New cryo-electron microscope to ‘revolutionize’ research at UT Health San Antonio

A new cryo-electron microscope acquired in July has revolutionized the future of scientific research at UT Health San Antonio, researchers at UT Health San Antonio said.

Cryo-EM is the result of a $5 million investment by UT Health San Antonio. The researchers said it was the first of its kind in South Texas and was unlike any other microscope in their arsenal.

D., assistant professor of biochemistry and structural biology at UT Health San Antonio. “You can think of it as the thoroughbred racehorse of microscopes,” said Elizabeth Wasmuth. “[It’s] one of the most powerful microscopes you can imagine.”

Wasmuth explained how cryo-EM can do much more than other microscopes.

“It basically fires electrons through a very focused beam that allows us to see tiny molecular machines inside our bodies. [the] the resolution of individual atoms,” he said.

The bag holding the cryo-EM.  It is a rectangular metal box with a mostly white panel, almost reaching the ceiling, with a black panel in the middle of the front and a small digital display in the upper right corner.

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Texas Public Radio

Case involving cryo-EM at UT Health San Antonio.

This allows researchers like Wasmuth to get so many close and clear images of proteins that they can create 3D models of them, making them much easier to study.

This is similar to the process that visual effects artists in movies use to recreate someone’s face or a setting using CGI – it can be perfectly reproduced digitally by taking enough pictures from different angles and lighting conditions.

Understanding these proteins is important for slowing, preventing or curing diseases — in Wasmuth’s case, for prostate cancer.

“The primary drug target for prostate cancer would be … the protein that binds testosterone,” he said. “If you block the ability to bind testosterone, you can slow prostate cancer progression for a while. But even the best therapies we currently have don’t work in the end.”

The protein is structurally so dynamic and fluid that scientists haven’t figured out how to control it, Wasmuth said. But much more progress has been made as the former research institute works with a cryo-EM.

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Wasmuth’s colleague, associate professor of biochemistry and structural biology, Dr. Sean Olsen said the benefit of cryo-EM isn’t just the technology itself — researchers are able to remotely use cryo-EMs at other institutes. Having it on the site at the same time essentially means unlimited access.

Picture of a streetlight pole on the UT Health San Antonio estate with UT Health San Antonio banners on the side.

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Texas Public Radio

UT Health San Antonio site.

“Much faster,” Olsen said. “The faster you examine the samples, the faster you can identify conditions suitable for successful structure detection. And the faster you do that, the faster you’ll be able to get it into the drug discovery pipeline.”

He added that speed means more publications, which means more grants to fund research, which in turn fuels the effort to develop life-saving drugs.

“Many of the elusive proteins will be therapeutically relevant, and that means if we can determine the structures of these elusive proteins, then we can get a head start on targeting them therapeutically in diseases,” Olsen said.

The presence of cryo-EM in the field also makes it a powerful recruiting tool for UT Health San Antonio to entice state-of-the-art researchers from around the world to join the South Texas institute.

The applications of cryo-EM are huge, from prostate cancer and Alzheimer’s to diabetes and hypertension, Olsen and Wasmuth said, and a wide range of researchers have the opportunity to use the equipment for their own research.

Instruments for sampling into cryo-EM grids sitting on a table.  Alongside the cryo-EM are tweezers, a spray bottle, and several large pieces of equipment.

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Texas Public Radio

Tools used to get samples into cryo-EM.

When it came to setting up the cryo-EM, Wasmuth and Olsen said figuring out where it could lead at their UT Health San Antonio facility was a grueling process.

This is because cryo-EM is so sensitive that vibrations from floors or walls or electromagnetic interference from other equipment can affect the images it is intended to collect. The institute installed it in a basement office, away from other tools and machinery, and cushioned the walls and ceiling to add extra layers of protection.

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When it comes to the operation of cryo-EM, a man is key. A facility manager, Dr. Lijia Jia has specialized training in cryo-EM and is responsible for the day-to-day operations of the microscope and troubleshooting any problems that arise.

The microscope itself is housed in a casing that reaches almost to the ceiling of the room in which it sits, and is internally surrounded by liquid nitrogen, which keeps components and samples cold despite the heat generated by firing electrons.

The researchers place their frozen samples on dozens of what they call cryo-EM gratings, which are tiny penny-like disks that are then inserted into the microscope for imaging.

Dozens of copper-colored cryo-EM grids in a glass bottle held by Elizabeth Wasmuth.

Josh Peck

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Texas Public Radio

Cryo-EM grids in a glass bottle.

“So our facility manager would pick up the grids…we have a robotic arm that comes in and takes the grids from the liquid nitrogen container and then puts it back on the microscope stage where it sits back in the liquid nitrogen in the cryogenic containers.” aforementioned. “ [electron] the gun is here. It throws electrons into the grid and collects gigabytes of real movies.”

Because so many pictures are taken—thousands of the proteins’ individual orientations—wasmuth said a dataset for a sample could be as large as five terabytes, requiring incredibly powerful computers to analyze the images.

“Definitely a bottleneck, yes,” he said. “Man power and computer power. We are currently generating more data than we can handle. That’s the next bottleneck we’re trying to address right now.”

Some of the incredibly powerful computers that need to process what cryo-EM is pumping out are sitting in the next room where Jia works.

“[Jia is] We are working day and night to make all these discoveries possible as one individual,” Wasmuth said. “And basically doing Herculean tasks like preparing all these cryo-grids, viewing them all, and making a structural determination of what we put into microscopes for almost all cases.”

Both Wasmuth and Olsen cautioned that cryo-EM is used in the earliest stages of the drug discovery process, a process that can take years or even decades to result in FDA-approved treatments. But they said it sheds light on a path they would have had to guess at in the dark before.

“The best analogy I can make is the development of the COVID vaccine, for example,” Wasmuth said. “It was made by Big Pharma, which owns all the infrastructure. If you don’t have infrastructure, you can’t explore. And now we finally have the infrastructure, and that’s extremely exciting.”



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