by Johnny Jet
Searching for the cause of chronic fatigue syndrome: XMRV turns out to be another blind alley
[Via Field of Science Combined Feed]
Chronic fatigue syndrome (CFS) causes severe fatigue that can last for months at a time. CFS is difficult to diagnose and even more difficult to treat, and its cause has long been a mystery. In 2009, in an apparent breakthrough, scientists reported that a virus found in mice, called XMRV, might be the long-sought cause of chronic fatigue. Their results were reported, with great fanfare, by Judy Mikovits and colleagues in the journal Science (Lombardi et al., Science 2009;326:585), with reports in respected outlets such as the New York Times making it seem that the answer had been found.
Now it turns out that, like many initially exciting reports, this one has a much more mundane explanation: contamination.
As happens all too often when a “surprising” discovery is announced, the result turns out to be an experimental error. Contamination is a common type of error in modern molecular genetics, because nothing is actually visible to the naked eye, and we have to rely on very sensitive methods (such as PCR) to detect what is present. In this case, the experimenters had a common mouse cell line in their lab (not unusual), and it turns out these mouse cells were contaminated with a virus called MLV, which looks a lot like XMRV.
The new study by Hue et al. from University College London (Retrovirology 2010, 7:111) is titled “Disease-associated XMRV sequences are consistent with laboratory contamination.” The title pretty much tells the story, but here’s a brief synopsis.
[More]
The first report that a retrovirus might be the cause of Chronic Fatigue Syndrome came out about a year and a half ago. But very quickly came conflicting reports that the retrovirus was not involved.
Now comes what appears to be the definitive answer – the supposedly specific tags used to identify the retrovirus actually cross reacted with another similar virus. And this other virus was found to contaminate cells in the labs doing the work.
The original paper presented some data that they interpreted as signifying that XMRV could be a cause of disease. Others then went out to verify this and showed that the original interpretation was wrong.
This is how science works. The thing that Feynman talked about was that scientists need to be aware of how easily they can be fooled and to strive to make sure that all controls have been done.
Here, we have a case of a lab that did not seem to fully perform this self-examination. They should have been the ones to find the contamination, rather than have others do it.
But whether done by the original scientists or by others, science works towards finding out what is really happening.
Now if only the media would realize the tentative nature of most science.
A Man With A Ph.D. 
As long as scientists are human and very, very competitive, there will be announcements to the press that turn out to be wrong. Don’t blame the media. Blame the labs and universities.
PS: Does this mean they have to give the grant money back?
I’m talking about the media going off the deep end with some of these claims. They are certainly much more circumspect with regards to other issues.
It would certainly be a very different, and much poorer world, if people had to repay money if they were wrong. People would certainly be less risky.
Please bear in mind that this information you are giving is 100% WRONG.
There was an orchestrated effort to publish 4 studies in “Retrovirology” in the same day claiming that previous studies on XMRV were fruit of lab contamination.
Nevertheless the truth of the matter was that these four
Retrovirology papers show that identification of XMRV can be fraught with contamination problems, but they do not imply that previously published studies are compromised by these findings. Previous studies used 4 different methods of detection, not only PCR, besides they isolated the virus and found an immune response and antibodies which could not be possible if it was lab contamination.
The conclusion is that these four papers point out how identification of XMRV from human specimens can be complicated by contamination, but they do not mean that previous studies were compromised. They serve as an important reminder that future experiments to identify XMRV need to be appropriately controlled to ensure that the results are not compromised by contamination.
XMRV has been linked to cancer and ME/CFS and is estimated that 7% of population carry this retrovirus of unknown pathogenic potential. Red Cross has banned CFS patients to donate blood until the role of XMRV is clarified to protect the blood supply. Many countries are following Red Cross policy such as Belgium, USA, Australia, Canada, New Zeland, UK, Norway, Malta, Japan…
This is a major public health concern with a size higher than the aids epidemic in Africa. Please do retract yourself in this statements you make in this article, others have already retracted such as Chicago Tribune:
http://www.chicagotribune.com/news/opinion/letters/chi-101223racaniello_briefs,0,1990620.story
Thanks in advance
CFS patient
100% wrong? Really? Nothing you have said indicates that XMRV causes CFS. One paper indicates they have found a possible link while several other labs are unable to replicate the work indicating any link.
Now we have work that indicates that contamination with other viruses can be a problem, a problem that might not have been properly controlled for.
I think that it will take more work to clear this all up but I will remain skeptical of any direct cause of XMRV for CFS until that happens.
I have seen no science that informs the question of the XMRV link to ME/CFS.
There is no definitive answer to anything. Four simultaneously released papers that just propose theories as to why the original Mikovitz paper could possibly have found a sample not representing the population studied are not convincing.
Mikovitz has repeatly shown evidence contamination did not occur. Why do you want to be so quick to assume so much?
That is not science.
Well, the link of XMRV to CFS is quite tenuous at this point. Others have had difficulty repeating the original results and have found possible reasons for why.
The lack of reproducibility indicates that Mikovitz and others probably do not have complete understanding of what s going on. I certainly do not expect work to stop.
Science moves forward in fits and starts. I expect it will get us to a more complete answer eventually.
What a pity you didn’t take time to question those involved in the original study, below is a statement on the recent contamination studies from the WPI.
Turning Today’s Discoveries Into Tomorrow’s Cures
January 1, 2011
XMRV: A Human Retrovirus with Unknown Pathogenic Potential, Not a Lab Contaminant
The recent proclamation that “XMRV is not the cause of CFS,” came from an individual who did
laboratory experiments to show how PCR experiments can become contaminated. These results
have nothing to do with the reality of a disease or the methods used by those who have detected
XMRV in the blood and tissue of patients found to be infected. The positive studies, which
cannot be explained away by PCR experiments, are those which have used multiple methods to
show that XMRV is a live replicating gamma retrovirus in human blood and tissue samples using
the gold standard methods of viral isolation and antibody testing, in addition to PCR.
Unsupported conclusions, such as the one offered by the Wellcome Trust spokesman, often
create sensational headlines but do little to move science forward. Authors of the positive
XMRV studies have been extremely careful not to claim causality, realizing that more scientific
research is required to make such a statement. However, one fact still remains clear. Not one of
the negative studies changes the results of the scientific research done by Lombardi et al., Lo et
al., Urisman et al., and Schlaberg et al.
The WPI-led scientific study, which rigorously ruled out contamination, revealed high
associations of gamma retroviruses with physician-diagnosed CFS patients, using four different
methods of detection. Recent commentary associated with the negative research papers on
XMRV, which used only one testing method, claimed that these studies proved that XMRV was
not the cause of human disease. On the contrary, what the authors of the “contamination studies”
confirmed is something that most experienced scientists already know; there are risks associated
with using PCR if one does not properly control for contamination. They cannot conclude that
other research groups had the same problems or that “XMRV is not the cause of CFS”.
Most significantly, the recent Retrovirology publications failed to address the most
important pieces of scientific evidence of human infection in the previous XMRV studies,
including the fact that XMRV positive patients produce human antibodies to gamma
retroviruses, XMRV integrates into human tissues, and infectious virus has been cultured
from the blood of hundreds of patients with a diagnosis of Chronic Fatigue Syndrome and
M.E. Humans do not make antibody responses to mouse DNA sequences from
contaminated lab experiments. The Retrovirology studies only point out that XMRV
research cannot be done in a mouse laboratory without extreme caution and should not
rely solely on PCR methods.
Many researchers realize that the question of gamma retroviruses and human disease cannot and
should not be dismissed lightly. Retroviruses integrate into their host’s DNA causing life long
infection. Human retroviruses, such as HIV and HTLV-1, are causative for immune
deficiencies, neurological disease and cancer. Animal studies involving XMRV demonstrate that
the virus moves quickly away from the blood to various organs within the body, such as the
spleen, lymph nodes, GI tract, and reproductive organs. This helps to explain why the virus is
difficult to detect in blood even as it replicates in the tissues of those infected. Other studies
using mouse models of Murine Leukemia Virus infection, a close relative of XMRV, have
shown significant tissue involvement soon after infection, resulting in many physical symptoms
of disease including cognitive deficits and immune deficiencies, symptoms which are well
documented in patients with XMRV associated diseases.
Many anxious patients have asked, “Where do we go from here?” and “Is this the end of XMRV
research?” The answer to the second question is an unequivocal “no.” As to the first question, a
quick check of the status of ongoing research in various labs confirms that the research groups
who have been working on XMRV over the past year are still hard at work developing better
assays to check the world’s blood supply for the new retrovirus, finding correlates of immune
dysfunction, engaging in animal studies, extending their findings to other groups of patients, and
in general, enthusiastically continuing their research. They understand that novel scientific
discoveries, which threaten current dogma, will continue to be challenged until the evidence can
no longer be denied. For instance, there are still those few who question the fact that HIV is the
cause of AIDS. It took Nobel Prize winner, Dr. Barry Marshall, 17 years and three trials in
which he infected and then cured himself of H-Pylori associated ulcers, before the medical world
would accept the fact that the bacterium causes the disease. Today we are engaged in a new
battle to prove that human gamma retroviral infections, such as XMRV, are underlying
pathogens in neuro-immune diseases and untold cancers.
It is clear that more research must be done to clarify the role of gamma retroviruses in human
disease. However, when a pathogen such as XMRV is found in over 80% of those tested with
the same diagnosis, causality is clearly a reasonable hypothesis that begs further scientific and
medical research. It is a known fact that important questions of causality can often be answered
through well designed clinical trials. For those who have suffered for years from these
debilitating diseases, novel drug trials cannot begin soon enough.
WPI’s collaborative research projects are revealing the infectious and inflammatory nature of
neuro-immune diseases, providing strong evidence against the use of CBT and exercise therapy
as rational “treatments” for those who are ill. Such knowledge underscores the urgent need for
much more private and federal funding of biological research to provide diagnostic tests and
effective drug therapies for the millions who are ill, stop the spread of infectious retrovirus(es),
and end the devastating cycle of disease.
.
Annette Whittemore
President
Whittemore Peterson Institute
Thanks for the words but in the future, could you just provide a brief quote and a link? I’d prefer to have conversations in the comments rather than cut and pasting.
I wish Richard Gayle would follow his own advice, and recall the “tentative nature of most science.” The Mikovits team at WPI have been very careful not to claim that XMRV is the cause of CFS–they have allowed the statistics to suggest that, as they clearly do, but they have not claimed it as yet demonstrated.
Coffin, one of the lead authors of two of the studies cited, was also clear that these studies DO NOT show that XMRV is NOT the cause of CFS–they only show that researchers will have to be very careful of the possibility of contamination. The WPI scientists were very careful.
One prominent retrovirologist, Racaniello, came out with a hasty early judgement rather like Gayle’s, and has since offered a sincere retraction.
The Mikovits team has since published a small poster account of a small number of patients with both CFS and the cancers that tend to be associated with CFS (various lymphomas, etc) being treated with antiretrovirals, and improving in CFS and tumour markers, as well as general clinical symptomatology.
No, the causality of XMRV for CFS has not been proved yet, neither has it been claimed by the WPI researchers, but the case is looking stronger every week.
Let Richard Gayle wait for real science to do its job, as he recommends, and not jump to hasty media-style conclusions.
Chris Heppner
Perhaps XMRV will be shown to be involved at some point. I would certainly hope for that as CFS is such a nasty disease. In my opinion, though, the data do not support that yet.
If you read my initial report on the original work, I was quite hopeful at the time. But the model that XMRV is linked to CFS has taken some severe hits since then, with this latest one, greatly damaging the model.
In another complex disease, AIDS, the initial work that HIV was associated with the disease was greeted with skepticism. But further research increased the likelihood that the original work was correct. Here we seem to have a model moving in the opposite direction.
It will take some heavy lifting to successfully rebuild this model. I expect there will be more work done before all is said and done.
Just because you have a PhD doesn’t mean you have gone through the process of using your brain in this case. No positive studies have been invalidated. The NIH and FDA wouldn’t be doing a multicenter study if this was a blind alley. I suggest you go to the trouble of actually reading the positive studies – both for XMRV and MLVs.
I have read several of the positive studies. And I have read several of the negative studies. The model that XMRV is even linked to CFS (which I was enthusiastic about when I first wrote about his) seems weaker to me today than it was in 2009. That does not mean the model is a blind alley but a lot more work will have to be done to clarify what is going on.
I hope the NIH study finds something but simply because they are doing the study does not prove that there is anything going on. That is what they hope to find perhaps but I have been involved in studies that were done with a lot of hope that failed to find anything. That is the nature of such studies. They sometimes do go down blind alleys but, if constructed properly, they inform us about which is the correct alley to go down.
You say: “Here, we have a case of a lab that did not seem to fully perform this self-examination. They should have been the ones to find the contamination, rather than have others do it.”
You need to read the actual papers, not the press releases and the poorly thought out blog you reference here. There has been no evidence of lab contamination whatsoever at WPI or in the work of Alter/Lo/Komaroff of FDA/NIH/Harvard that came out in support of WPI’s findings. Dr. Mikovits researched HIV/AIDS for 20 years at NIH. She and her team know perfectly well the pitfalls of lab contamination, despite the innuendo that these contamination papers needed to “educate” virologists and retrovirologists on the matter.
The “we can’t find ANY XMRV” studies came out fast and furiously immediately after the WPI findings were published. They first tried to claim the WPI cohort was “regional” and when that was disproven, they lit upon the “contamination” strategy. This is a containment operation by the psychiatrists of UK’s National Health Service, where the insurance giant UNUMProvident is an advisor to the Works and Pensions department, advising them on how to deny disability payments to as many people as possible. I suggest you google UNUM and UNUMProvident for information on how this company operates in the UK and the US.
Their strategy is to have CFS seen as a mental illness. Disability insurance pays for only 6 months of treatment for mental illness. A retroviral illness lasts a lifetime and in the case of ME/CFS doesn’t kill nearly as quickly as HIV/AIDS. Antiretroviral drugs are a lot more expensive than Prozac.
Before you write another word about CFS, you need to read Osler’s Web by Hillary Johnson. (Osler was a physician who believed doctors could diagnose by listening to the patient – not by having them pee in a cup and extracting some blood for tests that are not able to find unknown illnesses.) Since you won’t bother to read the book, I suggest you read the section of her blog titled CDC Scandal. It gives the history of diversion of research funds and the “don’t confuse me with the facts” attitude CDC has had since the mid-80’s. http://www.oslersweb.com/newsletter.htm
Science didn’t “do its job” then and it still isn’t doing it when money and politics top critical thinking. It took a Congressional investigation in 1996 to get the CDC to stop stealing CFS research money. Since then, they have simply used the money to do “studies” purporting to find that CFS is mental illness, despite the department responsible for CFS research being located under the Chronic Viral Diseases Branch of the Nat’l Center for Emerging and Zoonotic Infectious Diseases.
Science has not yet done it’s job and it is you who are going the wrong way and need to go back. Virologist Vincent Rancaniello realized he’d been snowed by the “contamination papers” media blitz. He went back and retracted his intial quotes confirming them and he apologized for misinforming his readers. You should do the same.
I’ll write another post clarifying some things because it appears that I was not as clear as I thought I was. Sometimes happens.
I know about the terrible approaches taken to make CFS a mental disease. I have had friends and relatives dealing with this. So I was very enthusiastic when the first paper came out.
It seems to me that the model for XMRV being linked to the disease is weaker today than it was in 2009. That is why I wrote this post. Now you are stating that this is mainly because of a conspiracy of doctors and insurance companies to try and keep costs down.
That is possible. After all, the tobacco manufacturers spent lots of money on research to confuse things with regards to lung cancer. But it is also possible that you are wrong there, that XMRV is not involved and all the money spent on this research could be spent in other places to find the real cause.
That is why more research must be done but it must be done with a skeptical eye and careful controls.
I’m going to post something to
If I may add a brief PS to my previous comment, let me recommend this conversation with Eric Klein, one of the team that made the original discovery of XMRV in some prostate cancer; it strikes me as eminently informed and balanced, though it does not focus on CFS:
http://cfidsreport.com/News/11_Full_Interview_Eric_Klein_On_XMRV.html
Chris
According to your bio: you are a biochemist with 30 years of lab experience in biotech both at universities. You are NOT a Virologist or a Retroviroligst. Please remember what your educational and work background are in. When someone like Dr. Mikovits writes on these topics, she has the horsepower to do so – you do not. Stick to your own topics that you really know. Retrovirology is NOT your field.
You have little idea of my background or what I have been involved in. I’ve been researching viruses since graduate school. For example, I was VP of Research for 5 years at a biotech company that uses viral vectors in areas such as immunology, vaccinology, oncology and gene transfer. I have worked on projects looking at HIV, encephalitis, influenza and many other diseases. As our lab consisted for much of the time of 2 people, including me, I was directly involved in this at the bench. I have used just about every technique described in the papers I mentioned.
I certainly have the background to examine and criticize the technical aspects of the work. And finally, if the only people allowed to comment or criticize scientific papers are only those from that specific field of research, then peer review would not be possible. Most papers or grants are reviewed by scientists with a general knowledge of the field but not necessarily with a specific knowledge of the particular research area.
You say “all the money spent on this research could be spent in other places to find the real cause.”
What money? WPI’s research was done with a $5 million donation from the parents of a young woman who has had CFS since she was 12. The NIH has dedicated $5 million dollars to CFS research for 2011 – the same as last year, despite the findings in 2009 and 2010. WPI requests for funding are being turned down.
From NIH, funding estimates for 2011: aphasia ($23 million); ataxia telangiectasia ($13 million for the approx. 6,800 US patients); autoimmune disease ($923 million); brain disorders ($3,733 million); cancer ($6,036 million); burden of illness ($46 million); cardiovascular ($2,115); Charcot-Marie-Tooth Disease ($15 million!!!); clinical trials ($3,132 million); depression ($426 million); peptic ulcer ($17 million!!! – contact Barry Marshall, please! He’s already solved this one!); dystonia ($17 million); emerging infectious diseases ($2,194 million); estrogen ($248 million); fibromyalgia ($12 million); fragile X syndrome ($29 million); Frontotemperal Dementia ($23 million). Then there’s the $3.184 BILLION for HIV/AIDS and $603 million for AIDS Vaccine research.
I do not claim to know that XMRV is the cause, or one cause, of ME/CFS. I just want it thoroughly investigated before the burial. It is very disappointing when people like you aren’t more discerning, yet accuse the public and the media of not being discerning. For those of us who have been following both the science and the politics for decades, the media blitz coming out of UK and a low-quality publication like Retrovirology (impact factor 11 vs 27 for Science), and the timing of that media blitz, throws up a red flag.
You say the model for XMRV being the cause of CFS is weaker than it was in 2009, but you only cite papers that come from the groups that already claim to know what causes CFS: erroneous illness beliefs, mental illness, depression. McClure got her 14 year old samples from Simon Wessely, the psychiatrist who has been applying pretzel logic to the biomedical evidence in ME/CFS for decades. She then declared she was “1000% sure” there was no XMRV in UK. She also declared she “washed her hands” of CFS research, but here she is back, infering contamination in every lab must be true because it is known to be true is some labs. This is not scientific objectivity. It’s propaganda. It is full of innuendo, with deniability for later when it will be shown they were wrong. As Dr Klimas said, lab contamination won’t grow antibodies or show immune response.
At any rate, Dr Ila Singh has found that 3 antiretroviral drugs approved for HIV are also effective against XMRV and MLVs in vitro. Some physicians are prescribing these ARVs off label. Many patients and their doctors are reporting stunning improvements. Dr Mikovits will report on this and other facets of XMRV research on Jan. 17 in Santa Rosa CA.
Two XMRV + physicians with CFS have also reported on their experimental treatment with ART. See here for details: http://biomedicalmecfs.blogspot.com/2011/01/two-physicians-try-antiretroviral-drugs.html
I’m a virology grad student at UMD. My concern with the validity of the Mikovits research is reproducibility of the results. A blind study headed up by Ian Lipkin will test fresh blood samples from 100 CFS patients and 100 healthy people from different areas of the country. Labs from the FDA, CDC and Whittemore Peterson Institute will all test the the samples for XMRV. If one lab finds a (+) result but another doesn’t, a duplicate sample will be sent with a new blind code. If they get the same results – it’s
valid.
Remember Koch’s postulates from High School?
– The microorgamism must be found in the organism
inflicted with the disease
– The microorganism should cause disease when
introduced into a healthy organism
– Must be reproducible
We will all know the truth – hopefully soon. I have a friend with prostate cancer. – MK (link below)
http://www.mecfsforums.com/wiki/Ongoing_ME_or_CFS_related_XMRV_studies
Maybe XMRV is nothing, but I’m XMRV positive. I contacted the CDC & a local researcher working with the NIH. Still playing phone tag with the doc from the CDC, but will be donating blood to the researcher trying to tie XMRV to any human pathogens. This very respectable researcher, who has contributed vastly to HIV studies, stated he was impressed by the serology test available. How do I have an immune response to something that’s a lab contaminate from human derived XMRV serology test? I do not have a CFS diagnosis, but my body has been deceiving me since I contracted the worst flu ever in 1989 in which I have never recovered.