Caltech’s David Baltimore discusses the debate over origins of SARS-CoV-2

There has been renewed discussion and interest into understanding the biological origins of SARS-CoV-2, the virus that has caused the COVID-19 pandemic. Similar viruses before it have been shown to have jumped from animals to humans; yet this link has not yet been definitively found for SARS-CoV-2.

Caltech’s David Baltimore, president emeritus and Distinguished Professor of Biology, is a virologist who received the Nobel Prize for his research into viral genetics. Baltimore was an organizer of the first Asilomar Conference on Recombinant DNA held in 1975 to discuss ethics and regulation of biotechnology. We sat down with him to discuss the debate over the origins of SARS-CoV-2.

What are the arguments that suggest SARS-CoV-2 is a naturally evolved virus? What is the evidence that suggests that it may have originated in and accidentally released from a laboratory in Wuhan, China?

The argument that it’s a naturally evolved virus is from the belief that through the time of evolution, any sequence of RNA or DNA could evolve.

Biologists have seen what evolution can create: the whole natural world around us. We believe that evolution can do anything. But the fact that evolution might have been able to generate SARS-CoV-2 doesn’t mean that that’s how it came about. I think we very much need to find out what was happening in the Wuhan Institute of Virology. I think that we can’t say for sure yet whether the SARS-CoV-2 virus came from natural origins or if it was genetically manipulated somehow.

Recently you were quoted as saying: “When I first saw the furin cleavage site in the viral sequence, with its arginine codons, I said to my wife it was the smoking gun for the origin of the virus. These features make a powerful challenge to the idea of a natural origin for SARS2.” Can you unpack this quote for us?

Let me be clear, even though I used the phrase “smoking gun,” I don’t really think there’s a smoking gun in the genome itself.

Now, within the SARS-CoV-2 genome there is an insertion of 12 nucleotides that is entirely foreign to the beta-coronavirus class of virus that SARS-CoV-2 is in. There are many other viruses in this class, including the closest relative of SARS-CoV-2 by sequence, and none of them have this sequence. The sequence is called the furin cleavage site.

To back up a little bit: In order to infect a cell, the spike protein on the surface of viruses like SARS-CoV-2 needs to first be cut, or cleaved. The cut needn’t be terribly exact, but it needs to be cut. Different viruses attract different kinds of cellular “scissors,” so to speak, to make this cut; the furin cleavage site attracts the furin protein providing the most efficient way to make a cut. You don’t need a furin cleavage site to cut the protein, but it makes the virus more efficiently infectious.

So where did it come from in SARS-CoV-2? There are other viruses that have furin cleavage sites, other coronaviruses, though not the family of beta-coronaviruses. So this sequence’s nucleotides could have hopped from some other virus. No one has identified a virus that has exactly this sequence, but it could have come from something close, then evolved into the sequence that we see today.

I’m perfectly willing to believe that happened, but I don’t think it’s the only way that that sequence could have appeared. The other way is that somebody could have put it in there. You can’t distinguish between the two origins from just looking at the sequence. So, naturally, you want to know were there people in the virology laboratory in Wuhan who were manipulating viral genetic sequences? It’s really a question of history: What happened?

When I first saw the sequence of the furin cleavage site—as I’ve said, other beta coronaviruses don’t have that site—it seemed to me a reasonable hypothesis that somebody had put it in there. Now, I don’t know if that’s true or not, but I do know that it’s a hypothesis that must be taken seriously.

Why is it important to know where the virus originated?

Well, I think we want to know the pathway of generating highly infectious new viruses that could cause pandemics because we want to protect ourselves against this happening again. If it happened by natural means, it means that we have to increase our surveillance of the natural environment. We have to try to find the hosts that provide an ability for the virus to change its sequence, to become more infectious. This would mean we need to keep surveillance on markets, on zoos, on places where viruses could jump from one species to another.

But if SARS-CoV-2 came about by an artificial means, it means we’ve got to put better defenses around laboratories. I’m not suggesting that it was deliberately released if it came from a laboratory, but we have to realize that whatever a laboratory does might get out of the laboratory and create havoc. It means that work of this sort should only go on in what are called biosafety level 4 laboratories.

In the past, you have spoken a lot about the ethics surrounding gene editing technologies like CRISPR/Cas-9. Though the origins of SARS-CoV-2 are still unclear, are there renewed ethical concerns about manipulating viral genomes?

We have a whole toolbox of ways of manipulating the sequences of viral genomes. Those become much more dangerous if they can get out of the lab and cause trouble. That was the genesis of the first Asilomar meeting in 1975. In that meeting, we were discussing ethics around recombinant DNA technology. We were worried that genetically manipulated things could get out of the laboratory and be dangerous. I must say that, at that time, I didn’t take the issue of whether, in the process of laboratory experimentation, we might generate dangerous new organisms as seriously as it now appears to me.

But in order to try to understand crossover events and prepare for the next pandemic, scientists need to be able to study viruses in the lab. How do we balance safety with the potential good that can come from studying viruses?

We want to know what tricks viruses have evolved, because those are useful to us in a lot of ways: They tell us what to keep an eye on, what to watch out for. Viruses are very inventive in that sense. They have all sorts of tricks, many of which we haven’t seen in organisms other than viruses. We want to know about all of these so that we can be prepared to counter them.

Work in virology is very important from that point of view and also actually gives us tricks that we can use in designing, for instance, gene therapy vectors that are carriers of beneficial genes or therapeutic molecules. At Caltech, my colleagues are developing these types of viral vector technologies that could treat, for example, Huntington’s disease.

When I looked at the world of viruses 20, 30 years ago, I was a younger virologist. It seemed to me that there was very little that viruses did that was good. Most of what they did was bad, caused disease of various sorts, even cancer. Today, there is the ability to manipulate viruses. Researchers can remove the genetic material that makes a virus dangerous, that makes people ill, and instead use the virus as a package to get a desired therapeutic into cells. That’s an incredibly powerful, positive thing that viruses can do. They don’t naturally treat diseases, but we can manipulate them so that they become vectors that allow us to fight diseases.

Editor’s note: This interview was conducted and originally published by the California Institute of Technology and is republished in the Bulletin courtesy of Caltech.