Building better tools to decipher the lipidome

Matthew Mitsche, a junior associate editor of the Journal of Lipid Research, began his scientific journey in chemical engineering, where he built a strong foundation in logic, quantitative thinking and problem-solving. That training shaped how he approached questions, but his curiosity soon expanded beyond traditional engineering, drawing him toward the biological questions that underlie human health.

Matthew Mitsche

That drive led him to pursue a Ph.D. in biophysics and physiology, an interdisciplinary field that merged his love of precision with a fascination for living systems. At Boston University, he joined the lab of Donald Small, a pioneering figure in protein and lipid research, where he began studying how lipoproteins assemble, using apolipoprotein B as a model system.

In Small’s lab, Mitsche used a technique called drop tensiometry, which involves adding peptides to a solution and measuring how they alter the surface tension at a lipid–water interface. At the same time, the research landscape was shifting toward increasingly data-intensive approaches. Drawing on his chemical engineering background, Mitsche quickly resolved key technical challenges and streamlined data analysis. His coding skills reduced analysis from days to minutes, offering an early glimpse of the efficiency and creativity that would come to define his work.

As he neared the end of his graduate work, Mitsche decided that, to push his research questions further, he needed to learn mass spectrometry–based lipidomics. This rapidly growing field, which combines analytical chemistry with mass spectrometry, is becoming essential for answering complex questions about lipid metabolism in cells.

To address this gap, Mitsche joined Helen Hobbs and Jonathan Cohen at the University of Texas Southwestern Medical Center as a postdoctoral fellow. While working on a cholesterol transporter, he learned mass spectrometry, or MS, with Jeff McDonald, as well as stable isotope labeling, or SIL, a technique used to track metabolite biosynthesis. Mitsche said the team had been struggling for nearly a decade to uncover the function of an enzyme called patatin-like phospholipase domain-containing protein 3, or PNPLA3, which is the strongest known genetic risk factor for nonalcoholic fatty liver disease, or NAFLD.

“It’s frustrating,” Mitsche said. “But, that’s the way it goes.”

Motivated to better understand the molecular drivers of metabolic disease, Mitsche launched his own lab as an assistant professor in the Center for Human Nutrition, UT Southwestern Medical Center.

Mitsche said that one of his major goals was developing technology that improves the signal-to-noise ratio, or S/N, of SIL on fatty acids. More broadly, he aimed to build tools that could efficiently analyze lipid metabolism across all major lipid classes.

During a three-week on-site visit with Thermo Scientific engineers, he implemented short SIL labeling periods with deuterated water to improve S/N performance on an ultrahigh-resolution mass spectrometer. Without the robotic arm needed for direct infusion, he manually injected thousands of samples and adjusted the instrument parameters until the shorter labeling period produced a stronger signal. When he returned with the data, he showed his department chair that the instrument performed as expected and justified the investment.

“It was nice, fun but intimidating, as (I was) the first one to use a new instrument,” Mitsche said.

That mix of challenge and discovery reflects how he approaches science more broadly.

“I am ultimately an engineer,” Mitsche said. “Almost everything I have done has been focused on developing and applying new technologies to problems and new ways to approach problems. Working with doctors, as most of my mentors (have), grounded me to solve real-world medical problems.”