Key takeaways
- UCLA has one of the first Krios G4 cryo-electron microscopes at a university in the U.S.
- The Krios G4, which reveals atomic details smaller than the wavelength of visible light, renders them in three dimensions, offering researchers the only way to capture dynamic structures of viral proteins in action.
- With nearly double the resolution and nine times the speed in acquiring image data, the cryo-electron microscope is expected to help with new discoveries and innovations in fields such as cancer and Alzheimer’s research.
Back in 2008, the California NanoSystems Institute at UCLA, or CNSI, debuted a one-of-a-kind resource for understanding biology at the smallest scales — a state-of-the-art cryo-electron microscope.
By probing biological structures frozen in glassy ice, scientists and engineers use the transmission electron microscope to reveal atomic details far smaller than the wavelength of visible light and render them in three dimensions. Only this type of microscope can see biological structures at this scale. That ability made possible breakthroughs in UCLA research about cancer, Alzheimer’s disease, viruses and much more. Today, the Krios G1 and three succeeding generations of electron microscopes are at work at hundreds of university and industry labs around the world.
The work done at CNSI with the Krios G1 has helped cement UCLA’s leadership in providing the most fundamental view into biology.
“CNSI showed what this instrument can do,” said Hong Zhou, founding director of CNSI’s Electron Imaging Center for Nanosystems, or EICN, and a professor of microbiology, immunology and molecular genetics at the UCLA College. “We demonstrated the technology’s potential in a series of studies that helped establish confidence for the entire field of cryo-electron microscopy.”
The EICN team is far from through innovating in cryo-EM. The next generation of the technology, the Thermo Fisher Scientific Krios G4, is now online and available to users from UCLA and researchers from other campuses and industry labs.
Specifications of the Krios G4
The Krios G4 at EICN is currently the only one at a public university in the U.S. fully loaded in an advanced configuration — equipped with a highly coherent source, energy filter, counting camera and streamlined acquisition software. The high-end microscope, named after the Greek god of constellations, represents a dramatic leap in features compared to its ancestor, with nearly double the resolution and nine times the speed in acquiring image data. The instrument’s stewards believe these features will help unlock an even bigger boost in scientific progress.
“Cryo-EM has already enabled an exponential change in how we do structural biology,” said Adam Stieg, CNSI’s associate director of technology centers and a UCLA research scientist. “A new microscope isn’t the destination; it’s the beginning of the next journey. This will help us define the next frontier.”
The development of cryo-EM has proved such a boon to biomedical science and engineering that it was the subject of the 2017 Nobel Prize in chemistry. The method lacks certain limitations that hinder older ways of atomic imaging. For instance, cryo-EM is the only way to capture dynamic structures of viral proteins in action.
In fact, a widely distributed COVID-19 vaccine was informed by imaging from the G1 in the EICN. Artificial intelligence can now build on knowledge of this type of experimentally determined structures to design new drugs and vaccines, as shown by the algorithm for determining the structure of proteins that earned its inventor a share of the 2024 Nobel Prize in chemistry.
Looking ahead to the future of research
The addition of the Krios G4 at CNSI not only offers new capabilities but also improves access to cryo-EM. The Krios G1, which can be booked months in advance, will remain online, doubling the resources available 24-7 for studying biological structures on campus.
“The Krios G4 is about more than continuing CNSI’s legacy,” said Matthew Mecklenburg, managing director of the EICN. “It fulfills a very real need in our community.”
Zhou emphasizes that, beyond its many benefits for discovery and innovation, the new microscope bolsters CNSI’s educational mission. Trainees in the biosciences will gain experience with a topflight instrument, and computer science and engineering students will have the chance to apply machine learning and other computational techniques to abundant data generated by the Krios G4.
“CNSI is a hub that provides the physical technology, the expertise and the data,” Zhou said. “That means new opportunities for students who want to design applications.”
As with most anything in the world of science, collaboration was key for both developing the Krios G4 and bringing it to UCLA. The team at the EICN stayed in touch with Thermo Fisher Scientific throughout the creation of the instrument, and the CNSI researchers continue to invent new methods for analyzing cryo-EM results, including through the use of AI.
The instrument itself was funded through a public-private partnership — launched with a grant from the National Institutes of Health, then backed with institutional resources from CNSI, the David Geffen School of Medicine at UCLA and the UCLA College via the division of physical sciences, as well as philanthropic support from the Alfred E. Mann Charities Technology Development Fund.
“This is an all-hands-on-deck approach,” Stieg said. “Through a community investment, researchers at all levels, and around the region, are going to be able to do things that we couldn’t do otherwise.”