Tag Archives: dual-use

Lipsitch and Galvani Push Back

COMMENTARY: The case against ‘gain-of-function’ experiments: A reply to Fouchier & Kawaoka

Over at CIDRAP, Marc Lipsitch and Alison P. Galvani have responded to critics— specifically, Ron Fouchier and Yoshihiro Kawaoka—of their recent study in PLoS Medicine. It is a thorough rebuttal of the offhand dismissal that Lipsitch and Galvani have met from Fouchier and Kawaoka and the virology community more generally.

This is a fantastic addition to the dual-use debate. Too often, stock answers given for the benefits of dual-use are put forward without sustained analysis: things like “will help us make new vaccines,” “will help us with disease surveillance,” or “will raise awareness.” Lipsitch and Galvani have drawn up roadmap of challenges that advocates of gain-of-function studies—specifically those that deal with influenza—must confront in order to the justify public health benefit of their work. We should hold researchers and funding agencies accountable to this kind of burden of proof when it comes to dual-use research.

Dual-use flow chart. Logical structure of the potential lifesaving benefits of PPP experiments, required intermediate steps to achieve those benefits (blue boxes), and key obstacles to achieving those steps highlighted in our original paper (red text). Courtesy Marc Lipsitch, 2014.

Dual-use flow chart. Logical structure of the potential lifesaving benefits of PPP experiments, required intermediate steps to achieve those benefits (blue boxes), and key obstacles to achieving those steps highlighted in our original paper (red text). Courtesy Marc Lipsitch, 2014.

Lipsitch and Galvani’s response is also important because it critically addresses the narrative that Fouchier and Kawaoka have woven around their research. This narrative has been bolstered by the researcher’s expertise in virology, but doesn’t meet the standards of biosecurity, science policy, public health, or bioethics analysis. It’s good to see Lipsitch and Galvani push back, and point to inconsistencies in the type of authority that Fouchier and Kawaoka wield.

UPDATE 06/19/14, 16:32: as I posted this, it occurred to me that the diagram Lipsitch and Galvani provide, while useful, is incomplete. That is, Lipsitch and Galvani have—correctly, I believe—illustrated the problems dual-use advocates must respond in the domain the authors occupy. These are challenges in fields like virology, biology, and epidemiology.

There are other challenges, however, that we could add to this diagram—public health and bioethical, for a start. It’d be a great, interdisciplinary activity to visualize a more complete ecosystem of challenges that face dual-use research, with an eye to presenting avenues forward that address multiple and conflicting perspectives.

How not to critique: a case study

The original title for this piece was “How not to critique in bioethics,” but Kelly pointed out that this episode of TWiV is a case study in how not to go about critiquing anything.

Last Monday I was drawn into a conversation/angry rant about an article by Lynn C. Klotz and Edward J. Sylvester, that appeared in the Bulletin of the Atomic Scientists…in 2012. After briefly forgetting one of the cardinal rules of the internet—check the date stamp— I realized the error of my ways, and started to inquire with my fellow ranters, in particular Matt Freiman, about why a 2012 article suddenly had virologists up in arms.

Turns out that the Bulletin article was cited by a study on dual-use authored by Marc Lipsitch and Alison P. Galvani; a study that was the subject of a recent post of mine . The Bulletin article draws from a working paper where the provide an estimate for the number of laboratory accidents involving dangerous pathogens we should expect as a function of hours spent in the laboratory. Lipsitch and Galvani use this figure in their analysis of potential pandemic pathogens (PPPs).

Freiman joined Vincent Racaniello, Dickson Despommier, Alan Dove, and Kathy Spindler on This Week in Virology (TWiV) on June 1 to talk about (among other things) Lipsitch and Galvani’s research. What followed is a case study in how not to critique a paper; the hosts served up a platter of incorrect statements, bad reasoning, and some all-out personal attacks.

I’d started writing a blow-by-blow account of the entire segment, but that quickly mushroomed into 5,000-odd words. There is simply too much to talk about—all of it bad. So there’s a draft of a paper on the importance of good science communication on my desk now, that I’ll submit to a journal in the near future.Instead, I’m going to pick up just one particular aspect of the segment that I feel demonstrates the character of TWiV’s critique.

“It’s a bad opinion; that’s my view.”

Despommier, at 58:30 of the podcast, takes issue with this sentence in the PLoS Medicine paper:

The H1N1 influenza strain responsible for significant morbidity and mortality around the world from 1977 to 2009 is thought to have originated from a laboratory accident.

The problem, according to Despommier, is that “thought to have originated” apparently sounds so vague as to be meaningless. This leads to a rousing pile-on conversation in which Despommier claims that he could have just easily claimed that the 1977 flu came from Middle Eastern Respiratory Syndrome because “he thought it;” he also claims that on the basis of this sentence alone he’d have rejected the article from publication. Finally, he dismisses the citation given in the article as unreliable because it is a review article,[1] and “you can say anything in a review article.”

At the same time, Dove notes that “when you’re on the editorial board of the journal you can avoid [having your paper rejected].” The implication here is that Lipsitch, as a member of the editorial board of PLoS Medicine, must have used that position to get his article to print despite the alleged inaccuracy that has Despommier so riled up. Racaniello notes that “[statements like this are] often done in this opinion–” his full meaning is interrupted by Despommier. It’s a common theme throughout the podcast, though, that Lipsitch and Galvani’s article is mere “opinion,” and thus invalid.

Facts first

If he’d done his homework, Despommier would have noted that the review article cited by Lipsitch and Galvani doesn’t mention a lab. What it does say is:

There is no evidence for integration of influenza genetic material into the host genome, leaving the most likely explanation that in 1977 the H1N1 virus was reintroduced to humans from a frozen source.[2]

So Lipsitch and Galvani do make an apparent leap from “frozen source” to “lab freezer.” Despommier doesn’t pick that up. If he had, however, it would have given us pause about whether or not is a valid move to jump from “frozen source” to “laboratory freezer.”

Not a long pause, however; there are other sources that argue that the 1977 strain is likely to have been a laboratory.[3] The other alternative—that the virus survived in Siberian lake ice—was put forward in a 2006 paper (note, after the publication of the review article used by Lipsitch and Galvani), but that paper was found to be methodologically flawed.[4] Laboratory release remains the most plausible answer to date.

The belief that the 1977 flu originated from frozen laboratory sources is widely held. Even Racaniello—at least, in 2009—holds this view. Racaniello argued that of multiple theories about the origin of the 1977 virus, “only one was compelling”:

…it is possible that the 1950 H1N1 influenza virus was truly frozen in nature or elsewhere and that such a strain was only recently introduced into man.

The suggestion is clear: the virus was frozen in a laboratory freezer since 1950, and was released, either by intent or accident, in 1977. This possibility has been denied by Chinese and Russian scientists, but remains to this day the only scientifically plausible explanation.

So no, there is no smoking gun that confirms, with absolutely unwavering certainty, that the 1977 flu emerged from a lab. But there is evidence: this is far from an “opinion,” and is far from simply making up a story for the sake of an argument. Lipsitch and Galvani were right to write “…it is thought,” because a plausible answer doesn’t make for unshakeable proof—but their claim stands on the existing literature.

Science and policy

The idea that Lipsitch and Galvani’s piece is somehow merely “opinion” is a hallmark of the discussion in TWiV. Never mind that the piece was an externally peer-reviewed, noncommissioned piece of work.[5] As far as TWiV is concerned, it seems that if it isn’t Science, it doesn’t count. Everything else is mere opinion.

But that isn’t how ethics, or policy, works. In ethics we construct arguments, argue about the interpretation of facts and values, and use that to guide action. With rare exception, few believe that we can draw conclusions about what we ought to do straight from an experiment.

In policy, we have to set regulations and guidelines with the information at hand—a policy that waits for unshakeable proof is a policy that never makes it to committee. Is there some question about the true nature of the 1977 flu, or the risks of outbreaks resulting from BSL–3 laboratory safety? You bet there is. We should continue to do research on these issues. We also have to make a decision, and the level of certainty the TWiV hosts seem to desire isn’t plausible.

Authority and Responsibility

This podcast was irresponsible. The hosts, in their haste to pan Lipsitch and Galvani’s work, overstated their case and then some. Dove also accused Lipsitch of research misconduct. I’m not sure what the rest of the editors at PLoS Medicine think of the claim—passive aggressive as it was—that one of their colleagues may have corrupted the review process, but I’d love to find out.

The podcast is also deeply unethical, because of the power in the platform. Racaniello, in 2010, wrote:

Who listens to TWiV? Five to ten thousand people download each episode, including high school, college, and graduate students, medical students, post-docs, professors in many fields, information technology professionals, health care physicians, nurses, emergency medicine technicians, and nonprofessionals: sanitation workers, painters, and laborers from all over the world.[6]

What that number looks like in 2014, I have no idea. I do know, however, that a 5,000–10,000 person listenership, from a decorated virologist and his equally prestigious colleagues, is a pretty decent haul. That doesn’t include, mind you, the people who read Racaniello’s blog, articles, or textbook; who listen to the other podcasts in the TWiV family, or follow the other hosts in other fora.

These people have authority, by virtue of their positions, affiliations, exposure, and followings. The hosts of TWiV have failed to discharge their authority with any kind of responsibility.[7] I know the TWiV format is designed to be “informal,” but there’s a marked difference between being informal, and being unprofessional.

Scientists should—must—be part of conversation about dual-use, as with other important ethical and scientific issues. Nothing here is intended to suggest otherwise. Scientists do, however, have to exercise their speech and conduct responsibly. This should be an example of what not to do.

Final Notes

I want to finish with a comment on two acts that don’t feature in Despommier’s comments and what followed, but are absolutely vital to note. The first is that during the podcast, the paper by Lipsitch and Galvani is frequently referred to as “his” paper. Not “their” paper. Apparently recognizing the second—female—author isn’t a priority for the hosts or guests.

Also, Dove and others have used Do Not Link (“link without improving ”their“ search engine position”) on the TWiV website for both the paper by Lipsitch and Galvani, and supporting materials. So not only do the hosts and guests of the show feel that the paper without merit; they believe that to the point that they’d deny the authors—and the journal—traffic. Personally, I think that’s obscenely petty, but I’ll leave that for a later post.

Science needs critique to function. Critique can be heated—justifiably so. But it also needs to be accurate. This podcast is a textbook example of how not to mount a critique.

  1. Webster, Robert G, William J Bean, Owen T Gorman, Thomas M Chambers, and Yoshihiro Kawaoka. 1992. “Evolution and Ecology of Influenza A Viruses” Microbiological Reviews 56 (1). Am Soc Microbiol: 152–79.  ↩
  2. ibid., p.171.  ↩
  3. Ennis, Francis A. 1978. “Influenza a Viruses: Shaking Out Our Shibboleths.” Nature 274 (5669): 309–10. doi:10.1038/274309b0; Nakajima, Katsuhisa, Ulrich Desselberger, and Peter Palese. 1978. “Recent Human Influenza a (H1N1) Viruses Are Closely Related Genetically to Strains Isolated in 1950.” Nature 274 (5669): 334–39. doi:10.1038/274334a0; Wertheim, Joel O. 2010. “The Re-Emergence of H1N1 Influenza Virus in 1977: a Cautionary Tale for Estimating Divergence Times Using Biologically Unrealistic Sampling Dates.” PLoS One 5 (6). Public Library of Science: e11184. doi:10.1371/journal.pone.0011184; Zimmer, Shanta M, and Donald S Burke. 2009. “Historical Perspective — Emergence of Influenza a (H1N1) Viruses.” New England Journal of Medicine 361 (3): 279–85. doi:10.1056/NEJMra0904322.  ↩
  4. Worobey, M. 2008. “Phylogenetic Evidence Against Evolutionary Stasis and Natural Abiotic Reservoirs of Influenza a Virus.” Journal of Virology 82 (7): 3769–74. doi:10.1128/JVI.02207–07; Zhang, G, D Shoham, D Gilichinsky, and S Davydov. 2007. “Erratum: Evidence of Influenza a Virus RNA in Siberian Lake Ice.” Journal of Virology 81 (5): 2538; Zhang, G, D Shoham, D Gilichinsky, S Davydov, J D Castello, and S O Rogers. 2006. “Evidence of Influenza a Virus RNA in Siberian Lake Ice.” Journal of Virology 80 (24): 12229–35. doi:10.1128/JVI.00986–06.  ↩
  5. I’m aware that peer review is not sufficient to make a work reliable, but absent evidence that the review process was somehow corrupt or deficient, it’s a far cry from mere opinion.
  6. Racaniello, Vincent R. 2010. “Social Media and Microbiology Education.” PLoS Pathogens 6 (10). Public Library of Science: e1001095.  ↩
  7. Evans, Nicholas G. 2010. “Speak No Evil: Scientists, Responsibility, and the Public Understanding of Science.” NanoEthics 4 (3): 215–20. doi:10.1007/s11569–010–0101-z.  ↩

Bad Bioethics Headline: 1918-like flu edition

Terrence McCoy has an article in the Washington Post‘s “Morning Mix” on the 1918-like flu virus gain-of-function study. It provides a bit of extra information beyond the coverage at the Guardian, and is worth a read.

The article, unfortunately, has a terrible headline. A “we need an award for Bad Bioethics Headlines” headline.

The headline reads “Was it ‘crazy’ for this scientist to re-create a bird flu virus that killed 50 million people?” There are some glaring errors, or misinformation, embedded in this headline; errors that, unfortunately, aren’t explicitly dealt with in the content of the article. And the errors, to a certain extent, undercut the seriousness of the work done.

1) First, nothing was “re-created.” The 1918 strain of H1N1 influenza has already been recreated using reverse genetics—in 2005. This work is also widely considered dual-use research of concern.

The work performed by Kawaoka and his team, however, is not a recreation in the traditional sense—the sense we mean when we talk about piecing together a poliovirus, or synthesizing Spanish flu. Rather, this new research involved piecing together a “1918-like” virus—one whose proteins differ by a few amino acids from the one that emerged almost a century ago—using segments of avian influenza. This wasn’t a recreation; it was just creation pure and simple.

2) The influenza pandemic in 1918 isn’t really “bird flu” in the conventional sense. Sure, it is likely that the strain of flu in 1918 emerged from an avian (and swine) reservoir at some point, but that’s because of the 18 different types of hemagglutinin (the “H” in H1N1), and 11 types of neuraminidase (the “N” in H1N1) that we know of, all of them can survive in birds. So all flu has something to do with birds.

We tend to label viruses as "bird" or "pig" viruses when we're talking about the most common host.

We tend to label viruses as “bird” or “pig” viruses when we’re talking about the most common host.

But that’s definitely not what we typically mean when we talk about “bird flu.” Avian influenza is used to describe influenza viruses that arise predominantly or exclusively in birds. What makes H5N1, or H7N9 scary is that they are viruses that predominantly occur in birds, that are crossing over to humans. Fortunately, H5N1 hasn’t been terribly successful at this, and H7N9—while more successful—is not at pandemic levels. Yet.

The “recreated” virus isn’t an avian influenza virus in the same way. The influenza that served as its template is ostensibly “human” or at least “mammalian” flu, that to the best of our knowledge came about from both avian and swine viruses that combined to make a human-transmissible superbug. The parts from which this novel strain was stitched together are bits of bird flu.

The point Kawaoka has been trying to sell the world on is that he wanted to find out—for the good of us all, he has claimed—if something like 1918-influenza could emerge from H5N1. Apparently, the answer is yes.

These all matter because they bear heavily on the “why?!” of this story. This virus didn’t come out of nature, but rather was made in a lab. And it hasn’t been recreated, but outright engineered. As with other gain of function studies, proponents of this story like to say that this will raise awareness about the pandemic preparedness, disease surveillance, and so on. I’ve voiced my skepticism about this before.

It also matters because—as the study notes—the virus created isn’t as harmful as 1918 influenza, but more harmful. Kawaoka’s paper notes that the virus his team created is more pathogenic than an authentic avian influenza virus, or the 1918 influenza pandemic strain. We’re not dealing with Spanish influenza: this is a human created, mammalian transmissible strain of flu that outperforms the “Mother of All Pandemics” in trials. That’s scary. And, while they were only testing the strains on three ferrets at a time, which isn’t enough to give us an idea of how this would affect humans in an outbreak, it is certainly enough to give us pause.

There is power in the platform. The Washington post, by its own numbers, has a readership of 24 million people. It should probably work a little on its headlines.



Circulating Avian Influenza Viruses Closely Related to the 1918 Virus Have Pandemic Potential

Circulating Avian Influenza Viruses Closely Related to the 1918 Virus Have Pandemic Potential

The latest in dual-use gain of function research, Yoshihiro Kawaoka and his team seem to be intent on one-upping Ron Fouchier when it comes to spurious research. This time, the group used reverse genetics to cobble together a “1918-flu like virus, composed of avian influenza virus segments.” The new virus demonstrates higher pathogenicity in ferrets than the case-fatality rate of the original 1918 flu virus. For reference, the 1918 pandemic killed 50 million people.

The summary of the article:

  • Current circulating avian flu viruses encode proteins similar to the 1918 virus
  • A 1918-like virus composed of avian influenza virus segments was generated
  • The 1918-like virus is more pathogenic in mammals than an authentic avian flu virus
  • Seven amino acid substitutions were sufficient to confer transmission in ferrets.

In a commentary in the Guardian, the same types of justifications were rolled out by Kawaoka: awareness, medical countermeasures, and surveillance. Still lacking an argument as to why gain-of-function really promotes these, over other (less dangerous) research if at all.

Superflu: reply to Vox

Vox recently ran a piece by Susannah Locke on a new study in Cell, in which scientists showed only five mutations are needed to make H5N1 avian influenza transmissible in ferrets. (I’ve talked a bit about this here.) The research is controversial because it is dual-use: it could be used to advance our understanding of viruses, but it could also be used to create a deadly pandemic. You might remember a similar controversy about H5N1 back in 2011; some of the same players in that saga are involved here. In particular, the group is headed up by Ron Fouchier of Erasmus University.

Dual-use doesn’t get a lot of play in the news, so it is always nice to see some coverage. The article in Vox, however, doesn’t give the full story. In particular, the article doesn’t pay attention to some of the nuances of the 2011-2012 debate that inform—or should inform—thinking on this new research. Vox isn’t taking responses or op-eds from outsiders right now, so instead I’ve made a few notes below.

Stupid, or Simple?

A lot of the trouble back in 2011 was unavoidable: the National Science Advisory Board for Biosecurity (NSABB), for the first time in its history, recommended the partial censorship two scientific papers based on their ability to enable acts of bioterrorism. This move was always going to sit poorly with the life sciences community, where openness is the norm. And, though the NSABB later reversed their recommendation in response to revised copies of the papers, the episode prompted a year-long moratorium on H5N1 research that would lead to similar types of result, as well as new regulations at the NIH over the funding and pursuit of this so-called “gain-of-function” research.

Part of that furor, however, was caused by Ron Fouchier. Fouchier, who claimed at the 2011 European Scientific Working group on Influenza meeting in Malta that his group had created “probably one of the most dangerous viruses you can make” also referred to his work as a “really stupid experiment.” These and other bold claims circulated widely during the debate, and were assuredly a source of stress as researchers, government officials, and journalists sought to work through the issues.

Fouchier’s claims were hardly what caused the NSABB’s recommendation. But it certainly stirred up a storm, and bought about a lot more scrutiny of dual-use than normally occurs. Unsurprisingly, Fouchier stopped using such bold rhetoric. But in doing so he further muddied the waters of the public debate, by excessively playing down the risks of his research.

A great example can be found in Fouchier seeking to qualify his “really stupid” statement:

In his Malta talk, Fouchier called this a “really stupid” approach, a phrase widely interpreted to mean he regretted it. In fact, he says, he just meant that the technique, called passaging, is a simple one compared to the sophistication of creating targeted mutations. The confusion may have stemmed in part from the fact that the Dutch word for “stupid” can also mean “simple.”

So something was possibly lost in translation. Yet Fouchier’s about-face doesn’t mesh well with other claims he’s made about the risks of his research: for example, that “bioterrorists can’t make this virus [that my team created], it’s too complex, you need a lot of expertise.”

He wants to say that the experiment is simple, but also that it’s too complex for bioterrorists. Yet we already know that bioterror, whether it be committed in Oregon or Japan, is not necessarily the purview of the academy. We also know, from history, that having a high technical competence is far from a guarantee moral probity.

Fouchier’s also doesn’t address the risks that come from widespread attempts to reproduce these results. A recent article in Slate illustrated how SARS, foot and mouth, and H1N1 flu have all escaped their labs. We shouldn’t just be concerned about a bioterrorist brewing a batch of superflu, but just the significance of run-of-the-mill laboratory accidents.

How dangerous?

In trying to understand the risks of the H5N1 studies, few things are more contested than the case-fatality rate (CFR) of H5N1: how many people with the disease die, divided by the number of people who get the disease. The WHO lists 650 reported cases of H5N1, with 386 deaths, giving rise a CFR of 60%. That’s a really big number—most influenza pandemics have a CFR of less than 0.1%.

Supporters of the research have insisted that 60% can’t be the true CFR. The reason they give is that there must be more cases we don’t know about; cases that either aren’t reported, or cases where infected individuals don’t display symptoms severe enough to trigger detection. For each case we don’t know about that isn’t fatal, the CFR drops. And if the CFR drops, then gain-of-function research is less of a problem.

Appealing to the CFR, however, runs into two problems. For a start, there simply aren’t—at least as far as we can tell—that many people walking around with H5N1 who aren’t being picked up. A study in 2008 suggested that there may be subclinical infections in Thailand; research in China, however, found that there was little evidence for subclinical infections. An investigation into two villages in Cambodia found that only a small number of individuals tested positive for H5N1: 1% of the sample.

But a bigger problem is that 60% is a huge CFR. “Spanish Flu,” which killed 50–100 million people in 1918, only had a CFR of around 2.5%. Standing a potential human-transmissible H5N1 against Spanish Flu should give people nightmares. But what it means for Fouchier and company is that even if it turned out that for every 1 case of H5N1 we found, we missed 24 more, we’d still cause to be worried.

Power in the platform

This all matters, quite simply, because there is power in the platform. Public debates rise and fall on the data supplied, and who is given the authority to depict a particular debate. Fouchier is an expert; of that there is no doubt. But he is an expert in influenza. Not bioterrorism, not public health, and not dual-use. He’s also been demonstrably confusing when it comes to the ways he presents his research.

It’s troubling, then, that the Vox piece is almost entirely based on Fouchier’s account of what happened—an account which is, as above, sketchy. It’s really good to see dual-use in the news, but on this issue more than one perspective is necessary. The history of dual-use should be written by more than one group.

The Center for Biological Futures over at The Fred Hutchison Cancer Research Center maintains a good repository of documents relating to the H5N1 dual-use case in 2011-2012.

Gain-of-function: redux

The gain-of-function crowd are at it again. A new study, released in Cell, has described how H5N1 highly pathogenic avian influenza can be engineered to become transmissible between mammals, using five mutations. The new research builds off the 2011-2012 work of Ron Fouchier and Yoshihiro Kawaoka; work that caused a ruckus for its potential for misuse, and led to the National Science Advisory Board for Biosecurity (NSABB) initially recommending the censorship of the papers.

The NSABB hasn’t commented on the Cell study; according to Michael Osterholm, the group hasn’t met in 18 months. Near as I can tell, they didn’t meet or we’re consulted about a similar study in H7N1. In both cases, the informal risk assessments pointed to the benefits of the studies outweighing the risks. And that, apparently, was that.

The lack of consultation with the NSABB is concerning. It raises questions about what exactly that board is doing about the concerns that define its existence. It also stomps all over a staple of good ethics and regulation: treat like cases alike. Rather than assuming that the likeness of these publications warrants immediate publication, however, we should remember the history. The NSABB’s decision was controversial, and followed serious deliberation. This should have, at the least, led to these new studies being flagged for review by the NSABB. That the NSABB wasn’t involved is, to me, more problematic than the new publications.

Make no mistake, there will be more research like this: the flu lobby has informed us that this is the case. In the wake of the Tamiflu revelations—that the antiviral stockpiled by governments the world over doesn’t work, and actually causes serious adverse events in children—pressure for gain-of-function research is also likely to increase. As governments scramble to appear to be doing something, I suspect more of these publications will be funded.

But to what end? The arguments haven’t changed since 2011. Predicting viral mutation with an eye to vaccines or surveillance isn’t a good strategy at all, because what we can create in the lab isn’t necessarily what nature will brew up. It is like playing blind darts: you aren’t likely to succeed, and could put someone’s eye out in the process. This isn’t an argument that can be sustained, and requires a misinterpretation of how viruses work to seem convincing.

Moreover, knowing the specific evolutionary pathway of a virus is hardly the most burdensome part of vaccine production. Vaccines need to be created, tested, stored, distributed, and used. These latter stages are incredibly time-consuming and costly. Gain of function research doesn’t add to these steps in a meaningful way.

Put another way, if the flu lobby were some of my former undergraduate chemistry students, I’d be failing them for not being able to identify the limiting reagent in this reaction, much less give me a valid rate equation.

It also detracts from the fact that the politics and logistics of vaccines don’t make them great tools in the event of a pandemic. And without Tamiflu, our best options are the social and political—and ethically fraught—solutions that rely on people and public health. Isolation; quarantine; surveillance. These raise important rights and privacy issues that haven’t been adequately discussed. I don’t think many people are ready for what quarantine means in the event of a serious outbreak.

The malevolent uses of dual-use research of concern, however, become more acute the less prepared we are. Gain-of-function research needs an institution to benefit us; it needs us to be unprepared or complacent to harm us. We’re definitely unprepared right now.

I’m not saying we should censor the new H5N1 or H7N1 research. I’ve made it clear elsewhere that we are not be wrong to do so, but in this case that ship has long since sailed. What we need to do now is have a bigger, better conversation about pandemic preparedness, public health, and dual-use.

NB: Written in transit. I’ll endeavour to have more comprehensive links up when I’m back at my computer.


Dual-use and the fatality rate of H5N1

The long-winded “Seroprevalence of Antibodies to Highly Pathogenic Avian Influenza A (H5N1) Virus among Close Contacts Exposed to H5N1 Cases, China, 2005–2008,” came out in PLoSOne this week. It is a good day for people like myself who have concerns about gain-of-function research that seeks to modify— or results in the modification of—highly pathogenic H5N1 avian influenza.

The study’s importance goes back to the controversy in 2011 and 2012 surrounding papers submitted to Science and Nature respectively by Ron Fouchier and Yoshihiro Kawaoka, in which they showed how H5N1 could be modified to transmit between mammals (in this case, ferrets). The papers were identified as cases of dual-use research of concern (DURC):

research that, based on current understanding, can be reasonably anticipated to provide knowledge, products, or technologies that could be directly misapplied by others to pose a threat to public health and safety, agricultural crops and other plants, animals, the environment or materiel (source)

The editors of Science and Nature agreed, initially, to censor the papers at the request of the National Science Advisory Board for Biosecurity. The continuing debate—following the release of modified versions of the papers—turns on a lot of things. Of note, however, is the insistence of virologists such as Morens, Subbarao, and Taubenberger, among others, that:

whatever the case, unless healthy seropositive people detected in seroprevalence studies temporally and geographically associated with H5N1 cases are all falsely seropositive, their addition to exposure denominators greatly decreases case-fatality determinations.

That is, the potential for asymptomatic and undetected H5N1 infections would lead to a far lesser case fatality rate than the current figure, which sits at the staggeringly large 60%. (For context, the 1918 “Spanish” flu that killed 50–100 million people had a case fatality rate of about 2.5%.)

Convincing the NIH, the NSABB, and the public that the H5N1 studies are safe and laudable exercises relies in part on the claim that the 60% figure isn’t all it is cracked up to be.[1] This new study throws weight behind the concern that H5N1 is really as lethal as it seems, and that it is manifestly dangerous to do things like alter its method of transmission, host range, drug resistance and so on (experiments Fouchier now wants to do on H7N9—see here and here).

Downplaying the risks of H5N1 would be just as irresponsible as it would be to claim, for example, that Fouchier’s lab engineered a supervirus;[2] we need to be mindful of the potential for good and bad uses of this research, and acknowledge the contingencies and assumptions upon which our predictions rely. The “DURC-is-safe” group, as Garrett called them today, have relied on problematising the case fatality rate of H5N1. Support for that type of claim is rapidly shrinking.

  1. In point of fact, in the last article I released on this topic, a reviewer attempted to undermine my argument using exactly such a claim. It is a really common point of contention in the literature.  ↩
  2. Which, incidentally, is what Fouchier was getting at when he said it was “probably one of the most dangerous viruses you can make” and that it was a “stupid” experiment. Words he really quickly went back on once he realised, in the words of Gob Bluth that “he’d made a huge mistake” by fear-mongering.  ↩

Revisiting Dual-Use and Corruption

The US has been busy publishing policies on the regulation of research that has both benevolent and harmful applications, also “dual-use” research. The polices focus on dual-use research of concern (or DURC), a fashionable way of identifying a subset of dual-use research that:

based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security. [USG, p. 2]

Two policies  on DURC showed up at the end of February, the first being the long-winded “Framework for Guiding U.S. Department of Health and Human Services Funding Decisions about Research Proposals with the Potential for Generating Highly Pathogenic Avian Influenza H5N1 Viruses that are Transmissible among Mammals by Respiratory Droplets.” This  framework has been floating around in draft form since December 2012, and I argued in January that we should be concerned—among other things—about corruption.  If research that posed a significant risk to human health was diverted to agencies that pursued classified research, there is a potential for a scenario where classified agencies start pursuing DURC that might be better refused funding or redesigned to produce more benefits with less risks of misuse. Classified dual-use research in the DoE and CIA has a patchy and controversial history, and the aim of policies that purport to regulate DURC, if anything, should be to reduce the amount of potentially harmful research happening, not increase it or move it away from public accountability.

Happily, the gain-of-function framework was amended along lines that mitigate the potential for corruption.  But a related problem has appeared with the release for consultation of the “United States Government Policy for Institutional Oversight of Life Sciences Dual Use Research of Concern,” a broader policy aimed at assisting federal agencies in making decisions about what dual-use research to fund.

When addressing the review process of dual-use research, the policy addresses the question of what types of groups are suitable as review bodies.  This is where the policy should give cause for concern. As it currently stands, review bodies may include:

(1) a committee established for dual use review; (2) an extant committee (such as an Institutional Biosafety Committee [IBC]) … or (3) an externally administered committee (e.g., an IBC or review entity at a neighboring or regional institution or a commercial entity). [USG, p. 11, emphasis mine]

There isn’t anything wrong with an extant or external committees involving themselves in the review of dual-use research on the face of things. But there are certain types of involvement that tend to lead to bad outcomes.  The types of outcomes I’m most concerned with here are those where the stated aims of the policy are corrupted—when the policy .

When it comes to dual-use, we should be careful about the types of entity we let function as committees. Commercial entities that participate in research in areas typically associated with dual-use life sciences research (e.g., virology, synthetic biology) might possess the relevant expert knowledge to make calls on the funding of DURC, but have self-interested reasons in making sure DURC is pursued for publication, profit, or patent.

The policy makes an attempt to address this, requiring that any member of the review entity be recused if they have a direct financial interest, except “to provide specific information requested by the review entity.” But this is really limited as a safeguard, as it still allows for a lot of involvement by those with direct conflicts of interest, as long as the committee is the one doing the asking. It doesn’t cover less direct involvement—one doesn’t need to have direct financial involvement with a piece of research to have a conflict of interest. Finally, the legislation recuses individuals, but not groups.  So while some members of a commercial entity may have direct financial interests and be recused, there is no provision for excusing a commercial entity qua group from functioning as a committee.

Why is this important? Because the history of oversight of research is also a history of conflict of interests and corruption. The last decade has seen a cavalcade of horrors when it comes to the ways that institutions nominally dedicated to the public good are compromised by vested interests.  When pharmaceutical companies can employ researchers as consultants and as researchers on their drugs, conflicts of interest exists.  When the Department of Defence can covertly mill weapons-grade anthrax in the name of a biodefence program without public oversight, conflicts exist. And should companies engaged in or benefiting from DURC be allowed to decide for themselves what types of research should or shouldn’t be funded, conflicts and corruption will occur.

All in all, researchers who study DURC should be excited about some legislation coming out that is more than the existing advisory capacity of earlier modes of review.  But the legislation coming out is worrying—there is the possibility for stacking the review process either in (unjustified) favour of government interests, or private. The debate so far has focussed on the former, but there is also good reason to be suspicious of the latter.