UC Berkeley physicists have developed a laser phase plate for electron microscopes that significantly boosts image contrast, potentially allowing researchers to visualize small human proteins that were previously invisible. By using an intense continuous-wave laser to shift the phase of an electron beam, this technology overcomes long-standing signal-to-noise limitations in cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET), according to research published in the journal Science.
How does the laser phase plate improve microscopy?
The laser phase plate increases the contrast of images by manipulating the electron beam, allowing it to capture structures that are too small or faint for traditional imaging. According to UC Berkeley physics professor Holger Müller, the device uses the world’s most intense, focused continuous-wave laser to interact with the electron beam. This interaction creates a 90-degree phase shift in the beam, which enhances the visibility of small molecules like hemoglobin and delicate cellular structures such as mitochondria. While traditional cryo-EM often struggles with objects smaller than 70 kilodaltons, this new method aims to resolve structures as small as 17 kilodaltons.
The device is named “Theia,” after the ancient Greek Titaness of light and radiance. It incorporates a mirrored cavity that reflects the laser beam over 10,000 times to reach an intensity of 75 kilowatts, exceeding the power used in industrial welding.
What is the difference between cryo-EM and cryo-ET?
Cryo-EM and cryo-ET serve different purposes in structural biology, though both rely on frozen samples to prevent radiation damage. Cryo-EM is primarily used to determine the structure of isolated molecules or proteins in a solution, providing high-resolution “snapshots.” In contrast, cryo-ET assembles multiple angular views of a sample to create a 3D image, enabling scientists to observe proteins within their natural, crowded cellular environment. Bridget Carragher, founding technical director of imaging at Biohub, notes that cryo-ET is essential for finding specific “leaves” in the “forest” of a cell, but it requires the dramatic step forward in contrast that the laser phase plate provides.
Why does this matter for drug discovery?
Most human proteins are currently too small to be analyzed by standard electron microscopy, creating a major gap in biomedical research. By enabling the clear imaging of proteins down to one-third the size of current capabilities, the laser phase plate could accelerate the discovery of new drugs. Stephani Otte, Vice President of Imaging Science at Biohub, states that this technology represents a “step function change” for biology, as it allows researchers to watch molecular machines operate inside living cells in real-time. This shift from static, isolated imaging to dynamic, in-context observation could fundamentally alter the understanding of disease mechanisms.
Pro Tip: The Evolution of Phase Contrast
The concept of phase contrast dates back to 1930, when Dutch scientist Frits Zernike discovered that shifting the phase of light could make transparent biological samples visible without staining. The new laser-based electron microscope essentially updates Zernike’s Nobel Prize-winning work for the nanoscale, replacing optical light with an electron beam.
Frequently Asked Questions
- Why can’t we just use standard microscopes for small proteins?
Standard light microscopes cannot resolve objects at the molecular scale. While electron microscopes have the magnification power, small proteins lack the necessary contrast to stand out against the background noise of the cell. - Does this process damage the cell samples?
Electron beams inherently damage biological samples through heat. However, the use of cryogenic freezing—a technique pioneered by Robert Glaeser—significantly slows this destruction, allowing for detailed imaging before the sample degrades. - When will this technology be widely available?
Researchers are currently collaborating with Thermo Fisher Scientific, a primary manufacturer of cryo-EM machines, to refine the technology. Images and details of the development were published in the June 11 issue of Science.
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