Science Interviews

Interview

Sun, 15th Jan 2012

Potentially Pandemic H5N1

Mark Peplow, Nature
Ron Fouchier, Erasmus Medical Center, Rotterdam

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Chris -   A controversy that's even got governments involved! In September 2011, Dutch researcher Ron Fouchier gave a presentation at an Influenza Conference in which he showed how he’d been able to make, relatively easily, a form of bird flu – H5N1 that can transmit readily between mammals which is something that the naturally occurring form of the virus thankfully can't yet do. The results describe the structure of what Ron Fouchier himself describes as ‘probably one of the most dangerous viruses that you can make’ were sent to the journal Science for publication.  But the paper has been suppressed on safety grounds, that the details could aid terrorists in creating weapons of mass destruction. 

The journal Nature also has a similar bird flu paper waiting in the wings for the same reason.  And now, both papers are currently under review by the US National Science Advisory Board for Biosecurity.  So how should sensitive, but nonetheless very important, scientific results like this actually get handled?  To find out more, I spoke with Mark Peplow, News Editor at Nature which this week asked authorities around the world this very same question.

Mark -   Okay, so this all revolves around some research which has been done on the avian flu virus – H5N1.  Two groups of researchers have basically made a mutant form of this virus which is more easily transmittable between mammals.  Actually, they've tested it in the lab and it’s ferrets that they use as it’s more easily transmitted, just by ferrets breathing the same air and that raises concerns that these viruses, if they escaped, could also be transmitted between humans and potentially trigger a huge pandemic.

Chris -   There are two aspects to this, aren’t there?  One, is should we be releasing the information as to how to make this very pathogenic viruses that transmit very efficiently because there's a question over, whether this is safe from a bioterrorism perspective. The other is, the public health perspective, in order for scientists to be able to work out how to mitigate this threat, they've got to know what the threat is.

Mark -   Yeah, that's right and it’s something that sometimes gets lost in some of the news reporting around this and that these mutant strains weren’t born out of some reckless desire by mad scientists to push the boundaries of high risk science. 

So the issue is, like you said, should this work be published?  An awful lot of scientists say, “Yes, it absolutely should be published in full because it’s important to understand how deadly these viruses are and potentially develop treatment against them.”  On the other side, there are some people out within the security community, but even scientists as well, that argue that the benefits that you gain from this sort of work are just not great enough to counter the risk of an accidental release or the possibility that a terrorist could get hold of the recipe, if you like and cook up some of these viruses themselves. 

InfluenzaThose in the security community take a broader issue which is some of the mechanisms for oversight of this sort of work really aren’t sufficiently well-developed.  They're saying, “Look, the argument about this is coming up when this work has already been done.  It’s about to be published” and the security community is saying, “Look, we need a much more stringent oversight system to make sure that these conversations start happening before the experiments go on and not after them.”

Chris -   And where does a journal like Nature stand on this?  You've got some information that you want to publish which is for the good of the scientific community but may have political consequences.  At what point does it become a problem with someone saying, you can't put that out?

Mark -   Well because I'm the News Editor of Nature, I can't actually speak on behalf of the section of Nature which publishes scientific manuscripts, but I know what our Editor in Chief Phil Campbell’s position is on this and that is that they acknowledge the concerns about this work and at the moment, there is no decision about whether to publish the papers or whether to publish a censored form of the papers.  What we’re waiting for is for the US government to provide details of, if the papers are censored, how it would allow genuine researchers to obtain that detail that would inform their own work.  And as long as there is a safe but efficient system for getting that information, that scientific information, to legitimate researchers who need it, then both Nature and Science have said in statements that they would be happy to publish the papers in a reducted form so you basically outline what the researchers have done, but you don't give any of the recipes in public for how they did it.

Chris -   Mark Peplow.  But what is the work at the centre of this scientific storm?  Ron Fouchier, the author of one of those papers.

Ron -   We’ve been working on H5N1 viruses that are circulating currently in Indonesia and causing massive outbreaks and we’ve been studying transmissibility of this virus to humans and between humans.

Chris -   Many people say H5N1 isn't a big worry because if it was going to jump into us, it would have done already.  How do you respond to that?

Ron -   Well, it is a big worry even when it jumps into us now because it kills people.  It killed more than 400 people already and of course so far, there have been isolated cases but the fear is that the virus will adapt and will change genetically, such that it will become transmissible.  And every case of infection of a human is a chance for the virus adapting to the human situation.

Chris -   So when a virus does jump out of one host species like a bird in the case of H5N1, so it gets into humans, what does it actually take for it to grow efficiently in a human, a different host and then spread from one host to the next?

Ron -   We know pretty much what it takes to infect the first human.  We know very little of what it then takes to be transmissible between humans.  They have to adapt to attach to other cells than they are used to attaching to, these cells express receptors and they have to adapt to new receptors, and they also have to adapt to produce enough virus such that the virus can spread and it does so by making genetic changes in the polymerase complex, and the polymerase complex is responsible for multiplication of the virus.  But really, we don't know anything about what it takes to then become transmissible.

Chris -   Many of the cases of H5N1 we’ve seen tend to stop with the person that gets infected, so they get it from a bird but then they don't pass it on.  So how come they die of it, yet not pass it on?

Ron -   So many of the human cases of infection, they contract the virus in odd ways – by drinking raw duck blood for instance or by getting the snot out of the beak of a fighting cock.  And so, they get huge amounts of virus in and they get it generally deep down the respiratory tract.  And deep down the respiratory tract, the virus can replicate quite efficiently.  These individuals develop pneumonia and they die as a consequence of that.  The virus is not particularly well adapted to replicate in the upper respiratory tract and we have always said that as soon as the virus gains the ability to replicate in upper respiratory tract of humans, then we might be in trouble.

Chris -   So how are you trying to work out what it’s going to take?

Ron -   We borrowed evidence from previous pandemics when avian viruses changed and then caused infections in humans.  And some of the changes that occurred in those pandemic viruses, we have introduced by genetic manipulation into H5N1 virus.  And that H5N1 virus now replicates in the upper respiratory tract of mammals.  Now that virus has many of the hallmarks of a pandemic virus, but we found initially that it’s still is not transmitted.  It’s very surprising and so what we did then is put it into a mammal and let the virus adapt to the mammal for a few rounds and then take that virus, and then that virus will become transmissible.  And so, by intelligent experiments, we were able to introduce three mutations into the virus and then because we didn’t know the rest of it, we let the mammals do the rest of the story, and they accumulated two or three additional mutations or enough to make this virus transmissible.

Chris -   Every time the virus goes into a new mammalian host, it has a new chance to adapt.

Ron -   Yes, that's correct.  So that's the message that we’re sending out.  Many of the mutations that we have introduced with genetic modification are already found in the field.  So it’s now a matter of chance of a mammal running into a chicken that has a virus with those mutations.  And then in that mammal, it can accumulate the extra mutations and then we would be in trouble.

Chris -   You're saying that the mutations that you put into your experimental virus already exist out in nature if you know where to look for them.

Ron -   Yes.  So far, there have been about 500 million birds infected and we have sequenced the genome of about 1,000 of them and in those 1,000 genomes, we already find the exact same mutations that we find in the transmissible virus, just not in the combination of 5 or 6 that we find in a transmissible virus.

Chris -   Once you put those mutations or changes into H5N1, does it remain as pathogenic, as virulent, as the wild type or does it have to surrender some of that virulence in order to become fit to reproduce in humans instead of its more native bird?

Ron -   Well we had all hoped and also thought that this virus would be reduced in virulence, but the first quick and dirty experiments that we have done suggests that the virus is just as hot as the wild type virus, and it kills a ferret in 3 days.  In humans, kills 95% of the individuals that get infected.

Chris -   What's the moral of the story?

Ron -   To be honest, I think that many scientists have – well not just scientists but also the policy makers are relaxing a little bit too much on H5N1 at the moment.  Many scientists believe that only H1, H2, and H3 viruses can cause pandemics rather than H5, and many scientists think that it has to involve pigs.  Many scientists think that viruses need to shuffle their genes, rather than just build in mutations.  And this investigation really showed that we should not be so relaxed about how to deal with the H5N1 virus, and I think the policy should be, to start stamping out H5N1.

Chris -   And that was Ron Fouchier from the Erasmus Medical Centre in the Netherlands.  He was speaking with me at the ESWI Influenza Conference held in Malta last September. 

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Most interesting question. 

It first leads to the question on whether one should even be tinkering with constructing a synthetic super-virus (for scientific purposes)?  What if a power outage or something caused a containment breach?  Perhaps PETA will choose to raid the lab at an inopportune moment.  Or, it could just get stolen.  What about disgruntled employees?  Keep in mind that many of the Anthrax attacks on the USA originated in US Laboratories.

At this point, we haven't cured the common cold.  A lab bred super-virus could be extremely difficult to control.  With low natural immunity in the population, one could create a societal dependence on annual vaccines, something that would not be evenly distributed around the planet.

I suppose one should foster a scientific discussion about 4 possible methods of making the species "leap".  Are there more possibilities?
New mutations
Recombination with Human (or other mammalian) viruses
Recombination with existing Avian viruses
Artificially Lab Created

I would ask if there is something that is preventing these mutations from happening, or recombining in nature.  For example, a virus with all the necessary genes to be infectious to humans might not be infectious to birds, and thus would not be naturally selected for.

Anyway, I agree.
Perhaps they could build some kind of an inter-lab communication network, but the specific details on the recombination does not need to be published in an open scientific journal. 

Keep in mind, there are several countries that have not signed the 1972 Biological Weapons Convention, and some countries who have signed it are in an ambiguous state due to major political changes since the original signing.  Including the Republic of China apparently signed it, but the People's Republic of China has not (I think). CliffordK, Tue, 17th Jan 2012

Oh, also,
Do these labs carry insurance?

What would the potential liability be if a laboratory released a synthetic pandemic that killed in excess of 1 billion people, and created the need to annually develop and distribute billions of vaccinations, including vaccinating every child? CliffordK, Tue, 17th Jan 2012

You'd have to prove that the lab was responsible. This might prove tricky in this circumstance because, as Ron Fouchier points out in the interview, all of the mutations that were required to generate their mammalian-transmissible H5N1 strain are already found, albeit singly at present, in naturally-occurring isolates of the virus. chris, Wed, 18th Jan 2012

There are some conspiracy theorists that think HIV/AIDS was a synthetic lab-created virus.  I think that is dubious.  However, I know that things like Anthrax can often be traced back to the laboratory where it came from, but that may be tracing the actual spores, and not the infections.

I suppose one would not know how close were are to seeing the species jump without identifying the genes that would be necessary for it to happen.  And, this might help to develop a disease for a hypothetical disease.  However, I still think it is playing with fire. CliffordK, Wed, 18th Jan 2012

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