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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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« Underused Lab Solvents | Main | Even Worse Than Reality »

June 7, 2011

Murine Viruses and Chronic Fatigue: Does the Story Continue

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Posted by Derek

Well, one day after writing an obit for the XMRV story comes this abstract from Retrovirology. The authors, from Cornell and SUNY-Buffalo, say that they've detected other murine retrovirus transcripts from CFS patients (but not in most controls), and that these are more similar to those reported in last year's Lo and Alter paper in PNAS than they are to XMRV itself.

So perhaps the story continues, and what a mess it is at this point. I continue to think that the XMRV hypothesis itself is in serious trouble, but murine retroviruses as a class are still worth following up on. This is tough work, though, because of the twin problems of detection and contamination, and it's going to be easy for people to fool themselves.

Meanwhile, Retraction Watch has more on Science's "Expression of Concern" that I wrote about yesterday. It appears that the journal asked the authors to retract the paper (so says the Wall Street Journal, anyway) but that co-author Judy Mikovits turned them down (as might have been expected from her previous stands in this area). Science released their editorial note early because of the WSJ piece.

Comments (15) + TrackBacks (0) | Category: Infectious Diseases | The Scientific Literature


1. Shewolf on June 7, 2011 11:47 AM writes...

Here are some ideas for some other Editorial Expressions of Concern related to CFS. :) www;

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2. Keith on June 7, 2011 12:24 PM writes...

It was not just Judy Mikovots that turned them down on the retraction request. All the authors of the original paper were in agreement that the paper should not be retracted. That included Silverman from the Cleveland Clinic who is a Co-discoverer of XMRV and the collaberators at the NCI.

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3. Dav on June 7, 2011 12:53 PM writes...

As with MLVs, it was always going to be a family of viruses. XMRV is still there too. It is one variant of HGRV. Did you not see the abstract from one of the authors of Knox et al. Where they describe a new assay for detecting XMRV. Having used it in blood donors, although they have optimised it to monkeys. They found 8/1000 infected with XMRV.

Science is now speaking to the authors of Paprotka et al because of the issue over which mice cannot have been used in creating 22Rv1. They will be the ones retracting their paper. And it was all of the authors of Lombardi et al that said no to a retraction of Lombardi et al., except Peterson. That includes Silverman and Ruscetti. As they know there is no proof of contamination.

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4. Cristina on June 7, 2011 1:50 PM writes...

The most important remaining questions are: does XMRV infect and replicate in humans, is it a genuine human virus apart from being an easy and frequent contaminant, how did XMRV end up in humans and is XMRV infection associated with disease?

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5. Cristina on June 7, 2011 1:52 PM writes...

The most important remaining questions are: does XMRV infect and replicate in humans, is it a genuine human virus apart from being an easy and frequent contaminant, how did XMRV end up in humans and is XMRV infection associated with disease?

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6. Dav on June 7, 2011 2:25 PM writes...

It has been shown integrated into human DNA. Lo et al found that the virus had mutated after 15 years in the same patients.

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7. since on June 7, 2011 4:50 PM writes...

The Cornell/SUNY study you mention was blinded, again making the contamination argument difficult to explain with any logic--how do patient samples consistently get contaminated and not the controls? That is why we have control groups in science in the first place.

Also, to expand upon what Keith said, all of the coauthors of Lombardi 2009, except for one, attended a conference call in which there was unanimous agreement not to retract.

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8. Anonymous on June 7, 2011 7:36 PM writes...

I'm a science reporter and blogger on CFS Central and interviewed Dr. Harvey Alter when his paper was published. The MLVs that he found, he said, are variants of XMRV.

“Viruses tend not to be homogeneous,” Alter explained to me in a telephone interview. “The fact that we didn’t find XMRV doesn’t bother me because we already knew that retroviruses tend to be variable. They mutate a lot, basically. This is true of HIV and HCV [hepatitis C virus]. It’s not one virus. It’s a family of viruses.”

As far as the retraction of the Mikovits paper, it's not customary for journals to ask scientists to retract a paper--unless fraud is involved, which is not the case with the Mikovits paper.

Scientists disagree all the time. Whether Mikovits is right is anyone's guess. But expecting a consensus this soon is silly. The situation smacks mostly of politics, not science.

Given the new Cornell study and a study by Abbott Labs released yesterday that found XMRV antibodies, it's clear that the jury on the retrovirus is still out. Alter's study also found 7 percent of healthy U.S. blood donors had MLVs, and the Abbott Labs study confirmed XMRV antibodies in U.S. blood donors.

Both studies signal a contamination of the blood supply. In addition, the Japanese have also found XMRV in that country's blood supply. Given that the public's health is at stake, it would be unreasonable and perhaps even criminal to stop the investigation now.

Mindy Kitei
CFS Central

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9. PeterW on June 7, 2011 9:02 PM writes...

Derek, as someone actively in the Science field what's your view of the activity and effort put into publicizing the view that the case is closed on Murine viruses and that they are not a major factor or concern, and not associated with CFS? ie. Is the level of public positioning normal for a controvery like this?

Whatever your view (and I would like to hear it) these are my observations:-

A lot of the "discussion" has been technical. Which appears to be generate much controversy. Looking instead at the behaviour of the parties involved you get this picture; (very generalized of course):-

Group 1 = Those that claim that the MLV concerns are valid since disease associations are possible/probable. And most certainly not ruled out therefore more careful work is warranted.

Group 2 = Those that claim that MLV in the context of human disease has been largely disproven; that they are of minor interest and should be investigated at that level only.

Group 3 = objective fence sitters (not many apparently :-)

The idea that Group 1 is too keen and therefore not rationally looking at their work or conclusions has been well publicized. That assertion is of course plausible.

Re Group 2. Someone not involved in this controversy would conclude that they have a substantial amount of evidence suporting their position. Here is the part that I don't understand:- their's is currently the predominant view. If it is correct then that predominant view would become overwhelming if events were allowed to run their course. As other work is completed and more details are understood. What are now divergent "facts" will be reconciled and explained. End of story.

But, instead of allowing an orderly unfolding of knowledge many in group 2 are seemingly compelled to want to stop the discussion and close the chapter. Some more strongly than others. I won't go into the detail here but these opinions and vents surrounding them are on public record.

All science and technical arguments aside, from a purely behavioural viewpoint it sounds like Shakespeare's lady who "doth protest too much". Or, "what you are saying sounds right. But why are you acting so unusually?" In doing so Group 2 invite distrust.

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10. anciendaze on June 8, 2011 11:34 AM writes...

Back at the time of original publication XMRV was observed to be 94% homologous to X-MLV and 95% homologous to an endogenous sequence. Defining any putative viral pathogen this way invites attacks on one of two grounds: it's really a mouse virus; it's really endogenous. This has been the standard method of disposing of 'rumor viruses' for about 30 years.

On the other hand, the Lo/Alter results were dismissed as suggesting an entirely different virus. Harvey Alter, who knows a thing or two about viruses, has said "this is what viruses do". If this were hepatitis C, limiting it to about 1% variation would guarantee you would not find it. Both of these reports, and the results by Hanson, describe indications of active gamma retroviruses in humans.

My view on the Lombardi/Mikovits results may be unique. I do not say they have totally excluded contamination. At the level of sensitivity needed, the only way to do that would be to exclude human subjects. I do feel they have taken adequate precautions with controls to gain useful information even in the presence of contamination. This is a distinction between an assay used in research and one used clinically. People trying to use this clinically are given warnings about significance. Before such a test can be used for widespread screening, it will need to do better. This is not reason to curtail research into possible human gamma retroviruses.

Even if we are seeing endogenous sequences transcribed, we need to find out what is activating them. The possibility that an undetected exogenous retrovirus can activate very similar endogenous sequences, which are not replication-competent on their own, has to be seriously considered.

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11. JuliaHugoRachel on June 8, 2011 12:08 PM writes...

I Like your Comment:
"So perhaps the story continues, and what a mess it is at this point. I continue to think that the XMRV hypothesis itself is in serious trouble, but murine retroviruses as a class are still worth following up on. This is tough work, though, because of the twin problems of detection and contamination, and it's going to be easy for people to fool themselves."

I've noticed that many words from many scientifc studies are being taken out of context from these studies,(albeit from well meaning folks)then used out of contect to fit an individual viewpoint, patients are angry and there is an abundance of chatter about "conspiracy". I tend to be evidenced based, so unless you can show me the legal document proving a conspiracy OR a Theory, I err on the side of the objective.

If this Paper is pulled for Fraud, then legal reasoning will be published accordingly. But for now, The burden of proof is on the scientists who created this paper. If it cannot be re-created, then it can not be proven, nor can it legally begin to be used as treatment on patients.

WPI has all the faith in the world that their paper holds water and is 100% accurate, therefore, I am sure they shall prove this. They stated last weekend in an article in Reno, Nevada that the "WPI is opening to Patients in Jukly 2011".

Until then, this is becoming speculation, assumptions are running rampant and the blame game is getting old.

I would love to see more funding, more research and more energy put forward towards offense rather than defense. Lets get more studies done. This is an interesting field, holding promising characteristics for new types of Laboratory testing methodologies, collaborations amongst a plethora of research specialists & cohorts and a chance to advance medical history.

I would love to see the energy flow of this river change right now to that of discovery; discovery of the truth.

Julia Hugo Rachel

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12. Michael Lerman on June 8, 2011 12:57 PM writes...

In 2003 I was severely criticized for doing experiments in NCI aimed to prove that the ovine lung cancer virus (JSRV) may enter human lungs and cause the same form of lung cancer in humans, namely bronchioloalveolar adenocarcinoma (BAC). The human and ovine receptors for the viral entry are almost identical by sequencing. At the time the prevailing dogma among epidemiologists was that animal viruses do not enter human bodies and do not cause human diseases. Well, times have changed and nobody disputes that animal viruses may enter and replicate in human tissues. I think it’s a trivial task to prove that XMRV can enter and replicate in human tissues, however the real problem will arise how to apply the Koch postulate and prove the causal relationship between XMRV and CFS. On the other hand, it seems to me that there exists some kind of a mental block to accept causality in biology

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13. Dav on June 9, 2011 8:48 AM writes...

Actually it will be relatively easy to test Koch postulates. Clinical trials of ARVs will be a start. The same rules apply as they did with HIV on this one.

@JuliaHugoRachel: Burden of proof lies with all those producing negative papers that do not adhere to the scientific method. It is they that have chosen not to replicate or clinically validate their assays. Lombardi et al also included Ruscetti and Silverman. Please don't forget they disagree with you also.

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14. DeltaV on June 10, 2011 11:25 PM writes...

If it exists...

1. It's a retrovirus, so rapid mutation is expected and as a result quite a bit of genomic diversity.

2. Why ARE there healthy 'infected' controls... really, this is a point worth considering, becuase perhaps these people are more susceptible for some reason.

3. I would like to see a complete micronutrient status breakdown for cfs/fibromyalgia sufferers with xmrv vs controls with and without xmrv. Immune response or viral replication is bound to skew some of them. Biological kit, the stuff you're born with and the infections you get aren't built solely out of hyydrogen, oxygen and carbon. Seriously... I know there have been papers documenting disturbances in zinc metabolism in fibromyalgia. What about selenium... You want 'biomarkers', look to the basics first...

If it doesn't exist...

1 Why are these related contaminants cropping up.. repeatedly.

2 If not xmrv then what, physical and emotional stress seem to worsen both cfs and fibromyalgia, is it that they are detrimental to mounting a robust immune response due to increasing endogenous corticosteroids..

3 Speaking of cortisol, they're seems to be some sort of disturbance, bordering generally on the subclinical deficieny side of things, again is this to aid in immune response and if so, why only in these diseases.

4 Last but far from least, what about the sex differences. Why are these diseases so much more common in women. If xmrv, is it becuase they are more susceptible to a particular route of transmission... Or perhaps they are simply more susceptible to stress and it is a 'hormonal' problem with it's etiology at the top of the hpa axis, namely a 'dysregulated' hypothalamus.

Or are they losing trace minerals the immune system or brian requires, via a natural route... once a month perhaps.. speaking of which, there is a study showing these disorder having a higher prevalence in thassalemias and another showing the same in individuals with a history of iron deficiency anemia... Might there be a connection there... And another that they are also more common after a second pregnancy... Iron anyone?... Isn't it also neccessary for dopamine, norepinephrine and serotonin in no particular order... Aren't there studies suggesting RLS has an increased prevalence in these diseases, isn't that related to iron deficiency in dopamine producing areas of the brain.... No lets chase a mutating murine retrovirus instead, sounds like a plan... Much more fun, who wants to read about boring old iron metabolism.

Next month we'll be building an existential microscope capable of resolving emotions at never before imagined resolutions. Requirements... Odd numbers of people in yellow t-shirts holding hands standing in circles around burning copies of the principia mathematica...

Common sense is rarely common, but common consensus is fairly easy to find, you just have to look for the one you want, all aboard... Apologies for the redundancy and the structure of some of the post, i'm not bothering editing, all the salient stuff is there.

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15. Dave on March 9, 2012 5:04 AM writes...

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