For decades, biological imaging has been a game of trade-offs. If a scientist wanted to see the complex cellular structures, they turned to electron microscopy. If they wanted to track a specific protein, they used fluorescence. However, seeing both at the same time, in the same image, remained an elusive goal. 

The problem with traditional methods lies in their inherent limitations. While fluorescence is excellent for labeling, it lacks context. However, a team at Harvard University has found a solution, bridging this gap with a technique called multicolor electron microscopy.

Debsankar Saha Roy, a Harvard postdoctoral fellow in the laboratory of Maxim Prigozhin, explained:

"The resolution is limited to about 250 to 300 nanometers, so you can't see individual proteins clearly. But the bigger issue is that you don't see the structure of the cell. You see whatever is labeled, but you don't see everything else around it."

To solve this, the researchers looked toward a phenomenon known as cathodoluminescence. Instead of trying to overlay two different images taken at different times, which is a process fraught with alignment errors, they designed a system that extracts two types of data from a single electron beam.

Roy said:

"I've always been fascinated by developing new microscopy techniques that can image things we haven't seen before. We're building a multicolor electron microscope—a technique that combines the benefits of electron microscopy and fluorescence microscopy."

The mechanism is a departure from how scientists think about light and electrons. He added:

"We're not sending in light—we're sending an electron beam. We have probes that you can attach to a protein that emit visible light when excited by electrons. This process is called cathodoluminescence. So from the same electron beam, you get two sets of information: the colored signal from the probes, and also the detailed structural image from the electrons."

During their experiments, the team stumbled upon a revelation that simplifies the entire process. They found that the specialized nanoparticles they were developing weren't the only tools available. 

According to Roy, when the standard dyes used in fluorescence microscopy interact with electrons, they emit visible light. Moreover, there is no need to create new dyes and protein labelling methods since they are already developed, more so available.

This capability has already been tested on mammalian cells and even fungus-infected flies, proving its utility across different biological tissues. However, the researchers are not stopping at flat, two-dimensional images. The objective is to bring this vivid color into three-dimensional modeling.

Roy stated:

"We want to extend this multicolor electron microscopy approach to 3D. To get there, we aim to implement this technique in ultrathin sections of cell embedded matrices and/or in cryo-electron microscopy—that's the next step."

Read the full article here to learn more about multicolor electron microscopy.

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