Our Take
First peer-reviewed evidence that laser phase contrast solves cryo-EM's small-protein problem, but the threshold for clinical deployment remains untested outside Berkeley's custom setup.
Why it matters
About 90% of the human proteome consists of proteins too small for current cryo-EM to image clearly. A reproducible, publishable method to access this space forces structural biologists to reconsider what's now possible in drug discovery and disease mechanism research.
Do this week
Structural biology leaders: request a technical briefing from Biohub on the dual-laser version timeline and availability before committing equipment budgets, so you can plan sample prep workflows accordingly.
UC Berkeley's Laser Phase Plate Clears a 15-Year Cryo-EM Barrier
Physicists at UC Berkeley and Lawrence Berkeley National Laboratory, led by Holger Mueller, published a peer-reviewed paper in Science demonstrating that a laser-driven phase plate (LPP) can image proteins below 70 kilodaltons, a size range that has been effectively invisible to cryo-electron microscopy since its Nobel-winning debut in 2017.
The laser phase plate works by using an intense continuous-wave laser, focused to a few microns with a power greater than military-grade systems, to shift the phase of the electron beam itself. This produces phase contrast without dimming or destabilizing the beam. When installed in a custom Thermo Fisher Titan Krios microscope, the LPP improved specimen-motion correction, recovery of information from early frames, particle visualization, and 3D classification and alignment using standard defocus ranges and reconstruction workflows.
Mueller's team tested the system on hemoglobin and apoferritin, validating that small proteins long considered too noisy for structural analysis now yield measurable resolution gains. The team is targeting proteins as small as 17 kilodaltons in ongoing work.
Cryo-Electron Tomography Stands to Gain More
The advance may have an even larger impact on cryo-electron tomography (cryo-ET), which assembles multiple angular views of a molecule into 3D structure. Cryo-ET is used to image crowded cellular material and small complexes in situ, but it has been severely limited by contrast. Bridget Carragher, founding technical director of imaging at Biohub, described the problem: "It's like a forest of trees, and you're trying to find one leaf on one tree in there." The laser phase plate promises to close that gap.
Biohub is now developing a dual-laser version of the system to reduce component wear and minimize aberrations, signaling commercial intent to move beyond the single prototype.
This Closes a 15-Year Coverage Gap in Structural Biology
Cryo-EM won a Nobel Prize in 2017 for enabling protein structures without crystallization. But the technique has a hard ceiling: proteins below roughly 70 kilodaltons suffer from poor signal-to-noise ratios, rendering them invisible in practice. This ceiling excludes approximately 90% of the human proteome, according to the paper's own framing.
A peer-reviewed, reproducible method to image small proteins shifts what is knowable about disease mechanisms, protein-ligand interactions, and enzyme function at a scale that has been inaccessible. Structural biologists and pharma researchers have had to resort to crystallography, NMR, or X-ray diffraction for small targets, each with its own constraints and failure modes.
Mueller stated the practical trade-off clearly: large, well-prepared samples may not need the laser phase plate to produce high-quality images, but small proteins and poor specimens benefit dramatically. The technology also opens cryo-ET to samples previously too faint to reconstruct.
What Structural Biologists Should Do Now
Assume the technology works as published but prepare for a lag between peer review and routine availability. The current system is a custom-built Titan Krios at Berkeley. Biohub's dual-laser version is in development, not yet deployed. Field adoption will depend on commercial instrument vendors (primarily Thermo Fisher) integrating the phase plate into standard configurations, or on contract-imaging facilities offering access to prototype systems.
If your target is a small protein or a sample known to yield poor contrast, contact structural biology core facilities and imaging services to ask whether they have pilot access to laser phase plate systems. Document the size and sample quality of your current bottlenecks. This will help you prioritize whether to wait for wider availability or pursue alternative approaches in parallel.