Is the coronavirus behind COVID-19 turning into a more insidious pathogen? Or are such claims overblown?
A fast-moving debate over virus evolution illustrates how not-yet-vetted reports about the course of the coronavirus outbreak can go, um, viral — and how important social media channels have become in the global discussion of the science behind the pandemic.
The nature of SARS-CoV-2, the virus that causes COVID-19, is of such great interest because the disease is so deadly and disruptive: As of today, Johns Hopkins University reports nearly 3.7 million confirmed cases around the world, with a global death toll of more than 250,000. The United States accounts for 1.2 million cases and 71,000 deaths so far, and that toll could double before the worst is over.
Every day, several hundred new studies about SARS-CoV-2 and COVID-19 — most of which haven't yet gone through the traditional peer-review process — go online, to face scrutiny by researchers and a wide swath of the general public.
One study got more than the usual traction today: The research project, led by scientists at Los Alamos National Laboratory and the University of Sheffield, looked at the way 14 variants of the virus have spread across the world.
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The resulting paper was filed to the BioRxiv preprint server last week but has not yet been peer-reviewed. It concluded that one particular variant known as D614G is "of urgent concern." That variant, a descendant of a form of the virus that started out in China, began spreading in Europe in early February and eventually made the leap to other parts of the world.
"When introduced to new regions, it repeatedly and rapidly becomes the dominant form," the researchers noted.
The concern was that the virus had evolved to become more transmissible, and that interventions aimed at curbing the pandemic might not be as successful as hoped. People who survived a bout with one variant of the virus might still fall prey to the increasingly dominant variant, the researchers said.
"We cannot afford to be blindsided as we move vaccines and antibodies into clinical testing," lead study author Bette Korber said in a Facebook post quoted by the Los Angeles Times. "Please be encouraged by knowing the global scientific community is on this, and we are cooperating with each other in ways I have never seen … in my 30 years as a scientist."
It didn't take long for the scientific community to start assessing the team's conclusions — and the way they were being reported to the general public. Cornell University virologist Brian Wasik pulled no punches on Twitter:
This LATimes article is INFURIATING. So much misinformation based on just that preprint. They took quotes from the author's PERSONAL FACEBOOK PAGE. An anonymous quote that this is 'classic Darwinian evolution.' Commentary on viral load and pathogenesis from a toxicologist. pic.twitter.com/dN2T4oYOCa
— Brian Wasik (@BrianRWasik) May 5, 2020
And he wasn't alone. Columbia University's Angela Rasmussen said the report made her blood boil. "There is no evidence that the dominant strain is such because it is 'more contagious,' " she tweeted.
Harvard University's Bill Hanage laid out an alternate explanation in his own Twitter thread, posted way back on Friday. He argued that D614G might have become the dominant variant of the virus simply because of a metaphorical roll of the dice:
This preprint has been getting attention. It claims that the SARS-CoV-2 virus is mutating into a more transmissible form as the pandemic wears on. I think those claims are suspect, to say the least https://t.co/pmL7neWzR7 1/n
— Bill Hanage (@BillHanage) May 2, 2020
Major observation: a specific mutation in the spike protein of the virus has been in a higher fraction of cases as the pandemic has worn on in multiple places. Given the role of the spike protein in entry of the virus to cells this might be reasonable. Now for the cold water 2/n
— Bill Hanage (@BillHanage) May 2, 2020
We need to distinguish between selection, in which a variant becomes more common because it leaves more descendants, and founder effects in which a variant becomes more common because it was fortunate rolling the dice 3/n
— Bill Hanage (@BillHanage) May 2, 2020
by that, I mean this variant might have been lucky and got introduced to places outside Wuhan and different approaches to social distancing early on. It's not about the virus, it's the environment and the opportunities for transmission 4/n
— Bill Hanage (@BillHanage) May 2, 2020
You'll have to read through the entire 15-tweet thread to find out how Hanage uses data from Washington state to back up his view. Here's his bottom line: "Right now there are better ways of fighting the pandemic than worrying about different strains defined by one non-synonymous SNP. … If anyone who does not know what it is already googles 'non-synonymous SNP,' I will be delighted."
But wait … there's more: This afternoon brought a more ambiguous verdict from Trevor Bedford, the epidemiologist at Seattle's Fred Hutchinson Cancer Research Center who started tracing coronavirus evolution back in January. Ever since then, he and his colleagues at Nextstrain and the Seattle Flu Study have been comparing genetic fingerprints from viral variants to map how they're spreading globally.
Bedford said there's some evidence to back up the claims made by Korber and her colleagues, but that the case is "far from conclusive." He also stressed that D614G doesn't appear to be more dangerous than the other variants, even if it's currently more dominant. Here's the full thread:
I wanted to address the hypothesis put forward in Korber et al (https://t.co/ouM4IUyNrd) that the mutation in spike protein D614G causes an increase in transmissibility of SARS-CoV-2 virus. I find this hypothesis to be plausible, but far from proven. 1/16
— Trevor Bedford (@trvrb) May 6, 2020
I've been watching D614G closely as mutations in spike protein deserve added attention due to spike's role in binding to the human ACE2 receptor. 2/16https://t.co/SrQWpUwjfQ
— Trevor Bedford (@trvrb) May 6, 2020
This D614G mutation occurred in the transmission chain that initially seeded the European outbreak in ~Jan 2020. Almost all viruses possessing this mutation descend from this initial introduction into Europe. 3/16 pic.twitter.com/ASV0j8Ubf3
— Trevor Bedford (@trvrb) May 6, 2020
European viruses are enriched for D614G because of a founder effect in which the initial introduction included this mutation. If we look at the geographic distribution of D vs G in sequenced viruses we see Europe with G, Asia largely D and a mix in the US and Australia. 4/16 pic.twitter.com/W6gDFu3OZ2
— Trevor Bedford (@trvrb) May 6, 2020
The primary finding of Korber et al is that D614G appears to be increasing in frequency over time in sequenced SARS-CoV-2 genomes. I strongly caution against interpretation of selective effects in the global frequency of D614G. 5/16
— Trevor Bedford (@trvrb) May 6, 2020
Its global frequency is heavily confounded with epidemiological circumstance, ie perhaps G is prevalent because it got lucky in the European introduction. However, regional frequencies should be more robust to this confounding (although not perfectly so). 6/16
— Trevor Bedford (@trvrb) May 6, 2020
This figure recapitulates the Korber et al findings using @nextstrain. Here, I've shown states in the US and Australia with more than 70 sequences available and our estimate of frequency of D (green) vs G (yellow) from March 1 to April 15. 7/16 pic.twitter.com/gGdjt88Lv8
— Trevor Bedford (@trvrb) May 6, 2020
You can see that in every case the frequency of G increases in the course of these 45 days. 8/16 pic.twitter.com/1Oelq6SqvF
— Trevor Bedford (@trvrb) May 6, 2020
It's still very possible that this pattern could emerge from repeated introductions from Europe / NYC in the US spreading the G variant and multiple introductions from Europe spreading G in Australia. 9/16
— Trevor Bedford (@trvrb) May 6, 2020
The alternative explanation put forth by Korber et al is that this pattern is due to the G variant being more transmissible. I think this is possible, but it's difficult to distinguish between these hypotheses with this frequency data alone. 10/16
— Trevor Bedford (@trvrb) May 6, 2020
Additional evidence for the hypothesis of a functional effect of D614G comes from Korber et al's observation that the G variant has lower cycle threshold (Ct) value in clinical specimens from Sheffield. This indicates a possible higher viral load in these individuals. 11/16 pic.twitter.com/bDj4zwKJhN
— Trevor Bedford (@trvrb) May 6, 2020
Thanks to work by @wcassias and @pavitrarc, we see this difference in Ct between D and G replicated in @UWVirology specimens. Preliminary analysis here: https://t.co/EyOhTNSmIy. 12/16 pic.twitter.com/O0zt849vr5
— Trevor Bedford (@trvrb) May 6, 2020
There are confounders to worry about here as well (primarily time from symptom onset to specimen collection), but I believe replication in two study populations is suggestive of an effect of D vs G on Ct value and possibly viral load. 13/16
— Trevor Bedford (@trvrb) May 6, 2020
Both Korber et al and our analysis show no measurable effect on patient outcome. Hence, the hypothesis at this point is entirely in terms of transmissibility rather than severity. 14/16
— Trevor Bedford (@trvrb) May 6, 2020
Overall, I would refer everyone to @edyong209's piece on handling uncertainty during the pandemic (https://t.co/QRAw8l37JA). I don't agree with takes that there is "no evidence" that G is more transmissible. There is some evidence, but it's far from conclusive. 15/16
— Trevor Bedford (@trvrb) May 6, 2020
We have to live with this uncertainty over the functional impact of D614G while more data is gathered. We need:
1. Cell culture studies to demonstrate effect in vitro
2. Further clinical comparisons between patients with D vs G
3. More careful epidemiological analysis
16/16— Trevor Bedford (@trvrb) May 6, 2020
For folks who are willing to follow these threads closely, there's a payoff that goes beyond the immediate questions about transmissibility and variations in the virus. With the right kind of perspective, the combination of raw research and social-media assessment can provide a look at how the scientific sausage is made, analogous to the way those old-fashioned "Visible Human" figurines provided literal transparency for anatomy class.
Bedford himself marveled over how quickly things have changed during a session at February's annual meeting of the American Association for the Advancement of Science in Seattle.
"It's been a really interesting way that science has been proceeding, to have it being very rapid and open as it's done, not just waiting a year later for the paper to come out," he said. "This mirrors generally what's been happening with scientific communication surrounding the epidemic, where everything's kind of been flipped around. … It's been an amazing coming together of scientists around the world."
The past few weeks have demonstrated how messy the scientific process can be, but they've also demonstrated how its error-correction mechanisms work. And that's a good thing, even if it means dealing with some turmoil on Twitter.
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