, non-acidic end-products. The main problem with refined sugar (sucrose) is that, in addition to being rapidly metabolized to lactic acid, it is the substrate [precursor, or component needed to make a new molecule]  for an extracellular goo called dextran that helps to trap the acid next to the tooth surface. so the tooth winds up getting a more prolonged acid insult. ?

Q: Why will the new variant of S mutans replace the old one? Is it in some way better adapted to its host, or more efficient, more prolific reproducer, etc?
A: It has a strong selective advantage - it produces a natural antibiotic-like compound that kills all other strains of s. mutans.

Q: Aagghh! So I have this thing secreting antibiotic substances in my mouth on a continuous basis! What else will it (or might it) kill? I thought an advantage of the new treatment was to use some other means besides antibiotics to fight infection. Will this add to the problem of resistant bacteria?
A: All the evidence from animal and human studies indicate that the killing effect of the antibiotic is very specific for s. Mutans. To understand why this is the case you have to have a basic understanding of plaque (biofilm) architecture. Based on data from various microscopy techniques, we have assumed that plaque is an amorphous agglomeration of bacterial cells from as many as 500 different species. However, new methods (confocal laser microscopy) indicates that plaque, and biofilms in general, have considerable anatomy. Based on where it attaches to the tooth surface. S. Mutans apparently has a discrete habitat that is different from other species and physically separated. Thus, although the antibiotic produced by my strain has the potential to kill lots of other species, it does not do so because by the time it gets to them it has become too diluted. Another interesting feature is that this antibiotic is a member of a new class of molecules called Lantibiotics. Not that much is known about them yet, but one feature of our Lantibiotic is that sensitive bacteria do not seem to be able to gain resistance. We have exposed [literally trillions of ] cells of sensitive strains without finding any genetically stable resistant mutants. For reference this is 100-fold more cells than you'd typically need to find a mutant resistant to any other antibiotic including vancomycin. We don't yet know the basis for this observation but obviously it is of potential great importance.

Q: By the way, the newspaper article refers to your method as "replacement therapy". I had understood gene replacement therapy to refer to the insertion of engineeered genes into the subject organism, or patient (the critter with the disease). Did they get that wrong? I felt uncertain about using the phrase in what I wrote so far, but all I had for source was the clipping. 
A: The term replacement therapy was originally used to mean what I'm doing:  replacing a bad microbe with a good one. The term was co-opted to also mean providing hormones to subjects (e.g., Menopausal women), and more recently to providing an expressable genetic element. In this last case they usually specify "gene" replacement therapy.  

More about Monomers:

A single unit or molecule of a type that can be connected in a chain to form compounds with properties different from the single unit molecule. Monomer or "simple" sugars such as fructose and sucrose are responsible for the "sweet" taste we associate with "sugar" as a food additive. Glucose is the sugar stored in the liver for food energy, and is the principal energy-providing nutrient of body cells. Nerve cells and brain cells rely entirely on glucose for their food source.  When you put enough sugar molecules together, you get a Starch molecule, which is what we are eating when we say we are eating "carbohydrates".  Actually, all sugars, simple and complex, are carbohydrates.  When you string sugar molecules into a long enough chain, you get cellulose, which makes up the tough, stringy tissue of plants. Wood fiber is mostly cellulose, that is, very long sugar molecules. Cows and termites can digest cellulose.  We can digest some of them, too, if we cook them to break them down into starches and sugars.  People get their best nutrition from starches, found in wheat, rice, potatoes, and most other vegetable products.  Actually, meat contains a high percentage of carbohydrates as well as protein.   

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