It took 15 years, a laser bounced more than 10,000 times between mirrors, and a trick first discovered in 1930. The result is a microscope that can finally see some of the smallest working parts of life.
Physicists at the University of California, Berkeley, have built a “laser phase plate” that sharpens the images produced by cryo-electron microscopes, the workhorse machines scientists use to map the shape of proteins. Their results were published in the journal Science.
Together with UC Berkeley we are announcing the laser phase plate – a breakthrough in atomic resolution imaging. This is the brightest continuous wave laser in the world, 100 million times the intensity of the surface of the sun. Phase contrast plays an important role in microscopy, but it was thought close to impossible for electron microscopy, where it would require interfering with an electron beam. Holger Mueller and Robert Glaeser proposed exactly this using a standing wave laser. It has taken over 15 years to make this a reality. Biohub partnered with UC Berkeley and Mueller to support this work and to engineer and build the technology. Contrast has been the critical barrier to achieving atomic resolution imaging of the cell. In cryo-electron tomography, a cellular imaging technology that uses electron microscopy, the low contrast makes it impossible to resolve anything but the largest proteins within their cellular context. The laser phase plate removes that barrier. With advances in AI this breakthrough in contrast will start to open up a new frontier in structural biology, that will allow us to see the molecular machines of the cell, and how they assemble into far more complex and dynamic systems, and understand how they work.
— Alex Rives (@alexrives) June 11, 2026
The small-protein problem
Proteins are the tiny machines that run every cell in your body. Knowing their exact shape helps researchers understand disease and design drugs that fit them like a key in a lock.
Electron microscopes magnify roughly 10,000 times more than ordinary light microscopes, but they have a weakness. Small proteins barely show up. Standard cryo-EM struggles with anything under about 70 kilodaltons, a measure of molecular size. That is a big blind spot: proteins that small make up about 90% of the human proteome, according to the researchers.
Borrowing an old idea
The fix comes from Dutch physicist Frits Zernike, who discovered phase contrast for light microscopes in 1930 and won the 1953 Nobel Prize for it. Phase contrast makes nearly transparent things visible by shifting part of the light wave.
Berkeley physics professor Holger Müller proposed doing the same thing with electrons back in 2010. His team traps a continuous laser inside a mirror-lined chamber, where the light reflects more than 10,000 times and builds up to about 75 kilowatts, focused to a spot just a few microns wide. When the electron beam passes through that spot, its phase shifts by 90 degrees. That boosts contrast without weakening the beam.
The team added the device to a commercial Thermo Fisher Krios microscope and named the upgraded machine Theia.
“Theia is the Formula 1 microscope,” Müller said.
What it can do now
With the laser, the team imaged proteins as small as about 50 kilodaltons, though that is still hard. The long-term goal is 17 kilodaltons, the size of myoglobin, the protein that stores oxygen in muscle.
“For the most challenging cases — small particles, bad specimens — the laser produces a very considerable advantage,” Müller said.
The technology could also improve cryo-electron tomography, which images structures such as mitochondria inside intact cells. The nonprofit research group Biohub is building its own version with two lasers at right angles, and Thermo Fisher is working with both teams. Biohub’s Stephani Otte called it “a step function change for biology.”
The bottom line
This is what patient, practical science looks like. A researcher pitched an idea in 2010, his team spent 15 years making it work, and now there is a real machine that sees what others could not.
Better pictures of small proteins could mean faster answers about disease and smarter drug design down the road. Not every breakthrough is a gadget you can buy. Some just help the people who make the next one.