/ Maggie Koerth-Baker / 11 am Fri, Jan 13 2012
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  • Scary science, national security, and open-source research

    Scary science, national security, and open-source research

    I've been following the story about the scientists who have been working to figure out how H5N1 bird flu might become transmissible from human to human, the controversial research they used to study that question, and the federal recommendations that are now threatening to keep that research under wraps. This is a pretty complicated issue, and I want to take a minute to help you all better understand what's going on, and what it means. It's a story that encompasses not just public health and science ethics, but also some of the debates surrounding free information and the risk/benefit ratio of open-source everything.

    H5N1, the famous bird flu, is deadly to humans. Of the 566 people who have contracted this form of influenza, 332 have died. But, so far, the people who have caught bird flu don't seem to have contracted the disease from other humans, or passed it on. Instead, they got it from birds, often farm animals with whom the victims were living in close contact. H5N1 was first identified 14 years ago, and there's never been a documented case of it being passed from person to person.

    But that doesn't mean such a leap is impossible.

    That's because of how the influenza virus works. Influenza is made up of eight pieces of RNA, containing 10 genes, and they all replicate independently of one another and there's no system for error correction*. That means you have more opportunity for mutations to arise that change what the virus does and who it can infect. Think of it like dice. Genetic replication is like putting a die in a jar, shaking it up and seeing what you get. Everybody does that. But influenza has eight die, not one. So it accumulates mutations faster. As a bonus, influenza viruses that infect the same host can share genes—essentially creating a baby virus that carries traits from different parents.

    That's why, despite 14 years of relatively low-risk behavior, scientists are still concerned about what H5N1 might do in the future. All it would take, theoretically, is the right roll of the dice, and suddenly you have a flu virus with a 60% kill rate that can pass from person to person.

    At least, theoretically. Could that actually happen? And, if so, how likely is it that the "right" bad combination of genes will come up? You can see why these are important questions to ask, and that brings us to the controversy.

    Studying the genetics of H5N1 is nothing new. Its genome has been sequenced since 2004, for instance. But, until 2011, nobody had ever tested out a pretty fundamental idea in the control and management of H5N1: The theory that its genetics prevented it from simultaneously being both super deadly and passed from person to person.

    That theory hinged on what we know about one of the proteins in H5N1. Specifically, the protein designated H5. Here's the LA Times:

    Strains carrying the H5 type of a key influenza protein that helps the virus bind to cells in a host had never evolved to travel through the air from person to person. Even if H5N1 did evolve such an ability, some researchers reasoned that it might do so at the expense of its ability to take hold deep in the lung. And that would make it less lethal.

    As one scientist described it to the LA Times, this theory was, basically, "We've not seen this happen before so it can't happen." But that's not a particularly strong basis on which to pin all your fears about a global pandemic.

    That's why researchers in Europe and the U.S. decided to try something risky—see whether they could prompt existing H5N1 viruses to mutate into the very thing everybody's been dreading. Nobody knows a lot about this research, but, at Slate.com, Carl Zimmer explains what is known:

    They’ve carried out their experiments on ferrets, which respond to flu viruses much like humans do. What few details we know of the unpublished research comes from a talk Dutch virologist Ron Fouchier gave in August at a virology conference, along with subsequent news reports. Fouchier began the experiment by altering the H5N1 virus’s genes in two spots. Then he passed the virus from one ferret to another, allowing the virus to mutate and evolve on its own inside the animals. After several rounds, Fouchier ended up with an H5N1 virus that could spread through the air from one ferret to the other. If unleashed—and if proven capable of spreading from human to human with the same high mortality rate—it could make the deadly 1918 pandemic look like a pesky cold.

    So that's one part of the controversy. Was this a responsible thing to do?

    On the one hand, zomgwe'reallgonnadierunhide, right? On the other, this research has already taught us something really, really important. Not only can H5N1 make the leap to mammal-to-mammal transmission, but it did so faster and easier than the researchers had guessed. Knowing that matters, because it could help public health officials make better plans for where to use limited resources, and it could help other scientists figure out a way to fight a human transmissible H5N1 pandemic if it did happen in nature. But, if I may flip the waffle back over again, there are some legitimate scientists who don't think the benefits outweigh the risks of creating this thing. Carl Zimmer again:

    Ian Lipkin, the director of the Center for Infection and Immunity at Columbia University, believes there’s no reason to assume that the mutations that arose in Fouchier’s experiments would be the ones that would arise out in the real world. “On the other hand,” Lipkin says, “publishing this information would give people a roadmap to creating Frankenstein viruses.”

    And that brings us to the other part of the controversy: What to do with Fouchier's research.

    This is where the government gets involved. These studies were funded by the National Institutes for Health. When NIH got the papers, they passed them on to the National Science Advisory Board for Biosecurity. On December 20, the NSABB recommended that Fouchier's study, and a similar one conducted by the University of Wisconsin's Yoshihiro Kawaoka, only be published once key data and details are removed, effectively rendering the studies un-reproducible.

    The board can't technically force this. But the board is also a big deal and so Science, Nature, the NIH, and the paper's authors are all listening. That's why the papers haven't actually been published yet. The people involved are still figuring out how to handle them.

    This matters a lot. Reproducibility—being able to read another scientist's research paper and independently test out their conclusions—is a key part of how science works. Remove that element, and it becomes harder to verify claims like this, not to mention much harder to actually get the benefits out of this risky research. The people involved are trying to work out a system under which qualified scientists could have access to the full data, but others say that isn't good enough. Especially considering the fact that H5N1 wouldn't make the best bioterrorism tool, anyway. Peter Christian Hall writing for Reuters:

    [No one in the history of biological weapons] ever tried to weaponize a flu strain—for good reason.

    Influenza in general is an equal-opportunity menace, particularly dangerous when a strain is so unfamiliar that humanity lacks immunity to it. This would put at great risk anyone trying to assemble a pandemic H5N1 to launch at “target” populations. Indeed, such an attack would unleash global contagion that would swiftly and inevitably incapacitate an aggressor’s own people. Influenza doesn’t respect borders.

    Even arguably irrational terrorists like Aum Shinrikyo never got into anything near as notoriously unpredictable and uncontrollable as the flu, Hall writes. Of course, his argument is pretty similar to the one scientists used to use to reassure themselves that H5N1 couldn't be both deadly and human transmissible: We've not seen this happen before, so it won't.

    Of course, it's also worth pointing out that these experiments were a lot more technologically complex than the short description here makes them sound. This isn't just about taking a bunch of ferrets and making them sick. It required some serious lab equipment that not just anybody has access to.

    Moreover, this isn't the first time scientists have made a deadly flu virus in the lab. Back in 2005, a team reverse-engineered the 1918 pandemic flu. After a lot of debate, their research was eventually published in full, reproducible form. Peter Palese was one of the scientists on that team, and he's written an essay on Nature about his experience, as part of a plea to publish the H5N1 research in full, too.

    He makes a case both for the importance of risky research, and for why all science (even kind of scary science) needs to remain open source.

    During our discussions with members of the NSABB, we explained the importance of bringing such a deadly pathogen back to life. Although these experiments may seem dangerously foolhardy, they are actually the exact opposite. They gave us the opportunity to make the world safer, allowing us to learn what makes the virus dangerous and how it can be disabled. Thankfully, the discussions were largely constructive — within a week, the NSABB recommended that we continue to study the virus under biocontainment conditions, and publish the results so that other scientists could participate in the research. After we published our full paper in 2005, researchers poured into the field who probably would not otherwise have done, leading to hundreds of papers about the 1918 virus. As a result, we now know that the virus is sensitive to the seasonal flu vaccine, as well as to the common flu drugs amantadine (Symmetrel) and oseltamivir (Tamiflu). Had we not reconstructed the virus and shared our results with the community, we would still be in fear that a nefarious scientist would recreate the Spanish flu and release it on an unprotected world. We now know such a worst-case scenario is no longer possible.

    I make the same argument today that we made in 2005 — publishing those experiments without the details is akin to censorship, and counter to science, progress and public health. ... Giving the full details to vetted scientists is neither practical nor sufficient. Once 20–30 laboratories with postdoctoral fellows and students have such information available, it will be impossible to keep the details secret. Even more troublesome, however, is the question of who should decide which scientists are allowed to have the information. We need more people to study this potentially dangerous pathogen, but who will want to enter a field in which you can't publish your most scientifically interesting results?

    *This passage has been changed from the original. Thanks to Carl Zimmer for the corrections.

    / / COMMENTS

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    1. A less complex issue than it seems. If we know the results, the people who have the technology and know how to use it know enough. We can’t pretend that it takes a special person to do it. Knowing that it’s possible is enough for anyone with the technical know how.

      It’s like the whole who-ha over keeping the atom bomb a secret. It was almost unanimously agreed among scientists that all the Russians really needed to know was that it was possible. The passing of secrets merely sped up the process. The cat’s out of the bag as far as I’m concerned. If you’re worried about Al-Qaeda, don’t. Either you should already be worried, because you think they have access to this technology, or you’re sober enough to understand that Al-Qaeda’s just a paper tiger and a boogie man.

      1. The question is not about keeping it “secret.” After all, many labs will get the information. The strategy is “security through obscurity,” making it a little more difficult to find detailed technical information than simply going to PubMed. Yes, Russia, China, Isreal etc could build a bomb, but the technical details are not that easily discovered or reproduced. That is why so many countries like Iran have to work so long and hard at it. 

    2. We need to keep knowledge this out of the hands of Prince Phillip, who has desired to be reincarnated  as a deadly virus to cleanse the planet of “over-populated humanity” he so loathes.

    3. This isn’t just about taking a bunch of ferrets and making them sick.

      But it is also about that. This really depresses me–that we can do this in the name of science and human life and apparently not even think twice about it. People will say that worries about a pandemic that could kill millions justifies it, but people will say a lot of things.

      Otherwise an interesting and scary read.

    4. A pandemic might have a good outcome for the planet itself as long as there were enough humans left to shut down industry and nuclear reactors safely.

      There have been die offs and pandemics before, there will be more.  It will happen eventually either naturally or with help.
      It reminds me of Western US forest fires.  The forest service puts out the small ones year after year until enough brush builds up that eventually there is a fire that gets out of control.  After it has run its course, nature has a nice bump and life comes back with more vigor than before the fire.

        1. Die offs can sound really clean when you don’t look past population and resource statistics. Of course, they actually mean countless people, each with their own ideas, hopes, friendships, reduced through miserable vomiting, pain, and suffering until only worthless corpses remain.

          But I guess some people think it makes them far-sighted rather than callous to ignore that? Death of one man is a tragedy, and all.

    5. Good and interesting story. Just a minor correction: Influenza has a segmented RNA genome consisting of 11 genes (not 8 as written in the article) distributed between 8 RNA segments.

    6. Even arguably irrational terrorists like Aum Shinrikyo never got into anything near as notoriously unpredictable and uncontrollable as the flu, Hall writes. Of course, his argument is pretty similar to the one scientists used to use to reassure themselves that H5N1 couldn’t be both deadly and human transmissible: We’ve not seen this happen before, so it won’t.

      Not really the same.  

      In biological terms, “we haven’t seen this happen before …” should usually be modified with “… but if there are no hard-and-fast physical, chemical, or biological reasons why it shouldn’t, then we’re probably going to see it happen at some point“.  And to deny that is to deny the existence of complex and multi-factorial physical phenomena, which is patently daft, seeing as how those are precisely the forces which permeate, influence, and evolve the natural world.

      But when thinking about approaches that terrorists might use, “we haven’t seen this happen before…” should usually be modified with “… but it might be possible, because we haven’t always successfully been able to think in terms of their mindset“.  So denying that it’s possible, in this case, merely reinforces the failure to think differently.  However, by even being able to phrase the statement, you gain insight.  

      So; two very different arguments, which just happen to start the same way.

    7. Once this info is public all it will take is one mad billionaire and we have a pandemic on our hands… or one mad dictator in a place like North Korea.  Or maybe I was watching “The Satan Bug” the other night and am over-excited.

    8. This part is the bit that scares me about releasing this information:

      Influenza in general is an equal-opportunity menace, particularly dangerous when a strain is so unfamiliar that humanity lacks immunity to it. This would put at great risk anyone trying to assemble a pandemic H5N1 to launch at “target” populations. Indeed, such an attack would unleash global contagion that would swiftly and inevitably incapacitate an aggressor’s own people. Influenza doesn’t respect borders.

      And? So? People (some) are incredibly stupid and short-sighted and bat-shit crazy. If this is pretty easy to do, there might be a group that wouldn’t care that you killed his friends… as long as it wiped out “the Current World Order(tm).” Or who supposed that they could provide some kind of protection for “the chosen people.”

      I’m not particularly scared of terrorists, sharks and falling meteors. But flu scares me.

      Read Frank Herbert’s “The White Plague.” Dude engineers a flu-like virus to kill all the women on the planet after the IRA blows up his wife.

    9. Maggie, or anyone, can you elaborate on the notion that “Influenza has eight genes, and they all replicate independently of one another. That means you have more opportunity for mutations to arise that change what the virus does and who it can infect.”?

      I thought the number of mutations would be (mutation rate) x (genome size). The fact that it has 8 separate units is immaterial. I’m not a virologist, so maybe the initiation/termination part of replication is especially mutagenic?

      Also, when the article says, “Everybody does that. But influenza has eight die, not one.”  I’m not sure how that follows. Humans have 46 chromosomes, which have multiple independent origins of replication. So even if the virus has 8 “chromosomes”  (they’re not considered chromosomes for reasons I don’t know), that doesn’t make sense. Our ~30,000 genes are mutating independently, just like H5N1’s 8.


      1. “If a single host (a human, a chicken, or other animal) is infected by two different strains of the influenza virus, then it is possible that new assembled viral particles will be created from segments whose origin is mixed, some coming from one strain and some coming from another. The new reassortant strain will share properties of both of its parental lineages.”

        (From the Wikipedia entry on Reassortment)

        1. Thanks daen, but I don’t think reassortment is the issue. Backing up, my confusion stems from how the article goes about explaining how a jump of H5N1 from person to person might occur. It tries to say that viral replication is different from “everybody” by having eight genes.

          My understanding is that the higher mutation rate of viruses is due to the lack of proofreading capability of RNA polymerase. This leads to orders of magnitude greater accumulation of errors than with DNA replication (a good explanation:

          The reason I don’t think the article was attributing the higher mutation rate to reassortment alone due to the way it was said, “As a bonus…” making it seem like there were two mechanisms at play. Even if I read it the wrong way (not unlikely), and reassorment *is* the reason, humans have an analogous (or orthologous) mechanism, recombination, that occurs when we make gametes, so I don’t see how that would account for a higher mutation rate in viruses either.

           I’m not trying to be right. If there’s a mechanism unique to viruses or anything really that I don’t understand, I want to learn.

          Thanks again!

    10. Boing Boing of all places knows that Linux is more secure than Windows because more people have access to the source code. I sure hope biologists don’t learn this lesson the hard way…

      And to clear something up: you wrote:
      H5N1, the famous bird flu, is deadly to humans. Of the 566 people who have contracted this form of influenza, 332 have died…
      That statistic terrifies people and IT’S COMPLETELY WRONG! I’ll let Vincent Racaniello take over:This statement refers to the fact that nearly 60% of the 573 WHO-confirmed H5N1 cases have died. This death rate appears staggering until one considers how it is calculated. The WHO case definition for H5N1 influenza states that an individual must have a febrile respiratory illness, known exposure to H5N1 virus in the previous 7 days, and confirmation of infection by virus culture, polymerase chain reaction, or tests for antibodies. These conditions are highly unlikely to be fulfilled in rural populations where most H5N1 infections probably occur. The case fatality ratio can only be calculated by dividing the number of deaths by the total number of infections – and we do not know the latter number. Of ten large studies that have tested for H5N1 antibodies in rural populations, two were negative and 5 reported the presence of H5 antibodies in 0.2 – 5.6% of indiviudals. Much more work needs to be done to determine the actual fatality rate of influenza H5N1, but the WHO estimate is orders of magnitude too high.More at: http://www.virology.ws/2012/01/09/n-y-times-h5n1-ferret-research-should-not-have-been-done/

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