Ahistorical narratives in a time of science.

[Update: someone at The Atlantic confirmed for me that this was not so much their article, as it was run  “as part of our partnership with the site Defense One.” Defense One is a part of the AtlanticMedia group, which owns both publications. As the science editor for Defense One—where the piece was first published—it isn’t totally clear to me who edited Tucker’s work for content, other than… himself? Transparency and accountability, anyone?]

Patrick Tucker has a piece in The Atlantic titled “The Next Manhattan Project.” It concerns the current dual-use gain-of-function saga—now the so-called deliberative process about biosafety. It is, in short, a piece of ahistorical fiction. Here’s why—or, here is one list of reasons why.

1) “In January 2012, a team of researchers from the Netherlands and the University of Wisconsin published a paper in the journal Science about airborne transmission of H5N1 influenza, or bird flu, in ferrets.”

False. It was two papers: one in Nature by University of Wisconsin-Madision researchers; one in Science by Dutch researchers. When a writer for The Atlantic can’t Google something that happened 3 years ago, you can bet the previous century is going to be a challenge.

2) Eschewing the history behind current events: “[the 2012 paper (should be papers)] changed the way the United States and nations around the world approached manmade biological threats.”

False. The 2011 (it started in 2011, not 2012) controversy was a continuation of a, by then, decade-old debate about what is now called dual-use research of concern. This started in 2001, when a team of Australian researchers published work describing the creation of (in VERY simplistic terms) a super-poxvirus.There was a CIA report, and a NAS committee. Oh, and does anyone remember Amerithrax?

3) “it solved the riddle of how H5N1 became airborne in humans.”

False. Hilariously, the standard defense of the 2012 studies (remember, The Atlantic, plural) is that they don’t show how H5N1 can transmit via aerosolized respiratory droplets. Vincent Racaniello commonly refers to this as “ferrets are not people.” There’s a complexity about animal models that doesn’t lend to those kinds of easy conclusions. It wasn’t the end result of these papers (or the papers that followed), and it certainly wasn’t the intent of the researchers.

4) Eschewing the reasons behind the Manhattan Project.

The Manhattan Project has a complex history. A group of independent, politically minded—largely emigre—scientists; a world on the edge of war; a novel and particular scientific discovery with a potentially catastrophic outcome; and a belligerent power (well, powers—the Japanese and Russians had programs, in addition to the Nazis) the scientists had good reason to suspect was pursuing said technology.

The 2012 story has almost no parallel with these contexts—much less has an organizational, clearly defined set of ends, or unilateral mandate with which to achieve those ends. The existential threat in the background of the Manhattan Project is absent here—there is no Nazi power. If we truly considered H5N1 highly pathogenic avian influenza to be an existential threat, our public health systems and scientific endeavors would look totally different.

5) Misrepresenting the classified complex.

Despite it being the single comparison Tucker draws between the 2012 studies (plural) and the Manhattan Project, Tucker doesn’t discuss the classified complex as any more than a passing comment. He boils the entire conversation down to “but now the Internet makes classifying things hard.”

Never mind that the classified community was remarkably successful at its job, to the point where it invented ways to create information sharing within an environment of total secrecy. The classified community continues to do its work today—just because we don’t pay much attention to Los Alamos, Oak Ridge, or Lawrence Livermore don’t mean they don’t exist.

Tucker also misses some of the human factors that would actually make his claims interesting. Between Fuchs and the Rosenbergs, ye olde security could be compromised in much the same way as it is today: too much trust of the wrong people, and a bit of carelessness inside the confines of a community that thinks itself insulated. If anything, the current debate about dual-use is more about misplaced trust and overconfidence than it is about nukes.

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These are only five of a variety of problems with Tucker’s article. What bothers me most is that the headline grants a legitimacy to one perspective on the current debate that simply isn’t warranted. These scientists aren’t racing against the clock to avert a catastrophe—and if they are, their methods are questionable at best. The current debate is far more nuanced, and far less certain than the conversation that went down in Long Island in 1939. And that’s saying something, because the debate then was pretty damned nuanced.

What would the Next Manhattan Project really look like? Lock the best minds in biology in a series of laboratories across the country—or world, that’s cool too. Give them at least $26 billion. And give them charge of creating a cheap, easily deployable, universal flu vaccine.

That’d be great. Or, at least, it’d be much better than The Atlantic’s piece from yesterday.

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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.

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.

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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.  ↩

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.

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.

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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.  ↩