“As important as clinical treatment is — and I think it’s more important than research,” said Hajishengallis, “it can become routine.”
Realizing he would miss the stimulus of constant learning, Hajishengallis made the decision to continue his studies in the United States, enrolling in a doctoral program at the University of Alabama at Birmingham.
Since then, he has not lacked for opportunities to learn and discover. Naturally curious and intent on finding practical applications for his work, the results of Hajishengallis’s research may one day improve the lives of patients suffering from not only oral diseases but a whole host of conditions that involve inflammation, including arthritis, diabetes and heart disease.
Hajishengallis’s dissertation work focused on the development of a new platform for a vaccine that offers protection against tooth decay, a construct he’s since patented. After receiving his doctorate, he pursued postdoctoral studies at the University of Buffalo. There, his focus shifted to periodontitis, a condition involving inflammation and infection of the ligaments and bones that support the teeth. Periodontitis is what may occur when gingivitis goes untreated and persists.
At the center of much of Hajishengallis’s research, which he continued in faculty positions at Louisiana State University and, most recently, the University of Louisville, is the bacterium Porphyromonas gingivalis, which is responsible for many cases of periodontitis.
P. gingivitis doesn’t behave like most other pathogens, though. Scientists had previously observed that, even in diseased animals, P. gingivalis was rare, far outnumbered by other kinds of bacteria. Through experiments with mice, Hajishengallis noticed that adding P. gingivalis to the mouth caused a jump in the numbers of other bacteria. The composition of the bacterial community also changed upon addition of P. gingivalis. And when mice raised in a germ-free environment were given P. gingivalis, they did not develop the bone loss associated with periodontitis.
“So we started to espouse this heretical view,” said Hajishengallis. “It’s not actually the P. gingivalis that causes the bone loss; it’s the other bacteria. But they need P. gingivalis to do it.”
To describe this bacterium’s impact, Hajishengallis borrowed from the field of ecology, calling P. gingivalis a “keystone species.” In Montana, a keystone species might be the grizzly bear. In the mouth, it’s P. gingivalis.
“A keystone species is a species that is low in abundance but has an inordinately high impact on its community,” he said.
Publishing their findings last year in the journal Cell Host and Microbe, Hajishengallis and colleagues delved into P. gingivalis’s mechanism of action. They discovered that P. gingivalis subverts the immune system response by “hijacking” a receptor on white blood cells, rendering them unable to clear infection. As a result, other bacteria increase and, along with P. gingivalis, feast off the nutrients released by the inflammatory response and destruction of gum tissue.
Together with John Lambris, the Dr. Ralph and Sallie Weaver Professor of Research Medicine in Penn Medicine’s Department of Pathology and Laboratory Medicine, Hajishengallis demonstrated that by blocking the hijacked white blood cell receptor, they could stop the damaging inflammation catalyzed by P. gingivalis. The researchers are now testing this technique of blocking access to the receptor in more advanced animal models, hoping to develop a new therapy for periodontitis.
Another line of Hajishengallis’s recent work, culminating in a publication in the journal Nature Immunology, has also arrived at a potential drug against gum disease, as well as other inflammatory diseases that strike in old age.
He arrived at this enticing molecule by searching mice for proteins that were expressed in the mouth and that also declined as the animals aged. Among those that turned up was a protein called Del-1. But without much known about Del-1 that was relevant to gum disease, Hajishengallis left that finding by the wayside.
Not long after, he was attending a conference on the Greek island of Crete and happened to sit in on a talk by vascular biologist Triantafyllos Chavakis, then a researcher at the National Institutes of Health and currently at Technical University Dresden in Germany.
“He was presenting some new data on this protein called Del-1,” Hajishengallis said. “I had almost forgotten about it, but I had my laptop so I checked and said, yes that’s it!”
Chavakis had found that Del-1 prevented immune cells like neutrophils from moving to and accumulating at the site of infection or inflammation. Hajishengallis immediately began connecting the dots: Perhaps older mice — and people — are more likely to develop periodontitis because, as Del-1 levels drop, they are no longer able to prevent inflammatory cells from moving to the gums. Overwhelming inflammation is what leads to not only periodontal disease but also systemic diseases associated with old age, including diabetes, atherosclerosis and perhaps even rheumatoid arthritis.
Sure enough, Hajishengallis found that young mice bred to lack Del-1 developed gum disease, just as older mice did naturally. Injecting Del-1 into the mice’s gums protected them from this inflammation and bone loss. And interestingly, preliminary research indicates that humans with periodontal disease have low levels of Del-1 in their diseased gum tissues but maintain higher levels of Del-1 in their healthy tissues.
Moving forward, Hajishengallis plans to examine whether Del-1 and associated molecules might be potential drugs or drug targets. He also hopes to collaborate with new Penn colleagues who can share their expertise in other inflammatory conditions. His focus, more than ever, is to not only indulge his penchant for scientific discovery but to identify treatments that will help people in ill health.
“Scientific papers have a very short half life of interest,” Hajishengallis said. “What is of lasting value, and I will stand behind saying this, is whether they help to create some drug or therapy that will ultimately give back to society.”