Advancing Lyme Disease Research Through Quantitative Innovation

By Mase Peterson

Trever Smith II, research assistant professor at Tufts University School of Medicine (TUSM), uses quantitative approaches to improve understanding of Lyme disease treatment. With a background in studying Borrelia burgdorferi virulence and developing antibiotic interaction models for Mycobacterium tuberculosis, Smith now applies his expertise to Lyme disease research. Through the Tufts Lyme Disease Initiative, he leverages high-resolution microscopy and computational tools to refine therapeutic strategies. His work aims to optimize drug combinations and advance preclinical models, contributing to the initiative’s goal of eliminating Lyme disease as a public health threat.

In this Q&A, part of a feature series spotlighting members of the Tufts Lyme Disease Initiative, Smith shares insights into his background, his current research, and the unique perspectives he brings to the field. He also discusses the challenges and exciting opportunities in Lyme disease research, highlighting the collaborative environment at TUSM that fuels his passion for scientific discovery.

Tell us about your background and what brought you to TUSM.

“I am from Harrison, a town in Michigan in the middle of the Lower Peninsula. As a proud first-generation college graduate, I began my studies at a local community college before transferring to Cornell University to complete my bachelor’s degree. I then went to the University of Texas in San Antonio, where I obtained my PhD under the guidance of Prof. Janakiram Seshu, studying the molecular mechanisms of virulence in Borrelia burgdorferi, the agent of Lyme disease. I joined TUSM’s Department of Molecular Biology and Microbiology for my postdoctoral training in Prof. Bree Aldridge’s lab. During this time, I developed quantitative tools to analyze how different antibiotics eliminate Mycobacterium tuberculosis, the bacterium that causes TB. After my postdoc, I remained at Tufts and transitioned to a role as a Research Assistant Professor. It was during this time that I started to dabble in Lyme research again.”

How are you applying your expertise to Lyme disease research, and what new approaches are you bringing to the field?

“I am currently adapting tools from my postdoctoral research for use in Lyme disease research. My work focuses on how drug combinations affect the Lyme-causing bacterium using two approaches. The first is by directly measuring the outcome of drug combinations on the bacteria using a method called DiaMOND. This technique, successfully implemented in TB research, allows us to rapidly and efficiently identify drug combinations that are more synergistic, or less antagonistic active than individual drugs alone.

My second approach is to leverage microscopy and quantitative tools I developed in my postdoc to investigate drug mechanisms in Borrelia burgdorferi. The idea behind this approach is that drugs targeting the same process in bacteria produce similar responses. Think of it as how your wardrobe changes based on the time of the year. If it is summer, you may wear shorts, while you are likely wearing a coat in the winter. These differences in your appearance reflect your response to the temperature. Similarly, different types of drugs lead to distinct bacterial morphologies, which we can quantitively measure using a microscope and computational tools. We can then use these profiles to understand how drugs that target similar or dissimilar mechanisms correlate with drug interaction outcomes or lead to the destruction of the bacteria.”

What aspect of your research excites you the most?

“The most exciting part of my research is applying the tools I developed during my postdoc to study another bacterial pathogen. While there’s plenty of troubleshooting involved, that’s part of the fun. Having other Lyme research labs on the same campus is also a huge advantage. Seeing the exciting work happening around me is a constant source of motivation.”

What about TUSM and your research experience has prepared you to be involved in this process?

“During my postdoc, I learned many valuable skills, and I am truly grateful to Dr. Aldridge for her guidance. The way I now approach problems—using quantitative approaches to understand biological processes—has prepared me well to handle large datasets in an efficient and productive manner. Knowing how to work with big datasets is very handy, especially as the datasets produced from experiments seem to get bigger and bigger.”

What do you hope this research will achieve for patients with Lyme disease and the medical community?

“I hope my research can better inform the drug combinations we test in pre-clinical models and perhaps lead to a clinical trial one day. I also hope that the tools I develop are useful for the field and can be modified to address multiple aspects of Lyme research.”

What challenges do you foresee, and how are you addressing them?

“A lot of the challenges I encounter with my research involve translating something that may be easily obtainable in other bacterial systems for use in Borrelia burgdorferi. At times, just working with the bacterium is difficult. However, the Lyme research groups here at Tufts have been extremely supportive and welcoming. The collaborative environment fostered by the initiative is truly special and gives all its members a place to tackle some of the most challenging questions.”

Are there any untapped opportunities in Lyme disease research or perhaps within another public health initiative you’re eager to explore in your career?

“My previous statements kind of hinted at this, but the most exciting opportunity I continue to pursue is building strong collaborations with the researchers involved in this initiative. The combined expertise and knowledge from the Leong and Hu labs have been invaluable as I’ve re-entered Lyme disease research. Beyond that, I’ve developed strong, productive relationships with both groups, which has been key to advancing my work."

Tufts Lyme Disease Initiative

Tufts is home to one of the world’s most comprehensive groups of tick-borne disease researchers. Led by co-directors Linden Hu, Paul and Elaine Chervinsky Professor of Immunology, and Robert P. Smith, a physician at Maine Medical Center and professor of medicine, the team recently secured a $20.7 million federal grant, further solidifying Tufts’ position as a global leader in Lyme disease research.