Rumor Viruses author weighs in on XMRV debate

kurt

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This just out, a well reasoned dose of 'healthy skepticism' about XMRV in an Op-Ed by the author of the often quoted 'rumor viruses' article (that documents how and why so many retroviral hunts fail). There is some interesting information here that was not in the 'rumor viruses' article, apparently in an early failed retroviral hunt Weiss also had the problem of patient samples having higher positives than controls. Some ideas about why that happens in complex contamination situations are presented. Apparently this issue was also discussed informally at the recent international XMRV conference, the problem of over-handling the patient samples compared to controls.

A cautionary tale of virus and disease

Robin A Weiss

Division of Infection and Immunity, University College London, 46 Cleveland Street, London, W1T 4JF, UK

BMC Biology 2010, 8:124doi:10.1186/1741-7007-8-124

Abstract

The recent identification of the gammaretrovirus XMRV and a second gammaretrovirus of a different subtype in chronic fatigue syndrome has aroused much interest, not least among sufferers. However, it remains highly controversial whether the detection of these viruses represents true infection or laboratory artifacts.

Full Article: http://www.biomedcentral.com/1741-7007/8/124
The closing words are classic:

Rumor viruses are seldom eradicated; they remain latent, waiting to be reactivated in a new disease. Subtle diseases of unknown cause will remain susceptible to rumor viruses for as long as no other etiology is established.
 

Esther12

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Old news Kurt. I think we've already got two other threads on it! You've got to be quick here/

Weiss is the one who compared reporting on the XMRV-CFS link to MMR-Autism at the Science Media Center, so I don't have too much trust for the man. Whatever you think of the likelihood of XMRV working out this sort of media manipulation is a bad thing.

Are you still a sceptic then Kurt? I'm still assuming it won't work out, but I'm pretty close to 50-50 at this point.
 

eric_s

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[...]Apparently this issue was also discussed informally at the recent international XMRV conference, the problem of over-handling the patient samples compared to controls.[...]:
But in a properly blinded study this can't happen, so it should not be too hard to rule this out. Just design your study well. If you can't make the distinction between cases and controls, you can't over-handle one set.
[...]The closing words are classic:"Rumor viruses are seldom eradicated; they remain latent, waiting to be reactivated in a new disease. Subtle diseases of unknown cause will remain susceptible to rumor viruses for as long as no other etiology is established."
This is totally not directed against you, Kurt, but i think this sentence is crap. Retroviruses, and here specifically XMRV, do exist.
What he says would only make sense, if some people believe a certain type of virus exists, that in reality does not.
And a virus can't remain latent in one patient and then be reactivated in another, so the analogy is bad. What does he want to say? "Don't look for retroviruses in any disease"??
His sentence scares a lot of people who are already desperate enough. Of course contamination can happen and we can't be 100% sure yet in our case, but instead of saying that sort of "ghost story" like stuff, he would better go to work and find the source of the alleged contamination.
 

Mark

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I thought the presence of antibodies conclusively rules out contamination. Ok, so only 50% are showing positive for Antibodies, but it seems that still ends that argument.
Just to note that this argument isn't accepted by the XMRV sceptics/denialists. Weiss mentions it in the article, and says that the antibodies can be cross-reactive; they could be reacting to something else. The sceptics also ask, why don't they all have antibodies then?

Both arguments feel thin to me though. If there's evidence of antibodies, more commonly in ME patients than in controls, then those antibodies still have to be antibodies to something - and something rather similar to XMRV, at that. And as for why the antibody levels aren't 100%, well the WPI are already ahead on that too and there was another paper recently suggesting that those who had antibodies responded best to antiretrovirals, and those who don't have XMRV antibodies but do have XMRV are the sickest patients. Makes sense to me...
 

Mark

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Couple more points on Weiss' article:

The recent identification of the gammaretrovirus XMRV and a second gammaretrovirus of a different subtype in chronic fatigue syndrome has aroused much interest

This opening sentence strikes me as odd, along the lines of McClure's "let's be clear, this is a different virus". Pretty loose comments, surely, however you slice it? There were four distinct sequences, with variation between them as significant as the differences from XMRV. So why describe those four variants as "a second gammaretrovirus" - if they can all be one virus, why can't XMRV be the same virus too?



Most recently, to add to the confusion, a new paper [6] reports an association between CFS and a different retrovirus - a report erroneously described in some of the press coverage as confirmation of the original report of Lombardi et al.
This quote, again early on, looks to me like one of those comments that "gives the game away", to those in the know. As always in such cases: on more than one level.

"erroneously described in some of the press coverage" ?

- That's an error then, to call it confirmation? Really, "erroneous"? Why, then, does he not level that accusation directly at Dr Alter - since he himself made exactly that claim - "strongly confirms the WPI" - several times at the press conference? Why blame the press? That's either spin, disinformation, or ignorance, as those who listened to the press conference know full well.

- And which of the press coverage is he referring to here? Certainly a fairly small subset, given that the disappointment of the press coverage was precisely that these comments of Alter and Lo at the press conference weren't emphasised by any of the press that I saw - quite the reverse in fact: campaigners had to dig those quotes out themselves and try to get that word out as best we could. So it seems rather odd to complain about the press coverage and imply that this was the way the story was presented, because it really didn't seem that way to me at all.
 

urbantravels

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It wasn't presented that way in the vast majority of the media coverage. Amy Dockser Marcus at the WSJ, as usual, had the best and most informed take of all the mainstream media outlets.

Really, this is a lot of work to disabuse the general public of an idea that most of the general public has absolutely no clue about.
 

alex3619

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HI Mark

To me this is indicative of XMRV causation: if you can't fight the virus with antibodies, you are sicker than someone who can.

Just to reiterate something I have said elsewhere: it doesn't matter if XMRV is ultimately shown to be benign (something I don't think will happen), it can still cause CFS by inducing a permanent hyper-immune response.

Bye
Alex

And as for why the antibody levels aren't 100%, well the WPI are already ahead on that too and there was another paper recently suggesting that those who had antibodies responded best to antiretrovirals, and those who don't have XMRV antibodies but do have XMRV are the sickest patients. Makes sense to me...
 

Mark

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Just to reiterate something I have said elsewhere: it doesn't matter if XMRV is ultimately shown to be benign (something I don't think will happen), it can still cause CFS by inducing a permanent hyper-immune response.
Wow, that's a really good point, I'd never thought of that one! Thanks alex, that's really thought-provoking...
 

Mark

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I'm still assuming it won't work out, but I'm pretty close to 50-50 at this point.
Whoop! I've been meaning to ask how your percentage estimate was looking these days! I'm still stuck on 99% or so, and spending far too much time worrying about that niggling 1% doubt! :D
 

Mark

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What does he want to say? "Don't look for retroviruses in any disease"??
Yup, you got it! The sceptic argument is no more than an argument against any new retroviral association with disease. It applies, and is applied, to any and all such discoveries, automatically.

That's why I can't get my head round that whole attitude. It's the sort of thing that will always be right until it's wrong. If they were saying "well the findings do look strong, it certainly looks exciting, but I have to caution, these things are notoriously difficult to pin down and there are lots of ways it could all be wrong, we've had many false starts in the past" - well, I could understand that, that's what I'd expect, that sort of attitude would just be natural scientific caution and quite understandable.

But they aren't saying that. In relation to ME/CFS, with specially reserved doubt and scepticism, they are saying "no, no, no, this is nonsense, retrovirus discoveries are always wrong, what an irresponsible thing to suggest...I'll have a quick look to check but I'm sure it's nothing...". It seems clear that the reason they apply such special levels of scepticism to ME/CFS is because they are convinced that we're all not really sick, so it can't be true...boy have those sort of people got a rude awakening coming, sooner or later...
 

garcia

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Yup, you got it! The sceptic argument is no more than an argument against any new retroviral association with disease. It applies, and is applied, to any and all such discoveries, automatically.

That's why I can't get my head round that whole attitude. It's the sort of thing that will always be right until it's wrong. If they were saying "well the findings do look strong, it certainly looks exciting, but I have to caution, these things are notoriously difficult to pin down and there are lots of ways it could all be wrong, we've had many false starts in the past" - well, I could understand that, that's what I'd expect, that sort of attitude would just be natural scientific caution and quite understandable.

But they aren't saying that. In relation to ME/CFS, with specially reserved doubt and scepticism, they are saying "no, no, no, this is nonsense, retrovirus discoveries are always wrong, what an irresponsible thing to suggest...I'll have a quick look to check but I'm sure it's nothing...". It seems clear that the reason they apply such special levels of scepticism to ME/CFS is because they are convinced that we're all not really sick, so it can't be true...boy have those sort of people got a rude awakening coming, sooner or later...
Great post Mark!
 

Esther12

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I've been meaning to ask how your percentage estimate was looking these days!
It seems as much affected by my mood as the evidence. Hopefully I'm doubting over nothing, but a few things just don't seem right to me yet. I need a constant flow of positive new studies to overcome my instinctive scepticism!
 

anciendaze

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...Just to reiterate something I have said elsewhere: it doesn't matter if XMRV is ultimately shown to be benign (something I don't think will happen), it can still cause CFS by inducing a permanent hyper-immune response...
This is a second possibility, which I would not call benign. We could make the argument still weaker, without losing the importance of XMRV. It could (hypothetically) be completely benign. If it shows up as a marker at rates of 80%, it must be a clue to the pathology of the illness. No single physical sign has distinguished sufferers from the general population as effectively.

To correct any possible misconceptions due to misreading the above, I am personally convinced it is not benign, and is in fact central to the pathology.
 

kurt

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Yup, you got it! The sceptic argument is no more than an argument against any new retroviral association with disease. It applies, and is applied, to any and all such discoveries, automatically.

That's why I can't get my head round that whole attitude. It's the sort of thing that will always be right until it's wrong. If they were saying "well the findings do look strong, it certainly looks exciting, but I have to caution, these things are notoriously difficult to pin down and there are lots of ways it could all be wrong, we've had many false starts in the past" - well, I could understand that, that's what I'd expect, that sort of attitude would just be natural scientific caution and quite understandable.

But they aren't saying that. In relation to ME/CFS, with specially reserved doubt and scepticism, they are saying "no, no, no, this is nonsense, retrovirus discoveries are always wrong, what an irresponsible thing to suggest...I'll have a quick look to check but I'm sure it's nothing...". It seems clear that the reason they apply such special levels of scepticism to ME/CFS is because they are convinced that we're all not really sick, so it can't be true...boy have those sort of people got a rude awakening coming, sooner or later...
Mark, other than a few govt die-hard skeptics in the US and UK who have their own psyco-theory of ME/CFS they are trying to defend, I see no evidence that these other independent researchers are dismissing ME/CFS. To the contrary, many were very hopeful for us at first. One researcher I know personally got involved in XMRV studies because he had two personal friends with CFS and knew first-hand how sick they really were. I'm sure some of the other researchers also know the reality of ME/CFS.

And while you make a good point about this being a general-purpose skeptical view of all retroviral hunts, there is more going on here than universal skepticism. The problem is that these retrovirologists know how to read the signs of an evolving viral hunt. They see a pattern in what is happening with XMRV research that is familiar to them. I believe this article is important for us, because it is a rational skeptical argument, and we need more healthy skepticism. The target here is to find the truth and SOLVE CFS, and not to promote any particular hypothesis. So I want to hear both sides, the best arguments they have.

Also, I think we need to stay aware of everything going on in the CFS research and treatment world, not just the possible connection to MLVs, which ARE in fact common contaminants both in laboratories and in commercial reagents. One of my early complaints with the WPI Science article was that they spent very little space and since have spent little time discussing the possible confounds for their research. That always sends up a warning flag... Good scientists sometimes spend as much effort trying to disprove their own hypothesis as proving them. There has been little serious discussion by WPI about risks and alternate explanations. But at this point their hypothesis is only that there is a correlation, WPI and others have still not ruled out the possibility that if MLV viruses such as XMRV and PMLV are present in CFS that they are just opportunistic passenger viruses, there due to poor immune function. This should be a huge topic in WPIs discussions of XMRV or FDA's discussions about PMLV.
 

alex3619

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Hi anciendaze

I agree this is a possibility, XMRV might just be indicative of an immune defect. However, unless we have a defect that is specific to XMRV (which we might) I want to know why people who are immune compromised only have 10% XMRV and we have up to 98%. This makes the "defect" hypothesis contingent on our having an MLV specific immune defect. I find this unlikely, but without evidence I cannot rule it out either.

I am also still betting on XMRV/PMLV being pathogenic and causal. It has the highest probability at this point.

The second choice is XMRV inducing a kind of autoimmune disease.

Both of the above might have other pathogens as cofactors, especially Herpes family viruses.

Only then do I get down to the possibility of an immune defect.

Below that I would put possibilities like XMRV might be induced in CFS blood samples only because it is present in nearly all people: this is also dependent on an XMRV specific immune vulnerability, or the control samples would also be infected.

At this point I think the notion of contamination issues as very very unlikely.

As a completely separate point, I think that XMRV pathogenicity in CFS should be considered completely separately from cancer (prostate, CLL, MCL, etc). It might be pathogenic for cancer, but not directly for CFS, and we are again back at the immune hypothesis.

I am eagerly waiting for the study (Alter, Lo, someone else?) that shows XMRV integration into CFS patient genomes, especially if it is integrating somewhere interesting. This raises another possibility: what if we have something different in our genetics that makes us more vulnerable to damaging viral integration sites? Has anyone even considered this? Maybe it integrates differently into different genomes, and some have vulnerability to certain cancers, while others are vulnerable to CFS, while the rest have benign integration sites? In this case it would have nothing to do with weak immune systems or immune defects, and everything to do with DNA structure.

Bye
Alex
This is a second possibility, which I would not call benign. We could make the argument still weaker, without losing the importance of XMRV. It could (hypothetically) be completely benign. If it shows up as a marker at rates of 80%, it must be a clue to the pathology of the illness. No single physical sign has distinguished sufferers from the general population as effectively.

To correct any possible misconceptions due to misreading the above, I am personally convinced it is not benign, and is in fact central to the pathology.
 

urbantravels

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I'm sure you're not arguing that the last 30 years have been characterized by open-minded HEALTHY skepticism. I agree 100% with Kurt - the tough questions need to be made as tough as possible and answered as thoroughly as possible. This would make for a thorough investigation, not one driven by "true believers" of any variety.

What we HAVE had with CFS is a lot of "True Disbelievers" - those unwilling to vigorously investigate evidence of a biological cause because of an assumption that there really isn't one. That is not healthy skepticism - that is denialism that amounts to a superstition.
 

natasa778

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yes indeed currer, that little curiosity has been noticed and discussed earlier on, see the thread on Science Media Centre press release (Weiss + Mcclueless quoted, Weiss with that same freudian slip)
 

alex3619

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Hi currer

I think his worry cought be the implication. XMRV appears to replicate when the immune system is stimulated. This would include vaccines, since they are specifically designed to trigger an immune response.

Does anybody own a pair of X-ray glasses: it would be nice to be able to see the invisible elephants.

Bye
Alex

I think his reluctance to take CFS seriously could stem from his reluctance to consider whether vaccination might damage the recipient.
He has linked these two issues in his letter ALTHOUGH none of the published papers which found evidence of XMRV in CFS patients EVER suggested that the XMRV came from lab mice and got into people via vaccines.
I wonder why? Could there be an invisible elephant somewhere in the room?