Forsyth researchers win $5.4 million NIH award to pursue research on oral microbes

Oct 6 2017

A research team led by the Forsyth Institute today received a $5.4 million award from the National Institutes of Health (NIH) to pursue revolutionary research of microbes living in the mouth and within the human body. The research has the potential to accelerate work in diverse fields, including medicine, synthetic biology, agriculture and environmental sciences.

The prestigious NIH Director's Transformative Research Award has been granted to Forsyth Investigator Christopher Johnston and his colleagues and will be administered by the National Institute of Dental and Craniofacial Research (NIDCR). The grant recognizes exceptionally creative scientists pursuing high-risk, high- reward research that spans multiple disciplines and has the potential to challenge current paradigms. Johnston is one of eight investigators selected to receive this year's award, which is open to scientists at all career stages. He is also among the program's youngest grantees since its launch in 2009.

"This award will propel some truly game-changing research that promises to accelerate progress in oral health as well as numerous other fields," said Dr. Wenyuan Shi, CEO and Chief Scientific Officer of the Forsyth Institute. "Christopher's research is groundbreaking, and the Forsyth is deeply committed to supporting his development and encouraging other early-career investigators to emulate his achievements and success."

Microbes, which encompass bacteria, viruses and other microscopic organisms, pervade our world. They reside in soil, oceans, and plants -- even in and on our bodies. The microbes that live in the mouth, known collectively as the oral microbiome, are a topic of intense focus at Forsyth and other research institutions as they are thought to be the gateway to many diseases as they enter the human body. Some of these microbes promote disease while others can guard against it; determining whether a microbe is a friend or foe (or even both) requires painstaking scientific scrutiny.

Scientists who study these organisms face significant hurdles when it comes to establishing how microbes operate. The reason is quite simple: researchers lack the tools needed to study and ultimately understand most microbes. Specifically, researchers need to utilize genetic tools that allow them to probe the DNA of the microbe and manipulate it -- a process known as genetic engineering.

The limited genetic tractability of microbes is a significant problem: less than 1 percent of the bacterial species known today can be genetically modified in the laboratory. For microbes that are currently inaccessible, it can take months or even years for scientists to develop the capabilities to successfully modify the microbial DNA.

"One of the most pervasive challenges facing microbiology is that instead of focusing on the most interesting or even most important organisms, we tend to focus on the ones that work, that is to say, the ones that are amenable to genetic engineering," said Johnston.

Katherine Lemon, a collaborator on the new grant, agrees. "The technical roadblocks are complex," said Lemon, who is an associate member of the staff at Forsyth as well as a pediatric infectious disease physician at Boston Children's Hospital and assistant professor at Harvard Medical School. "We've been struggling to genetically engineer some of the key bacterial players on the skin and in the nose, with sometimes years of unrewarded effort."

Johnston's work seeks to change that. Together with his colleagues, including Cullen Buie, an associate professor of mechanical engineering at the Massachusetts Institute of Technology (MIT), he is designing a rapid, robust system that will enable scientists to genetically engineer practically any type of bacteria that can be grown in the laboratory. The system seeks to overcome the genetic and physical barriers that protect bacteria from viral and environmental assaults. These are the same barriers that serve to hinder and undermine scientists' attempts to genetically engineer the microbes.

"The impact of our work will be far reaching," said Buie. "From the understanding of important human pathogens to the discovery of antibiotics and the production of biochemicals, I truly believe we will revolutionize the study of all bacteriology."

Other collaborators on the project include Floyd Dewhirst, a pioneer in oral microbiome research, and Tsute (George) Chen, an expert in bioinformatics and computational biology. Once complete, the researchers will apply their powerful system to key bacterial members of the oral microbiome that have remained beyond scientists' reach, such as clinical isolates of Fusobacterium nucleatum. This microbe is a key component of the plaque that normally accumulates on tooth surfaces and has gained notoriety in recent years for its association with the growth of colorectal tumors.

"The ability to rapidly and systematically engineer any oral microbe will be a fundamental paradigm shift," said Dewhirst. "It will overcome a major barrier that now limits research on these species, which play a key role in both oral and systemic health."

Other scientific experts agree. "The proposed new methods will be extremely useful by overcoming a major barrier to introducing novel DNA sequences into bacteria," said Sir Richard Roberts, Chief Scientific Officer at New England Biolabs and 1993 Nobel Laureate in Physiology or Medicine. "They could also lead to interesting serendipitous discoveries and help identify additional barriers that are holding back microbial genetic engineering."

Once fully developed, this new system will also have a significant impact on the broader field of microbiology, opening up countless new organisms to genetic engineering and fundamental examination. The ultimate goal and ambition of the research is to ensure that any bacteria with relevance to human health and disease can be made genetically tractable within a matter of weeks -- not years.