The lab studies how the dynamic F-actin scaffolding creates particular cell shapes and how this contributes to normal cell function or dysfunction. The research is focused on red blood cells, the cells in the ocular lens and cells in the musculoskeletal system.

“We’re trying to understand the locations of F-actin structures [inside the cells], their dynamic organizations, shapes and the gradients of concentration, and how they contribute to cell functions. I just love that interplay,” Fowler said. 

Fowler and her team are examining two different aspects of F-actin in red blood cells: how the red blood cell precursors rearrange their F-actin to get rid of their nucleus, enabling the mature cells to circulate many times through the tiny capillaries; and how F-actin assembles into a thin network at the membrane (skin) of the cell and interacts with a motor protein called myosin to control cell shape and flexibility. 

The work with the ocular lens studies how F-actin structures in lens cells contribute to lens transparency and focusing for vision. The research in bone, cartilage and tendon cells examines how F-actin structures are maintained to prevent problems in the musculoskeletal system. The latter work is done with the Delaware Center for Musculoskeletal Research Center.

The broad impact of F-actin in cells was one of the reasons biomedical engineering doctoral student Heather Malino joined Fowler’s lab. She was attracted to the foundational aspect of the research, rather than specializing in practical solutions to health problems like prosthetics. 

“Learning about the fundamental biological phenomenon that happens can be really rewarding because you’re looking at the cellular and molecular processes,” she said. “You find out something about the lens, but cells are cells. So things that we learned about the lens, can also be more overarching to different processes in the body.”

Building on the past

The work builds on groundbreaking discoveries related to the F-actin network that Fowler has made throughout her 40-year career. As a post-doctoral fellow Fowler was the first to discover myosin in red blood cells. Without myosin motors pulling on F-actin networks to create tension, the red blood cell precursors would not be able to generate enough force to expel their nucleus, and the mature cells would not be able to withstand the repetitive cycles of deformation, folding and unfolding required during their lifespan.

She also discovered a previously unknown protein called tropomodulin. Tropomodulin stops the ends of the F-actin from growing or shrinking, stabilizing them at a certain length. When the filaments are the same length, the networks they create when binding to other proteins in various types of cells are stronger and more stable. If the filaments are different lengths, the networks are irregular and mechanically weaker, and cell shapes are abnormal.

Fowler showed that tropomodulin's function is critical for development of the heart and blood cells, and for proper function of many cells and tissues, including eye lens, neurons in the brain, epithelial cells lining the gut, endothelial cells lining blood vessels, as well as platelets, red blood cells. It is required for efficient muscle contraction in both skeletal and cardiac muscles.

“I started with a molecule that had a function in one tissue, and I thought the function had to happen in these other tissues,” she said. “I connected the dots.” 

Recently, Fowler was part of a team that discovered that a mutation in the tropomodulin proteins which prevents the protein from functioning properly causes a severe inherited cardiomyopathy in children. This is the first time the protein’s function has been directly linked to heart disease in humans. The research was published earlier this month in the journal Communication Biology. 

Fowler was recently recognized as a 2023 Lifetime Fellow of the American Society of Cell Biologists (ASCB), partly for her work on tropomodulin. She is one of 19 scientists from around the world to receive the honor this year. The society includes the top researchers in the field and counts several Nobel Prize winners as members. 

“Dr. Fowler has advanced our understanding of fundamental questions in cell biology,” Jia Song, associate professor of biological sciences, said in her letter nominating Fowler for the award. “Her groundbreaking work, published in more than 140 research articles, has significantly advanced our understanding of actin cytoskeletal function in architecture and behavior of diverse cells.”

Her advice for young scientists? Have a hypothesis, do good experiments, follow your notes, read widely and look for connections, especially when things don’t work as expected, as that may lead to the next experiment.

“You might show her something and you're not proud of it because it didn't work, but she's always wants to know that,” said Dimitri Diaz, a doctoral student in the lab. “Sometimes she loves the negative data more than the positive in some regards, because negative data doesn't mean it’s bad. It just means it didn’t work.”

Fowler attributes her long and prestigious career to lifelong curiosity and being comfortable with risk and uncertainty. 

“Something I personally discovered because I was curious and thought about it has now been written into a textbook as 'this is how muscle filament lengths are regulated.’ I like that,” she said with a smile.