‘Hurricane force’ debate about XMRV findings – ‘Science’ magazine, 7 January 2010

January 6, 2011

From ‘Science' magazine (“News of the Week”), 7 January 2010. Story by Jocelyn Kaiser with additional reporting by Martin Enserink.

Studies Point to Possible Contamination in XMRV Findings

The stormy debate over a potential cause of chronic fatigue syndrome (CFS) is nearing hurricane force. Last month, it prompted headlines suggesting that researchers have reached a dead end, scores of blog posts from disappointed patients, and accusations that scientists had gone beyond their data. The 14-month-old row intensified when four papers appeared in Retrovirology suggesting that reports linking the virus XMRV to CFS were based on false positives.

The debate began in 2009 with a report in Science that XMRV, a retrovirus recently reported to have been found in prostate tumors, had been detected in 67% of a set of CFS patients but in only 4% of controls (Science, 9 October 2009, p. 215). Since then, one other group has found XMRV- like viruses in CFS patients’ blood. But sev- eral teams have failed to detect the virus in CFS or cancer patients or in healthy peo- ple. Researchers have struggled to explain the discrepancies (Science, 17 September 2010, p. 1454).

The potential link to CFS has had important consequences: Some CFS patients have begun taking antiviral drugs, which can have side effects. Last month, after being briefed on the original XMRV studies, advisers to the U.S. Food and Drug Administration recommended that CFS patients be barred from donating blood.

The Retrovirology papers point to contamination as a possible source of positive results in previous studies. The polymerase chain reaction (PCR) test used to detect XMRV (a mouse retrovirus adapted to infect humans) could actually be picking up minute amounts of mouse DNA or similar mouse viruses.

Two of the four studies in Retrovirology used highly sensitive assays for mouse DNA and found that samples positive for XMRV-like viruses also tested positive for mouse DNA. Another study found mouse viral RNA in a commercial PCR kit. And the fourth study argues that XMRV sequences previously reported in patient samples don’t show the diversity expected if the virus were spreading through the human population. Instead, these authors report, the sequences are similar to those found in a popular pros- tate cancer cell line, 22Rv1. This cell line, used in lab experiments, was already known to contain an XMRV-like sequence.

Greg Towers of University College London (UCL), who led the study of XMRV diversity, says the evidence linking this virus and human disease “is really looking pretty shaky now.” The Wellcome Trust, which cosponsored the research, and UCL issued a press release last week declaring flatly that the Towers study showed that “chronic fatigue syndrome is not caused by XMRV,” a message some newspapers repeated. Towers says he was “comfortable” with the release. But John Coffin of the U.S. National Cancer Institute (NCI) and Tufts University Sackler School of Graduate Biomedical Sciences in Boston, who co-authored two of the contamination papers, is wary.

He says these studies “just point out how careful one must be.”

Virologists who have found a virus-disease link disagree with coverage of the Towers paper. “The data shown … do not justify some of the sweeping statements made,” says Ila Singh of the University of Utah, Salt Lake City, who has reported XMRV in prostate cancer samples. Moreover, the lead author of the Science paper on CFS and XMRV, Judy Mikovits of the Whittemore Peterson Institute (WPI) in Reno, Nevada, points out that PCR wasn’t the only test her studies used: For example, Mikovits’s team also showed that XMRV-positive patients make antibodies to the virus and that XMRV isolated from their blood can infect cultured human cells. Mikovits said in a statement, “Nothing that has been published to date refutes our data.”

One outspoken scientist wavered on the significance of the Retrovirology papers. Columbia University virologist Vincent Racaniello, who runs a popular virology blog and podcast, initially e-mailed a Chicago Tribune reporter to say that they were “prob- ably the beginning of the end of XMRV and CFS.” But he retracted that statement (and a similar comment to Science) after reviewing the studies more closely. “It’s pretty complicated,” Racaniello concludes.

Some had hoped that a project in which several U.S. labs are testing for XMRV in the same samples would clear up the picture. But so far this effort has been incon clusive. Four CFS patients’ blood initially tested positive for XMRV at WPI and the U.S. Centers for Disease Control and Pre- vention but not at an NCI lab. When all three labs tested new samples from the same patients, none found XMRV—for reasons that aren’t yet clear, says Coffin. The group now plans to test blood from several dozen CFS patients and controls.

A bigger study is now under way. Funded by the U.S. National Institute of Allergy and Infectious Diseases, virologist W. Ian Lipkin of Columbia University is lead- ing a project that will collect blood from 150 CFS patients and 150 controls from six U.S. clinical sites. The samples will be tested blindly by several labs. Because all the clinicians have agreed on standard methods, the study should help resolve concerns that differences in how CFS patients are selected or how samples are handled could explain clashing conclusions, Lipkin says: “Results will be definitive.”

As the new study gets started, some wonder whether it’s worth the $1.3 million it will cost. Jonathan Stoye of the MRC National Institute for Medical Research in London concedes that the Towers study was “over- hyped.” But he says “it’s pointing people in a certain direction,” away from chasing an elusive link to XMRV. Still, he says, a larger study may be the only way to satisfy patients.

4 thoughts on “‘Hurricane force’ debate about XMRV findings – ‘Science’ magazine, 7 January 2010”

  1. “Jonathan Stoye of the MRC National Institute for Medical Research in London concedes that the Towers study was “over- hyped.” But he says “it’s pointing people in a certain direction,” away from chasing an elusive link to XMRV. Still, he says, a larger study may be the only way to satisfy patients.”

    Satisfy patients? How patronising. If the science was at a conclusive dead end amongst the medical fraternity, then there wouldn’t be any debate, but there is.

    It’s a logical fallacy to present as fact, the conclusion that because XMRV can be found as a result of contamination, the results of other tests must be false positives. Particularly when the people who ran those tests can’t seem to communicate the simple message that, subsequent tests have not replicated their methods.

    I’m sure there are many M.E/CFS patients like me who are for the most part lost in the haze of high level medical science.

    The one thing that doesn’t pass us by however, is the false-factual presentation of logical fallacies that fail to prop up the assumptions of arrogant people.

    There’s such a thing as leaving no stone unturned and being thorough. Do M.E patients not have the right to expect this standard of practice from medical professionals?

    The problem is few of us get any dignity, they don’t run heuristic tests on NHS patients in the main. Instead a diagnosis is often gifted by finding an appropriate doctor to take you through an abstract list of symptoms.

    The medical profession as whole needs to stop deriding people if they aren’t even prepared to investigate their health properly in the first place.

    I’m afraid to say, but the biggest challenge for those of us with M.E, after all this time, still remains one of image.

    It’d be a financial black hole were we to demand heuristics, but how else can we be afforded dignity? Since I’ve had this illness, I once received a blood test that suggested my body was fighting off something due to increased liver function. I have to practically wave such scant confirmation in the faces of dead eyed medical professionals.

    If I bring up anything else that is wrong with me in a GPs office, the statement is followed by immediate inquisition. M.E falls on dead eyes.

  2. How would a larger study of Hue et al. settle the debate. I assume Stoye means an association study. However, it is unscientific of him to think that one large study would settle anything. There are so many confounding variables that only multiple studies will solve this debate.

    It is worth noting that the Department of Health has been mislead on PCR, as they state in a standard letter sent out on the 17 December:

    “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.

    The methods used to seek evidence of XMRV infection in English blood donors, which employed PCR and included appropriate controls, are able to detect the XMRV genome with high sensitivity and specificity.”

    Viral culture has been shown, by published studies, to be the most sensitive method, PCR the least sensitive method. Furthermore, those studies using the VP62 clone to calibrate their tests, have never demonstrated the ability of their assays to detect the real virus. A clone is NOT the real virus. They MUST retest having calibrated to the real virus. (Danielson et al.)

  3. As I understand it JT Wellcome are considering their position given others’ retractions or ‘distancing’ from the actual comments made by Greg Towers that are the source of some people’s consternation.

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