XMRV and CFS – It’s not the end

Yesterday the Chicago Tribune published my reaction to the four papers on the retrovirus XMRV published this week in the journal Retrovirology. I was quoted as saying “These four papers are probably the beginning of the end of XMRV and CFS”. I wish to retract this statement and explain my reasons for doing so.

Early Monday a reporter for the Chicago Tribune, Trine Tsouderos, sent an email asking for my thoughts on four XMRV papers that had just been released (paper one, two, three, four). I read all four papers and decided that they raised serious concerns about the role of XMRV in human disease. Specifically, the four papers demonstrated different ways that assays for XMRV could be subject to contamination with murine viral sequences. I wrote an email to Ms. Tsouderos outlining my summary of the papers, and later that day her article was published. My statement was reproduced exactly from the email I had sent her, so I was not misquoted.

I then set out to write about the papers for my blog about viruses. I read the papers over again, and began checking XMRV sequences in Genbank. I also began an email correspondence with authors of three of the four papers, and spoke with my virology colleagues here at Columbia. As a consequence of this additional research I decided that my initial impression of the papers was incorrect, which is evident in my post entitled ‘Is XMRV a laboratory contaminant?‘. Almost immediately after publishing the piece readers began to ask why my comments to the Chicago Tribune had such a different tone. I concluded that a retraction and explanation were necessary.

Upon re-reading three of the four Retrovirology papers it became clear to me that they show that identification of XMRV can be fraught with contamination problems, but they do not imply that previously published studies are compromised by these findings. Clearly any new studies done on XMRV should keep in mind the potential for contamination from PCR kits and murine nucleic acids.

I was initially more troubled by the fourth paper by Hue and colleagues. There are four major findings in this paper (gag PCR primers are not specific for XMRV; the virus is present in 5 human tumor cell lines; two XMRV isolates are nearly identical to a virus from the human prostate cell line and also contain an insertion from the murine retrovirus MoMLV; and there is more nucleotide diversity in viral sequences from 22Rv1 cells than in all the patient XMRV sequences). The fact that two XMRV isolates seem to be laboratory contaminants – judged by the presence of MoMLV sequences – was initially unsettling until it became clear that other XMRV isolates do not have this insertion. That leaves the fourth finding – that XMRV from 22Rv1 cells appears ancestral to, and more diverse than, all the human XMRV sequences. I decided that this result was less troublesome than I had originally believed, in part because it is not clear that the differences among the 22Rv1 viruses did not arise during PCR amplification.

My conclusion is that these four papers point out how identification of XMRV from human specimens can be complicated by contamination, but they do not mean that previous studies were compromised. They serve as an important reminder that future experiments to identify XMRV need to be appropriately controlled to ensure that the results are not compromised by contamination.

In other words, these four papers are NOT the beginning of the end of XMRV and CFS. Rather, research on the role of this virus in human disease must proceed, with large, case-controlled epidemiological studies, as suggested by others.

I would like to apologize to anyone who was offended, angered, or disappointed in any way by my statement to the Chicago Tribune. It is my goal to educate the public about virology, and clearly I did not do that very well.

There are at least two lessons that you can take away from this incident. First, that I make mistakes, and that I’m willing to admit it. Everyone does, including scientists. Second, if I had difficulties interpreting these papers, how would non-scientists fare?

Comments on this entry are closed.

  • Fwong52 23 December 2010, 5:21 pm

    Thank you, Dr. Racaniello, for your courage and integrity!

  • H Goodwin 23 December 2010, 6:20 pm

    All press releases going to the media in the UK have to be approved and vetted by the UK Science Media Centre, on which sits Professor Simon Wessley, the man who has successfully persuaded most of the medical and scientific establishment in the UK to believe ME/CFS is psychosocial, not biological, in origin.

    This is why the UK media carry so little coverage of any progress on biological research. As anyone who has been in PR and media for more than 5 minutes could tell (and I have been in that industry for 26 years) this is a fine example of issue hijack – co-ordinating the carefully-timed release of various pieces of information and its appropriation to support a specific, political cause. This is the best example I’ve seen since the ‘dodgy dossier’.

  • H Goodwin 23 December 2010, 6:27 pm

    Many of the UK news providers take their feed from Reuters – hitting them with some hard truths on this story could do no harm at all.

  • Cort 23 December 2010, 6:35 pm

    Well Gob987 I hope you’re right. I think you might agree, though, that the research community is unsure (hence Dr. Racaniello’s retraction) and some researchers taking sides. You might also agree that we want to get beyond this state we’re in and I really think you should because there will be treatment trials or studies on causation until the research community comes to a consensus. So my questions are – how does the research community get beyond this muddle its in? Wow do we move on? Hopefully to the place where XMRV is accepted….

  • Margaret 23 December 2010, 6:39 pm

    Thank you for the retraction, but please take care with quotes in the future. Headlines create perception, perceptions become unshakable truths, and news travels fast, far and oft times twisted.

    Found this today.

    Iran headline; “Chronic fatigue syndrome not caused by XMRV virus, study finds.”
    http://www.tehrantimes.com/Index_view.asp?code=232661

  • Omerbasket 23 December 2010, 7:15 pm

    I would still like your answer, Dr. Racaniello, for the following question: Why do you host in your TWiVs Allan Dove – the one who told ME/CFS patients to try not to fall of the balcony? Would you host a person that said such a thing about AIDS patients? About cacner patients? About diabetes? About Crohn’s Disease? About Parkinson?

    I find it very irritating that you did not make a comment about that stuff, which appeared in two of my previous comments (on this post and on the former post).

  • Anonymous 23 December 2010, 7:47 pm

    Researchers are not taking sides, they are conducting science, that is the only way to advance the discussion. The Wellcome Trust however are taking a side in order to halt research.

  • profvrr 23 December 2010, 8:00 pm

    Please remind me on which show Alan made that comment. I believe we
    have all made inappropriate comments one time or another. I don’t want
    to control what people say – I don’t want to censor them. In the long
    run (covering all of virology) Alan makes an important contribution,
    providing the journalistic viewpoint that none of us have. And don’t
    be irritated if I don’t answer your questions – I can barely get to
    the science questions.

  • Anonymous 23 December 2010, 8:03 pm

    And the Wellcome Trust would not have put out that press release unless they had the blessing of the MRC who co-authored Hue et al.

  • Alan Dove 23 December 2010, 8:04 pm

    Thanks for taking my comment completely (and I suspect willfully) out of context, Omerbasket. Those who’d like the backstory can read an archived version of the blog post Omerbasket is referring to at http://alandove.com/content/2010/08/xmrv-cfs-and-the-nature-of-science/ and make up their own minds.

    The actual meaning of my statement, taken in context, was “don’t take drastic actions based on insufficient evidence.” I stand by that advice.

  • Anonymous 23 December 2010, 8:29 pm

    Why on earth would you ever say that anyway?

  • profvrr 23 December 2010, 8:32 pm

    Here is the original statement: “A postmodernist can scream until he’s
    blue in the face that the Newtonian frame of reference is just one of
    many equally legitimate world views, and that non-Newtonian claims to
    reality have just as much validity. Nonetheless, if he steps off a
    tenth-floor balcony, he will accelerate downward at 9.8 meters per
    second per second (minus air resistance). It works every time.” The
    point is that some laws of science, such as gravity, are readily
    apparent; he used jumping off a balcony as an example. Even if you
    don’t believe in gravity, if you jump off a high place, you will
    accelerate at a rated calculated by Newton. It had nothing to do with
    ME/CFS.

  • Anonymous 23 December 2010, 8:42 pm

    Why does Alan now suggest it was about ME?

  • determined 23 December 2010, 9:01 pm

    Thank you for the link, Dr. Dove. I’m glad you realize that a handful of “belligerent jerks” do not represent us.

  • lancelot 23 December 2010, 9:05 pm

    Alan Dove i just read your article and it is very offensive. saying that CFS could be a psychiatric cause is as plausible as a psychiatric cause to AIDS, diabetes, heart disease, or MS. There is no doctor or researcher in the United States today saying that except for the 2 CFS directors who were fired at the CDC. You are more than 20 years behind and shall i say, IGNORANT still. You need to learn everything you can about ME/CFS before you speak again and try not to learn it from your psychiatric wife! Geez, who the heck are you to talk about ME/CFS in this way?

    Educate yourself and be a friend to the CFS community like other journalist- amy dockser marcus and hillary johnson.

  • Guest 23 December 2010, 9:10 pm

    I’m afraid this comment by Alan Dove perfectly illustrates the problem, Dr. Racaniello. Mr. Dove’s sneering attitude to these patients offends even those of us who are non-patient observers and regular readers of your fine science blog. I am disappointed in his outburst here. He cannot seem to help himself. The best advice here would be to keep him far away from your blog posts and videos on this XMRV subject.
    I assume, and hope, Mr. Dove is not an academic in the classroom, as the power differential that one learns to navigate as a lecturer appears to be lost on him. Like the great imbalance in power between students and teachers, there is a chasm in the power and resources of we who are healthy and can walk away from this battle and enjoy our lives, and those who are weakened and torn down by long chronic illness, particularly this evidently-much-abused patient population. It is unseemly and deeply offensive to see Mr. Dove continue to taunt this ill population that has manifestly been long-abused by a neglectful and disrespectful medical community. To repeat – Mr. Dove should be prohibited from addressing XMRV topics (and baiting patients) – particularly during the holiday season.

  • Laurence Swift 23 December 2010, 9:12 pm

    It may well have been Greg Towers who bluntly stated that XMRV does not cause M.E. There was someone else – Prof Peto? – who said much the same. But all 4 papers were lumped together and all get tarred with the same brush.
    They all used the inappropriate DNA/PCR methodology, and we all know from reading the original Lombadi et al paper that you need to do more than this – you absolutely need to culture the virus. This is what I don’t understand – they should all have done their homework much better and read all the WPI work, then there would have been no point in producing these papers, as everyone is well aware of the dangers and ease of contamination using only PCR tests.
    Personally i think they were mostly aiming to rubbish the Lombardi etc work in the eyes of the public by getting these negative headlines all over the papers.

  • dawker 23 December 2010, 11:14 pm

    There was the start of a discussion with Alan Dove here, but it doesn’t look like it got very far: http://forums.aboutmecfs.org/showthread.php?6902-Alan-Dove-responds-to-his-XMRV-CFS-ME-critics…-from-TWIV-podcast../page17

  • Anonymous 23 December 2010, 11:42 pm

    Peto is working on the PACE Trial. That tells us everything

  • Anonymous 23 December 2010, 11:47 pm

    Oh come off it. That family have put millions into research for this disease, because their own daughter is sick. The money that the WPI raises goes back into research. That comment is a distraction from the real issue, which is where is their research leading us.

  • Anonymous 23 December 2010, 11:48 pm

    The Wellcome Trust press release was not certain, it was propaganda.

  • Anonymous 23 December 2010, 11:52 pm

    They didn’t this time, they took everything from the Wellcome Trust press release, almost verbatim. Even the BBC has now altered it’s article from ME ‘not caused by the XMRV virus’ to ME, or chronic fatigue syndrome, ‘not caused by the XMRV virus’, say researchers. In the previous article there was also no comment from Mikovits or Shepherd, so it was a very one sided piece of propaganda.

  • Anonymous 23 December 2010, 11:54 pm

    The man that 22Rv1 is from was probably infected with an earlier version of the retrovirus.

    Doesn’t everything have a genetic component.

  • Anonymous 23 December 2010, 11:59 pm

    You deleted my previous comment – no idea why, so I will try again.

    ME is not considered a mental health disease, it never has been. There is abundant evidence of the faulty biology at work in these patients, even if the cause is not known. Just as it is for MS or Parkinson’s. There is no need to take your point of view from idle gossip.

  • Anonymous 24 December 2010, 12:21 am

    I don’t think Alan tried to discuss anything. He posted his opinion, that’s all.

  • retrovirus likely 24 December 2010, 7:27 am

    No no, this is what it said:

    “I can’t stop thinking like a scientist, and won’t stop speaking and writing like one. What I will try to stop doing is arguing data against people whose objections rest on emotion. You’re entitled to your beliefs. Just try not to step off any balconies.”

    Alan Dove is NOT thinking like a scientist. He is the one thinking on emotions. His emotions tell him CFS is probably psychological. His emotions tell him ART therapy for CFS is ridiculous. He is utterly ignorant on what CFS even is and will not be capable of thinking like a scientist on the issue until he educates himself, and he has demonstrated that he does not wish to do that.

  • retrovirus likely 24 December 2010, 7:44 am

    12

  • retrovirus likely 24 December 2010, 7:46 am

    CFS, retrovirus, HIV

    Why do some of my posts get deleted instantly?

  • retrovirus likely 24 December 2010, 7:47 am

    “[CFS] is an acquired immune deficiency syndrome and we are presently searching for evidence of retrovirus infection in our patients.”

  • Receptor 24 December 2010, 9:40 am

    Could we please come back to topic?!

    This blog has some unique feature. We not only have experts and people who are interested in virology from all over the world here but we also have affected patients who could suffer from a virus. Instead of fighting each other we should use our energy to answer the most important question:

    Is XMRV pathogenic and does it infect humans?

    Answering this question is why many people are here and why many people get emotional about it. If I had HIV and the people I am dependent on would tell me that I have a psychological disorder and through that would deny not only treatment but also further research I could not stay calm either. So we need to answer this question.

    I’m quite sure that if Prof. Racaniello would need some computational power, thousands of people would instantly provide theirs for grid computing. Many people are willing to spend time and effort to answer the XMRV question but unfortunately there is currently no way to do so. It seems that scientific discussion is the only thing possible right now. Other people will have to do the job of verifying it.

  • Anonymous 24 December 2010, 11:43 am

    That does sound familiar. Which TWiV episode was it?

  • dawker 24 December 2010, 5:22 pm

    They don’t have to be. That’s not to deny the influence the SMC has over the UK media’s reporting of science, but it’s influence not control.

    The way the SMC has covered XMRV has been strange (news of the Alter paper was broken with a comparison to the scare over MMR and autism), but reporters don’t need to follow that line if they don’t want to.

  • Anonymous 24 December 2010, 8:43 pm

    The majority of patients have not put all their eggs into one basket. They are supporting a group who are looking for the cause, whatever it is. And the WPI were clearly not premature in publishing their paper. Furthermore, they have never brushed the idea of contamination to one side, and have always provided samples for others to test. Including the CDC, who tested 20 of them, and found no contamination. John Coffin has had samples from the WPI he could have tested, but has not. And the NCI also has samples that they are testing for contamination using Coffin’s method. So they cannot be described as trying to brush anything under the carpet. The research is progressing as it should. But it is the Wellcome Trust and Towers who want the scientific process to be different.

  • forgsquire 24 December 2010, 10:51 pm

    Does Greg Towers wish he could withdraw his comments? As an author of one of the papers his comment would have been made with months of contemplation. It was calculated, not due to an initial quick read, and I am sure he will never retract his remarks.

    However, I suspect the comment from Dr Racaniello that “I am certain that he also wishes he could
    retract his statements” is as close as a scientist can politely come to saying that Greg Towers is an utter fool.

    Regarding Ms. Tsouderos, all she had to do was to contact Dr Alter, Lo, or Mikovits, but yet she chose to print what she wanted to hear as soon as she could. She is as culpable as anyone for the error, more so considering that she has a duty to make sure the public hears the balanced truth and not biased or incorrect stories. We are all responsible for our actions, “he told me to do it” has never been an acceptable excuse.

  • Renee Richmond 26 December 2010, 9:20 pm

    Yes, anyone can make mistakes and in my experience, it is rare that someone in your line of work is willing to admit theirs. Thank you. If we are to take your apology sincerely, you will clearly be one of the major players in this arena with the abilities to see this thing through to fruition. Ultimately, only those who are truly committed to unraveling this mystery, above fame and fortune and all else, who are able to ‘bend’ and keep an open mind will lead us to our destiny. It is my hope that you are indeed one of these committed ones and we see you at the finish line.

  • Christina 26 December 2010, 10:26 pm

    I recently defended comments you made on this issue in another venue. I must tell you, after following your suggestion to read what you have linked above, I am now sorry that I did. I clearly did not have all the facts.

    Following the piece you linked were some very intelligent and thoughtful comments from readers including what I thought was a rather astute analysis, from a woman named Kim, to whom you replied:

    “Kim, regular TWiV listeners already know what my wife does for a living. You’re the only loser who had to waste three hours Google-stalking me to figure it out. Here’s to your future graduation from the eighth grade.”

    You are clearly not in control of your temper. There was nothing in her comment to suggest that she had googled you much less was “Google-stalking” you. Forgive me but I can think of no other word way to describe your reaction: you seemed more than a bit hysterical.

    Following this comment you write the following while describing ME patients: “belligerent jerks” and “screamers”.

    This follows a post in which you bemoan your fate: “I can’t stop thinking like a scientist, and won’t stop speaking and writing like one.” Well, sir, I think you managed to do all of the above: you stopped thinking like and writing like a scientist in one fell swoop. How can any trust your ability to regain your ability to think when you can so easily lose it?

  • Christina 26 December 2010, 11:18 pm

    Thank you, Professor, for your intellectual courage. You are a man of integrity.

  • Science_based 28 December 2010, 2:51 am

    I’d like to join the chorus of voices expressing appreciation and admiration for your refreshing integrity in following the facts, not the spin on XMRV. Regardless of whether XMRV proves to be causal in ME/CFS, we need to get to the bottom of this devastating disease that is literally destroying lives. And we need to fully investigate any and all disease associations with XMRV. Publishing a retraction on flawed conclusions that could stymie the pursuit of knowledge on XMRV is the ultimate expression of integrity.

    I do have to challenge you though on your final comment though: “If I had difficulties interpreting these papers, how would non-scientists fare?”

    While many of us are not medical professionals or scientists, the reality is that many of us also ARE. It’s simple math; 1 million Americans are believed to have ME/CFS. By simple logic, there are virologists, physicians, lab scientists… or mothers, fathers, sisters, and brothers of them, in this mix.

    So it should be no surprise that this patient community would have thousands of potential subgroup of XMRV scientists are blinkered by politics.

    The issue is not that patients are taking on airs by daring to educate themselves on retrovirology. It’s that fully-fledged virologists are allowing their political bias to smother their scientific impartiality. I shudder to think what kind of a toehold propaganda would gain, if we didn’t have the internet, and the voice of genuinely educated patients in this debate.

  • Science_based 28 December 2010, 2:55 am

    Correction: 4th paragraph of my prior post should read:

    So it should be no surprise that this patient community would have thousands of potential advocates who are both able to understand the science – and able to smell a rat – when so-called scientists are blinkered by politics.

  • Carolclifford 29 December 2010, 3:47 pm

    If results were caused by contamination why were healthy blood samples contaminated at a lower percentage? Your explanation is greatly appreciated.

  • Suze B 29 December 2010, 4:49 pm

    Actually, if you follow the money, you get Simon Wessley! He’s been making sure that all money directed to ME/CFS research goes to research studies he thinks are interesting and anything resembling an experiment to investigate the physiological basis for ME/CFS gets nil.

  • Erica Suichman 29 December 2010, 7:41 pm

    Thank you for your careful analysis of this complicated literature. I for one commend you for being brave enough to publically retract your initial responses. I think it is incredibly educational to non-scientists to understand that science is a process that requires much thinking, and that scientists don’t always agree, and often change our minds based on discussion with other scientists and/or more thought on a topic. So I thank you for doing such a nice job of articulating your thought processes in changing your mind. Erica

  • Dt201 30 December 2010, 9:21 am

    Does it not seem strange to you that the commercial arm of the Mikovits enterprise has been promoting and performing expensive PCR tests to “diagnose ME” on patients? Where do you think this money goes?
    Are any of these tests reliable, in the light of the new PCR contamination findings? Tell me, has Mikovits decided to reanalyze all their “positive” commercial diagnostic test results using their other methodologies, just to confirm none of their own tests are potentially contaminated? If not, why not?
    The WPI might be a very altruistic enterprise only interested in getting to the bottom of what causes ME, but the road to hell is paved with good intentions as they say.

  • Dt201 30 December 2010, 5:57 pm

    That would be Wessely, actually.
    And I disagree. Research money clearly goes into his research unit.
    But I don’t see him promoting his treatments as scientific on the one hand, while also setting up a private diagnostic or CBT therapy unit which charges ME sufferers vast sums of money for his services, which then goes into his back pocket.

  • a.scientist 31 December 2010, 12:23 am

    Perhaps the patient samples in the Lombardi study were contaminated due to different storage/processing?

  • a.scientist 31 December 2010, 12:37 am

    Actually, the psychiatric explanation has always been the ‘default’ explanation for the illness, at least in the UK, and (in my own experience) most UK doctors believe that it is psychiatric in origin.

    Currently the evidence for psychiatric causation appears to be stronger than for any kind of biological cause, including XMRV. The fact that there are ‘physical abnormalities’ does not exclude a psychiatric cause.

    Many CFS patients do indeed have a very strong bias against any type of psychiatric explanation for their illness, and whenever anyone tries to have a rational scientific discussion about psychiatric causation there is always a very vitriolic response from CFS patients.

    Alan’s response on his blog was certainly barbed, but no more so than Kim’s comment who he was replying to: “Here’s to your future exposure as a hack, and your wife’s future exposure as a quack.”

  • Anonymous 2 January 2011, 7:52 pm

    Sorry, but I have no idea where you have been getting your information from. Really puzzling.

    ME/CFS was first approved for entry into the WHO in 1965, and was entered in 1969, as a neurological disease. Where it remains to this day. The UK Government for many years now has repeated that it accepts this classification. Therefore the neurological, non psychiatric explantation is the ‘default’. Now, unfortunately due to lack of funding, psychiatrists have been educating others that this isn’t true, and that’s led to many tragic stories.

    The evidence for a psychiatric cause is pretty much non-existant. It is all theory. Whereas there are thousand of papers on the underlying biology. Prejudice doesn’t change this either.

    Many psychiatrist and those unwilling to educate themselves beyond prejudices and bigotry will naturally deny the existence of these studies, but there they are. Now, I’m sure you could make a psychiatric explanation appear rational if one felt it acceptable to deny the existence of said papers. And likely the attempt to use dangerous supportive ‘treatments’ would become the norm, except when faced with those who are educated in the disease. Yes there are many doctors, researchers, careers and patients who fit this description. They will all fight to stop others from ignoring the biology and causing irreparable harm to those people with ME/CFS. Then again you could be referring to the symptom chronic fatigue, which is only a symptom of diseases like MS, ME/CFS, cancer, or even psychiatric disorders like major depressive disorder. So perhaps again, you have heard wrong. I can provide sources if you like to all of the above.

    One person responding to Alan or that of Kim, does not affect any of the above, unless you have a interest in denying the facts.

  • a.scientist 3 January 2011, 7:45 pm

    The evidence for psychiatric causation includes the fact that stress is the most common precipitating factor and CBT is the only treatment that has been proven to work. The biological evidence doesn’t preclude a psychiatric origin – after all, every psychiatric illness also has a biological component. Many (all?) of the biological signs are also typical of psychiatric/stress-related illness as well – disturbed immune system, abnormal HPA axis and autonomic nervous system, brain fog, pain, etc.

    My ‘default psychiatric’ comment was in regard to the fact that UK government experts and CFS researchers such as Simon Wessely believe CFS to be psychiatric, and also the fact that CFS used to be known as ‘yuppie flu’ back in the 80s (implying that it is the same as burnout).

  • Anonymous 4 January 2011, 1:01 am

    Perhaps everything is contaminated. Still not evidence