UC Santa Cruz’s new cryo-electron microscopy facility has a unique structure that makes the technique accessible for local researchers and is attracting international business. Structural biologists recently published the first paper to include data from the facility.

The new facility on UCSC’s Science Hill houses a cryo-electron microscope — a tool that revolutionized the field of structural biology over the past decade. It allows researchers to visualize proteins by taking pictures of them. While similar instruments do exist within the Bay Area’s thriving pharmaceutical and biotech industries, UCSC’s Glacios microscope is one of fewer than 200 in the world. The facility is designed as a one-stop-shop that anyone can use, which makes the technology accessible to both local and international researchers and biotech businesses.

“It’s really impressive,” says Rose Marie Haynes, a microscopist at the Pacific Northwest Cryo-EM Center, the national center in Portland. “I don’t know of anywhere else that’s quite as streamlined. It’s definitely a valuable resource for anyone who’s getting into the field.”

Proteins are in your skin, blood, bones and every other tissue in your body. They run your internal clock, help you to heal, move your muscles, and enable every one of your senses. And they’re very, very small. For reference, the diameter of a human hair is around 100,000 nanometers. The diameter of a single protein is around 5 nanometers.

Structural biologists study the shapes of proteins. “If we want to understand biology, which means life, … it’s important to know how your protein looks,” says Vitor Hugo Balasco Serrão, the research specialist at UCSC’s new facility.

The shape determines the function. Proteins that have the wrong shape can cause diseases, like Alzheimer’s and Parkinson’s. And most drugs are based on protein shapes. Want to turn an overactive protein off? Find a compound that can stick to a crevice in that protein’s shape; it’s like jamming a stick into a bicycle wheel. But to study the structures of proteins, scientists have to be able to look at them.

Enter: the cryo-electron microscope. As its name implies, the technique is cold. Researchers place a tiny drop of water that contains the protein onto a small metal grid 3 millimeters in diameter. They plunge that grid into icy (-300 °F) liquid ethane so fast that the water flash freezes into a glassy form of ice, then shoot a beam of electrons through it. The electrons work just like rays of light through a camera lens; they create a 2D picture.

Powerful computers take thousands of 2D pictures and assemble them into a 3D model of the protein. That 3D model, which scientists refer to as a solved structure, can be used to design drugs, or learn about diseases. Remember that image of the coronavirus spike protein — the one that was in every article about COVID-19 for the past two years? That image was generated using cryo-EM. And it was a major reason researchers were able to design treatments and vaccines so rapidly.

Cryo-EM is much faster and more automated than traditional techniques, like X-ray crystallography. Melissa Jurica, a structural biologist at UCSC, says it speeds things up for researchers. “Instead of growing crystals, which would take weeks to months, now they get a sample and they can put it in the microscope and collect their data within a week and that is amazing,” she explained.

In 2017, Jurica led the charge to secure an instrumentation grant to pay for the $1.8 million microscope. Obstacles — including a room remodel, a lack of data processing infrastructure and the COVID-19 pandemic — delayed the grand opening. But Jurica worked hard to get the facility up and running, and researchers started collecting data in March 2022. Serrão said the final cost of the facility including building renovations and computing resources was close to $4 million.

The grant paid for the microscope, but to keep it running, they needed a business plan. Serrão had ideas, and the timing was perfect. “We just got super lucky [Serrão] was looking for a job at the time,” said Jurica. “He’s going to be the reason our facility succeeds.”

At nearly 8 feet tall, the scope takes up serious space. It clicks and wheezes as Serrão loads samples from researchers in Brazil. This is part of his business plan — anyone can use the scope, but they’re charged for the time. UCSC has some grant money available to help university researchers with the costs, and internal users get a discount, but everyone pays.

The UCSC facility is designed for doing the initial dirty work and optimizing the process. “Our facility is for sample preparation, optimization and screening,” says Serrão. Researchers can perfect important parameters, like ice thickness, sample concentration and grid conditions. They can get a decently high-resolution structure on the Glacios.

If they need even higher resolution, they can send their optimized grids to one of three NIH-funded national centers, located in Stanford, Portland and New York City, which house more powerful scopes. “Some people don’t need to go to another institution to polish off their data, some people do,” says Jurica. Time on the national microscopes is free as long as the project is accepted, so doing the screening work at UCSC helps researchers to write strong proposals that are likely to be accepted.

Researchers who depend on the technique can now work at UCSC. “We were able to hire Sara Loerch, who needs electron microscopy for her research program,” says Jurica. And the facility is speeding up research for structural biologists that were already there. “Labs that were specializing in other techniques are now all kind of moving toward cryo-EM,” says Jurica.

The unique setup makes the technique accessible to newbies. “One of the things that makes cryo-EM challenging to approach is that it requires so many different fields of expertise to go through the full workflow,” said Haynes. “The sample prep requires a crazy amount of biochemical knowledge. And then, if you’re extremely well-versed in that, it’s a pretty big learning curve to figure out the actual grid optimization followed by the screening and data collection, the processing, these are all totally different sets of skills. So offering a facility that goes through that entire process like as a one-stop shop makes it actually an approachable thing rather than having to piecemeal all of that together.”

Since they started collecting data, UCSC researchers have already solved seven protein structures. This is impressive; with other techniques it could take years to solve a single structure.

Scientists are forging ahead to explore some of the world’s most pressing biological questions. 13 UCSC labs currently use the equipment to study Alzheimer’s disease, nanoparticles, viruses, cell cycles in cancer and more. Serrão also has users from three local biotech companies and universities from the East Coast, Canada and Brazil.

To anyone who needs to visualize something very small, Serrão says: “Come over here, visit the facility, become a user, push your PI to say ‘Let’s do cryo!’ It’s a matter of scheduling a meeting and seeing if your stuff can be imaged.” And to anyone considering a foray into structural biology, he says, “It’s the future. If you look at every single pharmaceutical company or biotech company in the Bay Area, every single one has an electron microscope and every single one is hiring. And the salaries are great.”

Structural biologists published the first paper to include data from the facility on Oct. 28. A second paper is currently being peer-reviewed.

Anyone interested in the facility can learn more at www.ucsccryoem.org.