By Randolph Fillmore
When Martin Trapecar, Ph.D., came to Johns Hopkins All Children’s in May of this year, his arrival opened new doors for him to continue pursuing a question intriguing him since his high school days in his native Slovenia – “What does it mean to be alive?”
“That big question has always been my guiding light,” recalls the biomedical engineer and new assistant professor in the Division of Endocrinology, Diabetes and Metabolism in the Department of Medicine. “I was always fascinated by – and in awe of – nature. However, just understanding biological life in terms of molecules and genetic codes does not really explain what it means to be alive.”
Early in his academic career, he sought to answer the Big Question by investigating plant growth, microorganisms and how elements of nature come together to bestow the gift of life. This led to his investigation of the agricultural sciences by looking at the plants, weather, soil and the wellbeing of animals. He knew he had to be creative in finding answers and look at life from a variety of angles to see how nature composed a “symphony” of life.
Still Searching for Answers
After earning his Ph.D. in biomedical engineering from the University of Maribor in 2014, Trapecar set off on a journey that would eventually bring him to the United States, first as a postdoctoral fellow at the Gladstone Institutes of Virology and Immunology at the University of California San Francisco, then to the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts, where he served as a postdoctoral associate in the Department of Biological Engineering. It was at MIT that he worked with a most influential mentor, one who would point his guiding light toward new tools to unravel the mysteries behind many human diseases.
A Mentor’s Mentor
Trapecar is quick to credit all of his mentors along his academic path, but especially credits Linda Griffith, Ph.D., his adviser and mentor at MIT. Griffith is a professor in MIT’s School of Engineering and serves as “Teaching Innovation Professor of Biological and Mechanical Engineering.” She is a leader in the field of “physiomimetric models,” which involves the integration of tissue engineering and systems biology.
“Linda Griffith is a visionary,” says Trapecar. “She has been leading the way to humanize preclinical research by developing new tools to afford us better insight into human-specific biology.”
The Griffith lab at MIT has spearheaded a program to build the “Human Physiome on a Chip,” in which 10 microphysiological systems, including liver, gut, lung and reproductive systems, were interconnected in a physiologically relevant manner to serve as a model for researching a variety of biological actions and interactions.
While working with Griffith at MIT, Trapecar participated in the development of a physiomimetic model to study the human “gut-liver-brain axis” as it interacts with the immune system under both normal and disease conditions. This work led him to formulate new hypotheses and to look for possible target pathways related to the causes of inflammatory bowel disease and Parkinson’s disease.
“We try to create models of diseases to gain insight into how to treat them, but also to gain new understanding of the very fundamental human biology,” he explains.
In that effort, he has been using a tool that has popularly been called a “human-on-a-chip.” The catch phrase refers to a technology called microphysiological systems that allow scientists to assess many interactions, including the potential effects of new drugs in humans.
“We use this technology to recreate certain facets of human biology and to re-engineer more simplistic versions of disease,” he explains. “Use of human tissue and human cells under highly controlled conditions gives us the opportunity to zoom in to very intricate phenomena.”
These microphysiological systems offer and intriguing glimpse into how disruption in the crosstalk between tissues and the immune system can lead to the early emergence of autoimmune disease, such as inflammatory bowel disease and degenerative disorders. According to Trapecar, using sample human tissues, he can recreate conditions for better understanding the biological aspects unique to humans, as well as stresses and environmental conditions that affect tissues and cells. This is an interest shared by The Johns Hopkins University (JHU) colleagues in the Biomedical Engineering department in Baltimore, and Trapecar is eagerly pursuing cross-campus collaborations to pursue this passion and to integrate into the rich academic environment across the JHU system.
For example, just prior to his arrival at Johns Hopkins All Children’s, Trapecar and colleagues published a study in the journal Science Advances that investigated the use of a technology they developed to study gut-liver-brain interactions in Parkinson’s disease.
“Neurodegenerative diseases are one of the biggest challenges of our time because both environmental and genetic factors are intertwined and work to obscure what causes them,” says Trapecar. “Progress has been slow in the fight against neurodegenerative diseases, but our concept and experimental model of interactive immune-metabolic cross-talk between organ systems is a significant advance.”
In the study, Trapecar and his fellow researchers noted how the gut/microbiome-liver-brain axis links to genetic and environmental factors that contribute to neurodegenerative diseases (NDs) such as Parkinson’s.
“The gut-brain axis operates as a bi-directional communication system integrating the central nervous system with signaling pathways in the endocrine system, metabolism and the immune system,” explains Trapecar. “Our data suggests there is a dysregulation in the gut-brain axis and its metabolic environment in a number of diseases, from inflammatory bowel disease to NDs.”
Trapecar is also interested in identifying and getting a better understanding of which diseases may result from the disruption of organ-to-organ interactions. He suspects that many diseases can be traced to chains of events, some going back to early childhood, that may have contributed to the development of cancer or autoimmune diseases years later.
Diving into Research
The spark of discovering “What does it mean to be alive” is still bright for Trapecar who says he now has direction from two “northern stars” – gaining better understanding of metabolic and immune diseases and building better tools to help us understand them.
While the research he will be carrying out still aims at a better understanding of life, over the years he has focused more tightly on the relationship between – and connections important to – the complexities of both health and disease in the human body. In this regard, he identifies “multiorgan microphysiological systems” (MMPSs) to have the potential to revolutionize preclinical research.
“We are using MMPSs to provide new answers and clarity about metabolic disorders, inflammatory diseases and the immune system and to better understand communication between organ systems working to maintain a healthy homeostasis,” concludes Trapecar. “Our mission is to identify causal relationships between autoimmune, degenerative and metabolic disorders.”
Since his arrival at Johns Hopkins All Children’s, Trapecar established his lab in the Institute for Fundamental Biomedical Research and developed a website explaining his research.
Echoing his original Big Question about life, the question, “What are we curious about?” blazes across his lab homepage. The focus of his research will be on replicating complex human biology; investigating issue homeostasis and regeneration; gaining more insight into immunometabolism in health and disease; and finally (as a reference to what has been driving him since his teens) gaining a better understanding of humanness and the pursuit of life.
Trapecar is also building a group of dedicated researchers, helping to explore the fundamental origins of immune-metabolic diseases.