What was once invisible will become visible—and that changes everything
For more than a decade, a pair of researchers at UC Berkeley held fast to an idea their peers considered impossible — that an extraordinarily intense laser could illuminate what no microscope had ever clearly seen. This week, that conviction bore fruit: a laser phase plate, built and tested in collaboration with the Chan Zuckerberg Biohub, has demonstrated the ability to sharpen cryo-electron microscopy images well beyond current limits, bringing into focus the small proteins that constitute the vast, hidden majority of human cellular machinery. The achievement is not merely technical — it is an opening into a landscape of disease mechanisms and drug targets that science has long known existed but could never quite reach.
- More than 90% of human proteins are too small for existing cryo-EM technology to image clearly, leaving enormous blind spots in our understanding of how disease begins at the molecular level.
- The laser phase plate generates intensities 100 million times greater than the surface of the Sun — focused into a space one-thousandth the width of a human hair — demanding mirror alignments precise to within one-thousandth of a degree and sustained stability for up to half an hour at a time.
- Two independent teams — one at UC Berkeley, one at the Biohub — have now published working results, with the Biohub's dual-beam design reducing operational risk while both systems successfully improved contrast on biological targets including hemoglobin.
- Researchers are already pivoting toward cryo-electron tomography, which would reveal not isolated proteins but entire molecular machines operating inside living cells — a frontier that could compress careers' worth of structural biology into far shorter timelines.
- Commercial availability is projected within years, promising to distribute this capability to laboratories worldwide and transform what was once invisible into a legible map of cellular life.
For more than a decade, physicist Holger Müller and biophysicist Robert Glaeser at UC Berkeley pursued an idea most colleagues considered impossible: use an extraordinarily intense laser to sharpen the images produced by cryo-electron microscopes. This week, that pursuit became a published reality. Working alongside the Chan Zuckerberg Biohub, both teams announced they had built and successfully tested a laser phase plate — a device that dramatically improves contrast in cryo-EM imaging and opens the door to proteins that have remained invisible to science.
Cryo-EM is already a Nobel Prize-winning technology, capable of freezing biological samples and photographing them at near-atomic resolution. But it carries a critical limitation: more than 90% of human proteins are too small for it to image clearly. Hemoglobin sits right at the edge of visibility. Thousands of other proteins — each a potential disease mechanism, each a potential drug target — remain structurally unknown.
The laser phase plate addresses this by generating one of the brightest steady-state lasers ever built. Inside a cavity smaller than four inches across, a beam bounces between atomically smooth mirrors nearly 10,000 times, reaching intensities of 350 to 400 gigawatts per square centimeter — 100 million times more intense than the Sun's surface. This shifts the phase of the electron beam passing through a sample, producing dramatically sharper images. Maintaining alignment between the laser and electron beams — to within 50 nanometers, sustained for up to half an hour — requires a precision one researcher compared to a surfer holding perfectly to the crest of a wave.
Müller's team published their results in Science after testing six biological samples; the Biohub's parallel effort, featuring a two-beam design that reduces component stress, appeared as a preprint. Both demonstrated meaningful improvement, with hemoglobin — the more challenging target — showing the strongest gains.
The researchers now look toward cryo-electron tomography, which captures proteins not in isolation but within their natural cellular environments, revealing how molecular machines assemble and break down in disease. With better computational tools and AI-assisted processing, what once consumed an entire scientific career may soon be accomplished far more quickly. Müller hopes commercially available versions will reach laboratories worldwide within years. What was once invisible, as one Biohub leader put it, will become visible — and that changes everything.
For more than a decade, physicists Holger Müller and biophysicist Robert Glaeser at UC Berkeley had an idea that most of their peers thought was impossible: use an extraordinarily intense laser to improve the way scientists see the molecular world. Today, that idea has become real. Researchers at UC Berkeley and the Chan Zuckerberg Biohub announced they have built and successfully tested a laser phase plate—a device that dramatically sharpens the images produced by cryo-electron microscopes, a technology that has already revolutionized our understanding of how cells work at the atomic level.
Cryo-electron microscopy, or cryo-EM, is itself a Nobel Prize-winning breakthrough. It lets scientists freeze biological samples and photograph them at near-atomic resolution, revealing the intricate machinery that powers nearly every cellular process. But the technique has a critical blind spot: it cannot clearly image small molecules. More than 90 percent of the proteins found in human cells fall below the resolution threshold. Hemoglobin, the protein that carries oxygen through the blood, sits right at the edge of what current machines can see. Thousands of other proteins remain invisible, their structures and functions hidden from view.
The laser phase plate works by generating one of the brightest steady-state lasers ever built. Inside a cavity smaller than four inches across—tucked inside a microscope that towers 14 feet high—a laser beam bounces between two mirrors nearly 10,000 times. The mirrors themselves are polished to atomic-level smoothness, with a surface roughness of less than one angstrom, about the width of a single atom. The result is an intensity of 350 to 400 gigawatts per square centimeter, an energy 100 million times more intense than the surface of the Sun, concentrated into a spot one-thousandth the width of a human hair. This intense laser shifts the phase of the electron beam passing through the sample, dramatically improving contrast in the final image.
Müller spent more than a decade building the first working prototype. In 2021, the Biohub made what its leaders called a major bet on the technology, funding him with a grant that allowed him to purchase a state-of-the-art Thermo Scientific Krios microscope and customize it for the laser phase plate. The Biohub also built its own version—a more ambitious design featuring two laser beams oriented perpendicular to each other, each operating at half the power of Müller's single-cavity system. Operating at lower power reduces the risk of component damage and optical distortions, making the system more practical to use. Both teams published their results this week: Müller's work appears in Science, while the Biohub's findings are described in a preprint on biorxiv.org.
The precision required to operate these instruments is staggering. The mirrors must be aligned to within one-thousandth of a degree. The laser beam and electron beam must be aligned to within 50 nanometers—on a standing wave that is 500 nanometers across—to maximize contrast. As Bridget Carragher, the Biohub's Founding Technical Director of Imaging, put it, it is like a surfer holding perfectly to the peak of a wave, not for seconds, but for half an hour at a stretch. The UC Berkeley team tested the laser phase plate on six different biological samples of varying sizes and preparation methods. With hemoglobin, the more challenging target, they saw strong improvement. With aldolase, a muscle protein that conventional cryo-EM already handles reasonably well, the improvement was modest—exactly what the researchers expected.
The implications extend far beyond academic curiosity. Holger Müller noted that the average human protein is too small for current cryo-EM to image clearly. Each of those proteins represents a potential disease mechanism and a potential drug target. The laser phase plate could fill what he called an enormous gap in our knowledge of protein structures. David Agard, the Biohub's Founding Scientific Director of Imaging, described the cell as filled with everything scientists want to know but cannot see. For decades, structural cell biologists have dreamed of observing all those molecular interactions. With the laser phase plate, that dream is moving within reach.
The next frontier, researchers say, is cryo-electron tomography, a variant of cryo-EM that captures proteins not in isolation but in their natural cellular environment. This technique reveals how molecular machines actually assemble, interact, and malfunction in disease. Carragher said the team expects to begin data collection by the end of the year. A postdoc conducting a cryo-ET experiment today can spend an entire career on a single project. The laser phase plate, combined with better computational processing and artificial intelligence algorithms, could accelerate that timeline dramatically. Müller hopes that microscopes equipped with laser phase plates will be commercially available within the coming years, allowing laboratories around the world to access this technology. What was once invisible, as the Biohub's Vice President of Imaging Science Stephani Otte said, will become visible—and that changes everything about how we understand disease.
Citações Notáveis
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.— Holger Müller, UC Berkeley physicist
What was once invisible will become visible—and that changes everything about how we understand disease.— Stephani Otte, Biohub Vice President of Imaging Science
A Conversa do Hearth Outra perspectiva sobre a história
Why did it take so long to build something that was proposed fifteen years ago?
The engineering challenges were genuinely immense. You need mirrors polished to atomic smoothness, aligned to a thousandth of a degree, bouncing a laser beam nearly ten thousand times without the whole thing melting. Most people in the field thought it was theoretically possible but practically impossible.
So what changed? Why now?
The Biohub made a serious financial commitment in 2021. That gave Müller the resources to buy the right microscope, hire the right people, and iterate without constantly chasing grants. Sometimes breakthrough science just needs someone to say yes and write the check.
The intensity numbers are wild—100 million times brighter than the sun's surface. What does that actually do to the image?
It shifts the phase of the electron beam in a way that creates contrast where there was none before. Think of it like turning up the volume on a whisper. The protein was always there; now you can actually see it.
You said 90 percent of human proteins are currently invisible to cryo-EM. That's staggering.
It is. And many of those invisible proteins are exactly the ones involved in disease. Hemoglobin is just one example. There are thousands of others that could be drug targets if we could only see their structure.
What's the next step after individual proteins?
Cryo-electron tomography—imaging proteins inside actual cells, in their natural environment, seeing how they interact and malfunction. That's where the real biology happens. That's the dream.
How soon could a typical lab have access to this?
Müller thinks commercially available microscopes could arrive within a few years. But there's still work to do. The system is finicky. You have to hold it perfectly steady for half an hour at a time.