Researchers at UT Health San Antonio said a new cryo-electron microscope acquired in July has revolutionized the future of scientific inquiry at UT Health San Antonio.
The cryo-EM is the result of a $5 million investment by UT Health San Antonio. Researchers said it’s the first of its kind in South Texas and unlike any other microscope in their arsenal.
“You can think of it as the thoroughbred racehorse of microscopes,” said Dr. Elizabeth Wasmuth, an assistant professor of biochemistry and structural biology at UT Health San Antonio. “[It’s] one of the most powerful microscopes that you can imagine.”
Wasmuth broke down how the cryo-EM can do so much more than other microscopes.
“It fires electrons through a very focused beam that allows us to see the tiny molecular machines that are inside our bodies at basically [the] resolution of individual atoms,” she said.
This allows researchers like Wasmuth to get so many up-close and clear images of proteins that they can create 3-D models of them, which makes them much easier to study.
This is similar to the process used by visual effects artists in films to recreate someone’s face or an environment using CGI — getting enough pictures from different angles and lighting conditions so that it can be perfectly digitally recreated.
Understanding these proteins is essential to slow, prevent, or cure diseases — in Wasmuth’s case, for prostate cancer.
“The primary drug target for prostate cancer … happens to be the protein that binds testosterone,” she said. “If you inhibit the testosterone-binding capability, then you can, for some time, slow prostate cancer progression. But even the best therapies that we have now eventually stop working.”
Wasmuth said that protein is so structurally dynamic and fluid that scientists hadn’t been able to nail down how to control it. But since it was studied with a cryo-EM at her former research institute, much more progress has been made.
Wasmuth’s colleague, associate professor of biochemistry and structural biology Dr. Sean Olsen, said the benefit of the cryo-EM isn’t just the technology itself — researchers are able to use cryo-EMs at other institutes remotely. It’s also the fact that it’s on site, meaning essentially unlimited access.
“It's orders of magnitude faster,” Olsen said. “And the faster that you can go through the samples, the faster that you can identify conditions that are amenable to successful structure determination. And the faster you do that, the faster you're going to be able to put that into the drug discovery pipeline.”
He added that the speed means more publications, which means more grants to fund research, which fuels the effort to develop life-saving drugs.
“A lot of the difficult proteins are going to be therapeutically relevant, and so that opens doors in terms of, if we can determine the structures of these difficult proteins, then we might be able to have a head start on therapeutically targeting them for various diseases,” Olsen said.
Having the cryo-EM on site also makes it a powerful recruitment tool for UT Health San Antonio to persuade researchers doing cutting-edge work around the world to join the South Texas institute.
Olsen and Wasmuth said the cryo-EM applications are massive — from prostate cancer and Alzheimer’s to diabetes and hypertension — and that a wide range of researchers have already had the opportunity to use the equipment for their own research.
When it came to the installation of the cryo-EM, Wasmuth and Olsen said it was a strenuous process to figure out where it could go in the UT Health San Antonio facilities.
That’s because the cryo-EM is so sensitive that vibrations through floors or walls or electromagnetic interference from other equipment could impact the images it’s intended to collect. The institute ended up installing it in a basement office, far from other tools and machines, and padded the walls and ceiling to add extra layers of protection.
When it comes to the operation of the cryo-EM, one man is key. Dr. Lijia Jia, a facilities director, has specialized training in cryo-EM and is responsible for the day-to-day operations of the microscope and for troubleshooting any issues that come up.
The microscope itself is contained in a case that extends nearly to the ceiling of the room it sits in, and it is internally surrounded by liquid nitrogen that keeps the components and samples cool despite the heat generated by firing electrons.
Researchers place their frozen samples onto dozens of what they call cryo-EM grids, very small penny-like discs, which are then placed into the microscope for imaging.
“So our facility manager would take the grids … there’s a robotic arm that would come and take the grids from the liquid nitrogen container and then put it onto the stage of the microscope where it would sit again in liquid nitrogen in cryogenic containers,” Wasmuth said. “The [electron] gun is up here. It’s shooting electrons onto the grid, and it’s collecting literal movies that are gigabytes in size.”
Because so many pictures are being taken — thousands from individual orientations of the proteins — Wasmuth said a data set for one sample could be as large as five terabytes and require incredibly powerful computers to analyze the images.
“It’s certainly a bottleneck, yes,” she said. “People power and computer power. We’re generating more data than we can handle right now. So that is the next bottleneck that we are currently trying to address.”
Some of the incredibly powerful computers needed to handle what the cryo-EM pumps out sit in the room next door, where Jia works.
“[Jia is] working around the clock to make all of these discoveries possible as one individual,” Wasmuth said. “And basically doing the Herculean tasks of preparing all of those cryo grids, imaging all of them, and for almost all of the cases, doing the structural determination of what we’re putting on the microscopes.”
Both Wasmuth and Olsen cautioned that the cryo-EM is used at the earliest stages of the drug discovery process, a process which can take years or decades to result in FDA-approved treatments. But they said it shines a light on a path that they would have had to guess at in the dark before.
“The best analogy I can have is the development of the COVID vaccine, for example,” Wasmuth said. “It was done by Big Pharma who had all the infrastructure. If you don’t have infrastructure, you’re not going to have discovery. And now we finally have the infrastructure, and it’s extremely exciting.”
