Laszlo Nagy, M.D., Ph.D., likes to look at problems from a different direction.
When considering how the body responds to inflammation, the instinct of many is to suppress the cause of the inflammation. Nagy seeks to understand how the body functions correctly and how that knowledge might be applied to intervene to prevent or more rapidly heal inflammation rather than just suppress it.
Collaborating with Harvard University’s Matthew Spite, Ph.D., and others, Nagy and co-lead author Andreas Patsalos, Ph.D., recently published their work in the prestigious journal Nature Immunology that describes the role of white blood cells called macrophages in the muscle regeneration process. When operating properly, macrophages help clear the body of bacteria, viruses, fungi and parasites. When inflammation is present, macrophages can convert from pro-inflammatory to pro-resolving—cell-signaling molecules formed by the metabolism of polyunsaturated fatty acids—to help the healing process. But a malfunction or imbalance in macrophages can compromise the immune system and the response to inflammation.
“I wanted to identify the features of the healing macrophage,” says Nagy, co-director of the Johns Hopkins All Children's Institute for Fundamental Biomedical Research and professor of medicine in the Department of Medicine, Division of Endocrinology, Diabetes and Metabolism in the Johns Hopkins University School of Medicine. “People identify inflammation as something bad, and they want to suppress it, to eliminate it. My idea is that inflammation and inflammatory responses are in us for a reason and that is not to cause disease. We find them when there is a disease.
“I decided that instead of taking disease tissue and understanding what’s wrong with the macrophage, I first wanted to understand how the macrophage helps the tissue to function. Rather than try to suppress the inflammation, I want to identify pathways to help tissue to heal and regenerate.”
For the paper, Nagy and his collaborators created a comprehensive map of which lipids—fats or fat-like substances—are produced at different stages of the regeneration process and they outlined how specific lipids contribute to and promote muscle regeneration. For instance, a lipid known as Resolvin D2 shows promise as an accelerator of the transition from inflammatory macrophage to repair. Nagy and others plan more research to understand how the lipids contribute and how they might be used to address inflammatory injuries whether they are chronic conditions such as complications from diabetes or more routine conditions such as soreness in athletes.
“This whole process is very important. If you are able to regulate how the inflammatory macrophage becomes a repair type one, that’s like the Holy Grail because then you can control chronic inflammation,” Nagy says.
The Man Behind the Science
Nagy remembers himself as a sickly child, in and out of the hospital more than he cares to count.
“I was in the hospital too many times,” says Nagy, who outgrew the diseases and allergies that caused his uncontrolled coughing. “Somehow that implanted in my head that I should be able to understand diseases. There was no question in my mind that I should be a physician.”
Nagy’s father was a veterinarian and his mother a pharmacist, but Nagy decided to focus on human medicine. In his native Hungary, aspiring doctors enter a six-year medical program upon completing high school.
“After two years, I realized that what I really was interested in was the basic science,” he says.
Nagy earned his medical degree at the University Medical School of Debrecen, Hungary, but he never practiced clinically. He earned a Ph.D. also at that institution on work done at the University of Texas Health Science Center at Houston. Nagy did a post-doctoral fellowship at the Salk Institute for Biological Studies in La Jolla, California. He returned to the University of Debrecen, working his way up to full professor in the Department of Biochemistry and Molecular Biology. He still maintains a small lab and active collaboration in Hungary, which contributed informatics support for the macrophage study.
Nagy, who has a wife and two sons, most recently worked successfully on grant-funded research as a professor and founding director of the Genomic Control of Metabolism Program at the Sanford Burnham Prebys Medical Discovery Institute in Lake Nona, Florida. As Sanford Burnham prepared to close its Lake Nona campus, Nagy joined Johns Hopkins All Children’s in 2018.
“This is the right combination of things,” Nagy says of joining Johns Hopkins All Children’s. “I wanted to stay in Florida. It’s more a research institute than a university, but because it’s Johns Hopkins, it’s linked to a long tradition of academic medicine. I wanted to be in an academic medical center where I can have conversations with clinicians. They have a patient with a disease, and we try to apply this knowledge to solve that problem.”
Applying What They’ve Learned
Now that they understand that specific lipids can promote tissue regeneration, the researchers want to learn how to turn on—activate—or turn off lipids to enhance recovery. They will study how to enhance production of beneficial lipids or inhibit degradation of them. Nagy believes dietary interventions such as polyunsaturated fatty acid supplements might be able to contribute.
Nagy has several plans to follow up with more studies related to the role lipids play in muscle regeneration. He has an upcoming project with the Myology Institute at the University of Florida to study how the knowledge might be applied to Duchenne muscular dystrophy, an inherited chronic disease that results in rapid muscle deterioration. He plans to seek grant funding to apply the findings to diseases such as diabetes.
“The next step is to apply this to diseases where it is very relevant, such as Duchenne muscular dystrophy, where there is dissociation between inflammation and the repair activities,” Nagy says. “We hope to create a more coordinated cell response to injury and eventually improve lifespan or quality of life for those kids.”