Sometimes science works the way it’s supposed to. Scientists make hypotheses, test them by gathering preliminary evidence, and then argue about the inevitable conflicting results. Eventually better and better evidence is gathered until a consensus is achieved. Actually, I think that is how science usually works, it’s just that most questions in science are narrow and technical and don’t command media or public attention. Those that do tend to be the more enduring controversies or where a particular special interest (ideological, social, corporate, etc,) is involved.
In medicine scientific controversies may take on a life of their own, or become manufactured controversies (manufactroversies) that endure long past any genuine scientific debate. Such false controversies are often driven by patient groups who feel they are not being treated fairly or honestly, or by practitioners who do not want to give up on their favorite (lucrative) modality. This leads to a disconnect between the scientific controversy and the public controversy – a frequent theme on SBM.
I am happy to report that one such controversy has taken a turn for the good – a recent study has provided fairly definitive evidence that chronic fatigue syndrome (CFS) is not associated with either the XMRV or the pMLV viruses. The study was a consensus trial with both sides in the controversy collaborating to address all the criticisms of the earlier conflicting studies.
Background on XMRV
Chronic fatigue syndrome (CFS) is an enigmatic disorder. The primary symptom is debilitating fatigue that does not resolve with rest. Fatigue, however, is a very non-specific symptom, meaning that it can potentially result from many underlying causes. Anything that saps the energy our body uses to function will cause fatigue. In part CFS is a diagnosis of exclusion – it is based upon the presence of fatigue in the absence of any identifiable underlying cause. Therefore not everyone with chronic fatigue has CFS.
The non-specific nature of the clinical syndrome also frustrates our attempts to find the underlying cause or causes (it may, in fact, be many diseases all with a similar clinical presentation). So many things can potentially cause chronic fatigue – where do we begin. However, a chronic viral infection has long been suspected as a likely cause, at least in some cases.
An initial study (Lombardi et al published in Science in 2009) found a potential association between CFS and a retrovirus called XMRV (xenotropic murine leukemia virus-related virus). This has led some desperate patients with CFS to take anti-retroviral drugs (used mostly to treat HIV – another retrovirus) off label in order to treat their CFS. But this study, while intriguing, was considered preliminary. A second study of a related virus published in the Proceedings of the National Academy of Sciences (PNAS) in 2010 supported the association between CFS and retroviral infection.
Many patients with CFS were delighted by these findings. They seemed to confirm that their mysterious ailment was legitimate and also held out the promise of treatment.
Subsequent studies, however, failed to reproduce the findings. A larger, more rigorous and comprehensive study published in 2011 found no association at all between XMRV and CFS.
We collected blood samples from 100 CFS patients and 200 self-reported healthy volunteers from the same geographical area. We analyzed these in a blinded manner using molecular, serological and viral replication assays. We also analyzed samples from patients in the original study that reported XMRV in CFS. We did not find XMRV or related MLVs, either as viral sequences or infectious virus, nor did we find antibodies to these viruses in any of the patient samples, including those from the original study. We show that at least some of the discrepancy with previous studies is due to the presence of trace amounts of mouse DNA in the Taq polymerase enzymes used in these previous studies.
Other negative studies also were published. They further identified possible evidence of contamination that could have caused the prior study to be a false positive.
Proponents of the XMRV hypothesis, however, were not impressed. They essentially dismissed the findings of this later study by saying that the wrong technique was used to identify XMRV.
To complicate matters further, the lead researcher in the original study, Dr. Judy Mikovits, was briefly arrested in November 2011, after she was fired from her institute, on the charge that she stole computer data and lab notebooks. The charges were later dismissed, but the episode solidified Mikovits as a martyr in the eyes of hopeful patients who did not want to give up on XMRV.
Eventually the weight of negative replications reached a critical point and both Science and PNAS retracted the original two positive studies within a week of each other. In the PNAS retraction the authors wrote:
“It is our current view that the association of murine gamma retroviruses with C.F.S. has not withstood the test of time or of independent verification and that this association is now tenuous.”
Prior to the retraction, however, the current consensus trial was already underway. That study, as was suspected, provides the final nail in the XMRV CFS hypothesis. The researchers report:
Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection.
The authors of this study include Mikovitz and Alter (an author on the PNAS study), as well as researchers who did not confirm the association. Mikovitz hoped to replicate her original findings, but like a good researcher she let the scientific chips fall where they may. The study found zero incidence of XMRV or pMLV in the CFS patients studied.
The XMRV hypothesis is now scientifically dead and buried, the latest study really serving as a memorial service for an already-dead hypothesis. Because researchers from both sides of the controversy were involved in designing a truly rigorous study that everyone could agree upon, there really is no wiggle room left for those who wish to support the XMRV hypothesis.
There are, of course, multiple lessons we can take from this episode. The first (and a very common theme on SBM) is that preliminary evidence is preliminary. Most of it will not pan out. This controversy resolved itself more quickly than most, but it still took several years. In medicine this means (as difficult as it may be) that patients and practitioners need to be cautious before they jump on preliminary findings.
Second – it is possible for scientists on opposite sides of a controversy to come together and resolve their differences with better evidence.
When this happens, then it is absolutely critical that the scientists on the “losing” side accept the results and make very clear and definitive statements to the public about their acceptance. Those who are invested in the failed hypothesis will be looking for any sign of dissent, any indication that there is a cover up or conspiracy. They will cling to any hint that there is something fishy going on, and they shouldn’t be encouraged by careless scientists.
Sometimes the scientists on the disproved side don’t give up, they allow proponents of their failed hypothesis to rally around them and choose to continue their career as a fringe crank championing a lost cause, rather than the honest author of a failed hypothesis.
I am glad to report that this does not appear to be the case with the XMRV story. It remains to be seen how the CFS community will respond.