Nicholas Palmer, a graduate student at the Perelman School of Medicine at the University of Pennsylvania, has been investigating how actin—a protein involved in cancer spread—changes shape during cell movement. Traditional imaging methods have not provided clear answers due to the small size of individual proteins.
To address this, Palmer used a high-powered electron microscope capable of producing detailed images of microscopic biological structures. He prepared millions of frozen protein samples and observed their structure using cryogenic electron microscopy (cryoEM). "When I saw this structure in particular, I jumped up and cheered," Palmer said. "As soon as I saw this, I was like, ‘I know exactly what the mechanism is.’"
CryoEM allows scientists to visualize proteins, nucleic acids, lipids, and organelles in detail. Researchers at Penn Medicine are using this technology to study diseases such as Alzheimer’s disease, cancer, and influenza.
“With this technique, we are seeing a shift towards a detailed understanding of proteins and other components inside the cell, and this is enabling new questions to be answered,” said Vera Moiseenkova-Bell, PhD, professor in Systems Pharmacology and Translational Therapeutics and director of Penn Medicine’s Institute of Structural Biology (ISB).
The ISB was established in 2023 to focus on the shapes and functions of complex biological molecules. It houses 30 research laboratories that use various structural biology techniques including X-ray crystallography and NMR spectroscopy. The institute encourages collaboration across departments at Penn to connect discoveries with clinical research.
E. Michael Ostap, PhD, senior vice dean and chief scientific officer at Penn Medicine whose work centers on cardiac muscle contraction proteins, compared cryoEM’s capabilities to watching an entire football game rather than just its beginning or end. “If you can actually see the different steps during an enzymatic reaction or other dynamic process,” Ostap said, “you can learn what components are important, as well as which components you might target in order to assist or inhibit important cell processes.”
CryoEM involves rapidly freezing samples at extremely low temperatures using liquid ethane before imaging them with electrons. This process preserves delicate structures by turning water into a glass-like solid instead of ice crystals that could damage specimens.
The resulting images are processed by computers that reconstruct three-dimensional models from thousands of two-dimensional snapshots—a method called single particle analysis. Cryo-electron tomography (cryoET), a related approach, takes multiple images from different angles for even more detailed reconstructions.
Compared with previous gold-standard techniques like X-ray crystallography—which requires forming rigid crystals—cryoEM provides easier sample preparation and reveals molecular behavior closer to natural conditions.
Penn’s Beckman Center for Cryo-Electron Microscopy houses two cryo-electron microscopes used by researchers from biomedical sciences as well as engineering disciplines across campus. The equipment was funded by support from the Arnold & Mabel Beckman Foundation and the National Institutes of Health.
Moiseenkova-Bell has initiated seed grants for collaborative projects involving cryoEM throughout the university. She envisions future efforts mapping every protein within cells for comprehensive understanding—a resource akin to a cellular map showing each component's role in health.
Recent findings at Penn Medicine demonstrate how investments in cryoEM are advancing knowledge about disease mechanisms and drug discovery strategies—including studies on parasites’ effects on cells; neurobiological disorders like Alzheimer’s; lysosome function; vaccine development; cardiovascular treatments; cancer metabolism; chromosome division; and actin dynamics during metastasis.
