Making the invisible visible – laser phase plate cryo-EM

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June 11, 2026

Making the invisible visible

A landmark achievement in microscopy is poised to reveal the molecular machinery of life inside cells, at near-atomic detail.

Imaging

A visualization of the dual-laser phase plate — a collaboration between UC Berkeley and Biohub. Two precision mirrors bounce laser light back and forth, building to an intensity 100 million times brighter than the Sun’s surface, enabling scientists to see the detailed inner workings of cells with more clarity and contrast than ever before. (Credit: Alexandre Dizeux)

Inside every living cell, tens of thousands of different types of proteins are at work: ferrying molecular cargo, relaying signals, repairing DNA, deciding whether a cell should divide or die. Most of these proteins are too small to image with existing microscopes. Those that can be imaged must be pulled out of the cell and studied in isolation — not in the crowded, dynamic environments that drive the processes of life.

That is about to change. In three papers, researchers at Biohub and UC Berkeley report successful results from a technology called a laser phase plate, which uses a laser 100 million times brighter than the Sun to significantly improve the contrast of images produced by cryo-electron microscopy (cryo-EM). The laser phase plate could make otherwise faint, blurry proteins inside intact cells visible, including many proteins most relevant to human disease.

"Rough estimates suggest that scientists can image 10% of the human proteome in purified form using existing cryo-EM — and fewer than 1% of proteins in their native cellular environment,” says Scott Fraser, president of dynamic imaging at Biohub. Scientists believe the laser phase plate could make more than 50% of the proteins that carry out cellular functions visible.

“This is just the first step,” says Bridget Carragher, founding technical director of imaging at Biohub. “It’s like seeing first light through a telescope. The science it enables — that comes next.”

In search of higher contrast

In the winter of 2019, 25 physicists and engineers gathered in San Francisco for a workshop on the future of electron microscopy. They had spent years pushing the technique known as cryo-EM to its limits — better cameras, better software, better sample preparation — but they had hit a barrier. Despite remarkable advances in mapping the structures of isolated large proteins, cryo-EM still could not produce crisp, high-contrast images of proteins inside a cell. Without the ability to study and understand proteins in their natural environment —binding, releasing, jostling against thousands of neighbors — it is challenging to design therapeutics.

The group laid out the many challenges they faced, including various approaches to solving cryo-EM’s contrast problem. Then Holger Müller, a physicist at UC Berkeley, presented what seemed to many like an impossible solution: a way to enhance cryo-EM that would employ a spot of laser light millions of times brighter than the Sun to shift the phase of electron waves, converting invisible differences in the position where the electron wave has peaks and troughs — its “phase” — into visible differences in image contrast.

It was widely considered one of the hardest engineering challenges in modern microscopy. "I think it’s fair to say everybody in the field when it was first proposed thought, well, nice idea, but that’s never going to happen," recalls Carragher.

But what if it could be done? For workshop organizer Stephani Otte, Biohub imaging science vice president, Müller’s audacious challenge was a call to action. "What I’m most interested in is taking what seems impossible and making it a reality," she says. "If somebody says it can’t be done, that’s the biggest motivating factor for me."

Toward the end of the workshop, Otte asked the group a question: of all the unmet needs in the field, what single tool would move science forward fastest? The answer was nearly unanimous: Müller’s laser phase plate.

Over the next seven years, Biohub bet big on the idea, funding Müller’s work at Berkeley, building on it, and developing a second, dual-laser variant at its research institute. Now, both versions of the microscope have launched. The science they will enable — a systematic, atom-by-atom view of the cell’s interior — has just begun.

Watch physicist Holger Müller of UC Berkeley explain how the laser phase plate works and the science behind this breakthrough in cryo-EM.

Resolving the cell in atomic detail

Biohub’s decision to go all-in on laser phase plate technology wasn’t just about tackling a tough engineering problem. It was about understanding the fundamental biology that drives disease and finding ways to treat or prevent it. As Otte points out, history has shown again and again that biology follows technology: when transformative tools become available, the field shifts....