Tag Archives: virology

A Chat with Mike Osterholm

I got a call last night from Mike Osterholm, noted epidemiologist and member of the National Science Advisory Board for Biosecurity (NSABB). He wanted to talk about H5N1 flu – if you don’t know why, scroll down to the previous few posts.

First, I want to thank Mike for calling. We had a good conversation in which I think we came to understand each others’ viewpoints a bit better, though we still disagree strongly on some key issues. That means that as I had hoped, the H5N1/censorship debate is finally moving forward. To clarify my own position, and also help those who aren’t in direct touch with NSABB members, here’s a synopsis of what we talked about. Bear in mind that this was not an “on the record” interview, so I won’t be quoting Mike, but I’m pretty sure he won’t mind me discussing our conversation publicly. If I misstate anything, I hope he posts up in the comments to correct it.

We talked briefly about his alleged dis of Peter Palese at the New York Academy of Sciences meeting Thursday night. Mike says he was misquoted, and I believe him. Let’s move on.*

Next, we talked about the controversial case-fatality rates for H5N1 flu. Mike has some valid methodological criticisms of some of the serological surveys, as I expected he would. I disagree with his assessment of the situation, but that’s not really relevant to what I see as the main point here. My real complaint is that the figures being cited for H5N1 fatalities shouldn’t be presented to the public in the first 50 words of an editorial – or anywhere, unless accompanied by a detailed explanation of their limitations. Comparing those rates to the mortality rates for, say, 1918 flu, is particularly misleading; the numbers were calculated by different standards. Indeed, if we apply a sufficiently strict definition of “case,” we can generate eye-popping figures even for the relatively mild 2009 H1N1 swine flu virus. Whether the 59% fatality rate for H5N1 is off by one order of magnitude or twelve isn’t the point. The point is that public statements that cite that figure and use it for apples-to-oranges comparisons are going to get called out by virologists as propaganda.

But all of that is really a sideshow. The main question we need to focus on is whether it’s appropriate to redact key data from a paper that reports unclassified research. Mike was blunt and consistent in stating that the NSABB wants this to be an isolated incident, not a general approach. That’s reassuring. Unfortunately, I’m afraid it’s not up to him. My biggest concern about the NSABB recommendation is that it sets a dangerous and potentially corrosive precedent, a possibility I don’t think the committee gave adequate weight.

I’m not terribly worried about the NSABB, or about what happens with the H5N1 data, so long as they’re eventually published. I’m worried about the much broader picture. We’ve now seen a government advisory board pressure publishers to censor what they publish, based on entirely theoretical “security concerns.” Because said advisory board’s media statements created a public panic over the issue, the publishers really can’t negotiate this censorship from a position of strength. They pretty much have to go along with it. Prior restraint on publication is an extreme, radical intervention, even if it’s applied indirectly, as this was. US courts have consistently (and correctly) ruled that this type of censorship is only barely acceptable if there is an absolutely compelling public interest in suppressing the information. Theoretical threats don’t cut it.

So would it now be okay for the Minerals Management Service, citing undefined “security concerns,” to pressure a publisher over an article on fracking? Can a politically-motivated appointee at HHS threaten to smear researchers who publish data on abortion? Could a rightward-facing President appoint an advisory panel to lean on climate change publications? These are the sorts of scenarios that worry me, and they seem much more likely than the idea of terrorists synthesizing super-flu. There’s a long history of governments – even in democracies – trying to censor information, while the number of deadly non-state bioterror attacks still stands at precisely zero. From where I sit, the potential harms of censorship far outweigh any benefits of trying to conceal the data, especially since that horse is already out of the barn.

To his credit, Mike didn’t push the bioterrorist angle. Instead, he brought up a new argument: that a biohacker hobbyist might try to generate the new H5N1 strains just for bragging rights. While that’s theoretically possible, it’s hardly a compelling reason to cripple an entire field of research. There are already regulations in place requiring people to work with these viruses under stringent containment conditions, and animal experimentation involves more paperwork than a satellite launch. It would be virtually impossible to do such work undetected. So while a few exceptionally motivated (and deep-pocketed) biohackers might try to do this, they’re extremely unlikely to succeed. Even if they did, it’s not at all clear that the resulting virus would be dangerous.

Ultimately, this comes down to the question that always plagues decisions based on the “precautionary principle.” Yes, we should avoid doing something that risks causing harm, but where do we draw the line on risk? Giving every nation equal access to enriched plutonium would probably be a bad idea. But should we shut down the CERN supercollider, lest it destroy the universe? Or mandate that everyone wear hardhats outdoors to guard against falling space debris?

Clearly, many risks don’t justify the interventions that would be required to mitigate them. I think that the risks of publishing the new H5N1 studies fall firmly into that category. Others are certainly free to disagree, but the time to have that discussion is before the work is done. And that was one point on which Mike and I seem to be in violent agreement; it was nice to chat, but neither of us wants to find ourselves having this same conversation again.

* (2012.2.4 18:30) I did not intend to minimize what was apparently an extremely acrimonious exchange, regardless of exactly what words were used (see comments below). My intent here is to move the public discussion forward, though, and dwelling on questions of tone won’t do that. Mike, if you’re reading this, I suggest giving Peter a call to see if you two can bury the hatchet. It wouldn’t hurt to drop Vincent a line, too. Reasonable people can disagree, but pissing people off, as you apparently did, won’t help your case.

Some Unsolicited Debate Coaching for Tonight’s Speakers

The New York Academy of Sciences is hosting a panel discussion tonight about H5N1 influenza, “dual-use” research, and scientific censorship. Of course this stems from the ongoing debate about the alleged development of mammal-adapted H5N1 strains (see my earlier summaries here and here).

So far, I’ve found the public discussions on this issue disappointing, not only as a virologist and journalist, but also as a former debate coach. Both sides are advancing arguments, but there’s been a distinct lack of clash. In order to have a debate, each side has to listen to what the other is saying, and then respond directly, point-by-point, to the claims. Simply restating your own claims doesn’t cut it. If the arguments don’t clash, we can’t find out which ones are sound. Let me give some examples.

Members of the National Science Advisory Board for Biosecurity (NSABB) have made numerous public statements and published several essays about their recommendation to censor the new research. In all of those statements, they repeat the claim that H5N1 flu is a concern because it is highly lethal. In fact, they almost always quote a specific number: 59% of people infected with this virus die.

In blog posts and academic journal articles, virologists have repeatedly pointed out that this statistic is quite likely several orders of magnitude too high. The response of NSABB members has been simply to repeat the erroneous statistic. This is a crucial question that lies at the center of the debate, but there’s no clash.

Meanwhile, several commenters (including Howard Markel in an Op-Ed in today’s New York Times) have pointed out that redacting key data from the new papers, as the NSABB advocates, is a pointless gesture. As Markel explains:

In this case, censorship is too little, too late. The data generated by one of the research teams was already presented at a conference in Malta in September, where copies of the paper were distributed. But even if the data weren’t already available, the key details could likely be inferred from other information that is already available. I recently spoke with several prominent influenza scientists, all of whom agreed that, based on the knowledge that certain mutations can make H5N1 highly transmissible in ferrets, they could consult previously published literature and probably figure out what those mutations are.

In addition, none of this research was conducted in classified facilities. Hundreds of people without security clearances have already seen the data, which have also been emailed across multiple minimally-secured servers in at least four countries. If evil-doers wanted this information, it would be trivial for them to figure out which door to kick down to get it. The only people who actually can’t get access to the data are the scientists who might actually be able to use it beneficially.

The NSABB response to this criticism has been deafening silence. Again, it’s a crucial issue, but there’s no clash.

In the NSABB’s official policy statement explaining the rationale for their recommendations, we are simply told that they found the risks outweigh the potential benefits. For the past month, scientists have pressed the group, collectively and individually, to explain exactly what evidence they considered in reaching that conclusion. The policy statement, though, provides no more detail than their earlier editorials. So even when it comes to the central thesis of the argument, we have no clash.

At this point, I strongly suspect that the scientific backlash against the censorship recommendation took the NSABB by surprise. The group appears to have been looking for a test case on which to launch a discussion, and when the new H5N1 work came up they decided this would be it. Board members talked amongst themselves, made their recommendation on (probably inadequate) evidence, and expected the scientific community to go along peacefully. The scientists had other ideas. Having drawn a line in the sand, though, the NSABB now finds itself unable to retreat from it without looking foolish.

So here’s what both sides of the debate need to accomplish tonight. The virologists need to state their counter-arguments once more, but in the process they need to insist on direct responses from the NSABB. Don’t let them simply restate incorrect figures for the fatality rate, or just stipulate that redacting the data will prevent a terrible harm. Be nice, but press firmly. Don’t take “because we said so” for an answer. However, be sure you listen to the responses – it’s likely that NSABB members have some criticisms of the data you’re citing, and you’ll need to answer those as directly as you expect them to answer you.

The NSABB should begin by explaining their decision process, transparently and plainly, and acknowledging that it may have been flawed. Hey, we’re all people, and we all make mistakes sometimes. Next, address each and every one of the virologists’ counter-arguments directly. No dodging or pretending not to hear. Be prepared to concede any arguments for which you don’t have solid, evidence-backed answers. That will actually boost your credibility. Being wrong isn’t a character flaw. Being wrong while insisting you’re right is. On issues where you do have evidence, though, go ahead and press on. You had reasons for making the recommendation you made. Explain them. Finally, back off the fear button. Telling scientists that they have to agree with you or Congress will implement “Draconian restrictions on research,” or asserting (without solid evidence) that terrorists are on the verge of developing high-yield bioweapons, is fear-mongering. Stop it.

The Day the Science Died

This afternoon, a coalition of influenza virologists released a statement saying that they are voluntarily suspending research on H5N1 “bird flu” for 60 days. This was in response to the Category 5 hype storm that has accompanied the publication of two papers about this virus. My previous post on this topic (and links therein) provides a quick review for those who haven’t been following this story.

I’m of two minds about the new moratorium. As a scientist, I think it’s moronic. H5N1 flu is biologically interesting, and could become a major public health concern if it ever manages to sustain human-to-human transmission. Though its lethality has probably been vastly overstated, there’s no doubt that it is capable of killing at least some people, under some circumstances. The demonstration that it’s possible for H5N1 to adapt to a mammalian host, even one that diverged from the primate lineage many millions of years ago, shows that we need to step up H5N1 research, not halt it.

However, the biodefense industry’s recent push to whip up fear has completely distorted the public’s perception of this issue. Millions of nonscientists are now convinced that the recent virus transmission work was dangerous, perhaps even foolhardy, and that terrorist groups could easily take advantage of the new findings to kill millions. None of that is even remotely true. Unfortunately, people who are in a panic aren’t capable of rationally evaluating the nuances, so the scientists who’ve been trying to defend ongoing H5N1 work are at a disadvantage. Saying they’ll suspend that work is the only reasonable public relations strategy at this point.

Around the same time the moratorium was announced, a partially overlapping group of virologists sent an open letter to the National Science Advisory Board for Biosecurity (NSABB), giving that board a thump on the head. It was the NSABB that started this whole circus, by calling for the new H5N1 publications to be partially censored. In the open letter, the virologists argue that this censorship is unjustifiably hindering scientific progress. They were apparently too polite to say that deliberately omitting data from a publication in response to a nebulous, entirely theoretical “security risk” is antithetical to the whole scientific enterprise, so I’ll do it for them.

The moratorium should help bolster public confidence in the scientists’ ability to address this issue themselves, while the letter to the NSABB lays the groundwork for a productive debate based on reason rather than fear. Hopefully, in a couple of months everyone will be able to calm down and get back to work.

XMRV and CFS: Were Mistakes Made?

On Monday, Retrovirology published four papers about XMRV, a virus that has quickly become a celebrity for its putative association with chronic fatigue syndrome (CFS) and prostate cancer. The papers – and an accompanying overview – describe several lines of evidence that XMRV could be a laboratory contaminant. In other words, there might not be any such virus in the wild, let alone one that causes disease.

Now that's a contaminant. Image courtesy Flickr user frankenstoen.

Now that's a contaminant. Image courtesy Flickr user frankenstoen.

Those findings alone would be enough to stir the ire of some CFS patients, but an accompanying press release put out by the Wellcome Trust to promote one of the papers went a step further, kicking off with this attention-grabbing lede:

A virus previously thought to be associated with chronic fatigue syndrome is not the cause of the disease, a detailed study has shown. The research shows that cell samples used in previous research were contaminated with the virus identified as XMRV and that XMRV is present in the mouse genome.

That story hit the wires immediately, and many news outlets reprinted it more or less verbatim. When reporters did bother to follow up with independent sources, they got virologists who had only had a short time to read the papers and think about them, leading to regrettable quotes like this.

As you’ve probably surmised by now, I’ve had the luxury of thinking about the work a bit longer, and don’t think these new papers settle the case. They do, however, raise a host of very significant questions about earlier XMRV research. They’re good science. Much of the earlier work on XMRV was also good science. The problem is that popular coverage of the whole field has left out most of the important caveats on both sides.

Blaming the media is too easy. Yes, they (okay, we) are part of the problem, but the scientists and patient advocacy groups are not guiltless. Ever since the Lombardi et al. paper appeared in Science last year, my TWiV co-hosts and I have been saying that the jury is still out about XMRV and CFS. It’s also still out about XMRV and prostate cancer, but that hasn’t gotten nearly as much hype.

Unfortunately, some researchers in the field haven’t been nearly as circumspect. Judy Mikovits, senior author on the Lombardi paper, has gone completely off the rails. Some of the authors on the new XMRV papers have also started playing fast and loose with the data. The Wellcome Trust’s press release, for example, quotes one of them:

“Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome,” says Professor Greg Towers, a Wellcome Trust Senior Research Fellow at University College London (UCL). “All our evidence shows that the sequences from the virus genome in cell culture have contaminated human chronic fatigue syndrome and prostate cancer samples.

“It is vital to understand that we are not saying chronic fatigue syndrome does not have a virus cause – we cannot answer that yet – but we know it is not this virus causing it.”

Towers’s peer-reviewed paper phrases it a bit differently, though:

Whilst our observations cannot conclusively prove that XMRV is not a human pathogen they appear consistent with the hypothesis that XMRV is not an exogenous virus transmitting among individuals.

I agree completely with peer-reviewed Towers, but think press-release Towers needs to calm down a bit.

XMRV: Cause or Bystander?

Xenotropic murine leukemia virus-related virus (XMRV), previously best known for showing how an awkward name can turn into an awesome abbreviation, has now become the hot new pathogen for virologists to hunt. As mentioned in numerous media outlets, some researchers have found that XMRV shows up in prostate cancer more frequently than it does in healthy prostate tissue. That finding led to rampant speculation about this retrovirus’s potential to generate tumors.

More recently, another group found that XMRV infection correlates with chronic fatigue syndrome, a very different – and rather poorly characterized – condition. Could this virus be the secret cause of all of our mysterious ills?

I think not. First of all, neither finding has been reproduced yet, and in fact the prostate cancer result might have been a fluke; scientists in Germany just released a report where they analyzed hundreds of prostate tumor samples for XMRV, and came up empty-handed:

589 prostate tumor samples were genotyped by real-time PCR with regard to the RNaseL mutation. DNA and RNA samples from these patients were screened for the presence of XMRV-specific gag sequences using a highly sensitive nested PCR and RT-PCR approach. Furthermore, 146 sera samples from prostate tumor patients were tested for XMRV Gag and Env antibodies using a newly developed ELISA assay. In agreement with earlier data, 12.9% (76 samples) were shown to be of the QQ genotype. However, XMRV specific sequences were detected at neither the DNA nor the RNA level. Consistent with this result, none of the sera analyzed from prostate cancer patients contained XMRV-specific antibodies.

Translation: at least in this rather large sample of German patients, it ain’t there. Germans still get prostate cancer, but they don’t have XMRV.

At the moment, my favorite hypothesis is that XMRV is just a bystander, showing up in patients whose immune systems have been strained by some other condition. Maybe the virus exacerbates diseases that have already started by other mechanisms, or maybe it’s just a symptom, and doesn’t cause any pathology at all on its own. The German-versus-American skew in the prostate cancer samples might reflect different background rates of infection by XMRV on different continents. The virus appears to have originated in mice, so it could even be caused by differences in local rodent populations.

To test that hypothesis, we should look for XMRV in other immunocompromised populations in the US. If the bystander hypothesis is right, we should find it in most if not all of them. Check samples from transplant patients, HIV patients, anyone on steroids, anyone with clinical depression, or really any handy group of sick people. My guess is that we’ll soon see XMRV cropping up in lots of interesting places.

TWiV “Live” from Philadelphia

The ASM folks did an excellent job editing the first video episode of “This Week in Virology.” We did this show on a stage in the ASM conference press room in Philadelphia last week. The actual live audience didn’t exactly pack the house, but she was very attentive. Meanwhile, about 50 people watched the streaming video online. Now, if you have unreasonable amounts of time to kill, you can catch the rerun.

TWiV Hits the Big Time

The podcast This Week in Virology has now reached the “featured” page at the front of the “Science and Medicine > Medicine” category on iTunes. Apparently, there are a lot of folks out there who love to hear a few microbiologists (Vince Racaniello, Dick Despommier, and me) ramble on about viruses for an hour a week. Check it out – that’s us in the lower right corner:

iTunes screenshot, showing TWiV on the Featured page.

If you don’t subscribe to the podcast yet, perhaps you should. That way, when we’re world-famous and you’re standing in the throng of fans waiting for an autograph, you can tell people that you were listening to us when we first hit the charts.

Green Mice, Hantavirus, and The “20/80 Rule”

An old epidemiological rule of thumb says that for any given contagious disease, 20% of the population will be responsible for 80% of the disease spread. The numbers are certainly not exact, it’s just a way of stating a commonly observed phenomenon: a small number of individuals is disproportionately contagious. The real question in controlling an outbreak is figuring out who those individuals are.

For hantavirus, a potentially deadly pathogen whose reservoir host is wild deer mice, the key 20% may be the oldest and largest mice:

University of Utah researchers dusted wild deer mice with fluorescent pink, blue, green, yellow and orange talcum powders to show which rodents most often fought or mated with others and thus were most likely to spread deadly hantavirus. The study identified bigger, older mice as the culprits.

“If mice were in contact with a powdered mouse, you’d see the colored bite mark on their ear or tail, or color on their genitals,” says Denise Dearing, a University of Utah professor of biology and senior author of the study published online Jan. 7 in the British journal Proceedings of the Royal Society B.

“You knew when they got lucky,” adds Christy Clay, who ran the study as part of her University of Utah Ph.D. thesis under Dearing’s supervision.

Fluorescently dyed green mouse released into the wild; image courtesy University of Utah.

Hiking boots: $100. Backpack: $200. Trail map: $5. Stumbling upon a pair of cute, fuzzy, fluorescently dyed mice going at it in the desert: priceless.

What Did Bob Gallo Do To The Nobel Committee?

In this age of scientific teamwork, international collaborations, and discoveries that always seem to arise simultaneously in multiple labs, the Nobel prize is an anachronism. By limiting each prize to no more than three recipients, the Nobel committee virtually guarantees that someone will be left out. This year’s prize in Medicine, however, is downright spiteful.

While there is certainly controversy about exactly who discovered HIV first, it seems reasonable to pick three researchers who stand out pretty clearly: Luc Montagnier, Françoise Barré-Sinoussi, and Bob Gallo. There’s little question that Gallo’s work on the virus was somewhat sloppy, and there’s no question that Gallo has managed to rub a lot of people the wrong way. Still, what the Nobel committee did is shocking. Montagnier and Barré-Sinoussi won this year’s prize for their discovery of HIV. As if to throw salt on the wound, the committee then added a third virologist to the bill, taking this opportunity to give the prize to Harald zur Hausen, who discovered that human papilloma virus causes cervical cancer.

Now, zur Hausen’s work is unquestionably important, but it’s also completely separate from the HIV work. Why cite this unrelated accomplishment in the same award? The only reason I can think of is that the Nobel committee wanted to highlight the fact that they can give the prize to three people. In other words, this year’s prize is more about excluding Gallo than it is about rewarding any of the actual recipients.

That’s just plain ugly.