A synchrotron is a circular particle accelerator that produces extremely bright X-rays used to study our world at the atomic and molecular level. Inside of the accelerator, a particle beam travels around a closed-loop path, generating x-ray radiation along the way. This radiation is used in experimental stations to probe matter and analyze many physical, chemical and biological processes. This video explains how synchrotrons work and how they are used to conduct experiments and study matter at the molecular and atomic level. Video is produced by SLAC National Accelerator Laboratory where the Stanford Synchrotron Radiation Lightsource (SSRL) is located.
Using the Stanford Synchrotron Radiation Lightsource, a team of researchers investigated the evolution of a protein that plays a crucial role in H5N1’s ability to transmit between species. Their analysis found that the protein is susceptible to a mutation that could help the virus attach to human cells, potentially increasing the risk of human transmission. The findings underscore the need for ongoing monitoring of H5N1’s evolution.
In the game of evolution, viruses are among the most adaptable players, constantly changing in response to their environments. Researchers in immunology and structural biology regularly monitor these changes, especially those that could pose a threat to public health. Scientists use X-ray facilities like the Stanford Synchrotron Radiation Lightsource (SSRL) at the Department of Energy’s SLAC National Accelerator Laboratory to examine the underlying structures of individual proteins, which influence a virus’ behavior and ability to spread between species.
Since the first recorded case of highly pathogenic avian influenza H5N1 – commonly known as avian flu or bird flu – in 1996, Ian Wilson, professor of structural biology at Scripps Research, and his colleagues have been closely tracking the evolution of several key proteins using SSRL.
Recently, Wilson’s team investigated the evolution of a protein that plays a crucial role in H5N1’s ability to transmit between species. Their analysis found that the protein is susceptible to a mutation that could help the virus attach to human cells, potentially increasing the risk of human transmission. The findings – – underscore the need for ongoing monitoring of H5N1’s evolution.
“Facilities like SSRL enable research on infectious diseases and pandemic threats, accelerating our ability to respond to global health emergencies,” said Aina Cohen, division director of Structural Molecular Biology at SSRL. “Discoveries made in areas like drug development, vaccine design and diagnostics can lead to more effective treatments, earlier disease detection and stronger preventive measures.”
Studying proteins with SSRL
Though H5N1 viruses are prevalent in birds and some mammals around the world, transmission to and between humans is rare. However, this could change as the virus continues to mutate. Wilson's team focuses on H5N1’s hemagglutinin (HA) protein, which enables the virus to attach to receptors on the surfaces of host cells. If this protein mutates from its current receptor specificity – which favors avian-type receptors – to one that effectively binds to human-type receptors, the potential for transmission to humans could rise significantly.
“Monitoring changes in receptor specificity – the way a virus recognizes host cells – is crucial because receptor binding is a key step toward transmissibility,” Wilson said. “That being said, receptor mutations alone don’t guarantee that the virus will transmit between humans.”
To build a timeline of the HA protein's evolution, Wilson's team analyzes proteins from samples collected in various years. These studies do not use live virus samples; instead, the research team generates proteins using data from the Global Initiative on Sharing All Influenza Data. The team then crystallizes these proteins and sends the crystallized samples to SSRL.
At SSRL's Beam Line 12-1, the Scripps team collects data remotely with assistance from on-site scientists at SLAC. By analyzing how X-rays diffract when passing through the protein crystals, researchers can reconstruct the protein’s 3D structure, gaining insights into the behavior of various HA proteins.
“The bright X-ray microbeams produced by SSRL, combined with a high level of experimental automation and user-friendly experimental control interface, make Beam Line 12-1 a premiere resource for these types of experiments,” Cohen said. “With decades of experience, SSRL staff support our users, helping them achieve the highest quality data.”
Building a timeline
In their most recent study, Wilson’s team examined two HA protein variants from 2016: the dominant 2.3.4.4b strain and the less common 2.3.4.4e strain. They investigated how each variant's receptor specificity responded to a specific mutation called “Q226L.”
Their analysis found that, following the mutation, the 2.3.4.4e strain was easily converted to bind to a human-type receptor, which could increase the likelihood of bird-to-human infections. Additionally, the mutation could make this strain better at adapting to the respiratory tract of humans, which could increase the risk of transmission between humans, although further research is necessary to confirm this.
“It’s important to clarify that, despite the potential for mutations, the virus would still need to undergo multiple genetic changes in nature to result in a fully adapted strain capable of efficient human-to-human transmission,” Wilson said.
This study provides a crucial timestamp in the evolution of the HA protein, particularly alongside previous research by Wilson and his team that , known as 2024 2.3.4.4b. That study found that the current 2024 strain was just one mutation away from achieving a human-type specificity, while earlier versions usually required three or more mutations to do so.
Taken together, these timestamps demonstrate how HA proteins from H5 strains have evolved over the years and indicates an increased susceptibility to mutations that could facilitate transmission to humans. While these studies highlight the necessity of monitoring H5N1's evolution, it does not indicate that a pandemic is imminent or that the virus has adapted for efficient human transmission. Moving forward, the research group aims to understand how mutations affect receptor specificity in various genetic contexts, including the latest strains, to identify those with potential for human infection.
SSRL is a DOE Office of Science user facility. The SSRL Structural Molecular Biology program is supported by the DOE Office of Science and the NIH National Institute of General Medical Sciences. This research at Scripps Research was supported in part by the National Institutes of Health.
About SLAC
SLAC National Accelerator Laboratory explores how the universe works at the biggest, smallest and fastest scales and invents powerful tools used by researchers around the globe. As world leaders in and bold explorers of the physics of the universe, we forge new ground in understanding our origins and building a healthier and more sustainable future. Our help develop new materials and chemical processes and open unprecedented views of the cosmos and life’s most delicate machinery. Building on more than 60 years of visionary research, we help shape the future by advancing areas such as quantum technology, scientific computing and the development of next-generation accelerators.
SLAC is operated by Stanford University for the U.S. Department of Energy’s . The Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time.
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