Laser Phase Plate Technology Achieves Sharper Cryo-EM Protein Images After 15 Years of Development
UC Berkeley physicists have successfully integrated a laser phase plate into a cryo-electron microscope, significantly boosting image contrast and resolution for small proteins. The technology, 15 years in development, uses an ultra-intense focused laser to shift the phase of non-scattered electrons, extending cryo-EM's reach to proteins previously too small to image clearly. The advance could unlock structural data for the vast majority of human proteins and transform how scientists study molecular machines inside living cells.
A team led by UC Berkeley physicist Holger Müller has demonstrated a working laser phase plate (LPP) for cryo-electron microscopy (cryo-EM), publishing results in the journal Science on June 11, 2026. The technique adapts the Nobel Prize-winning phase-contrast principle—originally developed for optical microscopes in 1930 by Frits Zernike—to the electron microscope, where biological samples scatter electrons rather than light. The laser, amplified to 75 kilowatts by bouncing more than 10,000 times between ultra-smooth mirrored surfaces, is focused to a few microns on the electron beam, selectively shifting the phase of non-scattered background electrons and thereby boosting contrast for small molecules. Side-by-side images of hemoglobin and nanoparticles, as well as 3D reconstructed protein density maps, visually confirm markedly improved resolution when the LPP is active. Current cryo-EM struggles to image proteins smaller than roughly 70 kilodaltons—encompassing about 90% of the human proteome—while the LPP has already enabled imaging down to 50 kilodaltons, with a near-term goal of 17 kilodaltons. A second LPP design using two crossed laser beams, developed in parallel at Biohub in Redwood City and described in a preprint, aims to reduce component wear and optical aberrations. Both groups are collaborating with Thermo Fisher Scientific, the dominant cryo-EM manufacturer, to advance the technology toward broader deployment.
Limitations & open questions
The study's own limitations include that imaging proteins down to 50 kilodaltons remains difficult rather than routine, and the 17-kilodalton target (e.g., myoglobin) has not yet been demonstrated—it is a stated near-term goal contingent on further development, including switching to a focused rather than defocused electron beam. The cost and practical accessibility of retrofitting existing cryo-EM instruments with a laser phase plate are not addressed, leaving open questions about how quickly the technology could be widely adopted beyond the two prototype labs.
How coverage differed
Both Phys.org and Nature News cover the story neutrally and with similar framing; Phys.org provides more technical and biographical detail about the development history, while Nature News emphasizes the scientific community's prior skepticism and the broader debate over feasibility, lending slightly more weight to the contested nature of the achievement.
What different sources said
- Phys.orgCenter
Physicists introduce phase contrast to electron microscopy, delivering sharper images of our body's tiniest proteins
- Nature NewsCenter
An innovative technology boosts image quality for protein structures
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