Assistant Professor Melody Campbell prepares a sample in the Shared Resources Cryo-EM Lab at the Fred Hutchinson Cancer Research Center in Seattle. (Fred Hutch Photo)
Dr. Melody Campbell was an undergraduate student when she first noticed the beauty and power of cryogenic electron microscopy (cryo-EM), a technique that uses extreme temperatures and an electron microscope to create 3D maps of proteins.
The image was stunning, and Campbell decided in that moment to focus her career on the revolutionary technique.
“I’m a visual person,” said Campbell, now an assistant professor in the Basic Sciences Division at the Fred Hutchinson Cancer Research Center. “You can learn so much about proteins by looking at them.”
In February, after more than a year of planning, Campbell launched a new lab at the Hutch, part of the organization’s effort to build and develop cryo-EM. The technique provides a spectacular and useful look at the structures of everything from DNA to proteins to viruses — including the relevant recent example of the coronavirus spike protein.
A clearer understanding of their structures could ultimately lead to new therapeutics and vaccines targeting illnesses from autoimmune diseases to cancer and infectious diseases.
“Cryo-EM is allowing structural biologists of all backgrounds, even an old crystallographer such as myself, to finally see the biological machines that we’ve longed dreamed of visualizing,” said Barry Stoddard, a professor in the Basic Science Division at Fred Hutch, who helped advocate for the new facility.
How cryo-EM works
Caleigh Azumaya, Cryo-EM facility manager, loads a sample into the Cryo-electron microscope. (Fred Hutch Photo)
Cryo-EM is a groundbreaking technique — three scientists won the 2017 Chemistry Nobel Prize for their work refining the tool — that allows researchers to see very small things such as viruses or proteins.
The technique freezes the particles at -180 degrees celsius, trapping them in a thin film of non-crystalline ice. That process not only protects them, but also keeps them in their native environment, free of chemicals or stains. Scientists then use an electron microscope and computer algorithms to create a 3D model of the structure.
Previously, biologists could view these tiny particles by crystalizing them and then using X-rays. But that technique generally only provided a static picture, Stoddard said.
Stoddard, an expert in protein structure, offered the analogy of a horse image. If you could only see a horse standing still in a pasture, it would be hard to visualize the horse running at the Kentucky Derby. Similarly, cryo-EM brings the complex movement and structure of molecules to life in high resolution, allowing researchers to better understand their movement and function.
Those detailed images of the structure are useful when it comes to the development of disease treatments. Many drugs, including those that fight cancer, work by binding to proteins. Seeing how proteins are structured can help researchers better understand their potential as new drug targets.
Campbell is especially interested in a family of proteins found on the surface of white blood cells. These proteins play a role in autoimmune and inflammatory conditions such as Lupus. A more detailed understanding of the proteins’ structure and function is the first step in developing tailored therapeutics.
Perhaps the most relevant recent example of how other scientists are using this technology in action is the red spike protein on the now iconic image of the coronavirus. Understanding how COVID patient antibodies bound to the virus’ spike protein eventually led to the development of robust therapeutics to fight COVID-19, Campbell said. Prior cryo-EM structures of related coronavirus spike proteins guided the development of the current widespread mRNA vaccines.
“Its shape is so important to its function and how it works,” Campbell said.
An ‘adventurous’ set up
Campbell and Azumaya stand in between 7-foot electron microscopes. (Fred Hutch Photo / Rachel Werther)
Setting up the Hutch’s new lab — which had about a $4 million price tag — was “quite an adventure,” that took about a year of preparation, Campbell said. The lab includes two electron microscopes: a Glacios and a Talos. Each are about seven-feet high.
“It’s ironic — they have to be bigger to see things that are smaller,” Campbell said with a laugh.
Along with their towering height, they also weigh thousands of pounds. In November, the new machines arrived via multiple crates on two huge trucks. It took a half day just to unload them.
But the setup challenges didn’t stop there. The microscopes are very sensitive to electromagnetic interference, which is common in big cities like Seattle.
“They’re really finicky machines,” Campbell said.
In fact, they’re so sensitive to vibrations that even talking loudly while working can lead to a blurry image. To eliminate the interference, the Hutch team implemented an electromagnetic cancellation device inside the microscope’s case that measures interference and sends out perfectly perpendicular waves to cancel it.
Specialized equipment is necessary to keep samples frozen at -180 degrees celsius, including a vitrobot or freezing robot. When in the microscope, samples must be kept in a vacuum to keep other particles out that might interfere with the electrons, the source of illumination.
Campbell and her team collected the new facility’s first high resolution images in March. The protein Apoferritin is found in the intestine. (Fred Hutch Image)
In earlier days, scientists working on small particle imaging sat in a dark room hunched over a microscope, collecting data with film, and moving the microscope’s stage for each image. Now, Campbell can tell the microscope what data to collect and then leave it alone for three days.
“That’s made cryo-EM much more interesting and accessible,” she said.
At the Hutch, there are plans to build up the facility and staff to invigorate and expand the field. Right now, they can look at a single protein or virus, but the hope is to expand to bigger structures like cells.
For now, a single protein is more than enough to keep Campbell captivated. She and her team collected the first high resolution images in March: the protein Apoferritin, which is found in the intestine and can store iron. Proteins are so small that they don’t have colors humans can see so Campbell applied a deep ocean blue, turquoise and vibrant green in honor of the Hutch’s color scheme.
“It was a test run but also really exciting because all these little things can go wrong,” Campbell said. “We already knew the structure, but it showed us everything was up and running as it should be — a big sigh of relief.”
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