Scientists have developed a new imaging technique that uses a new contrast mechanism in bioimaging to merge the advantages of two powerful microscopy methods, allowing researchers to see both the complex architecture of cells and the specific locations of proteins – all in vivid color and at nanometer resolution.
The discovery, called multicolor electron microscopy, addresses a long-standing challenge in biological imaging: scientists have traditionally had to choose between seeing fine structural details or tracking specific molecules, but not both at the same time.
The approach opens doors to studying everything from cell signaling to the organization of molecular clusters within cells, all while seeing exactly where these processes occur within the cell’s architecture. The research will be presented at the 70th Annual Meeting of the Biophysical Society in San Francisco from February 21 to 25, 2026.
I’ve always been fascinated by the development of new microscopy techniques that can image things we’ve never seen before. We are building a multicolor electron microscope—a technique that combines the benefits of electron microscopy and fluorescence microscopy.”
Debsankar Saha Roy, a postdoctoral fellow in Maxim Prigozhin’s lab at Harvard University
Traditional fluorescence microscopy works by attaching glowing labels to proteins of interest and then shining visible light into the sample to make those labels light up. This approach is excellent for identifying specific molecules, but has significant limitations. “The resolution is limited to about 250 to 300 nanometers, so you can’t see individual proteins clearly,” Roy explained. “But the bigger issue is that you don’t see the structure of the cell. You see everything that’s labeled, but you don’t see everything else around it.”
The electron microscope, on the other hand, can reveal cellular structures in exquisite detail—down to a few nanometers—but has traditionally been unable to identify specific molecules in color. Scientists have tried to combine the two approaches by taking separate images with each method and then overlaying them, but aligning the images accurately, especially in large samples like brain tissue, has proven extremely difficult.
The Harvard team’s solution is elegant: instead of using two separate imaging sessions, they use a single electron beam to accomplish both tasks simultaneously.
“We’re not sending light—we’re sending a beam of electrons,” Roy said. “We have probes that you can attach to a protein that emits visible light when excited by electrons. This process is called catholuminescence. So from the same electron beam, you get two sets of information: the color signal from the probes and also the detailed structural picture from the electrons.”
A key advantage of the technique is that researchers can use existing fluorescent dyes that are already widely available and well characterized. The team had previously developed lanthanide nanoparticles as probes for color electron microscopy and was working to attach them to proteins.
More recently, the team made a surprising discovery when they placed some common fluorescent dyes in the electron microscope. “The most surprising thing we noticed was that standard dyes used in fluorescence microscopy also emit visible light when you excite them with electrons,” Roy said. “This has never been seen before. And these dyes—and their protein-labeling methods—are already developed and available, there’s no need to create anything new.”
The team has already demonstrated that the technique works in mammalian cells and biological tissues, including flies infected with fungi.
Looking to the future, the researchers aim to extend the technique to three dimensions. Currently, the method produces flat, two-dimensional images. The next frontier is adapting it for use with cryo-electron microscopy—a technique where samples are flash-frozen, preserving cells in their native state and allowing scientists to image them from multiple angles to create three-dimensional reconstructions.
“We want to extend this colorful electron microscopy approach to 3D,” Roy said. “To get there, we aim to apply this technique to ultrathin sections of cell-embedded matrices and/or to cryo-electron microscopy – that’s the next step.”
