Almost a century ago, a breakthrough in microscopy gave scientists an entirely new way to examine the inside of cells. Known as phase contrast, the technique made previously faint or nearly invisible cellular structures much easier to distinguish. Its importance was recognized with a Nobel Prize in 1953.
Now, physicists at the University of California, Berkeley, have brought that same principle to electron microscopy, a technology capable of magnifying objects roughly 10,000 times more than conventional light microscopes. The researchers have developed a device called a laser phase plate that could significantly improve cryoelectron microscopy (cryo-EM). This powerful imaging method has transformed the study of protein structures and helped speed up drug discovery over the past decade.
Even so, it has a major limitation: Most human proteins are so small that obtaining clear images of them remains extremely difficult. The new laser technology could help overcome that obstacle, potentially allowing scientists to image proteins as small as one-third the size of those that challenge current microscopes. An even greater impact could come from improvements to cryoelectron tomography (cryo-ET).
This newer approach combines images captured from multiple angles to construct three-dimensional views of proteins and other molecules. Unlike techniques that study isolated molecules in a solution, cryo-ET can reveal how proteins are arranged and interact within their natural cellular surroundings. The increase in signal-to-noise ratio provided by this laser phase plate is expected to overcome these important limitations.” The breakthrough relies on what the researchers describe as the world's most intense focused continuous-wave laser.
Rather than simply illuminating a specimen, the laser interacts directly with the microscope's electron beam, altering its phase to increase image contrast. This adjustment makes it easier to distinguish small molecules, including hemoglobin, from their surroundings. It could also improve the visibility of structures inside cells, such as the nucleus and mitochondria.
Cryo-ET needs a dramatic step forward in contrast, so we can start to see what's going on inside the cell. That's what the laser phase plate promises to give us.” With financial support from Biohub, Müller acquired an advanced cryo-EM instrument and equipped it with the new laser phase plate. He named the resulting microscope Theia, after the ancient Greek Titaness associated with light and radiance.
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