Bartesaghi Receives $2.3 Million NIH MIRA Award to Advance High-Resolution Imaging of Proteins Inside Cells

Alberto Bartesaghi, professor of Computer Science, Biochemistry and Electrical and Computer Engineering, has received a five-year, $2.3 million Maximizing Investigators' Research Award (MIRA) from the National Institute of General Medical Sciences (NIGMS) to develop new computational methods that reveal the three-dimensional structures of proteins in their natural cellular environment. 

Proteins are the molecular machines that carry out nearly every function in living cells. Understanding their structures is essential for explaining how they work, how they malfunction in disease and how they can be targeted by new therapies. While recent advances have made it possible to visualize isolated proteins at near-atomic resolution, many proteins behave differently inside the crowded, complex environment of a living cell. 

Cryo-electron tomography (cryo-ET) is helping bridge that gap. By rapidly freezing cells and imaging them from multiple angles, the technique produces three-dimensional snapshots of intact cellular landscapes, allowing scientists to observe proteins and larger molecular assemblies in place rather than in isolation. But the method remains computationally demanding, and extracting high-resolution structures from often noisy imaging data is a major challenge. 

Bartesaghi's laboratory develops algorithms and software that push the limits of what cryo-electron microscopy and tomography can reveal. With support from the new award, the team will create computational methods to improve both the quality and diversity of structures determined through cryo-electron tomography and sub-tomogram averaging — an approach that combines information from many copies of the same molecular complex to produce sharper, more detailed reconstructions. 

The project seeks to make these techniques more broadly applicable across structural biology, enabling researchers to study increasingly complex biological systems directly within their native environments. Improved computational tools could help scientists better understand fundamental cellular processes and accelerate discoveries relevant to cancer, neurodegenerative disorders, infectious diseases and many other areas of biomedical research. 

“Being able to see proteins at high resolution inside cells, rather than in isolation, changes how we understand biology,” Bartesaghi said. “This award allows us to push cryo-electron tomography methods so we can solve difficult structures in their native cellular context.” 

The software developed through the project will be released through the Bartesaghi Lab's open-source nextPYP framework, allowing researchers around the world to incorporate the new methods into their own cryo-electron microscopy and tomography workflows. By lowering technical barriers and improving the accuracy of structural analysis, the platform aims to expand access to state-of-the-art imaging technologies and speed progress across the structural biology community. 

The award, an R35 Established Investigator Award, provides long-term support to investigators with exceptional records of scientific productivity, giving them the flexibility to pursue ambitious, high-impact research programs rather than a single narrowly defined project. MIRA awards are designed to encourage innovation while reducing the administrative burden associated with multiple grants, allowing researchers to adapt their work as new scientific opportunities emerge.