Emory biophysicist Shashank Shekhar’s research into tiny cellular force generators nets two major federal awards

Emory biophysicist Shashank Shekhar’s lab helped to turn four decades of cell biology on its head with the discovery that thin protein fibers known as actin filaments could grow from both ends, rather than just the barbed end.

Actin is a vital protein that gives cells their shape and drives cellular movement. The newly discovered mechanism opened new lines of inquiry for scientists researching everything from the spread of infectious diseases to muscle disorders to cancer cell metastasis.

This summer, Shekhar won two major funding awards in recognition of the huge impact of his work to understand the tiny threads: the elite National Science Foundation (NSF) Faculty Early Career Development (CAREER) Program grant and renewal of a National Institutes of Health Maximizing Investigators’ Research Award (NIH MIRA).

Together, the grants provide Shekhar and his lab $3.5 million in funding for five years of additional study of nano-scaled cellular processes and actin growth.

“What makes us unique is we are looking at basic biological problems from the perspective of physics, biology and chemistry and using both experiments and theory,” says Shekhar, assistant professor of physics in Emory College of Arts and Sciences with dual appointments in cell biology and biochemistry in Emory School of Medicine.

“I am grateful for the support,” he adds. “We question how actin does what it does and how it generates the forces for that. We are basically interested in actin dynamics.”

Accidentally finding a career in biophysics 

Shekhar’s interest in actin developed after he completed his undergraduate degree in physics and was pursuing his master’s in nanoscience.

He had “not a lot going on that week” when he sat in a Biology for Physicists workshop. One of the speakers shared a short movie showing the microscopic view of actin pushing Listeria bacteria around in a mammalian cell.

“That’s when I learned of actin and that it was a protein,” Shekhar says. “The bacteria learned that if it could polymerize actin on its back, it could hijack the cell and use actin to move using the host cell’s own energy and resources. That was fascinating to me.”

He was so interested in learning more that he searched for the few researchers around the world working with actin. He talked his way into a summer working in the French National Centre for Scientific Research under cell biologist Marie-France Carlier. 

Despite a lack of exposure to biology research — his Paris colleagues had to teach him how to hold a pipette — Shekhar was hooked. He earned his master’s in nanoscience and molecular bioengineering, then went on to earn his PhD in biophysics, building and using physics tools to pursue biological questions.

After two postdoctoral positions and a brief stint in management consulting, Shekhar arrived at Emory in the fall of 2020, focused on broadening scientists’ understanding of the molecular mechanisms involved in the regulation of actin dynamics.

Asking fundamental questions

Since the 1960s, molecular biologists have known that actin filaments form the key part of a cell’s structure, making them essential for muscle contraction, cell division and intracellular transport of materials such as organelles.

Three other proteins influence actin to either grow into those filaments, stop growing or disassemble the filaments. 

Shekhar’s team tags those single protein molecules with different fluorescent dyes that can be seen with high-power lasers under a microscope. Using single-molecule imaging, they have identified two specific proteins (leimodin and Vibrio outer protein F) that can drive growth on the other, pointed, end.

“He is asking very fundamental, important questions about how the machine that drives how our cells moves,” says Anita Corbett, Samuel C. Dobbs Professor of Biology and senior associate dean for research for Emory College.

“And,” she adds, “he is using cool fluorescent tools and microscopy to be creative in the way he asks the questions, so that we can see his answers with our own eyes. His approach combining biochemistry, cell biology and biological physics highlights the power of interdisciplinary research at Emory.”

The elite funding awards advance his innovative work. They also allow Shekhar to continue recruiting graduate and undergraduate students and postdoctoral scientists to work in his lab. He remains hands-on with many of the experiments but also encourages his trainees to take the lead.

For example, a PhD candidate in his lab, Sudipta Biswas, was first author on a new paper published in Nature Communications that shows mutations in leimodin can make actin filaments too short in muscle cells. The finding has direct implications for dilated cardiomyopathy, where shortened filaments lead to thinned heart muscle.

“This is very basic science, but if you can uncover the mechanism of disease, that is the first step to try to fix it,” Shekhar says. “I love how discoveries at a basic level may explain the mechanism of diseases, but I also want to understand how these proteins do what they do. I’m happy this job allows me to do both.”