'When you change something in a virus, you lose something else'

The contents of this blog post should have come out earlier (in a different form) but better late than never, eh? The Ebola outbreak has been more threatening than ever of going out of control (even as whether we’re really in control now is doubtful). As doctors and healthcare workers grappled with containment in West Africa, Michael Osterholm, the director of the Center for Infectious Diseases Research and Policy, University of Minnesota, wrote an alarmist opinion piece in The New York Times on September 11 that was more panic-mongering than instigatory. The thrust of Osterholm’s argument was:

The second possibility is one that virologists are loath to discuss openly but are definitely considering in private: that an Ebola virus could mutate to become transmissible through the air. … If certain mutations occurred, it would mean that just breathing would put one at risk of contracting Ebola. Infections could spread quickly to every part of the globe, as the H1N1 influenza virus did in 2009, after its birth in Mexico.

Sometime soon after, I spoke to a virologist at Columbia University, Dr. Vincent Racaniello, about Osterholm’s statements. I picked out Dr. Racaniello after stumbling on his virology blog (bookmark it, it’s very insightful) which at the time appeared to be one of the few voices of reason advocating caution in the face of the outbreak and pushing against the notion of an airborne Ebola virus with some crucial facts. Below, I reproduce parts of our conversation that address the nature of such facts and how they should guide us.

Note: For the TL;DR version, scroll right to the bottom.

What we know about Ebola based on what we’ve learnt from studying viruses

Some viruses are studied more than others because of their impact on human health. HIV, influenza, the herpes viruses… Herpes viruses infect almost every person on the Earth; influenza infects hundreds of thousands every year; HIV has infected millions and millions of people – so those get most of the attention, so people work on them a lot. Some of the things you find may be generalizable, such as the general need of a virus to get inside of a cell, replicate its genome. But each virus has specifics. Each is very different, the genome is different, the way the genome is encased is different, the way it gets into cells is different, and the ways they spread from person to person are often very different.

For example, if you study transmission of the influenza virus in an animal model, you may learn what controls the transmission of those viruses through the air, but you can’t assume that’s going to be the same for the Ebola virus. So people make the mistake of saying “Because this virus does this, then that virus must do the same thing”. That’s not correct. Unfortunately, it makes it complicated because every virus needs to be studied on its own. We can’t study influenza and hope to prevent Ebola.

How viruses evolve to become deadlier

From what we have seen, if you gain a function, you typically lose something else. When humans impose genetic changes on viruses, they’re doing so from their point of view as opposed to the way it happens in nature, where evolution does the job. When a virus in nature somehow evolves and becomes transmissible in some species, it’s because the virus with the right genome has been selected as opposed to in the lab where a human puts one or two mutations in a virus and gets a phenotype. We don’t know how to achieve gain-of-function in viruses in the lab. We have a lot of hubris, we think we can do anything with viruses. We introduce an amino acid change but who knows what it’s doing to the virus.

What we’ve observed over the years is that when you introduce changes in the virus in the laboratory to get a new property that you want, you lose something else. In terms of transmission, there haven’t been that many transmission experiments done with viruses to understand what controls transmission. H5N1 – avian influenza – ferrets is really the only one – and there, the gain of aerosol transmission caused the loss of virulence. It’s probably because you need other changes to compensate what you’ve done but we’re only looking at transmission.

In nature, perhaps that would be taken care of, so that’s why I say when you change something in a virus you lose something else. But this is not to say that this is always going to be the case. You can’t predict in viruses – you can’t predict in science, often – what’s going to happen. But what we can do is use what we know and use that to inform our thinking. For example, in nature, influenza viruses are very nicely transmitted, but they’re not all that virulent. They don’t have a 90% case-fatality ratio like Ebola, so I think there’s something there that tells us that aerosol transmission is a difficult thing to achieve. But we don’t know what will happen.

About what other evolutionary pathways Ebola has at its disposal

Viruses can be transmitted in a number of ways. They can be transmitted through the air, they can be transmitted by close contact of various sorts, they can be transmitted by body fluids, they can be transmitted by sexual contact, intravenous drug use, mother to child during birth, they can be transmitted by insect vectors, and of course some can be transmitted in our DNA – 8% of our genome is a virus. We have never seen a human virus change the way it’s transmitted. Once a virus has already been in people, we have never seen it change.

We’ve been studying viruses for just over a 100 years which is admittedly not a long time – viruses have probably been around since the beginning of the Earth, billions of years – but we go based on what we know, and we’ve never seen a virus change it’s mode of transmission. I’m not particularly worried about Ebola changing its routes of transmission. Right now, it’s spreading by close contact from person to person via body fluids and I think it’s going to stay that way. I don’t think we need to worry about it being picked up by a mosquito for example – that’s very difficult to do because then the virus would have to replicate in the mosquito and that’s a big challenge. And who knows, if it acquired that, what other property would be compromised.

What, according to Dr. Racaniello, we need to focus on

I think we need to really bear down on stopping transmission. It can be done, it’s not going to be easy, but it’s going to require other countries helping out because these West African countries can’t do it themselves. They don’t have a lot of resources and they’re losing a lot of their healthcare people from the epidemic itself. I don’t see what worrying about aerosol transmission would do. I don’t see it changing the way we treat the outbreak at all. I think right now we need to get vaccines and antivirals approved, so that we can get in there and use them. In the meantime, we need to try and interrupt transmission. In past outbreaks, interrupting it has been the way to stop the outbreaks. Admittedly, they’ve been a lot smaller, easier to contain. But SARS infected 10,000 people globally and it was contained by very stringent measures. That was a virus that did transmit by aerosol. So it can be done – it’s just a matter of getting everyone cooperating to do it.

If a virus can become more transmissible after infecting a human population

If you saw the movie ‘Contagion’ – in this movie, the virus mutated and increased its reproductive index, which I thought was one of the weaknesses of the movie. We’ve never seen that happen in nature, which is not to say that it hasn’t. When a virus starts circulating in people, it has everything it needs to circulate effectively. Often, people will bring the 1918 influenza virus which seemed to get more virulent as the outbreak continued but back then we hadn’t even isolated the influenza virus. It wasn’t isolated until 1933. So there’s just no way we can make definitive statements about what did or didn’t happen, but people speculate all the time.

I wish we could go back in time and sample all the viruses that have been out there but we’re going to have to see it happen. For that same reason, no virus has ever changed its transmission route in people. If it had, we could have taken the virus before and after the change and sequence it and say, “Aha! This is what’s important for this kind of transmission!” We don’t have that information so we depend on animals for this.

TL;DR:

• We can’t study influenza and hope to prevent Ebola.
• When you introduce changes in the virus in the laboratory to get a new property that you want, you lose something else.
• In nature, influenza viruses are very nicely transmitted, but they’re not all that virulent. I think there’s something there that tells us that aerosol transmission is a difficult thing to achieve.
• No virus has ever changed its transmission route in people.
• SARS infected 10,000 people globally and it was contained by very stringent measures. That was a virus that did transmit by aerosol. So it can be done – it’s just a matter of getting everyone cooperating to do it.