Virologists plan influenza H7N9 gain of function experiments

7 August 2013

A group of virologists lead by Yoshihiro Kawaoka and Ron Fouchier have sent a letter to Nature and Science outlining the experiments they propose to carry out with influenza H7N9 virus.

Avian influenza H7N9 virus has caused over 130 human infections in China with 43 fatalities. The source of the virus is not known but is suspected to be wet market poultry. No human to human transmission have been detected, and the outbreak seems to be under control. According to the authors of the letter, the virus could re-emerge this winter, and therefore additional work is needed to assess the risk of human infection.

The research that the virologists propose involve gain-of-function experiments which provide the H7N9 virus with new properties. The isolation of avian influenza H5N1 viruses that can transmit by aerosol among ferrets is an example of a gain-of-function experiment.

The proposed gain-of-function experiments fall into five general categories:

  • Determine whether viruses with altered virulence, host range, or transmissibility have changes in antigenicity, or the ability of the virus to react with antibodies. The results of these studies would suggest whether, for example, acquisition of human to human transmissibility would have an impact on protection conferred by a vaccine produced with the current H7N9 virus strain.
  • Determine if the H7N9 virus could be adapted to mammals and whether it could produce reassortants with other influenza viruses. The results of this work would provide information on how likely it is that the H7N9 virus would become better adapted to infect humans.
  • Isolate mutants of H7N9 virus that are resistant to antiviral drugs. The purpose of these experiments is to identify how drug resistance arises (the mutations can then be monitored in clinical isolates), determine the stability of drug resistant mutants, and whether they confer other properties to the virus.
  • Determine the genetic changes that accompany selection of H7N9 viruses that can transmit by aerosol among mammals such as guinea pigs and ferrets. As I have written before, the point of these experiments, in my view, is not to simply identify specific changes that lead to aerosol transmission. Such work provides information on the mechanisms by which viruses can become adapted to aerosol transmission, still an elusive goal.
  • Identify changes in H7N9 virus that allow it to become more pathogenic. The results of these experiments provide information on the mechanism of increased pathogenicity and whether it is accompanied by other changes in properties of the virus.

I believe that the proposed gain-of-function experiments are all worth doing. I do not share the concerns of others about the potential dangers associated with gain-of-function experiments: for example the possibility that a virus selected for higher virulence could escape the laboratory and cause a lethal pandemic. Gain-of-function is almost always accompanied by a loss-of-function. For example, the H5N1 viruses that gained the ability to transmit by aerosol among ferrets lost their virulence by this route of infection. When these experiments are done under the proper containment, the likelihood that accidents will happen is extremely small.

All the proposed experiments that would use US funds will have to be reviewed and approved by the Department of Health and Human Services:

The HHS review will consider the acceptability of these experiments in light of potential scientific and public-health benefits as well as biosafety and biosecurity risks, and will identify any additional risk-mitigation measures needed.

While I understand that the authors wish to promote a dialogue on laboratory safety and dual-use research, I question the ultimate value of the communication. Because the letter has been published in two scientific journals, I assume that the target audience of the letter is the scientific community. However, the letter will clearly have coverage in the popular press and I am certain that it will be misunderstood by the general public. I can see the headlines now: “Scientists inform the public that they will continue to make deadly flu viruses”. The controversy about the H5N1 influenza virus transmission studies in ferrets all began with a discussion of the results before the scientific papers had been published. I wonder if the publication of these letters will spark another controversy about gain-of-function research.

In my view, science is best served by the traditional process known to be highly productive: a grant is written to secure funding for proposes experiments, the grant proposal is subject to scientific review by peers, and based on the review the work may or may not be supported. The experiments are done and the results are published. I do not understand why it is necessary to trigger outrage and debate by announcing the intent to do certain types of experiments.

I am curious to know what the many readers of virology blog – scientists and non-scientists – feel about the publication of this letter. Please use the comment field below to express your views on this topic.

  • marion koopmans

    hi
    the headlines that you envision are indeed already visible on twitter. Not sure though: i think this communication is a case of ” damned if you do and damned if you don’t”. The ” classical” model of doing science seems to suffer from some erosion in the eye of the public, with growing distrust. Being transparant, and open for true discussion with respect for different views according to me is the best way forward, but engaging the public outside headlines is the challenge here. My impression is that US scientists are better trained in this….I am interested in models that others have used.
    Marion Koopmans, virologist
    @MarionKoopmans

  • ironorehopper

    Only to underline the very urgent and needed international coordinated multi-disciplinary research in better clinical management of severe influenza in humans and in an improved therapeutical regimens – in addition to a push in a vaccine stockpile – because in the face of a pandemic we have not enough medical countermeasures to save lives. Since 99% of world population will be without pandemic vaccine, it is extremely urgent a focus in this direction. Other venues may be explored for the sake of science, but the priorities are other. Fondly, Giuseppe Michieli, contributor of FluTrackers.com

  • ironorehopper

    Scientists do not live in a desert planet or in an Ivory tower. They have the same responsibility toward community all Others have.. Further, scientists are human – nod ‘gods’ – and their behaviour is influenced by external situations as other humans. Nobody is virgin, not for sure in lab settings.

  • Juanjo Lopez-Moya

    Dear Vincent,
    your prediction about headlines was fully accomplished in spanish newspapers when dealing with this today. Even if the text below stated (more or less) rightly the proposed set of experiments, the comments of readers reflected their fears.
    In my opinion this kind of announcements might be a shortcut for fund raising, using a very peculiar form of lobbying.
    I expect you to comment on this with Alan, Dickson, Rich and Kathy in the next TWiV episode.
    Best regards,
    Juanjo Lopez-Moya

  • http://www.mendeley.com/profiles/brian-p-hanley/ Brian Hanley

    I have a new paper out on the subject- Security in a Goldfish Bowl: the NSABB’s Exacerbation of the Bioterrorism Threat. http://www.omicsonline.org/2157-2526/2157-2526-S3-013.php?aid=11953

    (The journal has an irritating popup – “Like us on Facebook” please try to ignore it.)

    Gist – publicity drawing the attention of bioterrorists to plausible bioweapons is the primary contribution the NSABB makes by censorship recommendations. Attempting censorship by attracting the entire world’s attention to information of concern is obviously counterproductive.

    Conclusion – The best contribution the NSABB could make to biosecurity is to dissolve itself, take a vow of silence, and work with intelligence agencies.

  • Kyle

    The media can be a scientists best friend, or worst enemy.
    Unfortunately in this situation the headline you have proposed would sell more papers than “Scientists work to improve our knowledge of the flu virus”

  • Joe Comber

    I understand the perceived need for transparency in science. I honestly believe that part of the public “weariness” or, maybe distrust, of science is that they don’t understand why these experiments are being done. i think we as scientists can be a little more open about that. But what I don’t understand is the need for public reporting to invoke such controversy over the subject. Of course these are extremely important experiments to do through which we can learn incredible amounts of information about influenza biology, and hopefully, understand transmissibility better. Why go to the effort of proposing that this research is such a risk. Isn’t any research on viruses a risk to some degree? Where does it end?

    Besides can’t we see future headlines if these experiments aren’t done? “Lack of research on H7N9 virus leads to imminent doom.”

  • Wayne Michael

    I am not qualified to judge this matter, but I would like to know that there is a clear scientific consensus that the possible benefits from these experiments are worth the risks.

    From the press reports, I am not sensing that this scientific consensus exists. Is this an accurate perception?

    I also have to wonder if perhaps some of the goals of these experiments could be achieved with other, less lethal viruses. (The CDC web page states that more than 130 cases were reported, with 43 deaths).

  • Adam Rogers

    With respect, I think your issue, Dr. Racaniello, is more with the media’s methods than with the researchers’. One of the stated goals of TWiV is to try and improve the communication between the Scientific community and the general populace. I think that is the underlying goal of what these researchers are doing. Admittedly, the axiom that it’s easier to ask forgiveness than ask permission certainly applies here, but the furor surrounding the H5N1 experiments emerged, at least in part, over the public’s ignorance of the experiments prior to their being conducted. A big part of what has led to issues like the current funding crisis is the perceived wall that’s been put up between scientists and the general populace. I think the group is doing the right thing by putting the information out there ahead of time.

  • Magpie

    Difficult decision – but I think sadly necessary. I think the public does not want to feel “blind-sided” by only hearing about such research until after it’s done. By announcing it in advance, it’ll help gain acceptance in the long run. It’ll let them discuss the safety of the process before-hand. If people found out only afterwards, it might further damage their (hazy) view of virology – people will wonder how many other “scary” things are going on without them knowing.

    Honestly, it was Fouchier’s completely baffling pre-publication comments that sparked the mass hand-wringing we got from the H5N1 work, and we’re still seeing the effects. I still genuinely have no idea how he came to say such loopy stuff. Maybe he’d hit his head or something… But hey, if he’s going to try to repair some of that damage with more careful language, then more luck to him.

  • http://nsaunders.wordpress.com neilfws

    Steven Salzberg’s opinion is that they want to do this research because basically, it is all that they know how to do.

  • Joe Comber

    Personally, I think his assessment is incredibly short-sighted. It seems he fails to understand the potential impact of knowledge that could be gained by doing these experiments and has unrealistic expectations about the application of results. Also, it’s a “hey look at me, I’m a flu person who wants to be on the panel” piece without actually being a flu researcher. That doesn’t mean he’s not entitled to his opinion, but one we should take with a grain of salt.

  • Clyde Manuel

    The recent BMJ article reporting a case of possible human to human spread of H7N9 in China helps these researchers justify the proposed experiments. http://www.bmj.com/content/347/bmj.f4752

  • willradik

    My understanding is that if such a combination of virulence and transmissibility in an influenza virus is possible, it will appear given enough time, the current reservoirs, and the “estuaries” if you will, that Chinese poultry markets, for example, represent.

    If it’s quite possible it will appear naturally, why wouldn’t we want to try to discover it first and have the possibility of formulating vaccines, etc? Would we rather be taken by surprise?

    Both this letter and the Forbes article dissapoint me, especially Forbes article. It’s incredibly irresponsible to mislead the public into thinking the scientists are just doing this to satisfy their own egos.

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  • willradik

    Yeah like he says they’re not able to make vaccines… uh so that means no one could use the info they find to make vaccines? Give me a break. He should stick to the computers.

  • Usui Yuki

    I am one of the students studying about influenza A viruses. In my view, media such as newspapers and TV, occasionally misunderstand the context of science because they don’t have much knowledge enough to understand scientific papers appropriately. Therefore, it was a good decision that the researchers informed their compliance through the most rigorous journals (“Science” and “Nature”). The most important thing is that scientists and the public should discuss the risks of both doing the study and not. We should instead be prepared about possible laboratory leaks or terrorist attacks through careful planning.

  • gsgs

    we know that these viruses are possible. We had these pandemics
    in history.
    How virulent they are depends on our current immunity and on
    some “minor”, seemingly easier changes than transmissibility.
    Nature cannot so easily “find” these pandemic codings,
    it takes ~40 years in average.
    With computers,cell-cultures,mice,ferrets,guinea pigs,
    reverse genetics,…and enough money scientists can probably be better.
    When we may have some dozen or hundred pandemic viruses …
    They will be kept secret, of course, but some employee might leak
    earlier or later … And more and more labs will repeat and find new
    variants. This is not just about H5N1 or H7N9, it’s the way where this
    goes. Even if you think this is unlikely, what can it hurt to have a plan ?
    What to do, when/if the first lab announces, they succeeded ?

  • Joe Comber

    I honestly didn’t even realize that the blog post was the Forbes article. I wrote this last night (hope its okay to put this here….)

    https://sites.google.com/site/joethesciencetutor/science-story-of-the-week/H7N9-Research-Necessary

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  • gsgs

    here:
    http://www.cidrap.umn.edu/news-perspective/2013/03/scientists-seek-ethics-review-h5n1-gain-function-research
    I read that this “consensus” is only among flu-researchers but not among
    200 non-flu scientists, most of them virologists.
    However, I couldn’t verify this, the FVR-people don’t reply.,
    don’t show the data

  • Steven Salzberg

    This is an incrediby simplistic statement. I don’t want to be on the panel, as anyone who knows me and my work would realize. I think Fouchier et al are incredibly irresponsible, and they are too narrowly focused on their own work to realize that it (a) has only marginal scientific utility and (b) carries serious risk of harm. I fully understand the “potential impact”, which is minimal in terms of what it may teach us about naturally occurring H7N9 strains.

  • Kenzibit

    Haha…I get excited with news like this. I for one personally is in favor of this “gain of function experimemts” but what I do not understand is why they have to go public about it. I mean stuff like this always, in one way or the other go on in our labs and it’s only reported when results are out so what makes this soo special for them to bring it to the public domian before doing it?…is it because it’s a flu virus or because it’s a joint collaboration? Yet still I don’t think this is the first time. This can be somethine very small but can be extra hyped by the public into something else. The public see these things new yet still to us scientists, it’s most a times done in our labs to understand stuff or know more inorder to prepare for pathogens.
    In all I’m 100% in favor of “GoF” experiments but why they go public on it is what I don’t understand.

  • Joe Comber

    I don’t think my statements are any more simple than statements that you made in the Forbes article.

    The statement “they are too narrowly focused on their own work to realize that it (a) has only marginal scientific utility…” strikes me as odd. After all, everyone who does research thinks that their work has at least some (if not a whole lot of) “scientific utility”. To suggest that these researchers either a) are too close-minded to realize that it doesn’t and/or b) don’t care because they want to do it just to do it is a vindictive statement.

    Of course there are risks for the research but Fouchier (and the other 21 virologists) think these risks are worth it. Perhaps “serious risk of harm” is a little too inflammatory as a claim especially since Fouchier’s lab has already demonstrated that it can safely do these types of experiments without virus mutants escaping or endangering the public. And any virus research risky to some degree.

    Obviously there are other virologists and scientists (me included) that think that these experiments are worthwhile and the findings will potentially be more than “minimal”. Perhaps not solely for H7N9 viruses but maybe for flu viruses as a whole. I don’t think anyone can dismiss findings and their implications before the experiments are even done.

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  • Elizabeth Hart

    ‘Kenzibit’, re your comment “I mean stuff like this always, in one way
    or the other go on in our labs…” I’m interested in what sort of ethics process your research proposals undergo before being approved, can you please advise? Also, as a scientist, have you undergone any form of ethical training?

  • Elizabeth Hart

    ‘Magpie’, re your comment “Honestly, it was Fouchier’s completely baffling pre-publication comments that sparked the mass hand-wringing we got from the H5N1 work…”
    At the European Scientific Working group on Influenza (ESWI) meeting in Malta in September 2011, Fouchier said about his lab-created virus “this is a very dangerous virus”.(1) Subsequent to the furore surrounding his controversial research, Fouchier did a 180 degree turnaround on his claims about the lethality of his lab-engineered virus. Apparently the virus he created was neither as contagious nor as dangerous as people had been led to believe…(2,3,4,5,6)
    So ‘Magpie’, you think Fouchier’s pre-publication comments were ‘baffling’? Have you no idea why he might have beat this up for the ESWI meeting?
    Do you think it’s appropriate for scientists to get away with this sort of grandstanding behaviour, particularly on such an important topic?
    References:
    1. Katherine Harmon. What Really Happened in Malta This September When Contagious Bird Flu Was First Announced. Scientific American. December 30 2011.
    2. Robert Roos. With new data, NSABB may revisit H5N1 studies. CIDRAP News, February 29, 2012.
    3. Editorial. The Truth About the Doomsday Virus? The New York Times, March 3, 2012.
    4. Denise Grady. Genetically Altered Bird Flu Virus Not as Dangerous as Believed, Its Maker Asserts. The New York Times, February 29, 2012.
    5. Jason Tetro. The Hyperbole That Caused Global H5N1 Hysteria. The Huffington Post, Canada. Posted 06/22/2012.
    6. Herfst, S et al. Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets. Science. 22 June 2012. Vol. 336, no. 6088, pp. 1534-1541.

  • Elizabeth Hart

    Professor Racaniello, I’ve just listened to your interview with Robert Herriman on Dispatch Radio about the H7N9 gain of function experiments, and I’m astonished by some of your comments, for example:

    QUOTE: “So a ‘gain of function’ simply means that you take a virus and you change it in some way so it does something new, so it does something that it didn’t do before. That’s all that means. It’s quite simple. So you could for example take this H7N9 virus and make it resistant to an anti-viral drug, that would be a gain of function.” END OF QUOTE (Commencing at 01:32 on the video.)
    AND
    QUOTE: “So, to really understand how this virus works, and really any other virus, we do gain of function studies all the time. We don’t make a big deal of it, we don’t write letters telling the world that we’re going to do them because that’s not the way science works. Science works by just doing your experiments. We do this because we would like to see what kinds of changes would lead to a gain of function, and what would be the consequences. So, in the case of this virus, these investigators want to make the virus drug resistant. As you know, there are a couple of anti-virals that you can use if you get influenza – Tamiflu, Relenza – and these investigators want to make the virus resistant. And the reason they want to do that is to see if a drug resistant mutant would have any properties that would make it scarier in people. So there is really a goal to these experiments. They want to know if you change the virus what might be the consequences for people. And as I said this is done all the time but these virologists decided to tell the world about it.” END OF QUOTE (Commencing at 02.10 on the video.)

    Professor Racaniello, re your comment “we do gain of function studies all the time”. Can you please advise what sort of ethics approval processes these studies undergo? Also, do you see any ethical problems with scientists trying to make viruses drug resistant and “scarier in people”? Do you really think these experiments should be undertaken secretly?

  • Elizabeth Hart

    Further to my previous comment, my submission to the Centers for Disease Control and Prevention (CDC), Department of Health and Human Services (HHS) re Opposition to Lab-engineering of Potentially Lethal Pathogens (17 December 2012) provides more background: http://users.on.net/~peter.hart/Submission_to_CDC_HHS.pdf

  • Elizabeth Hart

    My open letter to the National Science Advisory Board for Biosecurity (NSABB) re the political and ethical implications of lethal virus development (31 January 2012) also provides more detail: http://users.on.net/~peter.hart/Open_Letter_to_Paul_Keim_NSABB_31_Jan_2012.pdf

  • http://gh.linkedin.com/pub/kenneth-yaw-agyeman-badu/1b/351/482 Kenzibit

    I think Elizabeth is against all these anf she doesn’t need to know more.

  • http://gh.linkedin.com/pub/kenneth-yaw-agyeman-badu/1b/351/482 Kenzibit

    We wouldn’t do these kind of experiments if we are not prepared or know what we are doing or undergone ethical process…Science is not biased and I know and understand most people…like yourslef form my point of view get scared about a ll this, main reason stuff like this shouldn’t come out. It creats panic. Elizabeth, let’s just end here….wouldn’t say more.

  • http://gh.linkedin.com/pub/kenneth-yaw-agyeman-badu/1b/351/482 Kenzibit

    Interesting…..I remember reading this some time ago.

  • Elizabeth Hart

    Professor Racaniello, your interview with Robert Herriman provides a useful example of a scientist’s attitude to controversial ‘gain of function’ research.

    In the interests of transparency and accountability, (and to view your comments I have quoted above in context), I have prepared a full transcript of your interview which can be accessed via this link: http://users.on.net/~peter.hart/Racaniello_GOF_transcript_10_August_2013.pdf

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  • Dan Stipp

    I don´t have a clear opinion about this. It was a consensus decision of the research group to announces the experiment goals, so a secure decision. However, knowing the kind of thinking of general population… I bet this report will result as the same way the H5N1 story: panic and fear of ferrret-influenzavirus.
    A population that only hear about viruses in the big screen (I am the legend, Contagion, Resident Evil…), unfortunately, it will not see the pros and even the cons about new influenza gain-function study.

  • Syed Zawar

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  • Gang Li

    I am quite support the gain of functions experiments personally with rigorous safety rules carried out by NIH and PI. Eventually it will benefit us, but to what extent I am not sure. Time will tell us.