In the Heart of the Action On and Off the Court
words by Doris Cortes Delgado / photograph by John Emerson
he crowd is cheering. The basketball game is in full swing. Suddenly the whistle blows. The referee stops the action. Someone is down and hurt. The someone is Daniel Fine. “I always dreamed of becoming a basketball player — ever since I was a kid,” he says. But his dream of being a professional athlete ended that day when he broke his sternum. It was his junior year of college and he wasn’t allowed back on the court for a year.
Fortuitously, one of the heads of the biomedical society, who was a big fan of the basketball team, knew Fine was a good student and asked him if he wanted to go into medicine. He said no but then was asked if he was interested in dentistry. “I mentioned that my father was a dentist and he told me to think about it,” he says. The seed was planted.
Fine grew up in Queens, NY, went to Jamaica High School and then to Queens College. After graduation, he attended the University of Pennsylvania School of Dental Medicine. “I was drawn to research,” he says. After designing a research project in his junior year, he invited a faculty member to collaborate with him on the project. “In retrospect, I think, ‘My God — that was pretty amazing, a faculty member working on my experiment!!’”
Not having a clear idea of where he was heading, Fine found himself attracted to periodontics — at this point in time considered to be the intellectual or research-oriented specialty in dentistry. He went on to N.Y.U., specializing in this area. There was one full-time researcher in the department at that time, who Fine says, “became my mentor and encouraged me to go on. I had never envisioned doing this. Without this example and the encouragement of Dr. Stahl, I would never have had the courage to choose an academic career.”
Fine sent out his application and received job offers from Harvard and SUNY Buffalo, but the University of Pittsburgh also offered him entry into their PhD program. He accepted, but soon after his arrival the PhD program lost its funding. The young investigator kept his focus with the help of Dr. Ralph Buchsbaum, author of the classic biology textbook, Animal Without Backbones, and managed to publish three papers in the next three years. “I found research really exciting,” he recalls.
He moved on to become a postdoctoral trainee at Columbia University’s College of Physicians and Surgeons with a joint faculty appointment in the dental school. “Although I had very little experience, I applied for an NIH grant as a co-investigator. It was the first grant I ever wrote and I got it,” he states. “It was beginner’s luck and jump-started my career in research.”
Fine stayed at Columbia for 25 years, working in the Pathology and Microbiology Departments in the Medical School and in the Department of Preventive Dentistry and Periodontics with Dr. Irwin Mandel, who just received the “Mentorship Award” at this year’s annual meeting of The American Association for Dental Research. “He inspired me to do serious dental research,” Fine explains.
After six years at Columbia, Fine took a sabbatical in London to study immunology at Guy’s Hospital. Seven years later he took another sabbatical, which led to a Senior Research Fellowship Award from NIH. A former student, Dr. Lawrence Tabak, the current Director of the National Institute for Dental and Craniofacial Research, suggested that he shift gears and study microbial genetics, so he contacted one of the outstanding geneticists at Columbia who, as fate turns out, worked in the lab next door to where he had studied at the University of Pittsburgh 15 years earlier. The collaboration with that geneticist, Dr. David Figurski at Columbia, proved to be highly successful and has yielded valuable information about Aggregatibacter actinomycetemcomitans (Aa), bacteria responsible for an aggressive form of periodontal disease that affects children of African descent.
Currently his lab focuses on both immunology and microbiology – host-parasite interactions in periodontal disease. As mentioned, he has had a long-time interest in Localized Aggressive Periodontitis (LAP), which affects African American children 20 times more than Caucasian children, often resulting in serious tooth loss. “Kids typically get cavities, not periodontal disease,” states Fine, “so this is an unusual form of dental disease.”
One day in 1994, after he presented his work at a local research conference, someone from UMDNJ approached him, asking: “How would you like to come to New Jersey Dental School and help us re-invigorate our research program?” Fine, seeing this as a unique opportunity, brought his entire lab and made the move to NJDS.
When he first arrived at the school, there was no Oral Biology Department. Two years ago, his department was named one of the top 10 oral biology departments in the country by The Chronicle of Higher Education.
He says his biggest contribution to research has been his team’s exploration of the bacteria Aa. “Our approach has been to examine this organism on a genetic level. We’ve dissected many of the virulence factors that this organism possesses that contribute to various aspects of the LAP disease process. We’ve been able to add useful information to the field of infectious diseases and microbial pathogenesis in areas far removed from the oral cavity. We also have been able to learn about our organism by studying the genetic profile of other similar bacteria. It is a great time to be doing research — so much is happening —and only time will tell how far we can progress. It is rewarding to know that our work has contributed to a better understanding of microbial diseases in general.”
His long-term goal is to fully understand Aa-induced LAP and come up with a way of diagnosing this disease early on with the ultimate goal of preventing its initiation. “If I could do that,” he says, “I would feel like I have really accomplished something relevant.”
As for his role as a chair of the Department of Oral Biology, Fine indicates that when he first came to UMDNJ, there were 22 laboratories but only a few were functioning; and there was no NIH-funded research. Now only one lab is empty. NJDS researchers currently attract about 4 to 5 million dollars in research annually. I have enjoyed being part of the process of change and renewal. “NJDS has turned out to be a great place to work and I enjoy it tremendously,” he says.
According to Fine, his research career path has not followed a straight trajectory and although he has had consistent research funding throughout his career, he feels that meaningful progress has resulted from renewal, constant learning, and association with enthusiastic and visionary colleagues. He feels that this need for renewal should come as no surprise since science is ever changing and requires a dynamic environment.
“What has been surprising and illuminating is that renewal and redirection have come from many sources that include former mentors, as well as students and colleagues. Environment is key,” states Fine “and I hope that the current economic issues that we are all facing are transitory, so that we can continue to move forward so that young scientists can sustain their enthusiasm for learning and progress.”
Fine’s family and other interests also keep him busy. He has four grown children, five grandchildren and a sixth on the way, and enjoys reading and music. His wife, an accomplished sculptor, recently convinced him to return to playing the piano and to resume writing music. “I think she’s afraid that when I retire, I’ll be too much to deal with,” he says.
When asked about his bowties, the researcher laughs. “It started as a practical joke,” he explains. “We had a professor at Columbia who was teaching us about indices that depended on minute visual discriminations. He was difficult and ornery and his trademark was his bowties. After one particularly stressful session, one of the students, Julie, who was not more than 4 11, suggested that the whole group wear bowties at our next session, which we did. When the professor came in the next day, I asked if he noticed anything different and his response was, ‘Did they paint?’ We all laughed because he missed the fact that we were all wearing bowties. Julie had one that was at least two feet long and he did not notice. I guess by now they’ve become my trademark, too.”
Listen to Your Bacteria
For the last 25 years our group has been studying a rare form of periodontal disease called Localized Aggressive Periodontitis (LAP) that affects African American children 20 times more than Caucasian children. Our focus has been on the oral microorganism, named Aggregatibacter actinomycetemcomitans (we call it Aa for simplicity), implicated in the cause of this rare form of disease. It turns out that Aa shows similarity to other more notorious bacteria that cause better known diseases such as Yersinia pestis (cause of the bubonic plague) and Mycobacterium tuberculosis (cause of tuberculosis). Along these lines, Aa expresses many features (known as virulence traits) and possesses many genes that are similar to these other better-known pathogens (Y. pestis and M. tuberculosis). As such, our group has used molecular approaches in efforts to unravel the traits possessed by this “pathogenic bacteria” in order to demonstrate its relationship to initiation and progression of oral infections. In the process, we have been able to show how these traits relate to other infectious diseases.
With respect to LAP, most adolescents are affected by cavities and rarely have periodontal disease, which is seen to the greatest extent in older adults. About 20 years ago, we discovered that African American children affected by LAP had minimal tooth decay. We speculated that there might be an element in the saliva of these children that could favor the growth of oral bacteria that cause periodontal disease (such as Aa) but would inhibit the bacteria that cause cavities (Streptococcus mutans). In our search through the literature, we discovered that a salivary glycoprotein called lactoferrin could affect attachment of Aa to oral tissues. Since it is well known that attachment is the first step in mucosal infections, we thought this area was worth investigating in greater depth.
Lactoferrin is a multifunctional salivary glycoprotein with two major roles: sequestering or removing iron from bacteria (hence the suffix ferrin), which helps reduce bacterial growth, and direct killing of bacteria. With respect to its role in killing bacteria, Lf appears to be most effective in its apo, or iron free, form. However, in its iron rich form Lf has another effect. It prevents many bacteria from attaching to tissues. We discovered that the relationship of Lf to Aa-induced LAP was even more complicated. In its iron free form, Lf did not kill Aa, but in its iron rich form, Lf significantly reduced Aa’s ability to attach to tissues. This suggested that Aa would have the greatest chance to survive in the oral cavity of children with LAP when these children had Lf in its iron free form (no killing of Aa and no affect on Aa’s ability to attach). We then conducted a case-controlled study to examine the iron levels in Lf obtained from the saliva of children with LAP as compared to age, gender, and race matched controls who were free of LAP. We found, as speculated, that children with LAP had Lf with minimal iron.
This led to our next study where we attempted to determine if children with LAP possessed a genetic mutation in their Lf gene (called a polymorphism) that might affect its iron binding and retention. To our surprise, we did not find a polymorphism in the iron-binding region, but did find one in the antibacterial region of Lf. We then conducted a series of experiments using an insect vector to express human Lf in its two polymorphic forms to determine whether the form expressed by the LAP subjects demonstrated any unique antimicrobial properties. We discovered that a shift in a single amino acid from arginine to lysine (the polymorphic form of Lf found in the LAP children) produced a dramatic effect on the organisms that caused cavities. Thus, the shift from arginine to lysine was shown to produce a form of Lf that killed S. mutans and other acid producing organisms but had no effect on organisms that caused LAP (Aa). With some minor modifications we then developed a fusion peptide (a synthetic protein) that we demonstrated was effective against cavity producing microorganisms. This fusion peptide is now being studied for use as a new antimicrobial agent to prevent or reduce cavities.
This work and much of the research done in our department has centered on a specific philosophical approach to science: namely, that we can learn about biology by studying the history of bacteria and how they have adapted to their environment on this planet. It is our belief that bacteria are clearly smarter than we are; they have been on this planet longer than we have, and will undoubtedly be here long after we’ve gone. As an example of the innate intelligence of bacteria, we have often heard the phrase, “there is no such thing as a free lunch.” For the most part this saying is true, but somehow bacteria have managed to live on us and in us at no cost. As a result of this innate ability, bacteria, it seems, have free housing, food and transportation. The great American philosopher, Mel Brooks, in his depiction of the “2000 year old man,” said in a prescient moment — when asked to explain his longevity — that his audience should “listen to an old aunt, listen to a wise uncle... listen to your pencil.” In keeping with this advice, the motto of our department has been, “listen to your bacteria,” and thus far, this approach has produced several patents that we hope can be translated into useful therapies for many conditions and diseases that extend far beyond the oral cavity. The UMDNJ Office of Patents and Licensing is currently working on a potential licensing agreement with a major, multinational consumer products company.
Our group is currently examining bacteria or host-derived products for treatment of dry mouth, yeast infections, and gastrointestinal infections. Other members of our department including Drs. Scott Kachlany, Jeff Kaplan and Narayan Ramasubbu are examining Aa-derived products for treatment of HIV, cancer, plant blight and skin wounds. After all, the mouth is the portal of entry into the entire body.