‘Trust science, not scientists’, Vincent Racaniello’s Virology Blog, 27 September 2011

September 28, 2011


From Vincent Racaniello’s ‘Virology Blog’, 27 September 2011

Whether or not the retrovirus XMRV is a human pathogen has been debated since the virus was first described in 2006. The answer is now clear: the results of Blood XMRV Scientific Research Group, along with a partial retraction of the 2009 Science paper describing identification of the retrovirus in patients with chronic fatigue syndrome (CFS) show that detection of XMRV in patient samples is a result of contamination.

The Blood XMRV group obtained new blood samples from 15 individuals previously shown to be positive for XMRV (Lombardi et al., 2009) or MLV (Lo et al., 2010) ; 14 of these were from CFS patients. Fifteen blood samples were also obtained from healthy donors. The samples were coded and sent to 9 laboratories for analysis. These laboratories (Abbott Molecular, Abbott Diagnostics, CDC, FDA/Lo, FDA/Hewlett, Gen-Probe, NCI/DRP, and WPI) conducted validated assays for viral nucleic acid, viral replication, or viral antibodies. Positive contra samples were also included that were ‘spiked’ with XMRV, in the form of cell culture fluids from the cell line 22Rv1. Each laboratory was at liberty to choose which assays to carry out.

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 FDA/Lo laboratory did not detect any positives by PCR, using the same nested assay that they had previously reported in their published study. The samples tested included 5 specimens that were positive in the Lo et al. study.

Lombardi and colleagues have previously concluded that viral culture is the most sensitive method for detecting XMRV; however the FDA/Hewlett laboratory failed to culture virus from CFS samples. This laboratory did culture virus from positive control specimens, demonstrating the sensitivity of their methods. The FDA/Ruscetti laboratory recovered virus from 3/15 CFS samples but also from 6/15 negative control specimens. WPI did not carry out viral culture assays due to contamination of their cell lines with mycoplasma.

Four laboratories tested the samples for the presence of antibodies that react with XMRV proteins. Only WPI and NCI/Ruscetti detected reactive antibodies, both in CFS specimens and negative controls. There was no statistically significant difference in the rates of positivity between the positive and negative controls, nor in the identity of the positive samples between the two laboratories.

These results demonstrate that XMRV or antibodies to the virus are not present in clinical specimens. Detection of XMRV nucleic acid by WPI is likely a consequence of contamination. The positive serology reported by WPI and NCI/Ruscetti laboratories remained unexplained, but are most likely the result of the presence of cross-reactive epitopes. The authors of the study conclude that ‘routine blood screening for XMRV/P-MLV is not warranted at this time’.

One of the authors on Lombardi et al., Robert Silverman, decided to reexamine some of the DNA preparations from CFS patients that were originally used to detect XMRV DNA by PCR. He found that all the positive specimens from CFS patients were contaminated with XMRV plasmid DNA. Therefore the authors of the original study have retracted Figure 1 (single-round PCR detection of XMRV in CFS PBMC DNA); table S1, XMRV sequences, and figure S2, phylogenetic analysis of XMRV sequences.

A puzzling aspect of Silverman’s results is that XMRV plasmid DNA was detected only in samples from CFS patients, not healthy controls. This pattern would not be expected if the specimens were properly blinded, that is, coded so that the investigators did not know which were controls and which were from CFS patients. The authors offer no explanation of these findings.

The paper reporting contamination of samples with XMRV is entitled ‘Partial Retraction‘. It’s not clear to me why the entire paper has not been retracted. After removing the PCR and nucleic acid sequencing results, there is no evidence indicating the presence of XMRV in the patient samples. The remaining experiments show detection of a retrovirus by cell culture experiments, and the presence of viral proteins or antibodies to the virus in clinical specimens. None of these findings prove that what is being studied is XMRV. The title of the original paper ‘Detection of an infectious retrovirus’, XMRV, in blood cells of patients with chronic fatigue syndrome‘, is unsupported.

In an accompanying article on the XMRV story entitled ‘False Positive‘, Judy Mikovits of WPI notes that “Anyone who says this is a lab contaminant has drawn the wrong conclusion and has done a disservice to the public”. She goes on to imply that a gammaretrovirus is likely involved in CFS. On the contrary, pursuing the CFS-gammaretrovirus hypothesis is a disservice to those with CFS, and detracts from efforts to solve the disease. There are no data to support such an association, and to suggest that a lab contaminant, XMRV, has pointed the way to a bona fide etiologic agent seems
implausible.

XMRV does not cause CFS. The virus arose in mice between 1993-96, and its detection in patient samples is clearly a result of contamination. Reaching these conclusions has required a long and often contentious journey that has highlighted the best and worst aspects of scientific research. There are many lessons to be learned from XMRV, but an important one is that science progresses not from the work of a single investigator, but from the collective efforts of many laboratories.
XMRV reminds us to trust science, not scientists.

9 thoughts on “‘Trust science, not scientists’, Vincent Racaniello’s Virology Blog, 27 September 2011”

  1. “XMRV reminds us to trust science,not scientists”.

    BUT we HAVE TO TRUST scientists who do the science?
    What other choice is there???

    1. I wouldn’t trust this blogger. He has been found making definitive statements in the past regarding the WPI and NCI’s finding of human gammaretroviruses without reading the papers he is blogging about. This is also not his field. He has never researched theses viruses.

      Silverman made an error in his lab and gave the viruses the wrong name. Mikovits presented evidence in Canada last Friday proving those same samples in the WPI and NCI never contained VP62. They are the same findings as Lo et al., but with several more experiments than that paper. They discovered human gammaretroviruses (HGRVs) are present in people with ME.

      This explains all the negative paper and the blood working group as VP62 doesn’t exist in nature. They were never looking for the same virus.

  2. i can’t believe what’s happening. xmrv is dead. the wpi should admit they were wrong. they are doing us a diservice now by splitting the community and diverting funds from the true cause and solution. all of you supporters of mikovits/wpi should have a good think about why you continue to have so much faith in them.

    1. A lot of WPI supporters knew XMRV (VP62) was dead before the BWG Phase 3 hit the press stands.

      The interest has long since shifted to the wider question of an association with HGRVs.

      Lets not forget that the original intention of the WPI was to find biomarkers for ME/CFS patients and their solid work on Cytokines/Chemokines not only stands, but has been repeatedly referenced at conferences by big ME names such as Komaroff.

      The reason many people, myself included have more faith in the WPI than many other organisations and institutions is because their agenda overlaps the patient agenda more than many. The institute was devised by a family who wished to cure their daughters terrible illness (ME).

      It does not guarantee infallibility of course.

      Since most of us are lay people we have to find reasons to trust Scientists, Racaniello’s title could not be further from the truth. Politics and agenda will never be removed from Science because Science involves humans.

      This issue has been well framed by the press, with the deeper questions failing to be asked in many cases. This engenders my mistrust.

      It’s not a financially simple issue either. You might be told that, finding something to cure a retrovirus would be lucrative and actively pursued. But if there is a HGRV link to ME there’s the matter of the test patent. Similarly there’s the matter of health insurance, or government healthcare costs that follow such a revelation.

      There are huge agendas at stake here. This summer the ME community has already witnessed the effects of prolonged media manipulation, full of unbalanced reporting.

      We are at sea in a battle of agendas, which while a contrast from years of neglect, still defines a similar level of human nefarity.

      Lombardi et al 2009 out of the WPI changed the game and made them look. It would be wise not to forget its impact, contamination or otherwise.

      1. I agree with many of the points you are making but i have no faith in the WPI whatsoever. When the dust settles i feel their involvement will have been negative. I thought they were going to be a big part of the solution until about 10 months ago but almost everything i’ve heard since has led me to think otherwise. I wish every penny that went their way had gone to ME Research Uk.

        1. “I thought they were going to be a big part of the solution until about 10 months ago but almost everything i’ve heard since has led me to think otherwise.”

          That’s an interesting point, most of the press about the WPI’s work has been negative. A lot of press has been made about the VP62 strain killing off a ‘viral etiology’ of ME simply isn’t true. There remains a lot of promising findings that hold from the WPI which simply are not publicised.

          If you look at the Wesseley saga in the summer, the reason he was able to have so much impact in the press, despite the complete absence of convictions for reference is because he works for the Science Media Centre. Having direct access to the press gives you the power to build public opinion.

          In the same manner, competitors to the WPI have access to the press and can support Scientists prepared to speak out against them in it. Conversely, an atmosphere is created where it is very difficult to speak out in support of the WPI without appearing to be ‘irresponsible’.

          A unfairness has been created where people like Racaniello and others can paternally instruct patients as being foolish to trust in a manner that demands our trust in them.

          I challenge anyone to look at the rate of XMRV patent registrations over the last couple years, look at the researchers and look at the pharmaceutical companies they are attached to.

          The key take home message is that, press volume does not assure you quality information. The Guardian is lauded as saintly for its coverage of the phone hacking scandal, yet when it came to the summer and the Wesseley press storm, they opted to ignore the responsibility of good journalism whatsoever.

          For my part, I donated to the Invest in ME centre for biomedical research since I’m a UK citizen. My support for the WPI tends to be more vocal.

          1. I figure I wont shy away from this. But it appears that the research program at the WPI led by Dr Mikovits is being shut down, so I don’t intend to offer my support in their direction unless they begin taking part in some new and promising research.

            It may in part have something to do with the fact that Dr Mikovits would no long support the test being offered by VIPDx (which is a responsible, given recent developments). I’ll leave others to make their own conclusions. No doubt it’ll create quite the wave of assumption.

            Anyone interested can read something about it here:-

            http://treatingxmrv.blogspot.com/

            I still think it’s a sad day and I hope this doesn’t become the second, maybe 3rd time the possibility of a retro viral link to ME isn’t fully explored.

            (Look up JHK virus and Elaine Defreitas if you’re interested)

            Dr Mikovits said that some of the other strains beyond Silverman’s VP62 were set to be sequenced in the next couple weeks, whether that remains in motion or will be put on hold, I don’t know. (Apparently the second positive paper by Lo/Alter found MLVs that weren’t the ‘VP62 Contaminant’ strain).

          2. Fair play to you Matt for coming back to comment after events overtook this debate. I certainly never expected this to happen and have read some pretty serious allegations which I hope are not true. I don’t think there have been many positives to take from the last 2 years of this saga but maybe the WPI can get back to researching ME.

  3. I wrote the following reply on Racaniello’s blog pointing out the logical fallacies in his arguments. It has gone unanswered:

    “On the contrary, pursuing the CFS-gammaretrovirus hypothesis is a disservice to those with CFS, and detracts from efforts to solve the disease.”

    Vincent, I find the above statement both highly bizarre and insulting. How does looking for the cause of a disease do a “disservice” to the victims of that disease? Perhaps you should ask the patients what they think.

    You then claim: “There are no data to support such an association.”

    This is false.

    Indeed you yourself say in the previous paragraph:
    “The remaining experiments show detection of a retrovirus by cell culture experiments, and the presence of viral proteins or antibodies to the virus in clinical specimens. None of these findings prove that what is being studied is XMRV.”

    On the one hand you admit a retrovirus is at play (though not necessarily “XMRV”). On the other hand you claim there is no data supporting a retrovirus in CFS! So which is it Vincent? You can’t have it both ways.

    Also you say that:
    “The FDA/Lo laboratory did not detect any positives by PCR, using the same nested assay that they had previously reported in their published study.”

    This is misleading. Although the FDA/Lo had previously used their BWG assay in their published study, that assay had actually failed to detect any positives in the published study. So the FDA/Lo results stand.

    There is most definitely data to suggest a retroviral association with CFS. We need to find out what that retrovirus is as a matter of urgency. Making glib statements about supposed “disservice” does not help that effort one bit.

    If anything should be retracted, it is your article.

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