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Big study linking Chronic Fatigue to virus may be fatally flawed
Saturday 7 May 2011
Big Study Linking Chronic Fatigue To Virus May Be Fatally Flawed
Chronic fatigue syndrome (CFS) causes severe fatigue that can last for months at a time. CFS is difficult to diagnose and even more difficult to treat, and its cause has long been a mystery. In 2009, in an apparent breakthrough, scientists reported that a virus found in mice, called XMRV, might be the long-sought cause of chronic fatigue. Their results were reported, with great fanfare, by Judy Mikovits and colleagues in the journal Science (Lombardi et al.,Science 2009;326:585), with reports in respected outlets such as the New York Times making it seem that the answer had been found.
Now it turns out that, like many initially exciting reports, this one has a much more mundane explanation: contamination.
As happens all too often when a “surprising” discovery is announced, the result turns out to be an experimental error. Contamination is a common type of error in modern molecular genetics, because nothing is actually visible to the naked eye, and we have to rely on very sensitive methods (such as PCR) to detect what is present. In this case, the experimenters had a common mouse cell line in their lab (not unusual), and it turns out these mouse cells were contaminated with a virus called MLV, which looks a lot like XMRV.
The new study by Hue et al. from University College London (Retrovirology 2010, 7:111) is titled “Disease-associated XMRV sequences are consistent with laboratory contamination.” The title pretty much tells the story, but here’s a brief synopsis.
XMRV (Xenotropic murine leukaemia virus-related virus) is the virus in question – the one that Mikovits claimed is the cause of chronic fatigue syndrome. It’s a retrovirus, and it is very similar to another mouse virus called MLV-X. It turns out the the PCR method for detecting XMRV uses short DNA sequences (“primers”) that will also detect MLV-X. These primers were previously believed to be specific to XMRV, but they’re not. Therefore, if you are looking for XMRV in a tissue sample, and the sample contains MLV-X, you’ll think you found XMRV. But what: why would human patients have MLV-X? Perhaps MLV-X is a cause of chronic fatigue? Good question.
Well, it turns out that a common mouse cell line called 22Rv1 is infected with MLV-X. It also turns out that all the XMRV sequences from human patients are far more similar to the exact same strain of MLV-X that is in the mouse cell line. The mouse cells were in the lab doing the experiments: ergo, it’s contamination. Elementary, my dear Watson. Or, as Hue et al put it:
“We provide several independent lines of evidence that XMRV detected by sensitive PCR methods in patient samples is the likely result of PCR contamination with mouse DNA…. We propose that XMRV might not be a genuine human pathogen.”
The initial Science paper by Mikovits and colleagues generated three published “Comments” in the journal, an unusually high number, which alone is enough to raise some red flags. The comments pointed out multiple methodological problems, including the possibility of contamination. In one of them, the authors (van der Meet et al) warned that
“Over the past few decades, we have witnessed a long series of papers claiming the discovery of the cause of CFS. None of these claims has been confirmed. Each time, this gives false hopes to large numbers of patients who seek a solution for their suffering. Shortcomings in the study by Lombardiet al. now raise concerns about the role of XMRV in the pathogenesis of CFS.”
After the 2009 Science paper, several other studies looked at patients with chronic fatigue syndrome and failed to find anyone with XMRV (for example, this study from the CDC last summer). This was strikingly different from Mikovits’ report that 67% of patients had XMRV. The latest report, by explaining where the false positive results came from, should put the final nail in the coffin for the XMRV hypothesis.
In retrospect, Science shouldn’t have published the flawed study, and you could argue that peer review failed. On the other hand, the final resolution illustrates the self-correcting mechanism of science at its best. All of this is very reminiscent of the scientific response to Andrew Wakefield’s notorious 1998 study claiming that autism was associated with the MMR vaccine: multiple followup studies, most of them conducted far more carefully, failed to reproduce the results. But in that case, bad scientists (Wakefield) aided by gullible journalists and non-scientists (Jenny McCarthy, Jay Gordon) have kept the story alive, causing continuing damage to children in the form of preventable illnesses and even deaths. Even after the story last week in the journal BMJ that explained Wakefield’s outright fraud, he continues to push his discredited notions. (I love the title of the BMJ’s editorial: “Wakefield’s article linking MMR vaccine and autism was fraudulent.”)
CFS has less visibility than autism, so I hope that scientific evidence will carry the day here. We still need to find the cause of chronic fatigue syndrome, and there’s no telling right now where the answer lies.
The above, with comments, originally appeared here.
The news has also been reported here:
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