The new technology was brought to fruition by more than 15 years of theoretical and experimental work by leading microscopy scientists.
Researchers in the United States have built a technology that boosts the performance of electron microscopes. Berkeley Lab and UC Berkeley physicists’ new technique offers detailed images of the small molecules and cell structures that are crucial to understanding biology and disease.
They have adapted the phase-contrast technique to cryo-electron microscopy (cryo-EM), which has about 10,000 times the magnification of light microscopy. Their laser-based phase plate produces sharp images of molecules that today’s cutting-edge cryo-EM systems struggle to capture.
The research team revealed that the new technology was brought to fruition by more than 15 years of theoretical and experimental work by leading microscopy scientists, collaboration with expert machinists, and support from Biohub.
More accurate atomic models of the molecules captured
The phase plate is paired with a new, custom Thermo Fisher Scientific microscope that was developed to maximize the benefit of the plate’s ultra-bright laser. Images taken by the system are notably clearer and sharper and contain greater detail that structure-solving software can process to generate more accurate atomic models of the molecules captured, according to a press release.
“Theia is the Formula 1 of microscopes. It has better resolution than the standard cryo-EM, even without the laser. With the addition of the laser phase plate, we hope that it really becomes one of the world’s best instruments overall,” said Holger Müller, a UC Berkeley professor of physics and faculty scientist in Berkeley Lab’s Biosciences Area who led the development effort.
“Before, studying structures with cryo-EM was like trying to look at paintings in a dark gallery. With Theia, it’s like the lights have been turned on for the first time.”
More accurate atomic models of the molecules captured
The team also demonstrated the system’s power by imaging aldolase, a protein in muscle that is relatively easy to capture with today’s cryo-EM machines, and hemoglobin — a protein that carries oxygen in blood. Hemoglobin is a smaller protein that sits at the lower size limit for current machines and is often used as a benchmark for cryo-EM performance. The laser-phase plate improved the resolution of the protein structure in both cases, but more so for the hemoglobin.
“We had a whole spectrum from larger particles that are not that challenging with extremely good specimen preparation to challenging small particles with bad preparation. Of course, the better the specimen, the less important it is that you have a top microscope. It was the most challenging ones is where we see the strongest improvements,” said Müller.
Team to expand microscope beyond single-particle analysis
The system is currently installed at UC Berkeley, and the team is now working to expand the microscope beyond single-particle analysis to perform a newer technique referred to as cryo-electron tomography (cryo-ET).
Similar to how CT (computed tomography) scans at the hospital generate images of body parts, cryo-ET assembles different angular views of a molecule or cellular structure into a 3D image. Cryo-ET will provide a huge leap in scientists’ ability to study cellular processes because it captures molecules in their natural states inside cells, unlike single-particle cryo-EM, and offers much higher resolution than light microscopy, as per the release.
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Prabhat, an alumnus of the Indian Institute of Mass Communication, is a tech and defense journalist. While he enjoys writing on modern weapons and emerging tech, he has also reported on global politics and business. He has been previously associated with well-known media houses, including the International Business Times (Singapore Edition) and ANI.