A new story by Sam Kean on XMRV appears in Science magazine today (Friday 15 January) – in which he discusses the impact on the debate of the Imperial College London replication study which couldn't find a trace of the virus in blood samples from CFS patients that they examined.
Science 15 January 2010: Vol. 327. no. 5963, pp. 254 – 255 DOI: 10.1126/science.327.5963.254
News of the Week
An Indefatigable Debate Over Chronic Fatigue Syndrome
by Sam Kean
Here we go again. The search for the cause of chronic fatigue syndrome, which just months ago seemed to be gaining traction, now seems likely to descend into the same confusion and acrimony that characterized it for years, as a supposed viral link to CFS published just last autumn might be unraveling.
Many patients with CFS—long-term fatigue and other ailments that have no known biological cause—report that their symptoms began after an acute viral infection, and scientists have tried many times, but never successfully, to pin CFS to viruses such as Epstein-Barr. Patients have faced skepticism for years over whether CFS is a “real” disease; a viral trigger could vindicate them and explain their nebulous symptoms.
That's why a paper published online 8 October 2009 in Science caused such a stir. A U.S. team reported finding DNA traces of a virus, XMRV, in the blood cells of two-thirds of 101 patients with CFS, compared with 4% of 218 healthy controls. Strangely, XMRV, a rodent retrovirus, had previously been implicated in an aggressive prostate cancer. No one knows how XMRV might contribute to either or both diseases, but the authors argued that the link made some sense: XMRV ravishes natural killer blood cells, which attack both tumors and cells infected by viruses.
Other scientists thought the link dubious, criticizing the team, led by Vincent Lombardi and Judy Mikovits at the Whittemore Peterson Institute for Neuro-Immune Disease in Reno, Nevada, for not explaining enough about the demographics of their patients or the procedures to prevent contamination (Science, 9 October 2009, p. 215). Several virologists around the world practically sprinted to their labs to redo the experiments, and the discovery that a clinic associated with some people at Whittemore was selling, among other CFS services, a $650 diagnostic test for XMRV made the issue more pressing. A U.K. team already exploring the XMRV–prostate cancer link won the race, submitting a paper to PLoS ONE challenging the claim on 1 December 2009. It was accepted for publication after 3 days of review.
The British team, led by retrovirologist Myra McClure of Imperial College London, examined DNA from the blood of 186 CFS patients ranging in age from 19 to 70, with an average age of 40. Most were markedly unwell. McClure's team used a PCR machine— which copies and amplifies scraps of DNA — to search for two viral sequences, one from XMRV and the other from a closely related virus. They discovered nothing. At a press conference discussing the results, published online 6 January in PLoS ONE, McClure was blunt and confident: “If there was one copy of the virus in those samples, we would have detected it.”
This null result prompts the question of what—if anything—was wrong with the original paper. The PLoS ONE authors seem to suggest that contamination was at fault, stating that they were careful to work in labs that had never handled XMRV and use PCR machines that analyze no mouse tissues. But McClure says her group merely wanted to make that explicit, not accuse anyone.
The U.S. team followed the same procedures, retorts Lombardi, a biochemist. He also expressed bewilderment that the McClure group didn't search its CFS samples for the same DNA sequence as his team had, raising the possibility that they had different results because they searched for different things. The McClure team, however, looked for not only an XMRV sequence but also a sequence in a closely related virus, MLV. That MLV sequence, highly conserved among viruses of its class, would presumably have been found if XMRV was present, they said.
One distinct possibility, says John Coffin, a microbiologist at Tufts University in Boston who studies retroviruses and wrote a separate analysis for Science when the original paper was published, is that both papers are right. He called the PLoS ONE paper too “preliminary” to settle the debate and said XMRV could show more genetic variety, and thus be harder to detect, than anyone assumed. It's also possible that distinct strains of XMRV appear in different parts of the world, as do the retroviruses HIV and HTLV (a leukemia virus). Intriguingly, although research teams in the United States have linked XMRV to prostate cancer, multiple teams in Germany and Ireland have failed to
find a connection.
Coffin says one more possibility, raised by many scientists, is that CFS is actually a suite of diseases that present the same symptoms and so might have many causes. Lombardi agrees. “It's naïve to think that everyone with chronic fatigue has the same etiology. There's probably going to be a subset of people with CFS that have XMRV, and it will probably end up being classified as XMRV-related CFS.”
All of this leaves doctors and patients in a muddle. There's no doubt they're hungry for information. Out of curiosity, Lombardi did a Google search on “XMRV” the day before the Science paper hit and found about 22,500 hits. Three months later, there are 400,000.
But some scientists, including Coffin and McClure, fear that the Viral Immune Pathology Diagnostics clinic (VIP Dx) took advantage of that hunger by offering the $650 diagnostic test for XMRV, 300 of which have been administered so far and which already has a 4 to 6 week backlog. “Leaving aside the issue of who's right and who's wrong,” says Coffin, “the original paper did not establish the virus [caused CFS] and didn't establish it as a viable marker.” So it's not clear what a patient or physician could do with a positive result. Steve Kaye, a colleague of McClure's at Imperial College London and a co-author of the PLoS ONE paper, noted with some alarm that the authors of the Science paper had speculated about treating XMRV with antiretroviral drugs, which can have harsh side effects.
However, VIP Dx developed its XMRV test only after a different company began offering one; VIP Dx officials saw their test as a more expert alternative. What's more, Lombardi—an unpaid consultant for VIP Dx who helped set up and manage the testing program—argues that the test is useful. Patients could in theory avoid infecting other people with XMRV and can have their diagnoses validated, if nothing else. His test
results also bolster the science in the original paper; he says 36% of tests have detected XMRV, including a few from the United Kingdom. (Test proceeds roll back into research and development at Whittemore, which licenses the test to VIP Dx. VIP Dx has also received financial support from the Whittemore family in the past.)
To resolve the dispute, both sides say they are willing to work with the other and possibly test each other's samples. In the meantime, more papers exploring the link are slated to appear in the next few months, and each side says it knows of work supporting its results.
All that suggests that the field will continue to churn. As McClure told Science, “we take no pleasure in finding colleagues wrong or dashing the hopes of patients, but it's imperative the truth gets out.”