Before: Paintings in a Dark Gallery. After: The Lights Turn On.
A team of physicists at the University of California, Berkeley, and Lawrence Berkeley National Laboratory says the lights are finally coming on for one of biology's hardest problems: seeing the smallest proteins in the human body.
Led by physics professor Holger Müller, the team has spent more than 15 years building a laser phase plate — an upgrade for the cryo-electron microscope that dramatically boosts image contrast, letting scientists capture sharp images of proteins far smaller than today's machines can normally resolve. Müller named the upgraded instrument Theia, after the ancient Greek Titaness of light and radiance.
"Before, studying structures with cryo-EM was like trying to look at paintings in a dark gallery," Müller said. "With Theia, it's like the lights have been turned on for the first time."
Why Life's Smallest Machines Stay Hidden
To appreciate this invention, you need to understand the microscope it improves. A cryo-electron microscope (cryo-EM) is one of the most powerful imaging tools ever built, with about 10,000 times the magnification of a light microscope. It earned its pioneers the 2017 Nobel Prize in Chemistry, and over the past decade it has accelerated new drug discovery by revealing the atomic-level architecture of the molecular machines inside cells.
The technique works like this: scientists freeze a sample so fast that water turns to glass-like ice instead of crystals, trapping thousands of proteins in a near-natural state. An electron beam passes through the frozen sample, and each protein casts a faint shadow. Computers then combine thousands of these shadow images — each showing a protein at a random angle — into one detailed 3D model.
The catch is that electrons interact only weakly with biological material. A protein barely bends or absorbs the electron beam, so its shadow is extremely faint, and image noise can drown it out entirely. The smaller the protein, the weaker the shadow. Today's cryo-EM machines struggle with anything below about 70 kilodaltons — a unit of molecular mass — and such proteins make up roughly 90 percent of the human proteome. Nine out of ten proteins in your body are too small to be seen clearly by one of the best microscopes on Earth.
Researchers cannot simply crank up the beam either: it heats and destroys the very molecules it is trying to picture. For years the field has needed a way to extract more signal from the same gentle illumination.
A 100-Year-Old Idea, Finally Made Real
In the 1930s, Dutch physicist Frits Zernike noticed something subtle: when light passes through a transparent cell, it is not only dimmed — it is also slowed down slightly, shifting the timing, or "phase," of its waves. The eye cannot see this shift, but shifting the unscattered light by 90 degrees turns those invisible phase differences into visible contrast. His phase-contrast microscope brought faint structures inside living cells into clear view and earned him the 1953 Nobel Prize in Physics.
Physicists dreamed of doing the same thing with electrons, which carry far more resolving power than light. But every attempt failed: any physical material placed in the beam either dimmed it, made the image unstable, or ruined the resolution.
In 2010, Müller and biophysicist Robert Glaeser — now a Berkeley professor emeritus and a pioneer of cryo-EM itself — proposed a workaround: put nothing physical in the beam at all. Use light instead. An intensely focused laser could shift the phase of passing electrons without dimming them, just as Zernike's plate had shifted light. The idea was published and admired — and widely considered nearly impossible to build.
Fifteen Years Building the Brightest Focus on Earth
The obstacle was sheer intensity. To nudge an electron beam's phase by the needed 90 degrees, the laser focus had to be extraordinarily powerful — far beyond what ordinary optics could deliver without melting.
Müller's team solved it with an optical trap. They bounced a continuous laser beam back and forth between two exquisitely polished mirrors inside a spherical cavity, recycling the light nearly 10,000 times until it built up to 75 kilowatts focused into a spot a few microns wide — about one-thousandth the width of a human hair. Müller calls it "the brightest continuous laser focus ever," noting it outpowers the lasers used for welding: the intensity reaches 350 to 400 gigawatts per square centimeter, roughly 100 million times more intense than the surface of the Sun.
The mirrors are an engineering marvel too, polished to less than one angstrom — about the width of a single atom — so they barely warm up, and the two beams must meet within 50 nanometers. "It's like a surfer trying to hold perfectly to the peak of a wave, not for seconds, but for half an hour at a stretch," said Bridget Carragher, founding technical director of imaging at the Chan Zuckerberg Biohub.
Remarkably, the entire optical cavity is less than four inches wide — a tiny heart tucked inside a microscope standing 14 feet tall. A turning point came in 2021, when the Biohub placed a big bet on the technology, funding Müller to buy a state-of-the-art Thermo Scientific Krios cryo-EM and customize it around the laser phase plate. That instrument is the one Müller named Theia.
The First Tests: Hemoglobin, Seen Clearly at Last
In June 2026 the Berkeley team published their results in the journal Science, showing that the laser phase plate produces sharper, higher-resolution images across six different biological samples of varying sizes and preparation quality. The pattern was exactly as hoped: the smaller and more challenging the sample, the greater the improvement.
The team highlighted two examples. One was aldolase, a muscle protein that is relatively easy for today's machines to image — it improved only modestly, as expected. The other was hemoglobin, the protein that carries oxygen in blood, which sits at the very lower limit of what current machines can capture. With the laser on, hemoglobin's reconstructed structure sharpened dramatically. "With the more challenging of the two particles, hemoglobin, we saw a strong improvement with the laser, but with the less challenging one, aldolase, the improvement is very small, as expected," said Jessie Zhang, a postdoctoral researcher in Müller's lab who co-led the study with Petar Petrov.
Where do the numbers stand? While cryo-EM today barely manages proteins below 70 kilodaltons, the laser phase plate made it possible — though still difficult — to image proteins down to 50 kilodaltons, smaller than hemoglobin. Müller's next target is myoglobin, a 17-kilodalton protein, and he believes a focused (rather than defocused) electron beam could deliver another factor-of-two boost in contrast on top of what has already been achieved.
The Bigger Prize: Watching Life Inside the Living Cell
Imaging isolated proteins is only half the story. The researchers believe the technology's greatest impact will come in cryo-electron tomography, or cryo-ET — a newer variant that combines many angular views of a frozen cell into a 3D image, revealing proteins not in isolation but in their natural environment, inside the cell, where they assemble, interact, and malfunction.
That environment is enormously crowded. "With cryo-ET, we're looking at small, very complicated cellular material that's incredibly crowded inside the cell," said Carragher. "It's like a forest of trees, and you're trying to find one leaf on one tree in there. Cryo-ET needs a dramatic step forward in contrast, so we can start to see what's going on inside the cell. That's what the laser phase plate promises to give us."
Stephani Otte, the Biohub's vice president of imaging science, put the stakes plainly: "We are going to be able to see how molecular machines operate inside the living cell, in context, for the first time. What was once invisible will become visible — and that changes everything about how we understand disease." Every corner of the cell is still being mapped — consider the strange microbe that redefines our idea of what a cell can be, and how much molecular detail remains to be imaged.
What This Means for Medicine
Here is the practical payoff. Nearly every drug in development works by binding to a protein — blocking a faulty enzyme, unlocking a receptor, jamming a virus's machinery. To design such drugs, researchers need the protein's exact 3D shape. "If you look at all the proteins in a human, they all have various sizes," Müller said. "And all of these proteins are potential disease mechanisms and drug targets. The problem is, the average human protein is too small to be imaged by cryo-EM. The laser phase plate could fill an enormous gap in our knowledge of protein structures that can't be processed with today's cryo-EM."
That gap also includes proteins that refuse to form crystals, which rules out X-ray crystallography, the main alternative technique. For those molecules the laser phase plate may be the only path to a clear structure — and structure is the starting point of rational drug design. Viruses are a prime example: read how missing-link viruses could rewrite the story of how life infects cells, a story sharper imaging will help tell. And modern genetic medicine leans on structure too — CRISPR breakthroughs depend on knowing the precise shape of the proteins they target.
What Comes Next
The Biohub has built its own next-generation version — a dual-laser system in which two perpendicular beams each run at about half power, so components are less likely to burn out and aberrations are reduced. The Biohub's bioRxiv preprint demonstrates the dual-laser plate imaging the iron-storage protein apoferritin with a marked contrast gain.
Müller hopes microscopes fitted with laser phase plates will be commercially available in the coming years. Biohub's team expects to begin collecting cryo-ET data by the end of 2026, pairing the new contrast with AI algorithms that are steadily speeding up the analysis of cellular tomograms. "Doing a cell biology experiment with cryo-ET today can take up a postdoc's entire career," said the Biohub's David Agard. "We need to speed that up, and the laser phase plate, along with better processing, all working seamlessly with AI algorithms, will get us there."
From Zernike's simple glass plate to a laser focus more intense than the surface of the Sun, the quest has always been the same: to see the molecular machinery of life as it really is. With the laser phase plate, the smallest and most elusive parts of that machinery are finally stepping into the light.
