New Gene Map of Deadly Bird Flu Points to Pandemic Concerns

[Reefa]

A farmer feeds chickens in China's Anhui Province in January 2014. China has seen a spate of bird flu cases this year.

When does scientific research cause more harm than good? That question has been at the heart of controversy over what should be published about avian flu.

A new study by virologist Ron Fouchier and researchers from Erasmus Medical Center in the Netherlands explores the ability of the H5N1 bird flu strain to become airborne transmissible between mammals. The researchers describe their work, published Thursday in the journal Cell, as providing key insights into how the bird flu virus might spread and, by extension, helping to prevent a possible pandemic.

But the research has been controversial. David Relman, professor of medicine, microbiology, and immunology at Stanford University in California, says such work could also provide insights into how to build a biological weapon. He says it is "irresponsible," entails "greater risk and fewer benefits" than presented, and could give someone "well-versed in reverse genetics" the ability to manufacture the deadliest version of the virus.

Stephen Morse, global co-director of the U.S. government–funded PREDICT Project consortium and an epidemiology professor at Columbia University Mailman School of Public Health in New York, says the research is addressing key questions but must be done carefully for many reasons. "If someone is infected in the laboratory, there would be serious consequences," he says.

Research like this study has been so fraught with concerns over its public dissemination that some governments, citing national security dangers, require an export permit before the paper can be published because of its potential "dual use" as a blueprint for a weapon.

Currently, the H5N1 virus hasn't been shown to be transmissible through the air, but this new work shows how mutations to the virus could give it that ability. Fouchier spoke with National Geographic about his controversial work and why it is vital to understanding flu and its inevitable outcome: a pandemic.

Could you explain what is new in your current paper?

In our work published in 2012, we showed for the first time that the H5N1 virus could acquire airborne transmissibility between mammals—between ferrets. We also showed that of the viruses that we genetically engineered and also adapted further to ferrets, the ones that became airborne transmissible had a minimum of nine amino acid substitutions.

In that initial paper we did not further map which of those mutations were essential for the airborne phenotype. So in the present manuscript, we started off with the viruses that were described in the 2012 paper, but now we chose the viruses with minimal sets of mutations.

We found that as few as five were sufficient to make the virus airborne. For each of these five mutations, we have investigated exactly what the biological traits were that were associated with those mutations, and we showed that the mutations that are critical for airborne transmission are mutations that increase the binding of the virus to cells in the upper respiratory tract of mammals, increase the stability of the virus, and are mutations that increase the replications, or the copying of the virus, while it is in the cell.

So the big difference between this paper and the previous one is that we now really narrow down the exact molecular basis for airborne transmissibility.

There is concern that by mapping this out, you are also essentially mapping out how to make a biological weapon. How dangerous, exactly, is your research?

Well, there are two concerns from people in the field. One is the accidental escape of viruses like this from the laboratory. The other is that people with bad intentions would try to re-create viruses like this and use them as a weapon.

To begin with the latter point, these viruses are not very lethal. When we do these transmission experiments in mammals, the animals don't die. So it is certainly not a lethal weapon in that sense. You also cannot aim this weapon: You cannot protect your own people and target other people, so as a weapon this makes very little sense at all.

Then, of course, there is the argument that maybe some idiot, some lone wolf, some terrorist would use it, but these viruses are not easy to make. You need a lot of expertise to be able to make viruses like this. And at the same time, you have to realize that nature has plenty of dangerous viruses already out there, so if you really want to do some harm with viruses, then maybe people would not have to rely on genetic mutation of viruses. They could just go out into nature and get some dangerous viruses out there.

You can never exclude the possibility that some idiot will start using viruses as bioterror agents, but that doesn't mean that you can't do research on it. I don't think we are enabling these idiots at all by doing research on these pathogens.

For the release of pathogens out of the laboratory, there have been enormous improvements since the 1970s on biosafety. We've heard rumors of this or that pathogen escaping from a laboratory, but the number of cases where this has actually happened is extremely limited. There is, of course, the SARS incident in Singapore in facilities that really weren't operating in the way they should. There are incidences reported every year, that's true, but these incidences have not resulted in releases of pathogens into the environment.

One of the arguments is that by mapping this information out, somebody could use reverse genetics as the end game to replicate the deadliest aspects of this virus. Is that possible?

Well, of course, our manuscripts contain detailed information on how we created those viruses, so in principle our manuscripts could be used as a recipe for anybody. But you need very sophisticated equipment and personnel to do these types of experiments. Even if you would succeed in that, which really is not easy, then still this is not a biological weapon. This is a virus that transmits between ferrets, but it's not clear that it would transmit between humans. And it certainly does not kill the ferrets. So it's not clear that it would kill humans. I don't see why this would even be considered a biological weapon.

Why ferrets?

There are many reasons. The anatomy of their airway systems is comparable to [that of] humans, and the receptor distribution for the flu virus is the same in ferrets as in humans. Ferrets develop a similar disease as humans do when infected with flu virus, and the severity of disease also corresponds. We know these ferrets are a good model because all human flu viruses are airborne transmitted in ferrets, and animal viruses that are not airborne transmitted in humans are also not transmitted in ferrets. So the ferret is as good a model as we'll ever get for flu.

What benefits does your research provide us when it comes to fighting flu and a potential pandemic?

It's very basic fundamental research on pathogens. Some pathogens acquire the ability to be transmitted, either through contact or, in this case, through aerosols or respiratory droplets. The infectious disease field on the whole has no knowledge whatsoever of what makes a pathogen airborne transmissible. To really understand this I think is a key issue in the investigations in the infectious disease community. We want to know why viruses kill humans or cause disease, but we also need to understand how they are transmitted.

This is very fundamental research; I cannot completely predict where it will be applied, but we need to look into how this virus works, and maybe identify ways of doing something about it. We used the H5N1 as a model virus because it's been feared this virus might acquire the ability of airborne transmission in nature, so we are hitting two birds with one stone: On the one hand, we are addressing fundamental questions, and on the other hand, we're trying to also increase our insight into what might happen in nature with this particular virus. Some of the mutations we've described are already found in the field in chickens or in humans.

Are you still involved with legal battles with the Dutch government over bringing your research to a global audience?

Yes, that's correct. I don't have a legal case with Dutch authorities, but Erasmus University does. When we submitted our manuscript in 2011, both the U.S. and the Dutch governments declared that, because of all the danger that was thought to be associated with this work, an export permit would be required, not only here but [also] in the U.S. In the U.S. they dropped that requirement instantly after the NSABB [National Science Advisory Board for Biosecurity] reversed their decision about redacting the manuscripts.

But the Dutch government still requires a permit. Erasmus has decided to appeal this decision, and that case will probably continue at the end of this year. In the meantime, I still have to get this export permit until the case is settled, so that's what we did with this manuscript. This is the second time I've had to apply for an export permit for a scientific publication.

Wasn't there also a broad moratorium on this kind of research until this past January?

The NSABB was asked to look at our previous paper in 2011 and also that of Yoshihiro Kawaoka [and co-authors]. The NSABB, which is a U.S. advisory body, said both manuscripts should not be published as presented—too much danger and very little benefit. That was their initial decision.

But after that, there was enormous commotion in the press: People were asking if this work is so dangerous, should we be doing it at all? And there was enormous discussion in the scientific community about whether a government body could regulate scientific communications. And there was commotion in political institutions like the White House in the U.S. about further regulation of science. There was commotion in the public about fearing mad scientists.

So there was so much commotion and so many new regulations and so much unclarity about safety conditions that the influenza field decided to voluntarily shut down this kind of research, initially for two months. Even the World Health Organization initially advised that [the moratorium] should last longer so that everyone could calm down and investigate what really happened here. [The WHO advised publication in full a few months later.]

Do you see general differences between the U.S. and Europe when it comes to sensitive materials being explored by scientists?

The U.S., of course, has more of a fear of terrorism because of 9/11 and the anthrax letters in 2001, so the U.S. has some experience that makes [the country] more triggered for this type of issue than Europe. There have been so many attacks in the U.S. that now there are organizations that deal with this full-time, an entire industry in the U.S. that operates on bioterrorism fear. That is much less the case in Europe. And Europe is generally very pro-transparency and against doing things in secrecy or classified.

How big of a risk is there that this strain of bird flu could really cause a pandemic?

Flu viruses are known to be the most threatening when it comes to causing pandemics. We've seen them, on average, every 20 to 30 years over the past two centuries. For flu, pandemics are an intrinsic part of the viral ecology. That's why we're so interested in doing this with flu rather than with other viruses. If you're asking how afraid we should be of another pandemic, I don't have to guess much—we know there will be another pandemic.

And we also know that this pandemic will be caused by a virus that transmits between humans, [as] we've seen this in recent centuries. That is why I think we should investigate how this airborne transmission works, so that maybe in the longer term we can do something about that transmission route. Even if we can't, maybe we can identify among all the various flu viruses in animals which [one] is most likely to cause the next pandemic. If we know that, then we can be better prepared for the next pandemic.

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