UC Berkeley physicists have developed a laser phase plate for electron microscopes, a breakthrough that enables researchers to visualize proteins and cellular structures previously invisible to science. By using the world’s most intense continuous-wave laser to shift the phase of an electron beam, this technology allows for high-resolution imaging of molecules as small as 50 kilodaltons, according to research published June 11 in the journal Science.
How does the laser phase plate improve microscopy?
The laser phase plate increases the signal-to-noise ratio in cryoelectron microscopy (cryo-EM), allowing scientists to distinguish small, faint molecules from the crowded environment of a living cell. According to UC Berkeley professor Holger Müller, the device works by interacting with the electron beam to change its phase, which boosts contrast for small biological structures like hemoglobin, mitochondria, and the cell nucleus. While traditional cryo-EM often struggles with objects smaller than 70 kilodaltons—covering the majority of the human proteome—this new method expands that capability significantly, with potential to reach 17 kilodaltons in future iterations.
The microscope used for this research, named “Theia” after the Greek Titaness of light, uses a laser intensity of 75 kilowatts focused to a few microns. This is more powerful than industrial welding lasers.
What is the difference between cryo-EM and cryo-ET?
While both techniques utilize electron beams, they serve different primary functions in biological research. Cryo-EM, which earned a Nobel Prize in Chemistry in 2017, is generally used to determine the structure of isolated proteins in a solution. In contrast, cryo-electron tomography (cryo-ET) assembles multiple angular views to create 3D images of proteins within their natural, crowded cellular environment. Bridget Carragher, founding technical director of imaging at Biohub, notes that finding specific proteins inside a cell is “like trying to find one leaf on one tree in a forest.” The laser phase plate provides the contrast boost necessary to make these internal cellular structures visible.
Why does this matter for drug discovery?
The inability to image small proteins has been a major bottleneck in medical research. Many human proteins involved in diseases are too small or lack the stability to be analyzed by standard imaging techniques. By enabling clear images of these smaller proteins, the laser phase plate could accelerate the development of new pharmaceuticals. According to Stephani Otte, Biohub’s Vice President of Imaging Science, the ability to see how molecular machines operate inside living cells represents a “step function change” for biology, potentially redefining how scientists understand and treat disease.
Comparison: Traditional Microscopy vs. Laser-Enhanced Imaging
| Feature | Standard Cryo-EM | Laser Phase Plate |
|---|---|---|
| Smallest Protein Size | ~70 kilodaltons | 50–17 kilodaltons |
| Imaging Context | Isolated in solution | Inside natural cells (via cryo-ET) |
| Contrast Method | Defocused beam | Focused beam + Phase shift |
If you are working with proteins smaller than 70 kilodaltons, researchers suggest that using a laser-enabled microscope is likely to produce higher-quality data compared to standard, non-laser-equipped cryo-EM machines.
Frequently Asked Questions
- What is a phase plate in microscopy? It is a component that shifts the phase of light or electrons to create visible contrast in otherwise transparent biological samples.
- Who led the development of the laser phase plate? The development was led by Holger Müller, a physics professor at UC Berkeley and faculty scientist at Lawrence Berkeley National Laboratory.
- Why is it difficult to image small proteins? Small proteins scatter fewer electrons, resulting in a low signal-to-noise ratio that makes them difficult to distinguish from the background.
- Is this technology available now? Yes, the team has successfully demonstrated the system on a Thermo Scientific Krios cryo-EM machine, with further development underway at Biohub.
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