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XMRV: Lo et al paper retracted by author

Discussion in 'Media, Interviews, Blogs, Talks, Events about XMRV' started by Firestormm, Dec 26, 2011.

  1. Firestormm

    Firestormm Guest

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    Registration is free: http://www.medpagetoday.com/InfectiousDisease/GeneralInfectiousDisease/30372

    Second XMRV-CFS Paper Pulled

    By John Gever, Senior Editor, MedPage Today

    Published: December 26, 2011

    The only publication to corroborate the now-retracted 2009 paper linking the mouse retrovirus XMRV to chronic fatigue syndrome (CFS) has also been retracted.

    Shyh-Ching Lo, MD, of the FDA, and colleagues published a statement Monday in Proceedings of the National Academy of Sciences disavowing the conclusions of their report originally appearing in the journal in August 2010.

    They said they remained confident in the integrity of their original work. But, citing numerous other studies that failed to replicate the findings, they said its actual validity had become questionable.

    "It is our current view that the association of murine gamma retroviruses with CFS has not withstood the test of time or of independent verification and that this association is now tenuous. Therefore, we retract the conclusions in our article," they wrote.

    The 2010 PNAS paper had been the only publication to support the 2009 Science paper, in which researchers from the Whittemore Peterson Institute in Reno, Nev., led by Judy Mikovits, PhD, and Vincent Lombardi, PhD, said they had found XMRV in samples from CFS patients but not healthy controls.

    Lo and colleagues had reported similar results. But other laboratories attempting replication had instead found evidence that reagents used by many researchers in the field were contaminated with XMRV. One group concluded that the virus was a lab artifact, originating in cell culture through a recombination event and never circulating in the wild.

    The final blow to the XMRV-CFS link may have been a paper appearing in September, which reported that consistent results could not be achieved in any of nine labs that had been sent blinded clinical samples. They included those of Lo and Mikovits.

    The retraction by Lo and colleagues comes just days after Science's editor-in-chief, Bruce Alberts, PhD, had retracted the 2009 paper on his own authority, after failing to win the original authors' unanimous consent.

    Alberts also pointed to the failure of replication attempts as well as what he said was "poor quality control" and omitted data in the 2009 paper.

    He had previously asked for a retraction in May but was rebuffed. Subsequently, he wrote, "The majority of the authors have agreed in principle to retract the report but they have been unable to agree on the wording of their statement."

    With a retraction signed by all authors unlikely, Alberts said, he retracted it on his own authority.

    "We regret the time and resources that the scientific community has devoted to unsuccessful attempts to replicate these results," Alberts wrote.

    Primary source: Proceedings of the National Academy of Sciences
    Source reference: "Retraction" PNAS 2011; DOI: 10.1073/pnas.1119641109.


    Retracted paper: 23 Aug 2010: Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome
    and healthy blood donors



    Retraction Watch:http://retractionwatch.wordpress.co...ct-pnas-chronic-fatigue-syndrome-virus-paper/

    Another shoe drops as authors retract PNAS chronic fatigue syndrome-virus paper


    Just days after the retraction of a paper in Science that had claimed a link between chronic fatigue syndrome (CFS) and the virus XMRV, the authors of a similar paper in the Proceedings of the National Academy of Sciences (PNAS) have retracted theirs.

    The PNAS paper, Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors, was published online on August 23, 2010 by Shyh-Ching Lo, Harvey Alter, and colleagues. Heres the notice, which PNAS says will be available on its site sometime this week:

    ''The authors wish to note the following: Although our published findings were reproducible in our laboratory and while there has been no evidence of contamination using sensitive mouse mitochondrial DNA or IAP assays or in testing coded panels, we have the following concerns:

    1. The original chronic fatigue syndrome (CFS) patient samples were of insufficient volume to distribute to other laboratories for independent confirmation.

    2. Only one (1) of many laboratories has found a similar association between polytropic murine leukemia viruses (pMLV) and CFS and a careful study of 100 CFS patients (2), as well as a coded panel recently constructed by the National Heart, Lung, and Blood Institute (NHLBI) (3), have found no evidence for either xenotropic murine leukemia virus-related virus (XMRV) or pMLVs in CFS patient samples.

    3. Our attempts, through collaborations, to demonstrate antibody in affected patients, to isolate the virus by culture, or to show integration sites in the human genome have failed to support the initial findings.

    4. While recall of eight patients from the original cohort 15 y later showed pMLV gag sequences in seven, the copy number was very low and phylogenetic analysis showed these sequences were not direct descendents of the original dominant strains (4). Still later samples from four of these patients tested negative in the NHLBI panel. While this result could be explained by viral clearance over time, it fails to support a sustained retroviral infection in human cells.''

    The notice refers to an ongoing study led by Ian Lipkin:

    ''Although a more definitive, National Institute of Allergy and Infectious Diseases (NIAID)sponsored, coded panel of samples from 150 well-characterized and geographically diverse CFS patients and controls is being assembled for further study, in consideration of the aggregate data from our own laboratory and that of others, it is our current view that the association of murine gamma retroviruses with CFS has not withstood the test of time or of independent verification and that this association is now tenuous. Therefore, we retract the conclusions in our article.

    We asked Columbia University virologist Vincent Racaniello, who has been following the CFS-XMRV story for years as part of his This Week in Virology podcast, to explain what the original paper found, and what the retraction meant:

    ''in 2009 Lombardi et al published a Science report indicating they had detected the new retrovirus XMRV first detected a few years earlier in prostate tumors in the blood of a high proportion of patients with chronic fatigue syndrome. Many other laboratories tried to reproduce this finding, but none found XMRV in CFS patients.'

    In 2010 Alter and colleagues reported finding retroviral sequences in blood from a substantial number of CFS patients. No viruses were isolated in this study; only viral sequences were obtained by PCR. These sequences were not XMRV, but rather were closely related to endogenous retroviruses of mice called polytropic murine leukemia viruses. (Polytropic means the viruses can infect many species, including mice; xenotropic means the viruses, though originating in mice, only infect non-mouse species).

    As to the retraction notice itself:

    Curiously, they begin the retraction by writing that they could not detect contaminating mouse DNA in their samples which was most certainly present and lead to their detection of MLV-like sequences in the first place. This failure remains puzzling and unexplained; but as they report in the next paragraph, they appear to have run out of material to distribute to other laboratories for independent confirmation. This is just as well: its better not to waste more time on what clearly is a case of contamination.

    Lo et al provide three additional reasons why they are retracting this paper. They note that no one has been able to reproduce their findings, including the Blood Working Group as discussed above. They have not been able to find (along with collaborators) anti-XMRV antibody, XMRV virus, or viral integration sites in patient samples. It sounds as though they have done quite a number of experiments with others using their precious samples so its not clear why their collaborators could not also look for contaminating mouse DNA (see previous paragraph). Finally, they mention their finding from the PNAS paper that a second set of samples taken 15 years later from the same CFS patients also were positive for MLV-like viruses. They write that phylogenetic analyses revealed that these sequences were clearly not descendants of the original strains. The sequence data used to make this conclusion were available at the time of the PNAS publication, so it is not clear why this evolutionary incompatibility was not noted at the time.

    The authors made the link between their paper and the now-retracted Science paper clear in their original papers conclusion:

    ''Although we find evidence of a broader group of MLV-related viruses, rather than just XMRV, in patients with CFS and healthy blood donors, our results clearly support the central argument by Lombardi et al. (3) that MLV-related viruses are associated with CFS and are present in some blood donors.''

    But that wasnt the case, says Racianello:

    ''The Lo-Alter finding was viewed by many as supporting the findings of Lombardi et al; but in truth they only confused the matter. The viruses pinpointed by Lo-Alter in CFS patients were not XMRV, and it made no sense that CFS would be caused by such a diverse range of viruses. A second report in 2011 reported MLV-like sequences in a CFS cohort but many other studies failed to find any kind of retrovirus in the blood of CFS patients.''

    Just this year it became clear that XMRV is a laboratory-generated recombinant virus: it arose during the passage of a prostate tumor in nude mice in the early 1990s. This made it highly unlikely that it could be associated with human disease. Lombardi et al retracted a part of the 2009 Science paper that reported nucleic acid sequence; they noted that their samples were contaminated with XMRV plasmids. What remained of the paper were serological and virus culture experiments that were not specific for XMRV. Last week the remainder of this paper was editorially retracted by Science. What that meant is that there is no longer any confidence that XMRV, or any related retrovirus, causes XMRV.

    So whats happened to the XMRV-CFS hypothesis since Lo and Alter published their paper?

    The first blow was the finding in several laboratories that reagents used to carry out PCR are often contaminated with mouse DNA. The presence of this adventitious DNA can lead to detection of MLV-like sequences that resemble those found in the Lo-Alter study. The implication was clear: the Lo-Alter findings were wrong, a result of contamination of PCR reagents with mouse DNA.

    The next blow was a report of the Blood XMRV Scientific Working Group, which was assembled to determine if XMRV constituted a threat to the blood supply. In this study, sets of coded samples previously shown to be XMRV positive, as well as samples from healthy controls, were blinded and provided to 9 laboratories for analysis by PCR, virus culture, and serology. Two laboratories reported evidence of XMRV in the coded samples. Only WPI identified positive specimens by PCR: two from negative controls, and one from a CFS patient. The Lo laboratory did not detect any positives by PCR, using the same nested assay that they had previously reported in their PNAS paper. The samples tested included 5 specimens that were positive in the Lo-Alter study. In other words, Lo-Alter could not detect retroviruses in the same samples in which they had previously detected them.

    And whats next? Does the retrovirus-CFS story have a future?

    With the retraction of the Lombardi et al and Lo-Alter papers, this brings to an end any hope that there might be a retrovirus associated with CFS. Many (including Lipkin) have suggested that a related human gammaretrovirus might be involved in CFS. But I dont see how a lab contaminant can point you in the direction of a bona fide etiologic agent. Contaminants just cloud our vision, they dont improve it.

    As for the Lipkin study the more I think about it, the less compelling it seems. Many laboratories have failed to find any retrovirus in CFS patients. The story is over. Why do we think that the results from one laboratory will clear the matter up further? On the contrary if the Lipkin study is positive, I would not believe it, in the face of all the other negative results we have seen. As I always say, trust science, not scientists.

    The paper, which has been cited 76 times, according to Thomson Scientifics Web of Knowledge, was subject to a minor correction of GenBank accession numbers.

    The timing of the two retractions bookending a holiday weekend appears to be coincidental. We asked Science last week whether they had tried to coordinate publication with PNAS, and the journal told us they werent aware of the PNAS retraction.

    The announcements themselves marked a bit of a switch; typically PNAS has not included retraction notices in its press materials, while Science has, as our sister blog Embargo Watch noted last week. The opposite was true this time. Weve urged journals that use press releases to to press-release retractions whenever they appear.


    More from Racaniello on his Virology Blog: http://www.virology.ws/2011/12/26/a...mia-virus-releated-sequences-in-cfs-patients/

    Tuller at New York Times: http://www.nytimes.com/2011/12/27/h...ng-xmrv-to-chronic-fatigue-syndrome.html?_r=1


    CFIDS Assoc America Research 1st: http://www.research1st.com/2011/12/...arch1st (Research1st)&utm_content=Yahoo! Mail
     
  2. Jemal

    Jemal Senior Member

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    Lets see if all the prostate cancer studies get pulled as well. If not, something is not right.
     
    anne_likes_red, currer and WillowJ like this.
  3. Sean

    Sean Senior Member

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    Not sure that retroviruses as a group have been disproved.
     
  4. Jemal

    Jemal Senior Member

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    Agreed, I don't think we know enough about other retroviruses yet to say they are not associated with CFS.
     
    beaker likes this.
  5. xrayspex

    xrayspex Senior Member

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    just adds bigtime to my distrust of whts going on......feels like more Osler's Web sort of behavior
     
    GaryK, currer and beaker like this.
  6. currer

    currer Senior Member

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    Am I the only one who remembers rumours from about a year ago that Ruscetti had been advised to dissociate himaslf from the WPI because it was going to be "taken out" and that MLVs were to be allowed to be associated with prostate cancer but that the CFS connection was going to be stopped?

    Can anyone fiind these rumours in the archive posts here?

    Certainly if they state that XMRV is a lab contaminant, as they do here, all the prostate cancer papers are equally false.

    Will they be retracted? Because they better be! Why does Silverman support the retraction of the Lombardi paper if it undermines his findings too?

    And we are expected to believe the PNAS retraction is "coincidental" to the Science retraction? Using independant judgement they just happened to decide to do this now?
     
  7. currer

    currer Senior Member

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  8. currer

    currer Senior Member

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    What amuses me is that the Lo paper was loudly denied any relevance to the Lombardi findings - remember that ?

    But if you want to close down HGRV research into CFS - I can see they havent forgotten the relevance of the Lo paper now though!
     
  9. biophile

    biophile Places I'd rather be.

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    I think this came from the "Patient Advocate":

     
  10. currer

    currer Senior Member

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  11. currer

    currer Senior Member

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    To be honest, what we are witnessing is a rather clumsy cover-up. Now to give science its due, even corrupted, it is difficult to distort scientific truth. Because there is too much real evidence left lying about and all the little bits of fact can be quite easily put together again.
     
    Wildcat likes this.
  12. oceanblue

    oceanblue Senior Member

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    I think that was the problem: they were unable to press on and build on their initial findings, which you would have expected them to do had the findings been real.
     
  13. Tony Mach

    Tony Mach Show me the evidence.

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    Nevermind that you fail to provide any evidence that there is a cover-up, but will you change your attitude when the XMRV/prostate-cancer link will be retracted? Or will you stay in conspiracy mode?

    And why do you think it is not necessary for Lo et al to
    - demonstrate antibody in affected patients
    - to isolate the virus by culture
    - show integration sites in the human genome
    ?

    Do you simply want to take their word it? "Yeah man, it is alright, we don't need to check if this is only contamination, because." Don't you want evidence that this retrovirus actually infects humans? If anything was sloppy, it was the initial work by Lo et al, not doing all necessary tests to check for contamination by verifying integration sites in the human genome for example (because this on of the proofs that a retrovirus actually infects humans and is not simply a contaminant). In this regard, only two groups of scientists have been sloppy: Lombardi et al and Lo et al.
     
  14. Tony Mach

    Tony Mach Show me the evidence.

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    Not only about Gamma-, but about Alpha-/Beta-/Delta-/Lenti-/Shuma-/Whatever-Retroviruses too! And Enteroviruses! And Alpha-/Beta-/Gamma-Herpesviruses! And Picornaviruses! And all kinds of DNA-viruses!

    What is your point? We don't know therefore it must be it? Evidence through absence of evidence?
     
  15. Jemal

    Jemal Senior Member

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    The point is some scientists like Racaniello are coming to conclusions that are too far-reaching, IMHO. I am not saying a retrovirus is causing ME/CFS, but I don't think it can be fully disproven at the moment either. I would like to see research continue.

    Anyway, I have read only a couple of posts from you, but you come over as a very aggresive poster. You have lost all my respect in just a few posts, congrats.
     
    pollycbr125 and Wildcat like this.
  16. Jemal

    Jemal Senior Member

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    Racaniello is a bit more cautious on his blog, saying a virus might be associated with our disease, but there is no published data supporting it. I don't know about that, but at least it sounds better than some of his statements in the media.
     
  17. currer

    currer Senior Member

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    I am curious to see the PAPERS where Lo looked for antibody, virus and integration sites. I cannot remember any such paper with his name on it.

    Lo used a different assay in the BWG to the one which found the original PMLVs and this assay is not proven to work.

    The copy numbers were low? So the PMLVs were there. We know that copy numbers in blood are low. This statement does not support retraction.

    I havent had time to look in more depth at this report, but I think one of the references was to the Towers paper on phylogenetic analysis and I remember I thought that paper very questionable when it came out. It read like a piece of journalism, not science. You cannot construct a phylogenetic analysis of retroviruses, because of the unpredictable nature of retroviral recombination. And Towers made a point of gag deletions being found, when this is quite a common retroviral deletion. Quite apart from the fact that we do not know how patients acquire MLvs, they may copy themselves in the blood over time, but equally different strains may be acquired from outside sources. Who knows?

    Without further research we will be none the wiser, and it looks as if only a very rash scientist would dare to investigate this field now.

    Yes, I would feel happier if they decide to retract and block research into prostate cancer and HGRVs too. That would at least be a logical move.

    The whole thing stinks in my opinion. It looks to me as if it has been carefully planned from the outset.

     
    Wildcat likes this.
  18. oceanblue

    oceanblue Senior Member

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    I was surprised by some of those rather savage quotes as it isn't normally Vincent Racaniello's style.

    Maybe VC edited his blog to be more circumspect after the original version had been correctly quoted. The current version reads:
    So perhaps the more strident version on Retraction Watch is what he really thinks - said in the heat of the moment - rather than what he's comfortable saying publicly.
     
  19. xrayspex

    xrayspex Senior Member

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    This isnt my field of expertise, can any of you tell me if there is a lot of research out there on the connection between various illnesses and viruses/retroviruses? My primary care physician told me that sjogrens is thought to be connected to (retro)virus. I have been thinking thats whats at stake here, that if it came out that a bunch of stuff like cancers, ms, RA etc were directly correlated to specific viruses it will mess up health care as it stands. HOwever if there is already a lot of research scattered indicating that why do you think they are picking on cfs? If there isnt a lot of research like that then maybe they would try to downplay the prostate cancer connection too...because I can't believe its just m.e. that they care so much about, seems like a lot more and bigger fish to fry to go to this effort.
     
  20. currer

    currer Senior Member

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    I think the problem with ME specifically is that it is a "new" disease - only come to prominence since the fifties.

    Autism is also in the same category.

    So people wonder where they came from. The odd "obscure " illness like Sjogrens would not be a problem if retroviruses were a cause but a common new illness (ME) would be too much like AIDS all over again.

    However cancers already are accepted as existing illnesses and if a subset of prostate cancers were caused by a retrovirus that might be more easily explained away as having always been the case than a "new" disease.

    xrayspex, the best site for the information you want is Jamie's blog as she has looked into it.
    I can only remember primary biliary cirrhosis as being a suspected retroviral disease, and there was a research paper linking some breast cancers to MLVs.
    http://cancerres.aacrjournals.org/c...dfcfbc8af27dedcf7a4ec962&keytype2=tf_ipsecsha

    Irrespective of retroviruses, I wonder whether the fact that some CFS cases follow vaccination hasnt been a major problem for us in getting research funding as this fact may not be a welcome one to the pharma industry.
     

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