As doubts about the retrovirus reach fever pitch, scientists focus on alternative directions for the field.
XMRV's 15 minutes of fame seem to be up.
The hypothesis that the retrovirus has a role in chronic fatigue syndrome (CFS) has been dealt a serious blow by the publication of two damning papers in Science1,2 and an "expression of concern"3 from the journal's editor over the original report that identified signs of XMRV infection in two-thirds of people with the condition but fewer than 4% of healthy people4. The authors of that paper, led by Judy Mikovits at the Whittemore-Peterson Institute for Neuro-Immune Disease in Reno, Nevada, declined a request from Science to retract it, calling it "premature" in a statement.
"It's a bust," says Jonathan Stoye, a retrovirologist at the National Institute for Medical Research in London, part of the UK Medical Research Council (MRC), who was one of the fiercest critics of the association between XMRV and CFS. "People who are interested in this condition will have to move on."
Yet scientists are not yet sure what the fallout will be for the future of research into CFS, also known as myalgic encephalomyelitis (ME).
Despite affecting an estimated 17 million people worldwide, CFS has always met with scepticism from some scientists, says Anthony Komaroff, a leading CFS researcher at the Brigham and Women's Hospital in Boston, Massachusetts. The likely fall of XMRV, he worries, will drive home that point. "That, in my mind, would be an intellectually inappropriate way to respond," he says, "because beyond XMRV there's evidence of an underlying biological process and infectious triggers that we need to understand better."
Fear and loathing
Simon Wessely, a psychiatrist at King's College London who is reviled by many with CFS for emphasizing the neuropsychiatric aspects of the syndrome, worries that XMRV will have a negative effect on CFS research.
Many scientists, eager to work on a new virus linked to human disease, were castigated by some patients and advocates when they didn't find XMRV and raised the possibility that the original report could be a product of lab contamination, Wessely says.
At a recent workshop on CFS, John Coffin, a retrovirologist at Tufts University in Boston whose team showed that XMRV is a laboratory hybrid unlikely to cause a natural human infection1, made a plea to patients. "We really went in with the idea of being able to push this field forward," He said. "Nobody went in with the idea of disproving this." He added that criticisms of his motivations from patient advocates were "painful" to read.
Wessely says although he is used to being subject to abuse, other researchers were "absolutely appalled" by their treatment. "This will convince another large group of decent scientists to say: oh no, I would rather go find the gene for homosexuality or do work on images of the prophet Mohammed than do this."
But Paul Kellam, a virologist at the Wellcome Trust Sanger Centre in Hinxton, UK, who co-authored one of the first studies pointing to contamination as an explanation for the CFS–XMRV link5, is more hopeful. "I think we're in a transition period at the moment," he says. "We've just got to wait for the dust to settle, but I think it will galvanize people in the end."
Nobody went in with the idea of disproving this. John Coffin , Tufts University
Advances in biotechnology mean that scientists interested in a complex syndrome of enigmatic origin such as CFS have the right tools to tackle it, Kellam says. Microarray chips that identify differences between genes expressed in the blood of people with CFS and those without the syndrome may identify biomarkers of the condition. Meanwhile, gene scans and, soon, whole-genome sequences of patients with CFS could single out variations that make a person more likely to develop the debilitating condition.
Identifying what triggers CFS will be more difficult, Kellam acknowledges. A single infectious agent, such as XMRV, is unlikely to explain the condition, but some patients seem to develop the condition not long after being infected with agents such as Epstein–Barr virus. Comparing the genomes of people who develop post-viral fatigue with those who recover from their infections would be "a logical approach", he says.
Better diagnostics needed
But in order for such studies to bear fruit, better ways of diagnosing and classifying patients with CFS are needed, Kellam says. Current diagnostic criteria, based on excluding other conditions with similar symptoms, are more useful in the clinic than in the lab, he adds.
"This is essentially preventing us from moving forward on good solid research that deals with biomarkers, diagnosis and eventually treatment," says Dennis Mangan, who heads the CFS programme at the US National Institutes of Health (NIH) in Bethesda, Maryland.
Mangan says that the NIH spends about US$6 million a year supporting CFS research, although he estimates that another $4–14 million in annual funding for research on pain, exercise and other topics is directly relevant to the condition and its symptoms. He says the NIH is exploring ways to better support CFS research, such as by calling for grant proposals specifically devoted to the condition. "It's an illness that's not going away and the NIH is not going to turn its back on it."
In Britain, the MRC is accepting research proposals for a new programme devoted exclusively to CFS. The goal of the programme is to draw top-notch scientists into the field, says Stephen Holgate, an immunopharmacologist at the University of Southampton School of Medicine, UK. "Part of the difficulty is that we don't have very many good scientists working in the field," he says.
Proposals for the £1.5-million programme, due by 7 June, must include at least one scientist who does not currently work on CFS. "I know it's small fry, but at least it's a start," says Holgate. "We want a fresh view."
Paprotka, T. et al. Science doi:10.1126/science.1205292 (2011).
Knox, K. et al. Science doi:10.1126/science.1204963 (2011).
Alberts, B. Science doi:10.1126/science.1208542 (2011).
Lombardi, V. C. et al. Science 326, 585-589 (2009).
Hué, S. et al. Retrovirology 7, 111 (2010).
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Callaway, E. Chronic fatigue syndrome: life after XMRV. Nature (2011). https://doi.org/10.1038/news.2011.347