What happens if the coronavirus’s spikes mutate?

First-of-its-kind study explores how changes in the virus’s ‘lock picks’ could help or hinder its ability to sneak into our cells

Editor's note: The story was first published on June 29 when the research published as a preprint on bioRxiv. It's been updated with a link to the final peer-reviewed paper in the journal Cell.

Illustration of the coronavirus studded with spike proteins
Fred Hutch scientists analyzed 3,000-plus potential mutations to a key piece of the coronavirus's spike protein. Illustration by Getty Images

The deaths, the economic crisis, the relentlessly rising number of COVID-19 cases — it all started with a tiny, now-infamous bit of protein.

We’ve all seen images of the spike protein that sits atop the coronavirus like a crown. It is the business end of the virus. One part of that spike — the receptor-binding domain, or RBD — acts like a lock pick, binding to a molecule called ACE2 on human cells and letting the virus slip inside.

Scientists at Fred Hutchinson Cancer Research Center have taken the first comprehensive look at how mutations to the RBD would affect that ability to bind to ACE2. The new research, published on Aug. 11 in the journal Cell, aims to shed light on how the coronavirus evolved to easily infect human cells — and to guide efforts to stop it.

“Almost all vaccines in development include the receptor-binding domain in order to trigger an immune response against the virus,” said Dr. Jesse Bloom, an evolutionary biologist and the study’s senior author. “So understanding how mutations affect the RBD can help guide the design of vaccines. This work is also important for understanding the virus’s evolution and, eventually, for understanding whether this virus can evolve to evade immunity.”   

What do the mutations mean?

Scientists on Bloom’s research team, led by Dr. Tyler Starr and Allison Greaney, measured how virtually every possible mutation to the RBD would affect its ability to stably fold and bind to ACE2. “Mutations” might sound ominous, but they are a humdrum part of viral existence, the study authors noted. As viruses spread, they make copies of themselves. Their proofreading is imperfect, and mistakes happen. Those mistakes are mutations.

In the team’s experiments, most of the mutations to the RBD hindered the virus’s binding ability. But a surprising number either were tolerated or helped the RBD bind more tightly with ACE2, said Greaney, an evolutionary virologist. The finding could explain the diversity in this domain that has accumulated over the evolution of these viruses — and shed light on their future evolution.

No mutations that strongly increase ACE2 binding have been spotted in patients with COVID-19, she cautioned. And a tighter bind doesn’t necessarily translate to a more dangerous disease.

“The virus already has a ‘good enough’ ability to bind to ACE2,” said Greaney, a graduate student at the University of Washington. “There’s no reason to believe that going beyond that level will make it more pathogenic or transmissible. But the RBD may be able to tolerate a number of mutations.”

As the pandemic progresses, this “atlas of mutations” can serve as a useful reference, she added. Scientists worldwide can now instantly “look up” any mutation that is seen in a viral sample taken from a patient. That can serve as an early detection system for whether unexpected mutational patterns begin to emerge.   

Maps to guide vaccine design

To take a wide look at RBD mutations, the researchers used an experimental technique called “deep mutational scanning.” It essentially is a warp-speed way to create a catalog of every possible mutation and then ask how each mutation affects the virus.

Dr. Jesse Bloom
"Understanding how mutations affect the (receptor-binding domain) can help guide the design of vaccines," said Dr. Jesse Bloom, an evolutionary biologist and the study’s senior author. Fred Hutch file photo

With help from Dr. Sarah Hilton, an evolutionary and computational biologist in the Bloom Lab, the team aggregated that data into heat maps and visualizations of how the mutations affected the form and function of the RBD. Those resources will hopefully help guide efforts to treat COVID-19, said Starr, an evolutionary biochemist.

That’s because the RBD is an important part of what our immune systems “see.” Patients who have recovered from COVID-19 naturally produce protective proteins called neutralizing antibodies that target the RBD. But many COVID-19 vaccine candidates aim to coax people’s immune systems to make them by exposing them to the RBD and not the deadly virus that makes it.

So a deeper understanding of how these antibodies can bind to the virus’s RBD is critical to building an effective vaccine and other antibody-based therapies, Starr said.

“Our maps immediately give insight to people who are engineering vaccines,” he said.

For COVID-19 vaccines that rely on the RBD, the maps can identify the most stable forms of the protein that could be mass produced, he said. The work could also guide efforts to create therapies that target certain parts of the RBD. 

Evolutionary past, present and future

More broadly, the research could shed light on how this family of viruses evolved — and how they jumped into humans, Starr added. “The work is a step toward understanding what it is about these viruses, and their RBDs in particular, that allows them to acquire this capacity to efficiently infect human cells.”

It can also help scientists assess the potential for the coronavirus to morph in response to human antibodies. The seasonal flu is a notorious shapeshifter; it’s why the flu shot you got, say, six years ago won’t offer protection this year.

“So one of our big goals was to ask whether these antibodies are targeting surfaces of the RBD that can tolerate mutations,” Starr said. “If these sites can tolerate mutations, then that gives the raw material that allows the virus to potentially escape antibodies.”

In other words: When a vaccine arrives, and our immune systems start churning out antibodies to block the virus, could the coronavirus evolve to evade them?

The answer: TBD.

What scientists can say is that the virus seems to tolerate mutations to this key piece of the coronavirus, and more elaborate methods of focusing immune responses may become necessary. “But just because we find that there are mutations that are tolerated, it doesn’t necessarily mean anything bad is going to happen,” Greaney said.  

The team posted their findings on bioRxiv in late June to share them as widely as possible before the peer-reviewed paper published in August.

“We went to a lot of effort to try to get the data out there as quickly as possible,” Bloom said. “We were able to draw some interesting conclusions from looking at the data, but we think the scientific community will draw plenty more.”

The National Institutes of Health, the Bill & Melinda Gates Foundation, the Pew Charitable Trusts and Fast Grants supported this research. Starr is a Howard Hughes Medical Institute Fellow of the Damon Runyon Cancer Research Foundation and an Innovation Fellow of the Washington Research Foundation. 

Jake Siegel is a former staff writer at Fred Hutchinson Cancer Center. Previously, he covered health topics at UW Medicine and technology at Microsoft. He has an M.A. from the Missouri School of Journalism.

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