Dr. Chase Beisel is an Assistant Professor at North Carolina State University who was recognized earlier this year with one of Bay Area Lyme Foundation’s prestigious Emerging Leader Awards. This honor is in recognition of and support for his lab‘s novel work exploring CRISPR technology as a potential treatment for Lyme infections.
Dr. Beisel’s work integrates molecular biology, chemical engineering, and mathematical modeling and has been acknowledged with several National Science Foundation (NSF), National Institute for Health (NIH) and other important awards. His foray into the field of Lyme is a new direction for his lab and ties directly to the Foundation’s aim of attracting some of the brightest and best minds in the country to apply innovative new approaches and methodology to accelerate the development of new diagnostics and treatments for Lyme disease. We are excited about his work and asked him to elaborate further in this recent conversation.
Your work is in the area of Lyme therapeutics, specifically, the current ELA-funded project is utilizing a genome interference technique known as “CRISPR.” Could you give us some more context?
CRISPR, which stands for clustered regularly interspaced short palindromic repeats, is most widely known as a revolutionary tool for editing DNA sequences. What is less appreciated is that CRISPR is part of a defensive immune system that recognizes invasive foreign DNA. The system creates CRISPR RNAs that seek out the DNA sequences of the invaders. When the CRISPR RNAs find a matching sequence, they instruct the Cas proteins to cut the sequence of invading DNA from the cell. The tool cuts DNA at a sequence of our choice, and we then can guide the repair process to dictate the new sequence. Notably, in bacteria, the DNA cut can’t be repaired easily, making cuts by CRISPR lethal. We were one of the first groups to show that this allowed CRISPR to be used as a targeted antimicrobial — essentially a “smart bomb” for bacteria.
The ELA award will allow my group to explore how CRISPR can be used as an antimicrobial agent against Borrelia, e.g., by introducing specific CRISPR-associated proteins [Cas] that can intercept the bacterial spirochetes and render them inert.
What is novel about your approach / methodology versus other forms of treatment?
Most prescribed antibiotics are broad-spectrum, indiscriminately killing many types of bacteria. This approach is proving to be problematic because of both the growing instances of multi-drug-resistant infections and the negative impact of broad-spectrum antibiotics on the many beneficial bacteria in and on our bodies. Our CRISPR antimicrobials could overcome these issues because we can program them to only kill selected bacteria, and they would be more effective against multidrug-resistant pathogens.
CRISPR is an intriguing technology because it is a naturally occurring adaptive defense system — often found in bacteria and other organisms — that we are essentially co-opting. The applications are many but especially interesting for Lyme the Lyme bacteria which have proven to be so resilient.
Are there any downsides to this approach? Would the therapy affect any other parts of the immune system or physical health of the patient during treatment?
We are in the early stages of developing the technology and we are still learning about its benefits and limitations. Currently the big challenges are how to best deliver CRISPR antimicrobials into the bacterial cell. However, we don’t anticipate any negative impacts on a patient such as adverse immune responses. The impact should be much more limited than broad-spectrum treatments.
At what stage would a treatment such as this one be relevant?
The treatment could be implemented at any stage of treatment in which the bacteria are still present — early or late stage. The challenges will be reaching a given infection site and effectively attacking Borrelia as it changes between early-stage and late-stage Lyme.
What is it about Borrelia? It seems to have amazing adaptive capabilities that seem to make tracking and eradicating it difficult. How similar or different is the Lyme-causing bacteria from other forms of bacteria that you study?
Borrelia is a really compelling test-case for CRISPR antimicrobials because of its resilience and adaptability. We have been working on human pathogens such as E. coli and Shigella that have been effectively treated with our antimicrobials in the laboratory. However, we fully anticipate that Borrelia will pose unique challenges that will require further development on our part. For instance, Borrelia has its genome split across one chromosome and numerous plasmids, any many of these pieces of DNA are dispensable for the bacterium to survive.
How has the Emerging Leader Award aided in your research?
The ELA was the motivation to begin working on Borrelia. Previously, I mostly focused on other types of bacterial pathogens, but the award is allowing me to branch out and develop potential treatments for Lyme.
Interesting. So Lyme disease was not the original focus… Tell us more about your background and how you came to know about Lyme disease and the potential for some novel research in this area.
My academic training is in chemical engineering. I was trained in designing and analyzing large-scale chemical processes. At the same time, I was always interested in applying chemical engineering principles to biology. This interest led me to pursue graduate research in RNA engineering and postdoctoral research on naturally occurring regulatory RNAs. These training experiences eventually led me to CRISPR because it relies on RNA to identify DNA targets. CRISPR has now become a major thrust of my research program, where we have ongoing projects to understand the fundamental biology of CRISPR-Cas systems and to exploit these systems for our own purposes. Developing CRISPR antimicrobials is a major part of these efforts. Lyme originally was not on my radar, but a serendipitous meeting with one of the foundation advisory board members alerted me to the ever-present challenge of Lyme and the need for new therapeutic strategies. This was sufficient motivation to apply for the Emerging Leader Award and begin exploring the use of CRISPR antimicrobials to treat Lyme.
Have there been any surprises in the work so far? Any big milestones you can share?
We started the project a month ago, so we are still ramping up the experiments. However, we have designed our CRISPR antimicrobials and we are developing the delivery approaches to get the antimicrobials into Borrelia. Growing Borrelia has proved to be a challenge, although the postdoc working on the project has an excellent background in culturing hard-to-grow bacteria. We are working to evaluate the lethality the CRISPR antimicrobials against a lab strain of Borrelia. If successful, we can begin exploring delivery vehicles. The work is early stage, although we hope to make substantial progress over the next few years to develop an alternative treatment strategy against this disease.
Knowing what you now know about Lyme disease, what do you think is most important for the general public to understand?
After attending the LymeAid fundraiser and a clinical workshop at Massachusetts General Hospital, I was surprised at how complex of a disease Lyme is and how much better the standard diagnostics could be. Lyme is not a simple, straightforward disease, and much more work needs to be done to improve diagnostics and treatments.
Thinking about the research community, what do you know now that you wish someone had told you when you were first starting your research career? How might you advise some of the young researchers either at your lab or in the field more generally?
Endeavor to find research problems that you find to be the most pressing and the most exciting, and think about problems in the long-term. It’s easy to get focused on a single project, but a long-term perspective helps you lay out the individual efforts that will get you there and justify your work not only for your fledgling students but also funding agencies and the public at large. It’s also ok if your vision changes–you just need something in place.
I have been truly touched by the stories shared by people afflicted with Lyme disease as well as their friends and family members. These stories gave tremendous motivation for our research–something that can be rare for scientists working on basic research and foundational technologies.
For more information about the Emerging Leader Award and past recipients, click here.
Photos courtesy of The Beisel Lab, NC State University.