The chronic fatigue virus: de-discovered?

By Carl Zimmer | May 31, 2011 10:41 am

One of the most important things that virus-hunters do is “de-discover” links between viruses and diseases. In other words, they follow up on studies that indicate a link and see if it can really hold up. Last year, a team of scientists published a paper in Science in which they reported that 67% of people they studied who suffer from chronic fatigue syndrome carried a virus in their system known as XMRV. Only 3.7% of healthy people did. That association then morphed into the idea that XMRV actually causes chronic fatigue (a condition that afflicts an estimated 60 million people worldwide). Some people with chronic fatigue have sought anti-viral medicines based on the finding, declaring that they’ve felt better as a result. But when a lot of other scientists tried to find XMRV, they failed to do so.

Today Science itself is publishing two papers that cast even more doubt on the link. In one study, scientists looked at 61 samples from the same medical practice where the original samples had come from. They couldn’t find any XMRV in people with chronic fatigue.

Another study supports what a lot of experts have been saying recently: that XMRV was not actually infecting the cells of people with chronic fatigue, but merely contaminated the samples once they were in labs. The researchers came to this conclusion through some evolutionary detective work.

XMRV was first discovered in 2006 in a line of human prostate cells, and since then it’s been reported to be present in 6 to 27% of human prostate cells. Before the link to chronic fatigue was claimed last year, some researchers argued that XMRV can also cause prostate cancer.

XMRV belongs to a family of viruses that infect mice and can sometimes even integrate their genes into their host’s genome. Yet Vinay Pathak of the National Cancer Institute and his colleagues could not find XMRV in mice. What they did find, however, were two previously unknown viruses that were strikingly similar to parts of XMRV. In fact, XMRV looks like a hybrid of the two viruses.

How could the viruses come together? And how could they end up in human prostate cancer cells? A crucial clue is the fact that scientists who study prostate cancer cell lines have to inject them into mice to keep them alive. They then “passage” the cells from one mouse to another. Pathak and his colleagues went back to the prostate cancer cells that scientists reared in mice in the early 1990s and couldn’t find XMRV. But they did find one of the two precursor viruses. Only in later generations of the cancer cells did they find true XMRV.

The scientists concluded that as prostate cancer cells were injected in mice, viruses migrated from the mice to the cancer cells. Then the viruses were carried to the next mouse inside the cancer cells.  At some point during these passages, two different mouse viruses recombined in the human prostate cells to produce XMRV. Thus, rather than being a virus that naturally circulates in humans or mice (or both), XMRV is a virus that emerged in human cell cultures in labs and can contaminate samples that scientists bring into their labs.

These two papers have prompted Science editor-in-chief Bruce Alberts to publish an expression of concern.” He writes that the initial findings of an XMRV-chronic fatigue link are “now seriously in question.” Amy Docker Marcus of the Wall Street Journal reports that Science asked the authors of the initial study to retract the paper, but they’re not backing down.

The next (and perhaps final) stage in this saga will come in the next few months. As I reported in the New York Times last fall, the National Institutes of Health launched a replication study in which the original XMRV team and other researchers who failed to find the virus will all search for the virus again, using exactly the same set of agreed-upon protocols.

For more on this story, check out Marcus’s excellent reporting over the past few months for the Journal, plus this piece in Nature.

Comments (13)

  1. And the lab connected to the authors of the original “discovery” are still selling their unregulated XMRV Test Kit see http://eurogene.blogspot.com/2010/09/murky-side-of-physician-prescribed-ldts.html

  2. Chris

    Yea Keith the WPI are really rolling in money over there…

  3. Sam

    Unregulated testing is allowed. Lombardi et al also validated their assays. It is when you make false claims about clinical validation that you get in trouble, or when the test is sanctioned by the FDA. But that’s ok because none of the negative papers have bothered with this step. Yes, they don’t know if their assays work. All brand new.

    The Coffin paper on origin is also absent a few crucial details, which without cannot prove the virus was created during xenografting. For instance, it is not clear if the mice that they find this claimed preXMRV1 & 2 in were even used. They have not checked wild mice for PreXMRV 1& 2. There are other ancestral viruses for XMRV in wild mice. Finally, their is no proof that their assays can detect the virus. So the earlier generations, not treated with testosterone, can still contain XMRV. Testosterone will increases the titre of the virus massively, so to a detectable level. But we know this is not what the virus does in a natural infection.

    There is also no attempt to explain the other strains identified. The polytropic and modified polytropic. Both of which Lo et al and the WPI have sequences for in the GenBank.

    So no the virus is human and replicating and still associated with prostate cancer and ME.

  4. Alan Dove

    @Chris I assume you meant that sarcastically, but the math is actually easy to do. VIPDx (the WPI’s commercial arm) claims at the top of their web site that they’d received 1,556 samples as of October 10, 2010. Their test costs about $500, so that’s $778,000 gross receipts in their first year of this business. That’s bigger than most NIH RO-1 grants. It’s safe to say the WPI/VIPDx team has a lot riding on XMRV being a real pathogen.

    @Sam This nonsensical talking point about “validated assays” is really annoying. Repeating it every few weeks, as you and the other WPI acolytes do, doesn’t make the argument any more reasonable. The negative studies have done just as much validation as Lombardi et al. and Lo et al. on their assays. Demanding “clinically validated” assays is just silly, because the crux of the matter is whether there are in fact any real clinical cases of XMRV infection. The evidence is now pretty overwhelming that there are not. As for the Coffin paper, it’s open access, so folks can just go read it themselves to see how thorough it is. I suggest they also check out Levy’s paper, released at the same time, which drives another big stake through the heart of the XMRV-causes-anything theory.

  5. Sam

    Alan you have wrong.

    None of the negative papers have clinically validated any of their assays. The Lombardi consortium did. The negative papers have only optimised for analytical sensitivity. You pretend there are no clinical positives, but what you really mean is that you don’t want there to be any until it is a researchers you approve of confirms the finding. Well this obviously has its own problems and is totally wrong.

    Take this article from the WHO into this very issue about how to get clinical positives. The Lombardi team did this.

    “Non-commercial or ‘in-house’ reference standards are legitimate only if they have been adequately validated. Sometimes, composite reference standards might have to be used in the absence of a single suitable reference standard. Results from two or more assays can be combined to produce a composite reference standard6.”

    “External validation can be performed by sending all positive specimens and a proportion of the negative specimens to another laboratory for testing.”

    http://www.nature.com/nrmicro/journal/v8/n12_supp/full/nrmicro1523.html

    And there is this from the FDA:

    “Clinical validation of these preliminary assessments is then accomplished through field testing of appropriate clinical specimens to provide final specifications for test kit performance characteristics.”

    “A minimum of 10 distinct HIV positive specimens obtained from different individuals would be advisable for each subtype/variant. In the event that 10 distinct clinical specimens of a specific viral subtype are not available, culture derived specimens may be used to supplement clinical samples.”

    “A minimum of 200 samples known to be positive for HIV-2 should also be tested in the evaluation of clinical sensitivity for single donation screening tests, including a subset that contain both HIV-1 and -2. These samples may be obtained from a repository.”

    http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/blood/ucm077067.htm

    The evidence is therefore pretty overwhelming that the original paper has not been challenged at all. No replication or validation.

    The Coffin paper is also terribly flawed and full of enormous holes. It should never have been published anywhere. All they have done is squander time and money.

  6. Rene

    The money the lab has got for testing is nowhere near the amount of money the Whittamores have put in in

  7. Alan Dove

    @Sam, you have the scientific process exactly backward. You have to start by testing the “null hypothesis,” not by assuming that your hypothesis is true.

    No assay can be “clinically validated” until the analyte has been shown to be *reproducibly* associated with disease. The quotes you copied and pasted from miscellaneous documents are all about clinical tests for pathogens that had already been found to be associated with specific diseases, such as HIV/AIDS. You’re demanding that we assume the Lombardi et al. results are unquestionably correct, and then only use assays that mimic their results. That’s a faith-based approach, not a science-based one.

    The deafening silence about the Levy paper is also rather telling. They re-tested the same samples, using some of the same assays as Lombardi et al. but controlling carefully for contamination, and found they were all XMRV-negative. Be sure you read all the way to the acknowledgements on that one, where they thank “D. Peterson” for providing the samples. That’s Peterson as in Whittemore-Peterson Institute. Are you going to claim he’s part of the conspiracy, too?

  8. The saddest part of this story is that NIH/NCI are going to spend more time and money to replicate the original “discovery” to convince the NCI team to back off and retract the Science Paper. Science itself made a mistake publishing this paper and has now the right to “disown” it. The reviewers of the manuscript should explain their recommendation to publish.
    In ancient Iran the physician who treated the deceased person was required to participate in the funeral and walk upfront the funeral procession.

  9. Jean

    @Alan, Dr Peterson left the WPI sometime ago under unhappy circumstances fwiw. Dr Mikovitz became interested in CFS because of the disproportionately high % of patients who have CFS. She noted that CFS, like prostate cancer had irregularities in the 2’5 synthase line, long established, so looking to XMRV & CFS is not a huge leap from there.

    I believe that the Whittemore’s found Dr. Mikovitz at NCI. Whittemore’s reason to research the disease is that their daughter has a severe case. This isn’t a $$$+ venture for them, they already knew how to do that. But no matter how much $$$$ they couldn’t restore their daughter’s health.

    Add into the soup that some specialists charge upwards of $6K for an initial visit & compare that to the $500 test.

    @ Michael Not one of the groups coming out with negative results has done a replication. One group came out a non-replication within 6 mos of the Science article having not found the virus, a laughably short time. Another non-replicator admitted to Dr Mikovits leaving out a step that Mikovitz felt was crucial, and hasn’t tried again. A third non-replicator had the astounding foresight to say that he didn’t think that he would find the XMRV -CDC’s William Reeves. There was a paper by Lo& Alter(FDA & NIH)which confirmed WPI’s findings. That paper was held back for more than a month to retest after CDC came up empty handed. So it’s high time that a replication study was undertaken. As there are some 800,000 people in the US suffering from this unimaginably debilitating & contagious (See Lyndonville, Royal Free Disease,..others)illness, it’s about time that serious study be undertaken. It’s not a new disease but a rediscovered one. It keeps getting rediscovered (and renamed) every generation or so after it’s been forgotten by yet another generation of doctors

    There is a great deal of speculation that could be resolved by doing some basic research on Google.

  10. Mr. Dick Turpin

    Given the many past hypotheses that tried to link CFS clinical symptoms with infectious agents (EBV being the most famous), none of which were borne out by data, skepticism has been warranted here from the beginning.

    At the end of the day, we would ask only one thing of the researchers: to prove that the XMRV virus CAUSES CFS symptoms (i.e., meets Koch’s postulates).

    Typically, that causation would be first shown in animals. However, no established animal model of CFS exists. So, without an animal model to show causality, the only option we have is to establish a link (i.e., a correlation) using epidemiological studies in CFS patients, which are statistically driven and only as robust as their numbers. (Mikovits has admitted this problem publicly in interviews. See, for example, http://www.nature.com/scibx/journal/v2/n40/full/scibx.2009.1492.html )

    Thus, the best we can do is show a correlation between frequency of the XMRV DNA sequence in patients and frequency of CFS clinical symptoms – and, so far, when we look at all the epidemiological studies published on XMRV and CFS (not only the Mikovits study), that correlation is looking very week – and we’re not even talking about cause here, which is the gold-standard in infectious disease.

    Laboratory contamination may or not have happened – and that issue should be sorted out – but even if it didn’t happen, these findings are still only correlative and not something anyone would want to base any kind of treatment on.

    Bottom-line: scientists cannot allow desperate patients to influence the way they carry out and report research. I’m very sorry if that sounds insensitive, but it’s for the best of both the scientific community and patient groups.

    Mr. Dick Turpin

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The Loom

A blog about life, past and future. Written by DISCOVER contributing editor and columnist Carl Zimmer.

About Carl Zimmer

Carl Zimmer writes about science regularly for The New York Times and magazines such as DISCOVER, which also hosts his blog, The LoomHe is the author of 12 books, the most recent of which is Science Ink: Tattoos of the Science Obsessed.

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