Cause: what is it? How do you know? These are questions we ask students all the time. They often are very challenging questions. Here's yet another example of why.
Chronic fatigue syndrome (CFS) is either a debilitating disease of unknown cause, or a sign of malingering in a patient who refuses to get off his or her duff and get back to life. The symptoms of CFS include unrelenting fatigue that lasts for more than 6 months, isn't relieved by rest, and can be worsened by physical activity or mental stress. The disorder frequently is not taken seriously by the medical system, largely because no definitive cause has been found. It's a frustrating disorder for patients, family members and physicians alike. Seventeen million people have been diagnosed with CFS worldwide -- at the very least, an increased understanding of the disease would be very welcome. But we all feel bushed from time to time, so do we all have CFS?
Last year, a paper was published in Science that began to give CFS sufferers some hope. The authors wrote:
Studying peripheral blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus–related virus (XMRV), in 68 of 101 patients (67%) as compared to 8 of 218 (3.7%) healthy controls. Cell culture experiments revealed that patient-derived XMRV is infectious and that both cell-associated and cell-freetransmission of the virus are possible. Secondary viral infections were established in uninfected primary lymphocytes and indicator cell lines after their exposure to activated PBMCs, B cells, T cells, or plasma derived from CFS patients. These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS.
Could this really be yet another mysterious disease caused by viruses? (Didn't we conquer infectious disease long ago??) The same authors went on to find XMRV in 98% of the next 300 patients they studied. Since XMRV is a retrovirus, the authors knew that the next step was to test anti-retroviral medications (such as those used for people with HIV) on CFS patients in whom XMRV had been found. Many people waited impatiently for the results of further studies to be released.
But, as reported in Science last week,
The plot thickens. This week, a long-awaited paper by U.S. government labs about the link between a virus and chronic fatigue syndrome (CFS) finally saw the light of day. The study confirms a controversial 2009 paper that reported CFS patients are often infected with the virus, called XMRV. Since then, four other studies have failed to duplicate those findings. Even skeptics are impressed by how much care the authors of the new study took to ensure accuracy. But that makes it even more baffling why some labs easily detect the virus while others can't find a trace of it in any patient.
Indeed, the new paper was accepted for publication last spring, but a paper that failed to confirm the XMRV findings, from a lab at the CDC, was accepted for publication at the same time, in the journal Retrovirology. In light of these findings, the authors of the PNAS paper requested more time to re-evaluate their own results, so the journal put the paper on hold while the authors considered their options. The negative paper from the CDC appeared in print in July, and the PNAS paper finally came out last week, with the added caveat that their results would be stronger if they found evidence of XMRV integrated into the patient's genome. Doing this will be difficult and time-consuming, as the editors of PNAS say in a commentary accompanying the paper, so they decided to publish this paper without waiting for these results.
And there are further complications.
The new paper, published on Monday by the Proceedings of the National Academy of Sciences (PNAS), also adds a confusing twist: Rather than XMRV itself, the team found a broader and more diverse group of closely related viruses. That leads some critics to say the paper is a new finding, not confirmation of the first one. "Let's be clear. This is another virus," says retrovirologist Myra McClure of Imperial College London, a co-author of one of the four negative studies.
However, the author of the 2009 paper is delighted with these new results, saying that she too has found more diversity in the viral load than reported by her group previously. Indeed, the new study further reports that they retested 8 people and found that, 15 years on, they still were infected with XMRV and that the virus had mutated, just as would be expected from a retrovirus. And many very well-qualified observers say this is a very solid study.
So, if the evidence from these two studies is so convincing, what could explain why the four earlier studies found no evidence of XMRV in the samples they tested? Did they use different diagnostic criteria for CFS? Did they not have reliable methods for detecting the virus? As far as we can tell, the explanation is still completely unclear. How does this get sorted out? Or are we always supposed to accept the most recent study?
As the commentary in Science concludes,
As part of the NHLBI program, researchers at FDA, CDC, WPI, and other labs have all blindly tested a panel of samples, some of them "spiked" with different amounts of the virus; all of them performed well. Further exchange of samples and reagents is now under way. "They should be able to clear this up by Christmas," says Kurth.
We write frequently about non-replicable results in genetics, for which there are many explanations, including different disease criteria, different causative genes in different families, genes with effects too weak to be statistically significant, and so on. But if a retrovirus actually does cause CFS, it's a single cause with a large effect, and that should be identifiable. So this does suggest laboratory methods and diagnostic criteria are the likely explanations of inconsistencies here, and it will be interesting to see what the exchange of samples and reagents yields.
In the meantime, patients are beginning to take things into their own hands and starting on courses of anti-retrovirals, which, if they do reduce the viral load, may in fact may be the only definitive way this will be sorted out.