Scientists have analyzed all possible mutations of a key element of the coronavirus. The data could help guide vaccine and drug development and indicate how the virus might spread.
HHMI scientists join many of their colleagues around the world in the fight against the novel coronavirus. They develop diagnostic tests, understand the basic biology of the virus, model epidemiology, and develop potential therapies or vaccines. We will share stories of some of this work.
As the novel coronavirus spreads, it picks up new mutations — for better and for worse.
Now, Howard Hughes Medical Institute researcher Jesse Bloom and his colleagues have cataloged how nearly 4,000 different mutations alter the ability of SARS-CoV-2 to bind to human cells.
Their data, publicly available online as an interactive map, is a new resource for researchers developing antiviral drugs and vaccines to fight COVID-19, the infectious disease caused by SARS-CoV-2. The work also reveals how individual mutations can affect the behavior of the virus, the team reports August 11, 2020 in the journal Cell.
“We don’t know how the virus will evolve, but now we have a way to look at mutations that may occur and see their effects,” says Bloom, a virologist at the Fred Hutchinson Cancer Research Center.
Each time a virus replicates, it can pick up new genetic mutations. Many of these mutations have no effect on the behavior of a virus. Others could make the virus better or worse at infecting people. How much mutations might make SARS-CoV-2 more dangerous has been an open — and controversial — question. Doctors and scientists have analyzed genetic differences in virus samples taken from COVID-19 patients around the world, looking for clues about the spread of the disease. But until now, no one had comprehensively linked potential mutations to their functional effect on SARS-CoV-2.
“We don’t know how the virus will evolve, but now we have a way to look at mutations that may occur and see their effects.”
Jesse Bloom, HHMI researcher at the Fred Hutchinson Cancer Research Center
The new study focused on mutations of a key component of SARS-CoV-2 – its “spike protein”. This protein binds to a protein in human cells called ACE2, a necessary step for infection. Mutations in the spike protein could alter how SARS-CoV-2 sticks to — and therefore infects — human cells.
Bloom’s team bred yeast cells to display a fragment of the spike protein on their surface. This fragment, called the receptor binding domain, makes direct contact with ACE2. The researchers systematically created thousands of versions of the fragment – each with different mutations. Then they measured how well these mutated fragments stuck to ACE2. This allowed them to assess how various mutations might affect binding domain function.
The data shows that many possible mutations could cause the virus to bind more strongly to human cells. But these mutations do not seem to take hold in the circulating versions of the virus.
“This would suggest that there is some sort of sweet spot, where if the virus can bind to ACE2 well enough, then it is able to infect humans,” Bloom says. “Maybe there’s no evolutionary need for it to improve.”
Other mutations made it harder for the spike protein to bind to cells or prevented the protein from folding properly into its final shape, the team found. Versions of the virus with these mutations might be less likely to take hold because they cannot infect cells as efficiently. The team’s targeted lab tests aren’t a perfect indicator of how mutations will affect the virus in the wild, where many other factors influence how efficiently it can spread – but they do provide a point of view. helpful start.
The data will also be valuable to researchers designing drugs and vaccines to fight COVID-19, says Tyler Starr, a postdoc in Bloom’s lab who led the project alongside graduate student Allie Greaney. Understanding the consequences of different mutations can guide the development of drugs that will continue to work as the virus changes over time. Additionally, Starr says, “it’s becoming clear that the antibodies that stick to that part of the virus are very good protective antibodies that we would want to get with a vaccine.”
Study co-author Neil King and his lab at the University of Washington are already working on such vaccines. His team designs artificial proteins that mimic the components of the virus. As part of a vaccine, these proteins could potentially cause people’s immune systems to produce antibodies that target the coronavirus. Researchers modify artificial proteins to make them more stable and easier to produce in large quantities than natural versions of proteins.
Data from Bloom’s team offers a roadmap for making these changes. “Normally when we try to figure out how to improve a protein, we end up in the dark,” says Daniel Ellis, a graduate student in King’s lab. “The information they gave us is a bit like a cheat sheet. It makes our lives incredibly easier.
Tyler N. Starr et al. “Deep Mutational Scan of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on ACE2 Folding and Binding.” Cell. Published online August 11, 2020. doi:10.1016/j.cell.2020.08.012