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Chronic Fatigue Syndrome is not caused by XMRV

20 Dec, 2010

Test-tubes for blood samples

Test-tubes for blood samples

New research shows XMRV virus is a lab contaminant.

A virus previously thought to be associated with chronic fatigue syndrome is not the cause of the disease, a detailed study has shown.

The research shows that cell samples used in previous research were contaminated with the virus identified as XMRV and that XMRV is present in the mouse genome.

XMRV was first linked to chronic fatigue syndrome – also known as myalgic encephalomyelitis (ME) – in a study published in October 2009, where blood samples from chronic fatigue syndrome patients were found to have traces of the virus. XMRV had also been identified previously in samples from certain prostate cancer patients.

The new study, published in Retrovirology, identifies the source of XMRV in chronic fatigue syndrome samples as being cells or mouse DNA rather than infection by XMRV. The research does not rule out a virus cause of chronic fatigue syndrome – it is simply not this virus.

The research team developed improved methods to detect XMRV against the genetic noise of other sequences and make recommendations for future study of virus causes of human disease.

“Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome,” says Professor Greg Towers, a Wellcome Trust Senior Research Fellow at University College London (UCL). “All our evidence shows that the sequences from the virus genome in cell culture have contaminated human chronic fatigue syndrome and prostate cancer samples.

“It is vital to understand that we are not saying chronic fatigue syndrome does not have a virus cause – we cannot answer that yet – but we know it is not this virus causing it.”

The team, from University College London, Wellcome Trust Sanger Institute and University of Oxford, showed clearly that the experimental design of previous studies would pick up sequences that resembled XMRV; however, in this improved study, they could prove that the signal was from contamination by a laboratory cell line or mouse DNA. The sequences from the contaminated cell line and chronic fatigue patient samples were extremely similar, contrary to the pattern of evolution expected during the infectious spread of a virus in a human population.

They also showed that the existing methods would indicate that one in fifty human cell lines they examined were infected with XMRV-related viruses: they showed that contamination of human tumour cells with XMRV-related viruses is common and that a principal prostate cancer line used is contaminated.

“When we compare viral genomes, we see signs of their history, of how far they have travelled in space or time,” says Dr Stéphane Hué, Post Doctoral Researcher at UCL. “We would expect the samples from patients from around the world, collected at different times, to be more diverse than the samples from within a cell line in a lab, where they are grown under standard conditions. During infection and transmission in people, our immune system would push XMRV into new genetic variants.

“Viral infection is a battle between the virus and the host and XMRV does not have the scars of a virus that transmits between people.”

Together the results demonstrate that XMRV does not cause chronic fatigue syndrome or prostate cancer in these cases. The team’s methods suggest ways to ensure that virus contamination does not confound the search for a cause of disease in future work.

The authors propose that more rigorous methods are used to prevent contamination of cell and DNA samples. They also suggest that consistent and considered standards are needed for identifying viruses and other organisms as cause of a disease.

“Increasingly, we are using DNA-based methods to accelerate our understanding of the role of pathogens in disease,” explains Professor Paul Kellam, Virus Genomics group leader from the Wellcome Trust Sanger Institute. “These will drive our understanding of infection, but we must ensure that we close the circle from identification to association and then causation.

The strongest lesson is that we must fully use robust guidelines and discriminatory methods to ascribe a cause to a disease.”

Notes to Editors

Chronic fatigue syndrome
Chronic fatigue syndrome (CFS) is also known as myalgic encephalomyelitis (ME). CFS is characterised by long-term tiredness or fatigue that affects the everyday life of patients. There is no known cure for CFS.
For more information, visit: http://www.nhs.uk/Conditions/Chronic-fatigue-syndrome/Pages/Introduction.aspx

Publication Details
Hué S, Gray ER, Gall A et al. (2010) Disease-associated XMRV sequences are consistent with laboratory contamination. Retrovirology. Published online before print.

Participating Centres

  • MRC Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London, United Kingdom
  • Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
  • Department of Zoology, University of Oxford, Oxford, United Kingdom

About UCL (University College London)

Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. UCL is among the world’s top universities, as reflected by performance in a range of international rankings and tables. Alumni include Marie Stopes, Jonathan Dimbleby, Lord Woolf, Alexander Graham Bell, and members of the band Coldplay. UCL currently has over 13,000 undergraduate and 9,000 postgraduate students. Its annual income is over £700 million.

The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.

Contact details

Don Powell
Press Officer
Wellcome Trust Sanger Institute
Hinxton, Cambridge, CB10 1SA, UK
Tel: +44 (0)1223 496 928
Mobile: +44 (0)7753 7753 97
Email: press.officer@sanger.ac.uk

Craig Brierley
Senior Media Officer
Wellcome Trust
Tel: +44 (0)20 7611 7329
Mobile: +44 (0)7957 468218
Email: c.brierley@wellcome.ac.uk

Ruth Howells
Media Relations Manager
UCL Corporate Communications
Gower Street, London, WC1E 6BT, UK
Tel: +44 (0)20 7679 9739
Mobile: +44 (0)7990 675 947
Email: ruth.howells@ucl.ac.uk

UCL out of hours contact: 07917 271 364

End of Notes to Editors

19 Comments leave one →
  1. 20 Dec, 2010 11:46 pm

    A far more balanced view on this topic has been posted here:

    http://blogs.wsj.com/health/2010/12/20/xmrv-raising-the-issue-of-contamination/

  2. KAL permalink
    21 Dec, 2010 12:06 am

    Not everyone believes the studies support Dr. Tower’s conclusions including other authors of the papers published today.

    According to the WSJ, John M. Coffin, a retrovirologist and a co-author of another of today’s Retrovirology papers, told Health Blog that while his group’s study demonstrated that mouse DNA is everywhere in labs, none of today’s published papers ”definitively show that any prior study is wrong.”

    Robert A. Smith, a research assistant professor at University of Washington in Seattle who wrote a commentary in Retrovirology summarizing the studies, told Health Blog that the possibility of contamination means that future studies must be done very carefully before conclusions about disease association are made. But he said he is unwilling to state that the reported link between XMRV and CFS or prostate cancer is no longer viable.

    So without conclusive proof either way, scientists are back to the drawing board knowing a bit more than when the last round of opinions were given.

    • oregano permalink
      22 Dec, 2010 6:42 pm

      Saying that “future studies must be done very carefully” has the embedded inference that the past studies were not done carefully.

      It’s a thinly veiled insult at those scientists who have, very carefully, found the MLVs and XMRV in their very well done studies. All the scientists at WPI /NIH/Cleveland Clinic and those who did the Alter/Lo/Komaroff paper were and are aware of the possibility of lab contamination and have done what’s necessary to avoid it. They don’t deserve this condescending finger shaking.

      It’s only “back to the drawing board” for those who’s campaign it is to impugn every study that connects a viral cause to ME/CFS.

      I remember when McClure said she washed her hands of ME/CFS research, after declaring herself to be 1000% sure there was no XMRV in UK. Then UK patients had their freshly drawn blood tested in the US and at least 50% were found to be positive for XMRV. All that “lab contamination” is only in those samples tested outside UK labs which can’t seem to even find it even in the “contaminated” samples?

      This is a shell game. To what lengths will UK scientists go to stop the ackowledgement that ME/CFS is a viral disease?

  3. Joanne Drayson permalink
    21 Dec, 2010 9:57 am

    Statement from the Whittemore Peterson Institute regarding Retrovirology December 20,2010by Whittemore Peterson Institute on Tuesday, 21 December 2010 at 04:13

    The Lombardi et al. and Lo et al. studies were done using four different methods of detection. They were not simply PCR experiments, as were the studies by McClure et al. and others who have recently reported their difficulties with contamination. Experienced researchers such as Mikovits, Lombardi, Lo and their collaborators understand the limitations of PCR technology, especially the possibility of sample contamination. As a result, we and Lo et al. conducted rigorous studies to prevent and rule out any possibility that the results reported were from contamination. In addition to the use of PCR methodology, the Lombardi team used two other scientific techniques to determine whether, in fact, we had found new retroviruses in human blood samples. We identified a human antibody response to a gamma retroviral infection and we demonstrated that live gamma retrovirus isolated from human blood could infect human cells in culture. These scientific findings cannot be explained by contamination with mouse cells, mouse DNA or XMRV-related virus-contaminated human tumor cells. No mouse cell lines and none of the human cell lines reported today by Hue et al. to contain XMRV were ever cultured in the WPI lab where our PCR experiments were performed. Humans cannot make antibodies to viruses related to murine leukemia viruses unless they have been exposed to virus proteins. Therefore, recent publications regarding PCR contamination do not change the conclusions of the Lombardi et al. and Lo et al. studies that concluded that patients with ME/CFS are infected with human gammaretroviruses. We have never claimed that CFS was caused by XMRV, only that CFS patients possess antibodies to XMRV related proteins and harbor infectious XMRV, which integrates into human chromosomes and thus is a human infection of as yet unknown pathogenic potential.

    “The coauthors stand by the conclusions of Lombardi et al. Nothing that has been published to date refutes our data.” Judy A. Mikovits

  4. Kathy Parker permalink
    21 Dec, 2010 10:01 am

    This study does not show that cell samples used in previous research were contaminated with the virus identified as XMRV or that it is not associated with chronic fatigue syndrome.

    Lombardi et al did not use 22Rv1 cells in the detection of XMRV in ME/CFS patients and you do not show that any other studies had contamination. Your study says that IAP primers did not amplify sequences from LNCap cells which were used by Lombardi et al to culture virus from ME/CFS patients’ plasma. In Virulence and at the First International XMRV conference Lombardi et al “further detail the multiple detection methods we used in order to observe XMRV infection in our CFS cohort. Our results indicate that PCR from DNA of unstimulated peripheral blood mononuclear cells is the least sensitive method for detection of XMRV in subjects’ blood. We advocate the use of more than one type of assay in order to determine the frequency of XMRV infection in patient cohorts in future studies of the relevance of XMRV to human disease. http://www.landesbioscience.com/journals/virulence/article/12486/ They now use culture and antibody testing to find XMRV and related viruses.

    Your study does point out some of the pitfalls of PCR testing and possible points of contamination.

  5. 21 Dec, 2010 8:57 pm

    > http://www.bbc.co.uk/news/health-12041687
    > ME, or chronic fatigue syndrome, ‘not caused by the XMRV virus’, say researchers.

    Rubbish – there is NO negative proof, i.e. no proof that ME is NOT
    caused by XMRV.

    > A new study has cast further doubt on the idea that a virus called XMRV causes chronic fatigue syndrome.
    > US scientists linked the condition, also known as ME, to a mouse-like virus in 2009 after finding it in blood samples.
    > Now, UK experts say the discovery was a “false positive”, caused by cross contamination in the lab. “Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome,” said Professor Greg Towers, a Wellcome Trust senior research fellow at University College, London, who led the research.
    >
    > “It is vital to understand that we are not saying chronic fatigue syndrome does not have a virus cause – we cannot answer that yet – but we know it is not this virus causing it.”

    It is not possible to make this statement when there is every bit of evidence pointing in the direction that it IS.

    > XMRV (xenotropic murine leukemia virus-related virus) is a virus found in mouse DNA.

    No it isn’t. By DEFINITION, the word Xenotropic means that it dose NOT infect murine species. At least not the normal laboratory mouse, Mus musculus, aka the House Mouse and pet white mouse.

    > It was discovered in 2006, and was later found in samples from some patients with prostate cancer and chronic fatigue syndrome. This lead to suggestions that the virus might be the cause of these conditions.

    No-one had any problem with the concept that XMRV might cause at least some of the cases of prostate cancer. But mention ME (or CFS) and all hell breaks loose. And the WPI only claimed an “association”, never a cause.

    > A paper providing some evidence in support of a link between chronic fatigue syndrome and the virus was published in the leading journal Science last year.

    “Science” wouldn’t publish the paper without extremely stringent standards of proof. Which includes eliminating any faint possibility of contamination.

    > In the latest work, the team, from London and the University of Oxford, used DNA sequencing methods to study XMRV.
    > They say their evidence, published in the journal Retrovirology, shows the virus found in patient samples arose from laboratory contamination.

    Good. THEIRS might come from contamination. Let them sort that out. It kind of rubbishes all their experiments if they can’t keep the possibility of contamination out.

    And the “journal” Retrovirology is not proving to be very open-minded except where it wants to be. It’s not a “real” journal, just an online vehicle for getting your stuff published – which you have to pay for anyway.

    > What is more, they think it is unlikely that the virus could actually infect people.

    In which case, how come the WPI cultured it from ME patients, and multiplied the virus up in human white cell cultures? They even found it in a 25 year old frozen sample.

    > Professor Tim Peto, consultant in infectious diseases at the University of Oxford, said the original paper in Science came as a great surprise to experts.
    > “It came as a great surprise when XMRV was first suggested as being linked to chronic fatigue syndrome and it was imperative that further tests be done to see if the findings could be repeated,” he said.

    Why the surprise? Any ME patient would have been able to tell them that we had a virus. It just hadn’t been pinned down – yet. Everyone has been expecting this discovery for years.

    > “There have now been a number of attempts which have failed to find the retrovirus in other samples, .. ”

    - these “attempts” were all the quick & dirty, cheap & nasty, studies cleverly designed to NOT find XMRV, using techniques like the inadequate PCR … they never even found XMRV in healthy patients at the base level of 3 or 4 %.

    >”and this research suggests that in fact XMRV is probably a contamination from mouse DNA. These latest findings add to the evidence and it now seems really very, very unlikely that XMRV is linked to chronic fatigue syndrome.”

    So now that the WPI have, using some 5 different techniques, found XMRV in 98 or 99% of their ME patients – how can they deny a “link”? And the WPI have never claimed a causal relationship – in writing – but that firm link indicates this, to anyone of modest intelligence.

    Anyone who has read the obligatory tome “Osler’s Web” will know the facts. Dr Paul Cheney, around 1985, took some of his ME patients’ MRI scans to an MRI expert, who showed him a set of identical scans – from AIDS patients. (see the videos on YouTube). Maybe they hadn’t sorted out the retroviral origin of AIDS at that time, but the penny will have dropped later. So we then knew a retrovirus was involved.

    Then in 1991 the researcher Elaine DeFreitas actually found a retrovirus in her ME patients, even showed electron-micrographs of the virus inside mitochondria where they disrupt the mitochondrial function of producing energy in the cell – hence the weakness or fatigue felt by patients. She couldn’t continue with the research as her funding was promptly withdrawn. Then Elaine caught RSD, apparently a related neuro-endocrine-immune disease.

    With all the government institutions turning their back on the biomedical cause of M.E., it was left to the “private sector” to fill the deficit. The Whittemore family, with their daughter Andrea an M.E. patient, engaged retrovirology experts like Judy Mikovits and established a private research centre, the Whittemore-Peterson Institute (WPI). Judy already suspected a retrovirus was involved and set out to prove it to the high standards of Science magazine.

    The rest is history. The story has advanced well beyond the petty squabbling about the issue of contamination – this is a dead duck. Several ME patients have started on ART’s (anti-retroviral therapies) and are blogging about their experiences – most are improving but it takes time. The ART drugs are based on those developed for treating AIDS patients – successfully. However XMRV is not the same as HIV and it may be possible to develop special drugs for XMRV which will be more effective – if the drugs companies remove their collective skulls from their colons and get on with the job. With perhaps seventeen million people worldwide affected, this could
    be very profitable.

    • julian assange permalink
      17 Mar, 2011 12:23 am

      Apparently some commentators here ‘know’ that XMRV causes CFS. So I guess everyone can put down their pipettes and forget about it because no further investigation is necessary.

      Kudos to the Towers lab for sticking to scientific principles in the face of widespread online bullying. The vitriol that is emanating from some CFS/XMRV advocates is sickening. Every single article on the web that raises a nuance of doubt about XMRV as a human pathogen immediately becomes the target of angry, spiteful commentary and belligerent, half-baked refutations.

      The evidence against XMRV as a cause of disease is now overwhelming. If you have CFS, these XMRV fundamentalists are making life a whole lot worse for you. Why would anyone want to research this disease now they know they will be relentlessly pilloried for making the ‘wrong’ discoveries?

  6. oregano permalink
    22 Dec, 2010 6:08 pm

    ” CFS is characterised by long-term tiredness or fatigue that affects the everyday life of patients.” -quote from this (Wellcome’s) website.

    This trivializing bit of nonsense gives the lie to any scientific openmindedness Wellcome may try to claim. “Tiredness” has nothing to do with anything, scientifically speaking. Why not just admit you are a one cog in the propaganda machine for those in UK who want to disappear the viral disease, ME/CFS?

    The Canadian Consensus Criteria is the most accurate in describing ME/CFS and it lists 7 categories of symptoms and signs, of which debilitating, unrelenting fatigue not alleviated by rest is only one.

    Your obituary for WPI and the MuLVs, including XMRV, that they and Alter/Lo/Komaroff have found in ME/CFS patients is premature.

    Eric Klein, Cleveland Clinic reported this about 15 hours ago:
    “We have reported XMRV integration in fresh frozen prostate tissue taken directly from patients at radical prostatectomy that has never been put in tissue culture and believe this is solid evidence of authentic human infection . See Dong et al PNAS 2007 and Kim et al. J Virol 2008″

    An immune response is not provoked by “contamination”.

    I give your article 5 stars for “media blitz” effort; 0 stars for ethics, honesty and accuracy.

  7. Jane permalink
    23 Dec, 2010 9:21 am

    I’m afraid your article is incorrect. On Monday five papers were published consecutively in Retrovirology, a pay to publish paper, which showed only that the labs that produced the papers had contamination, and were unable to find the new human retrovirus, XMRV.

    The Cleveland Clinic, the National Institute of Health, Cornell University, the Whittemore Peterson Institute, the Federal Drugs Administration and the National Cancer Institute all have labs that can detect this family of Murine Leukemia related RetroViruses. Would such prestigious labs not take great care in their testing procedures?

    The labs finding the virus, unlike the labs producing the papers published last Monday, used antibody, culture, and two other methods. The labs that say it is all contamination used PCR alone.

    See the retraction of a similar article by Dr Vincent Raciniello, here: http://www.virology.ws/2010/12/22/xmrv-and-cfs-its-not-the-end/

  8. 5 Jan, 2011 4:13 pm

    Re. Oregano’s comment on Wellcome’s definition of ME (or CFS as they insist on calling it), well said!!! This definiton is so lame and far from reality it is laughable.

    And Greg Towers, I can assure you that a virus *does* cause ME. How do I know? Simple: I became ill with Coxsackie B4 in 1983 and never recovered. It would be nice if I knew what the actual mechanism was, and hopefully biomedical research will reveal this sooner rather than later.

  9. julian assange permalink
    18 Mar, 2011 5:26 am

    Apparently some commentators here ‘know’ that XMRV causes CFS. So I guess everyone can put down their pipettes and forget about it because no further investigation is necessary.

    Kudos to the Towers lab for sticking to scientific principles in the face of widespread online bullying. The vitriol that is emanating from some CFS/XMRV advocates is sickening. Every single article on the web that raises a nuance of doubt about XMRV as a human pathogen immediately becomes the target of angry, spiteful commentary and belligerent, half-baked refutations.

    The evidence against XMRV as a cause of disease is now overwhelming. If you have CFS, these XMRV fundamentalists are making life a whole lot worse for you. Why would anyone want to research this disease now they know they will be relentlessly pilloried for making the ‘wrong’ discoveries?

  10. 19 Mar, 2011 2:57 am

    Then what were they measuring at the WPI? 3.7% of something in the the healthy people and 67% of something in the sick people. Why would the sick peoples samples have more lab contamination? Greg Towers, Dr Stephane, for the love of god, explain this – give us your reasons why you think this is possible. Are you suggesting the that WPI was faked? If not, then what? Come on, go ahead and say it.

    - John

  11. wingfingers permalink
    21 Mar, 2011 1:20 pm

    Still have ongoing problems with my M.E. since Feb 1995. It’s now been
    found to be probably caused by a virus, which everyone really knew all
    along. A retrovirus, an RNA virus that splices itself into the actual
    DNA of your cells. It affects up to 250,000 people in Britain alone
    and is the biggest cause of children being absent from school.
    Thousands of people have lost their jobs, their marriages, their
    houses, and are dependent on state disability payments, a huge drain
    on Britain’s economy. But the Government won’t take it seriously. They
    could have saved the taxpayer MANY BILLIONS of pounds over the years,
    and we could have had tests for the virus, treatments, and possibly
    vaccines, by now, if they’d invested money in the necessary research
    20 or so years ago. It’s never too late to start now.
    Instead, the virus has been pinpointed by a small private foundation
    in the USA, started by a couple whose daughter has been a sufferer for
    years. The wealthy husband put up the cash and they employed
    experienced retrovirologists who had worked with HIV. They have done
    very careful research to extremely high standards, high enough to get
    their paper published in “Science” journal.
    Meanwhile, here in the backwater of Old Blighty, our Medical Research
    Council (MRC) has been persuaded by the psychiatric profession into
    promoting the idea that the disease is a mental one and has only been
    funding research into psychiatric treatments, like CBT, and GET which
    is detrimental, so we are now well behind the real world. This
    Government attitude has led to several deaths directly from the
    disease, from ME-virus heart failure, prostate & breast cancers and
    dozens of suicides.

    The Vet’s Tenet – Everything is caused by Something. Remember this!

    I attended an All-Party Parliamentary Group on M.E. at the House of
    Commons in December ‘09 and the star turn was the Health Minister, who
    stated that he has no power to dictate to the PCT’s (primary care
    trusts, local medical services), or to the MRC as to how it
    distributes its money to researchers! Incredible. So what exactly IS
    his job, if he has no control over anything anyway? All State research
    funding is channelled through the MRC, now dominated by the
    psychiatrists.
    One group of “researchers”, involving the psychiatrist Simon Wessely
    who selected the patients, recently published a paper saying they
    couldn’t find the virus at all. Even though it’s present in a lot of
    normal people. Surprise surprise. They completely refused to use the
    same techniques in the lab as the US group. They used PCR on its own,
    missing out the essential step of breeding it up in an appropriate
    tissue cell culture. Actually, they didn’t WANT to find it, as Wessely
    is a well-paid advisor to the insurance giant UnumProvident, who would
    like to retire with a good pension from them.

    The psychologisation of the disease has been good for the US insurance
    companies who can deny paying out for mental diseases, but this has
    been hoodwinking our Government, who have had to cough up for
    Disability payments and Carers’ Allowances instead, not to mention the
    loss to our economy of people who once were perfectly functional and
    working taxpayers. This raises the question of why we have to follow
    the US’ bad example when we have a much better health system already
    in place.

  12. wingfingers permalink
    21 Mar, 2011 1:42 pm

    Interesting that Greg Towers and even Simon Wessley are saying that they don’t think XMRV is the cause of ME(CFS) but it could be a different virus. Let’s think about it.
    1) The cause of ME has been known to be a retrovirus since 1985 when Dr. Paul Cheney showed MRI scans of his patients to an imaging expert, who responded by showing him identical scans from HIV patients. Unlike in other brain damage images, the white spots moved around in consecutive scans.
    (2) a retrovirus was found in ME patients in 1991 at the Wistar Institute by Elaine DeFreitas and her EM pictures show it inside the mitochondria.
    (3) the retrovirus XMRV had been found in 98 or 99 % of carefully selected ME patients by the WPI.
    Now, if XMRV is NOT the cause of ME – what is? We have to postulate that XMRV is a passenger virus and that there is another as-yet-undiscovered retrovirus which accompanies the XMRV in all, or at least, 98% of cases. How feasible is that? Even if were shown to be true, the same antiretroviral therapy would be appropriate.

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