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Profile in Oral Health Trisha E. O’Hehir, RDH, MS Editorial Director, Hygienetown

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by Trisha E. O'Hehir, RDH, MS, Editorial Director, Hygienetown

Dr. Jeffrey Hillman is a quiet, thoughtful man who is curious about science and has the innate ability to objectively assess a situation or a scientific accident. He says it's because he doesn't study it in depth, but rather sees things from a global perspective. Take opera for instance. He enjoys the music, lyrics and acting for pure enjoyment. Taking it all apart, understanding the theory, separating each instrument and voice to study it in detail changes the focus and also takes the enjoyment and pleasure out of the experience. In science, Dr. Hillman focuses on the possibilities of what can be learned from experiments gone wrong, not simply on following the steps of an experiment to an expected outcome. He values each experiment gone wrong as the opportunity to raise or answer another question, perhaps not the question he was asking at that moment. The accidents that Dr. Hillman has pursued in his career have led to some amazing discoveries that have the potential to eliminate caries and periodontal disease and replace antibiotics for treating serious infections.

Dr. Hillman's work didn't start with oral probiotics. The foundation was laid with 25 years of research on genetically altered Streptococcus mutans to create a one-time replacement technology, SMaRT, to replace the oral bacteria responsible for dental caries with bacteria that don't produce lactic acid. Along the way, other discoveries were made. With the SMaRT replacement technology came the discovery of a novel lantibiotic produced by bacteria to destroy other bacteria. Discovering a platform to synthetically create lantibiotics might in fact replace the antibiotics that are currently failing. Oral probiotics are far from the end of Dr. Hillman's discoveries. Several new technologies are being investigated in the Oragenics lab today. He's pursuing a new direction in disease diagnosis based on rapidly identifying protein targets released from cells undergoing change. His team is also working on an exciting discovery that will impact one of the most serious medical problems we face today – obesity. They've discovered a natural molecule that can be taken orally to induce programmed cell death in fat cells.

Having read Dr. Hillman's research for many years, it was a pleasure to personally talk with him about his many discoveries, and the accidents leading to some of those discoveries.

Dr. Hillman, where did your research start?
Hillman: Prior to dental school, I worked in the lab of my first mentor, microbiologist Rob Gibbons, studying bacterial attachment to surfaces. At the time, no one could explain why you find certain types of bacteria on the teeth but not on the mucosa, and other types of bacteria that behaved in the opposite fashion. Gibbons thought there might be an enzyme in saliva that was responsible for the selective attachment. Without knowing much about bacteria, I discovered instead that the selectivity of attachment was a feature that is intrinsic to the bacteria. My work indicated that bacteria have surface molecules that interact very specifically with molecules on the enamel pellicle or on the surfaces of mucosal cells, a sort of lock-and-key type mechanism. The specificity of bacterial attachment has provoked a lot of research over the subsequent years, since the prospect of preventing diseases by preventing initial attachment of bacterial pathogens to surfaces seems so appealing. Unfortunately, it appears that bacteria typically have multiple attachment mechanisms, so there haven't been any landmark successes using this approach to date.

How did you get started with replacement technology?
Hillman: It was an accidental discovery two weeks after beginning work in molecular genetics at Forsyth in the 1970s. I had a grant to study attachment of bacteria to tooth surfaces. I was repeating a protocol on a strain of Strep. Mutans that I used as a graduate student to chemically alter the genes of E. coli. For an indication of mutagenesis, I was looking for unusual appearing colonies on a particular type of cultivation medium, which happened to contain a pH indicator. Among the many small, white acid-producing colonies, I noticed several large red colonies, and wondered what they were. I determined that they did not produce lactic acid. At the time, most people working in the area of dental caries believed that lactic acid production by Strep. mutans was directly responsible for dental caries, the so-called Acidogenic Theory of decay. It occurred to me that a lactic acid-deficient mutant of Strep. mutans offered the perfect opportunity to test this theory. Once I showed that these mutants did not cause decay, and thus proved the Acidogenic Theory, the idea of using them to prevent tooth decay through replacement therapy dawned on me. This dramatically changed the focus of my research from bacterial attachment to finding a replacement bacteria for the oral cavity, but not without some resistance from my grant supervisor. Luckily, he agreed to allow my grant to take a new direction that started the journey to these exciting new discoveries we have today.

Your work on SMaRT took 25 years. What kept you going for so long is this direction?
Hillman: The process was never boring; it was challenging and exciting. My focus was on answering questions about how to achieve the potential for what I saw as possible in my early research, that of eliminating dental disease by replacing the disease- causing bacteria in the mouth with genetically altered bacteria. There were several quantum leaps in the process that were very exciting. First, finding a starting strain of Strep. mutans for this work, which had a selective advantage over all other strains of this species, took several wrong turns and four or five years to achieve. Next, it took several years to figure out how to eliminate the ability of these cells to produce lactic acid. The problem here was the discovery that elimination of lactic acid production killed our strain because it created metabolic problems for the cells. This problem was overcome using recombinant DNA methods, which we developed specifically for this problem, but which are now in widespread use for a variety of applications. The result is the SMaRT strain that is genetically modified to produce no lactic acid, and it also produces an antibiotic that kills all lactic acid producing strains of Strep. mutans. Each step of the process led to our goal, but there were also interesting observations that we selectively pursued. These led to other exciting discoveries, like our lead antibiotic, MU1140. Although it took many years to achieve the SMaRT strain, the process along the way was interesting and rewarding.

Tell me about lantibiotics.
Hillman: Lantibiotics are potent antibiotics produced naturally by bacteria. The first lantibiotic was discovered in 1927, Nisin, and 50 others have been discovered since then.

Today we have many health-care associated infections and many are antibiotic resistant; for example methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and Clostridium difficile (C. Diff). This is a serious problem that continues to require newer and more powerful antibiotics.

In our work with the SMaRT strain, we discovered it naturally produces a potent antibiotic, which we call MU1140, that is active against all gram-positive bacteria. We developed a new organic chemistry technology to produce a synthetic lantibiotic, MU1140-S. This lantibiotic will potentially replace Vancomycin and Daptomycin, the current drugs of last resort for serious health-care associated infections, which are currently failing.

Are other synthetic lantibiotics being produced?
Hillman: No, we're the first to figure out how to make these unusual molecules. Until now, standard fermentation methods have been unable to produce even enough material to test any of the 50 known lantibiotics as therapeutic agents for use in fighting infections and diseases. The unique chemical structure of lantibiotics prevents the necessary purification needed for clinical testing.

In order to produce large amounts of MU1140-S, we developed a novel organic chemistry synthesis platform known as DPOLT. This new technology will make it possible to synthetically produce any of the 50 known lantibiotics.

How did you move from your work on SMaRT replacement technology to oral probiotics?
Hillman: In the early 1980s I attended a lecture given by Dr. Sig Socransky. I was intrigued by what he said about bacteria and periodontal disease. He said everyone has bacteria in their mouths that can cause periodontal diseases, but not everyone experiences the disease, at least not to the extent that they theoretically could. That made me wonder if perhaps there were bacteria normally present in plaque that inhibit the growth of the bacteria that cause disease. I talked with him about this after the lecture and asked him for plaque samples from healthy and diseased periodontal sites. Within two weeks, I had the answer – good bacteria were missing in the mouths of those with periodontal disease. We had other evidence that the good bacteria would disappear from a site before it started to break down, possibly because certain pathogens are known to produce an antibiotic- like molecule that specifically kills them.

Unfortunately, the idea of simply recolonizing a host with periodontal disease with the good bacteria proved to be ineffective: the good bacteria would disappear very quickly following their introduction, and we couldn't figure out what we needed to do to help them persistently colonize. This work was put on the back burner until I attended a meeting in Amsterdam in the late 1990s. It wasn't a lecture this time that caught my attention, it was the attendees lining up for the lunch buffet. Each person took a little bottle of something and drank it after lunch. It was a probiotic to promote GI health. The fact that an entire population was willing to take a probiotic daily changed my thinking from a one-time treatment, such as we plan for SMaRT, to the potential for a daily oral probiotic that would deliver good bacteria to the mouth. Probiotics have been around for centuries for balancing the microflora in the lower alimentary canal to favor health. I simply moved this centuries-old concept up to the mouth. The result is ProBiora3.

What is ProBiora3 and how does it work?
Hillman: ProBiora3 contains three naturally occurring strains of beneficial bacteria, including Streptococcus oralis, Streptococcus uberis and Streptococcus rattus. When taken daily, these good bacteria change the balance of bacteria in the mouth to favor health. We focused on bacteria to promote dental and periodontal health, but found a few beneficial side effects – fresher breath and whiter teeth. The good bacteria inhibit the growth of bacteria that produce volatile sulfur-containing compounds and they release hydrogen peroxide that whitens the teeth. ProBiora3 is found in EvoraPro, EvoraPlus and EvoraKids. These flavored probiotic tablets are dissolved in the mouth twice daily after regular brushing. EvoraPro is taken for ten days after seeing the hygienist, followed by regular use of EvoraPlus. We also have an oral probiotic for pets, Teddy's Pride, a powder that's sprinkled on a pet's food once per day.

Now that ProBiora3 is available commercially, what other things are you working on besides bringing SMaRT through all the complex FDA regulations?
Hillman: There are several other technologies we're working on, including two of particular interest – diagnostics and weight loss. While searching for protein targets associated with periodontal disease diagnosis we discovered a way to identify proteins that are released into body fluids when a cell undergoes any sort of change. These so-called shed proteins are excellent targets for medical diagnostics and for developing therapeutic strategies. Using blood, saliva or urine, the technology we developed is able to identify proteins shed from diseased tissues and cancers. This technology has already proven its ability to identify protein targets for Vibrio cholera, Escherichia coli and Pseudomonas aeruginosa and now we're working on Mycobacterium tuberculosis and bowel cancer.

Obesity has increased significantly in recent years and is responsible for serious medical problems in our country with large public health costs, so the potential for the work we are doing on weight loss is exciting. We have identified LPT3-04, a natural substance, which, when taken orally, targets fat cells to undergo programmed cell death.

The new technologies we've discovered are not all the result of experiments working out just as we expect. Accidents happen every day. Remaining open to those accidents and selecting which of the failed experiments are the right ones to pursue is the challenge. In dentistry, I see my work as part of a change from "sick care" to "health care," providing people with easy, safe and reliable ways to prevent oral diseases.

Conclusion:
A lot goes into the development of a product like the oral probiotic, Evora, or soon the SMaRT replacement technology. Many years, many experiments and a few lucky accidents are needed to transform the idea to eliminate dental disease into exciting new technologies to do just that.
Author’s Bio
Jeffrey Hillman, DMD, PhD, is the chief scientific officer of Oragenics, Inc. He received his undergraduate training at the University of Chicago, his dental degree from Harvard School of Dental Medicine and his PhD from Harvard Medical School. He began his research at the Harvard-affiliated Forsyth Institute in Boston. For personal health reasons, he transferred his research to the University of Florida College of Dentistry and founded Oragenics in 1996 to bring an array of products to market after more than 25 years of research. Oragenics, Inc., is a publicly traded biotechnology company with a significant pipeline of seven proprietary product and platform technologies, all discovered by Dr. Hillman.
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