A continuous laser focused to a few microns, carrying 75 kilowatts of power, has been used to sharpen cryo-electron microscope images of small proteins, the molecules that standard instruments struggle to resolve. The device is a laser phase plate, built by Holger Müller’s group at the University of California, Berkeley and Lawrence Berkeley National Laboratory, and reported in the journal Science. It is a proof of principle tested on six samples, not yet a tool any biology lab can buy.
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Conventional cryo-electron microscopy loses its grip on proteins below roughly 70 kilodaltons, according to the Berkeley team, and about 90% of the human proteome falls under that line. Those are the molecules the new plate is aimed at.
A laser phase plate for cryo-EM
Biological molecules are nearly transparent to an electron beam. They barely absorb electrons; instead they shift the phase of the electron wave, a change a detector cannot record directly. Standard cryo-EM gets contrast by deliberately defocusing the beam, which costs resolution. A phase plate converts those invisible phase shifts into brightness differences, the principle Frits Zernike developed for light microscopy in the 1930s and which won the 1953 Nobel Prize in Physics, as the Berkeley Lab news release of June 11, 2026, explains.
Earlier electron phase plates made of solid film cut the beam intensity too much, made images unstable or lowered resolution. The laser version avoids a physical material in the beam path. A continuous laser is trapped in a mirrored spherical cavity, where the light bounces back and forth more than 10,000 times, building up enough intensity to shift the electron beam’s phase by 90 degrees, the shift needed for ideal contrast. Müller and Berkeley professor emeritus Robert Glaeser proposed the idea in a 2010 paper in the New Journal of Physics, and the instrument took about 15 years to build. Installation and final development were completed in 2025.
The instrument, a customized Thermo Fisher Scientific Krios microscope named Theia, was modified with support from Biohub, the research nonprofit. Müller called it the Formula 1 of microscopes, and joked that it is not street legal, a nod to the training it demands of users.
Six samples, and the questions they leave open
The paper, “Laser phase plate improves structure determination of small proteins by cryo-EM,” appeared in Science (2026; volume 393, issue 6807, page 195). Petar Petrov and Jessie Zhang are co-first authors, and Müller led the work. The team tested six samples that varied in size and preparation quality, including aldolase, a muscle protein that current cryo-EM already images well, and hemoglobin, which sits near the lower size limit of existing machines. The laser consistently improved image resolution across the six, and the gain was largest for small or poorly prepared specimens. Hemoglobin showed the more pronounced improvement. Theia delivers better resolution than standard instruments even with the laser switched off, the Lab release says, so the comparison that matters is laser-on against laser-off on the same machine. Müller summed up the result by saying that for a small protein and a bad sample, laser-on is best, and that for the most challenging cases, small particles and bad specimens, the laser produces a very considerable advantage.
The record is thin on numbers. ScienceDaily’s summary of the work and the Lab release give no resolution value in angstroms, so the size of the improvement cannot be quoted here. They do say proteins as small as about 50 kilodaltons can be imaged with the plate, though that remains challenging. Müller’s stated goal is about 17 kilodaltons, the size of myoglobin, which would require combining the plate with a tightly focused electron beam. A focused-beam approach, he projected, could double the contrast and signal-to-noise ratio again; that is a projection, not a result.
That makes “finally” a stretch. Small human proteins remain hard to image even with the plate, and the lab’s own 2026 results stop well short of the 17-kilodalton target.
The competing laser design and the road to everyday use
A second team is building a different version. Bridget Carragher, David Agard and Pavel Olshin at Biohub in Redwood City, California, are co-corresponding authors on a design that uses two laser beams at right angles, each at roughly half the power, to limit component burnout and optical distortion. It is described in a bioRxiv preprint that has not been peer reviewed. Stephani Otte, Biohub’s vice president of imaging science, called the technology a step-function change for biology.
Several obstacles remain. Single-particle cryo-EM needs thousands to millions of isolated, carefully frozen molecules, and even small amounts of ice on a sample can interfere with imaging. Extending the plate to cryo-electron tomography, which images molecules inside their cellular surroundings, is in progress at Biohub. Streamlined versions for other labs are planned with Thermo Fisher but are not available. Funding for the 15-year development came partly from the National Institutes of Health, with the Berkeley Lab release also naming the National Science Foundation, the Gordon and Betty Moore Foundation, the Chan Zuckerberg Initiative and Berkeley Lab’s internal research program.
The prize at the end is biological. Zhang said the plate has the potential to let biologists see and understand more of the proteome in action, and ScienceDaily’s item says the approach could reveal how molecular machines interact. That promise is what the 2026 paper makes plausible and has not yet delivered.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
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