Medical research has benefitted from the scale, speed and efficiency of COVID-19 studies, and scientists are using the techniques developed to fight the pandemic in the race to stay ahead of emerging diseases.
For decades, scientists have used ultrabright X-ray beams to study the biological structures and mechanisms of viruses largely unknown to anyone other than infectious disease specialists. The Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science user facility at DOE’s Argonne National Laboratory, has been at the center of this research.
Then, in 2020, the SARS-COV-2 virus that causes COVID-19 emerged. The decades of cumulative research on other viruses proved instrumental to development of life-saving vaccines and treatments against COVID-19. It also helped shape everyday conversations, making terms such as “spike protein” and “antibodies” commonplace. Infectious disease specialists and structural biologists were no longer the only ones thinking about how viruses spread or stay contained.
Ultrabright X-ray beams, such as those generated by the APS, continue to be used for COVID-19 research. However, they are also helping scientists anticipate and understand threats posed by other viruses. The scientific community is combining the power of the APS with valuable lessons learned and applied during the recent intense period of COVID-19 research. There is a fresh sense of urgency, along with improved techniques and methodologies, to help science tackle tomorrow’s challenges.
The APS is a well-established facility for studying life science, including viruses, at the macromolecular level. When COVID-19 (as well as vaccines and therapies for it) became the preeminent focus of scientists around the world, the challenges of the new disease also intrigued groups that didn’t usually apply their knowledge and experience to virus research.
Joseph S. Brunzelle, a beamline scientist for the Life Sciences Collaborative Access Team (LS-CAT) and macromolecular crystallographer in Northwestern University’s Synchrotron Research Center, worked closely on COVID-related projects throughout the pandemic. He says he was struck by the impact of so many minds around the world focused on one thing.
“When you have that level of community focus, you really push scientific discovery,” Brunzelle said. “I am sure it has happened in the past for other projects, but I had never seen it in the medical science field. I was really impressed.”
The collective effort helped scientists from around the world establish a better understanding of protein structures, monoclonal antibodies and human immune response.
Additional funding helped, too. With money from Congress, all 17 DOE national laboratories formed a consortium — the National Virtual Biotechnology Laboratory — to work together on structural biology issues. They plumbed the considerable depth of the laboratories’ resources, including the Argonne Leadership Computing Facility (ALCF), to tackle computing issues and look at billions of small compounds, working to determine which one might bind to relevant viral proteins of SARS-CoV-2 and serve therapeutic purpose.
The sheer volume of COVID-19-related projects resulted in heavy application of techniques and methodologies available since the early 2000s, but perhaps under-appreciated: expression and purification of samples, modern crystallization, robotic technology and the software to collect and process beamline data efficiently and effectively. All these tools were suddenly even more relevant, necessary and put to the test.
James Crowe, professor of pediatrics and pathology, microbiology and immunology at Vanderbilt University Medical Center, is particularly appreciative of the gains made during the past two years.
“We put a lot of effort into finding antibodies very quickly and at a very large scale for COVID-19, which was necessary because of the emergency of the pandemic,” said Crowe. “Now we use the same methodologies for all of the viruses that we are studying. Virus research is benefiting from the increased scale, speed and efficiency that we learned.”
Crowe and his team at Vanderbilt have their attention trained on strains of henipaviruses, an emerging virus threat deemed high priority by the World Health Organization (WHO).
WHO has a sort of “Most Wanted” list for viruses. On that list are highly infectious viruses with high fatality rates prioritized for accelerated research. Aside from their potential threat to public health by natural transmission, highly pathogenic viruses may be used maliciously as a form of bioterrorism. It is critical to prepare for these viruses as well as to learn how human immune systems might fend them off.
Henipaviruses belong to a family of fruit bat-borne viruses. Although rare, the case fatality rate is estimated at 40% to 75%, and there are no licensed human vaccines or antiviral treatments for infection. The team at Vanderbilt, which has studied henipaviruses for nearly a decade, obtained blood cells four years ago from someone who showed immunity to a henipavirus. They used that sample, recent data from numerous crystal structure studies, and new data from proteins studies at LS-CAT at beamline 21-ID-G at the APS to learn more about where antibodies bind and how each region of a virus protein is important to a virus’s lifecycle. (Scientists do not study the live virus at the APS, but rather crystals grown from its proteins.)
Crowe’s team studied one of the two henipavirus surface proteins, which controls how the virus attaches to cells. The spikes on the virus surface are formed by pairs of identical proteins. Those pairs of proteins appear to associate closely but their pairing alternates between packing that is tight or loose over time. When the association loosens, certain parts of those molecules that are usually hidden become exposed temporarily. If antibodies bind to these normally hidden regions before the virus fuses to a cell, they can slow or stop the virus. The work suggests the antibodies might be useful as antiviral drugs, and also that those exposed sites of vulnerability could be good targets for vaccines.
Such scientific details may be complicated, but a silver lining of COVID-19 is that people have an inkling of what all of this means.
“In the past, when we discussed the role of antibodies and immunity, the general public really had no idea what we were talking about,” said Crowe. “Now there is a higher level of awareness of components of the human immune system, especially antibodies, and that allows us to explain our work better.”
The research team’s work was published in Cell.
Jason McLellan, an architect of COVID-19 vaccines, is using the Structural Biology Center at beamline 19-ID at the APS to find successful countermeasures against the Crimean-Congo hemorrhagic fever virus (CCHFV), which is also on the WHO list. CCHFV is the world’s most widespread tick-borne pathogen. It causes death in up to 40% of cases and is named a “priority A” pathogen by the WHO. Currently, there are no effective vaccines or therapeutics licensed against CCHFV.
As part of a consortium called Prometheus, which previously focused on highly lethal emerging viruses such as Ebola, McLellan and his team used crystallography to look at structural information on one of CCHFV’s proteins. It is the main target of antibody responses from natural infection. By improving understanding of how certain regions of the antibody block membranes from fusing, the team of researchers can turn its attention to epidemic preparedness. McLellan’s team published their work in Science.
One unfortunately tough lesson of COVID-19 is that a virus can rattle an unprepared modern world. Being ready for and responsive to a virus with pandemic potential is key.
“Years of scientific research on related coronaviruses, before COVID-19 became a pandemic, contributed to the rapid development of the COVID-19 vaccines,” said McLellan. “Thus the scientific community is emphasizing research on other emerging viruses such as CCHFV that may not be causing an epidemic at this point but still have potential for future outbreaks.”
Whatever the next outbreak, the APS will continue to provide important information about viral proteins and the ways antibodies or potential therapeutic drugs bind to these proteins. As it has for more than 20 years, the APS will continue to play a vital role in our understanding of infectious diseases, and our ability to stop them.
The Advanced Photon Source is a DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory. Additional funding for beamlines used for COVID-19 research at the APS is provided by the National Institutes of Health (NIH) and by DOE Office of Science Biological and Environmental Research. Supplemental support for COVID-19 research was provided by the DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19 with funding provided by the Coronavirus CARES Act.