Wellcome Trust researchers reply to XMRV criticism – ‘Scicasts’ blog, 13 January 2011

January 13, 2011


From “Scicasts”, a life sciences research blog, 13 January 2o11

London, UK (Scicasts) – Last week (on Thursday, January 6th, 2011), we published the story: Chronic Fatigue Syndrome Not Caused By XMRV Virus, reporting the Wellcome Trust's research which stated that XMRV virus – previously thought to be associated with chronic fatigue syndrome – is not the cause of the disease. We received many comments and e-mails from our readers criticizing Wellcome Trust's conclusions and we have asked their leading scientists, who published the report, to respond to our readers.

Below, is the official statement that we have received from Professors Greg Towers and Paul Kellam:

On 20 December 2010, the peer-review journal Retrovirology published a series of papers relating to XMRV, a virus previously linked to CFS/ME. These included our paper,Disease-associated XMRV sequences are consistent with laboratory contamination by Hue et al at University College London (UCL) and the Wellcome Trust Sanger Institute, with funding from a number of organisations including the Wellcome Trust.

In our study, we showed that it is extremely unlikely that XMRV is a human pathogen or one which transmits between humans. There has been much discussion of what exactly we can and did conclude from our observations. We would like to take this opportunity to reiterate the following.

Comparison of XMRV found in patients and XMRV found in the prostate cancer cell line 22Rv1 tells us that patient-derived XMRV sequences do not contain sequence variation that invariably accompanies transmission of retroviruses between individuals. XMRV is like any other virus: it has a genome, which, when replicated during the process of infection, accumulates mutations, with the number of mutations acting as a counter for the number of replication events. XMRV is not able to replicate without variation and we showed this by determining the sequence variation of the virus in the 22Rv1 cells. Thus we can conclude that XMRV sequences from CFS samples are not from a virus that has transmitted between individuals and thus cannot be the cause of chronic fatigue syndrome or prostate cancer.

The Scicasts blog contains some criticism [from its readers] of our methodology and the fact that we addressed only one component of the research originally published in Science. We used established scientifically accepted and rigorous protocols that are in no way dependent on user bias. We, and the other papers in Retrovirology, did indeed address one component of the research originally published in Science, namely that of PCR assays. However, this type of assay is used in all XMRV and CFS studies, is the most sensitive and when coupled with sequence analysis the most specific. Therefore by showing that the original assertions that are made using this assay are flawed we conclude that those studies are compromised.

Our study did not address the issue of anti-MLV antibodies in CFS patients and we therefore cannot conclude anything about these observations. However, we would expect to see the description of anti-MLV antibodies in CFS patients to be reported in more than one laboratory before this technique was used diagnostically. To the best of our knowledge, no other peer-reviewed research has been able to provide evidence of anti-MLV antibodies in CFS patients.

We recognise that chronic fatigue syndrome/ME is a very real and distressing condition. It is important to recognize that we are not claiming that CFS/ME is not caused by a virus – this may well still be the case. It is still not clear what causes the condition and it is important that scientists explore all avenues of research to identify its cause or causes and enable better treatments.

We are committed to understanding and identifying virus causes of human disease. We are similarly committed to giving both the scientific community and lay audiences accounts of the findings of their work, and that was what motivated us to issue our joint press release.”

14 thoughts on “Wellcome Trust researchers reply to XMRV criticism – ‘Scicasts’ blog, 13 January 2011”

  1. Tony – Thanks for posting this so quickly. I guess that is a pretty ringing endorsement of their initial statement.

    Fair-play. They haven’t ‘caved under pressure’ and are sticking to their guns.

    Still I doubt the XMRV debate will end there. Too much invested now.

    Hope it doesn’t cast a cloud over all the other research being conducted.

  2. There it is again “In our study, we showed that it is extremely unlikely that XMRV is a human pathogen or one which transmits between humans.” They haven’t proven anything, and can therefore not say XMRV isn’t the cause. They must retract this statement.

    Are they now not conducting research into this family of retroviruses and ME/prostate cancer? Who are they kidding?
    The Wellcome Trust and Towers only demonstrate that science is not their priority. Politics is.

    1. It’s as if they want to flatly ignore the potential of environmental causes as well. Even if they could irrefutably prove that the virus is not passed from human to human, that isn’t cause to declare the XMRV study scientific dead end.

      If anything to my mind, that sort of proves their only interest to begin with were the ‘public health implications’ and nothing else.

      1. How can they really say anything different?

        Their research ‘proved’ what it ‘proved’ I don’t think ‘we’ can expect them to say any more than what their research told them.

        This is not to say WPI and the rest shouldn’t be listened to or that the original and subsequent ‘testing’ is not relevant.

        Those whose research has supported that XMRV is a human pathogen and capable of being transmitted – not to mention those supporting the specific high incidence among those of us with CFS and/or Prostate Cancer – now have to defend through replication their belief.

        Prove the Wellcome Trust wrong.

        1. In the initial statement by the Wellcome trust they went as far as use their evidence to state that there was no link between XMRV and CFS.

          So they have a duty to back up such a statement, or retract it entirely.

          Instead they have clung to a smaller details which still seem to be held in a reasonable amount of contention based on the posts below this.

        2. Their study Hue et al. did not state that ME/CFS is not caused by XMRV. It did not say that XMRV is a mouse retrovirus. That is the important point. Only the press release falsely stated such a thing.

          Hue et al. provided several reasons why XMRV may not be a human retrovirus, but they did not prove anything, omitted a great deal of evidence, and used a dodgy form of statistical analysis.

          The Wellcome Trust and Towers should be ashamed of themselves.

  3. The scicast people took our comments seriously though. And Retrovirology have published “Baysian knowledge is not Scientific knowledge”, a rebuttal of Hue et al.

    http://www.retrovirology.com/content/7/1/111/comments

    I’m afraid the statement from Towers and Kellam above does not tackle the valid criticisms raised therein, and I’m surprised at the MEA not pointing this out.

  4. From the statement by Towers et al above
    “We, and the other papers in Retrovirology, did indeed address one component of the research originally published in Science, namely that of PCR assays. However, this type of assay is used in all XMRV and CFS studies, is the most sensitive and when coupled with sequence analysis the most specific”

    That is incorrect. The data presented by Mikovits clearly demonstrated that the PCR assay is the least sensitive method for detecting XMRV, supported by Schalberg et al (1) Danielson et al (2) Arnold et al (3) and Urisman et al (4).

    The PCR method referred to by Dr Towers has never succesfully detected XMRV, yet by saying that it is used he implies it is successful. There is no such thing as a type of PCR assay. The conditions used in the Lombardi study were highly specific and also involved biological amplification (5).

    1) Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR: XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Proc Natl Acad Sci U S A 2009, 106:16351-16356.

    2) BP Danielson, GE Ayala and JT Kimata; Detection of Xenotropic Murine Leukemia Virus-Related Virus in Normal and Tumor Tissue of Patients from the Southern United States with Prostate Cancer Is Dependent on Specific Polymerase Chain Reaction Conditions; J Infect Dis. (2010) 202 (10): 1470-1477. doi: 10.1086/656146

    3) Arnold RS, Makarova NV, Osunkoya AO, Suppiah S, Scott TA, Johnson NA, Bhosle SM, Liotta D, Hunter E, Marshall FF, et al: XMRV infection in patients with prostate cancer: novel serologic assay and correlation with PCR and FISH. Urology 2010, 75:755-761

    4) Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, et al: Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog 2006, 2:e25.

    5) Lombardi, V.C.; Ruscetti, F.W.; Das Gupta, J.; Pfost, M.A.; Hagen, K.S.; Peterson, D.L.; Ruscetti, S.K.; Bagni, R.K.; Petrow-Sadowski, C.; Gold, B.; Dean, M.; Silverman, R.H.; Mikovits, J.A. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009, 326, 585-589.

  5. The Department of Health recently stated that:

    “The stark differences in prevalence of apparent infection seen globally in what amount to similar studies do present issues that will need further investigation, but are unlikely to be solely the result of different methodologies. Officials are assured that detection of the XMRV genome based on amplification of the number of copies present (PCR) is widely regarded as the best and most sensitive method available for this purpose.”

    Is it the Wellcome Trust and Greg Towers who are misleading them?

    Why is the Department of Health being fooled by these ridiculous people?

  6. I expand here on my previous post.

    Greg Towers’s statement is both highly misleading and scientifically inaccurate and therefore should be challenged. Before doing so however it is worth noting his comments that point to the fact that the four studies published in the same edition of Retrovirology attempting to prove contamination formed part of a collective enterprise!

    “We, and the other papers in Retrovirology, did indeed address one component of the research originally published in Science, namely that of PCR assays. However, this type of assay is used in all XMRV and CFS studies, is the most sensitive and when coupled with sequence analysis the most specific”

    Firstly a scientific analysis should have considered all of the components of the science study as well as all of the other available published evidence that does not support the belief that XMRV is a contaminant.

    His comment regarding PCR as the most sensitive method of detecting XMRV is objectively untrue and frankly laughable coming from someone who purports to be a scientist.

    “We regret that these authors did not request positive control samples of our patients who exhibit XMRV PCR products even when assayed by the least sensitive detection method, namely PCR of DNA from unstimulated PBMCs. Given that only 7% of our 101 patients’ PBMCs exhibit products upon DNA PCR” (6)

    The data presented by Mikovits (6) clearly demonstrated that the PCR assay is the least sensitive method for detecting XMRV, supported by Schalberg et al (1) Danielson et al (2) Arnold et al (3) and Urisman et al (4).

    The PCR method referred to by Dr Towers has never successfully detected XMRV, yet by saying that it is used he implies it is successful. There is no such thing as a type of PCR assay. The conditions used in the Lombardi study were highly specific and also involved biological amplification (5).

    Towers’ comment is a clear misrepresentation of the facts. None of the studies addressed any of the evidence demonstrating that XMRV is not a contaminant.

    Towers carried out a Baysian analysis which does not produce objective scientific evidence so he can’t know anything based on the one line of evidence he used. Baysian evidence is a mixture of data and opinion and the relevant evidence is based on that prexisting opinion. A correctly performed Baysian analysis requires the input of all available evidence and not just one line, as  used in this study. Greg Towers, by using a Baysian analysis, strengthened his pre-existing belief that XMRV is a contaminant by inputting data into a Bayesian computer simulation appertaining to the one line of evidence which could conceivably be interpreted by him to be evidence of contamination. He ignored all other lines of evidence to the contrary. The “evidence” that he did input could equally have been interpreted as evidence against contamination.

    Now engaging in this activity could be described as many things but engaging in the scientific method is not one of them.

    Supplying such a misleading, scientifically inaccurate statement in defence of the study merely compounds the felony!

    1) Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR: XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Proc Natl Acad Sci U S A 2009, 106:16351-16356.

    2) BP Danielson, GE Ayala and JT Kimata; Detection of Xenotropic Murine Leukemia Virus-Related Virus in Normal and Tumor Tissue of Patients from the Southern United States with Prostate Cancer Is Dependent on Specific Polymerase Chain Reaction Conditions; J Infect Dis. (2010) 202 (10): 1470-1477. doi: 10.1086/656146

    3) Arnold RS, Makarova NV, Osunkoya AO, Suppiah S, Scott TA, Johnson NA, Bhosle SM, Liotta D, Hunter E, Marshall FF, et al: XMRV infection in patients with prostate cancer: novel serologic assay and correlation with PCR and FISH. Urology 2010, 75:755-761

    4) Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, et al: Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog 2006, 2:e25.

    5) Lombardi, V.C.; Ruscetti, F.W.; Das Gupta, J.; Pfost, M.A.; Hagen, K.S.; Peterson, D.L.; Ruscetti, S.K.; Bagni, R.K.; Petrow-Sadowski, C.; Gold, B.; Dean, M.; Silverman, R.H.; Mikovits, J.A. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009, 326, 585-589.

    6) JA Mikovits, VC Lombardi, MA Pfost, KS Hagaen and FW Ruscetti; Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome; Virulence; Volume 1, Issue 5 2010 pp 386-390
    DOI: 10.4161/viru.1.5.12486

  7. Well I can’t argue with that – or endorse it – as I don’t understand most of it.

    I don’t think anyone should criticise the MEA for simply posting a statement by the way. Just because they do so without comment does not mean it in any way reflects their views.

    You know most of this internet chatter about XMRV and the WPI leaves me behind as a sufferer. I just cannot understand it.

    How about thinking of the sufferer every once and a while and summarising things or speaking plain english so that ‘we’ stand a better chance of understanding?

    My comment is not directed at anyone personally on this forum but has been made by me and others elsewhere too.

    Thanks muchly

  8. Sorry about the technical nature of the earlier post

    basically Greg Towers carried out a computer simulation using something called a baysian programmeto predict the likelyhood of XMRV being a contaminant. Now there are about fifteen sources of evidence that cant be explained if XMRV is a contaminant.There is one source which could be interpreted either way. Greg towers and co decided to interpret this one source of evidence as evidence of contamination and inputted that opinion into the computer as established fact and left out all the other evidence completely. It is hardly suprising then that this programme once run predicted that XMRV is a contaminant.We are familiar with the rubbish in rubbish out syndrome. In this case the rubbish is also created by the evidence which was initially left out! This is rather equivalent to a company using such a programme to predict how a new plane of a competitor company will perform and “forget” to imput the fact that it has wings!

Comments are closed.

Shopping Cart