After years of studying how pathogenic bacteria make us sick, a physician and researcher at Tufts University School of Medicine is using her knowledge to create a new way of delivering medicine. Cammie Lesser, an associate professor, is re-engineering the tools of those bacterial bad guys to create “smart microbes” that secrete therapeutic compounds in the body at sites of disease.

“We’re trying to figure out how to transform bacteria into therapeutic devices,” she said. 

Lesser came to Tufts in March 2025 as part of a microbiome-themed cluster hire initiative between Tufts University School of Medicine and Tufts Medicine, along with Kevin Bonham, a gastroenterologist and assistant professor at the School of Medicine. The goal of the recent cluster hires is to increase interdisciplinary research across departments and divisions at Tufts Medical Center and the School of Medicine. 

The notion of the interdisciplinary focus suits Lesser. “As a physician-scientist, I’ve always been interested in trying to figure out how to increase interactions between physicians and scientists,” she said. 

Understanding Pathogens, Harnessing Them for Good

More than 20 years ago, Lesser set up her lab with a goal of understanding how bacterial pathogens do their dirty work. She became fascinated by the needle-shaped structures called type III secretion systems that pathogenic bacteria use to inject proteins directly into human cells. 

“These bacterial secretion systems have about 25 different parts that come together to form a beautiful nanomachine that basically serves as a conduit that transfers proteins from bacteria into human cells to help cause an infection,” she said. These proteins have functions ranging from dampening our immune response to setting up bacteria factories in our cells.

Lesser is an infectious disease doctor as well as a researcher, so while she was engaged in the basic science of discovering more about how secretion systems work, she was also thinking about how to help people. “In the back of your brain, the gears are always turning,” she said, “and at one point it clicked.” 

She decided to try to move a modified version of the secretion system from a pathogenic bacterium to a probiotic one – a type of E. coli that commonly lives in the human gut with no ill effects. Her goal was to enable the probiotic bacteria to secrete proteins of therapeutic value, specifically small antibodies called nanobodies. 

To test the idea, Lesser decided to apply it to the problem of reducing inflammation for people with inflammatory bowel disease (IBD). She and her collaborators had to figure out how to move the modified secretion machine into the probiotic E. coli and how to outfit it to secrete the desired nanobodies into the gut environment, rather than into human cells. They succeeded on both fronts and demonstrated the results in mice.

The new strategy has several advantages over current IBD therapies. Patients with moderate disease are often treated with large antibodies, given intravenously, that suppress inflammation. Because the molecules are given in the bloodstream, they can have unintended consequences. For example, patients can become immunocompromised and are susceptible to certain infections, like tuberculosis or brain abscesses. As a physician, Lesser has seen patients with these types of serious side effects in the hospital.

The nanobodies that Lesser’s engineered bacteria make and secrete recognize the same target as the large antibodies but are much smaller. That means the bacteria could be given orally rather than by IV. The bacteria would then set up shop in the digestive tract where they would pump out the therapeutics into the gut, the main site of disease. Delivering the antibody just where it’s needed would likely reduce side effects.

More questions remain to be answered before this smart microbe becomes available to use in the clinic, but Lesser is encouraged by her results so far. Lesser calls the microbe “PROT₃EcT,” short for “probiotic type III E. coli therapeutic.”

Collaboration Opens up New Avenues

PROT₃EcT can be engineered to secrete a variety of therapeutics, Lesser said, giving rise to many other potential applications. In fact, even before coming to Tufts, Lesser worked with John Leong, chair of the Department of Molecular Biology and Microbiology at the School of Medicine, to demonstrate the ability of these smart microbes to delay infections with a particularly virulent strain of E. coli. Lesser and Leong met 40 years ago at Brown University when she was a rising junior and he was a graduate student. “He became my mentor,” she said. “We initially published together in 1985 and most recently in 2024.” 

She is also planning to work with Aimee Shen, associate professor in the Department of Molecular Biology and Microbiology, to see if variants of PROT₃EcT can treat or prevent recurrent C. difficile infections.

Lesser looks forward to working with Bonham as well. “We’re both interested in the gut microbiome,” she said, “and we have complementary skill sets. There are ways we could synergize.” His computational and machine learning skills could shed light on how smart microbes could be developed to improve the composition of the gut microbiome in disease states, for example. 

The potential applications reach even to cancer. Bacteria such as E. coli grow well in cancerous tumors, so Lesser wants to engineer bacteria that could secrete proteins to kill the cancer. “I’m hoping to meet people at Tufts to help figure out what to target in tumors,” she said.

Lesser sees collaborations as a way to expand the reach and impact of her research and is looking forward to exploring the possibilities to do that at Tufts, with Bonham and others. “There’s room to grow here,” she said.