Ask a Caltech Expert: Professor Pamela Bjorkman on SARS-CoV-2
This article was reviewed by a member of Caltech's Faculty.
In a March 2020 webinar, Pamela Bjorkman, Caltech’s David Baltimore Professor of Biology and Bioengineering, provided an introduction to viruses, antivirals, and vaccines in the context of SARS-CoV-2, the virus that causes COVID-19. Here, she answers questions from the public.
Is there a means to determine whether a virus has developed naturally in the wild versus one synthesized or modified in the laboratory?
Updated July 2021
A year after the last update on the question of whether SARS-CoV-2 could have been engineered, I remain convinced that a deliberate creation of SARS-CoV-2 would be impossible for reasons listed in my post from 2020. Here I address the suggestion that the furin cleavage site in the SARS-CoV-2 spike protein implicates engineering in a lab.
Furin is an example of an enzyme called a protease that cleaves coronavirus spike proteins to allow conformational changes that are required for infection of cells after fusion of viral and host cell membranes. Although sarbecoviruses (i.e., SARS-like betacoronaviruses including SARS and SARS-CoV-2) do not contain furin cleavage sites in their spikes, these sequences are found throughout coronavirus spikes. Acquisition of a furin site in viral fusion proteins can be correlated with increased virulence; hence the idea that a furin cleavage site was added deliberately to a coronavirus spike sequence to make SARS-CoV-2 more of a pandemic threat than other coronaviruses. However, there would be no way of knowing if adding a furin site would lead to the increased transmissibility and asymptotic spread that resulted in the SARS-CoV-2 pandemic. In addition, if you look at the phylogeny of coronaviruses, particularly betacoronaviruses, you'll see furin cleavage sites within the spikes of many betacoronaviruses (including MERS), meaning many betacoronaviruses have acquired this sequence through natural evolution. Since only a small fraction of sarbecoviruses (the family of betacoronaviruses most closely related to SARS-CoV-2 and SARS) have been sequenced, it seems likely that a subset of sarbecoviruses have already evolved members with furin cleavage sites in their spikes. In summary, the finding of a furin cleavage site within SARS-CoV-2 is compatible with natural evolution.
Another possibility for a lab origin for SARS-CoV-2 is the lab leak hypothesis, i.e., that a research lab working on SARS-CoV-2 or a related virus accidentally released the virus. This is a possibility that requires further investigation, but despite some press reports, there is currently no scientific evidence for a laboratory origin for SARS-CoV-2. The main argument for the lab leak hypothesis, which does not qualify as scientific evidence, is the origin of the pandemic in Wuhan, home to the Wuhan Institute of Virology. (Read a description of the Wuhan Institute of Virology from a researcher who worked there until November 2019.) Until the pandemic was discovered, the city of Wuhan also included live animal markets, which could have spread coronaviruses acquired from bats among animals that were being sold, an origin similar to SARS spillover into humans. In the case of SARS, scientific evidence suggests a natural origin within bat caves in Yunnan province in China, even though the outbreak was first detected in Guangzhou, a city ~1,000 kilometers from Yunnan where live animal markets were prevalent.
The natural origin hypothesis for SARS-CoV-2 postulates that, similar to what is now understood as the origin of SARS, SARS-CoV-2 spilled over into humans from an animal reservoir (likely bats), perhaps through one or more intermediary animal hosts. In the case of SARS, it took ~10 years to find what are likely to be the closest bat virus relatives of human SARS that recombined to produce a SARS-related virus that spilled over into civets, which then infected humans. A recent survey of a small region of Yunnan province in China yielded 24 new sequences of bat viruses related to SARS-CoV-2 and SARS, and these are thought to be only a minor fraction of related bat viruses that are circulating among bats in Yunnan and other parts of Southeast Asia. Thus, not having yet found a natural origin for SARS-CoV-2 does not provide evidence for a laboratory origin for the current pandemic. Additional research needs to be done—ideally, more sequencing of bat, other animal, and pre-pandemic human betacoronaviruses to better understand natural evolution and spillover events.
Read more: The Origins of SARS-CoV-2: A Critical Review (Added August 27, 2021)
It's unfortunate that conspiracy theories are being spread (sort of like a virus) about the origins of SARS-CoV-2. When you look at the sequence of SARS-CoV-2, it's clear that it evolved from a particular bat coronavirus. There's no way, in my mind, that a scientist could design a viral sequence based on a bat coronavirus sequence or any other sequence to ensure that it would be very highly transmissible and also induce serious illness. From what we understand about COVID-19, the progress to ARDS (acute respiratory distress syndrome) is caused by our own immune system's response to the virus. I teach immunology every year, and I would have no idea how to design a coronavirus (or any other virus) to produce ARDS. Nor would any other scientist. So even if you believe that scientists would deliberately synthesize a deadly virus in the laboratory for release to the public, there's no way of someone knowing what they would have to start with and modify (e.g., a bat coronavirus) to make it easily transmissible among humans.
I'd like to add a few things to my previous response that are related to the fact that the scientific community has the entire genome sequence of SARS-CoV-2. When you look at the sequence (actually sequences, because there are different isolates), you find evidence of evolution in a natural host that would not be present if humans engineered the virus. Let's assume, for the sake of argument, that someone decided to try to modify SARS-CoV (i.e., "classical" SARS, the coronavirus that is most closely related to SARS-CoV-2) to turn it into SARS-CoV-2. I guarantee that they would not have made the changes that distinguish SARS-CoV and SARS-CoV-2. For example, some of the changes in the viral spike protein are counterintuitive to anyone who wanted to design tighter binding to the host receptor (ACE2). In addition, there are random changes throughout the viral genome that do not actually result in changes to amino acids (i.e., silent mutations), which would not be added by the hypothetical engineer. More importantly, there are changes to viral proteins whose functions are not completely understood (e.g., ORFs, or open reading frame proteins, and NSPs, or non-structural proteins). Somehow, the changes resulted in a new virus, SARS-CoV-2, that is much more transmissible than SARS-CoV, for reasons that no one understands. Since we don't understand the function of all of the viral genes in a coronavirus (or any virus for that matter), how could anyone design a virus that managed to come up with the perfect (for a virus) combination of high transmissibility and a relatively low rate of killing off its host? The simple and quick answer to this question is that it is absolutely impossible that this virus was engineered by scientists—no one knows enough about viruses, virus-host interactions, and the immune response to viruses to have engineered SARS-CoV-2.
Read more: The proximal origin of SARS-CoV-2 from Nature Medicine (Andersen, K.G., Rambaut, A., Lipkin, W.I. et al)
A friend recently sent me a link to a short talk about the role of 5G in the coronavirus pandemic. Can you comment on this?
There is NO scientific evidence that 5G or any form of "electrification" of the earth plays any role in viral infections. Yes, COVID-19 hotspots can overlap with areas where 5G networks have been tested, but 5G networks are also near major metropolitan areas that have high population densities. The 5G COVID-19 conspiracy theory is a classic case of confusing correlation with causation. There is a lot of misinformation floating around in the news and online. We recommend getting information from scientific websites or articles, from organizations like the World Health Organization (WHO) and the Centers for Disease Control (CDC), or from your own doctor. It is important to make sure that conclusions related as "facts" are actually backed up by scientific and/or medical evidence.
Why do we see a lot of recent epidemics/pandemics related to coronaviruses (SARS, MERS, and now COVID-19)? What is special about coronaviruses that makes us extremely vulnerable and unprepared for these viruses? How do we prepare for the next coronavirus?
Many coronaviruses arise in bats, which are great incubators for exchanging viruses with each other and creating new strains that can potentially cross over into humans. Given time, each new coronavirus would either die out in the human population (as has almost happened with SARS and MERS) or attenuate to the point that they cause only mild symptoms, such as common cold coronaviruses. But we can't wait long enough for SARS-CoV-2 to die out or attenuate. In the long term, I think we need a vaccine. In the short term, we can hopefully slow down transmission and help people survive infections with antiviral drugs.
Even if we develop a vaccine against COVID-19 quickly, it is not going to be a cure. Do we know how quickly COVID-19 evolves, and how do we deal with such moving targets? Any lessons we can borrow from the experience of developing flu and HIV vaccines (or failure to do so)?
The formulation of the annual flu vaccine is chosen by the WHO, which predicts which three or four influenza strains are likely to circulate during the next flu season. So, flu vaccines work best when the prediction is correct. Yes, there is information about how quickly SARS-CoV-2 evolves, and the good news is that it evolves more slowly than flu and a lot more slowly than HIV-1. Even though SARS-CoV-2 may not mutate to develop resistance, we might need an annual coronavirus vaccine if a vaccine and a natural infection produce only short-lived immunological memory.
Read more: What Immunity to COVID-19 Really Means from Scientific American
Is summer/heat really going to slow down COVID-19? Do we expect to eventually live with COVID-19 on a seasonal basis, just like flu? Or will COVID-19 be more like SARS?
I think no one knows the answers to these questions. When I see world maps showing COVID-19 in Southern Hemisphere countries where it is (or was) summer, I worry that summer/heat will not slow down the SARS-CoV-2 virus.