The Slow, Slow Road to De-Discovery

The virus known as XMRV does not cause chronic fatigue syndrome.

Achieving this particular bit of knowledge has taken a pretty spectacular couple of years.

In October 2009, Judy Mikovits, a scientist then at the Whittemore Peterson Institute in Reno, Nevada, and her colleagues published a startling paper. They found that 68 out of 101 people suffering from chronic fatigue syndrome (also known as myalgic encephalomyelitis) carried a virus called XMRV. Only 8 out of 218 healthy people had it. That’s 67% versus 3.7%. Mikovits and her colleagues raised the possibility that the virus played a part in the disorder, which affects an estimated 60 million people. If that were true, then there might be a straightforward way to treat people: wipe out the offending virus.

Very quickly, a number of other scientists replicated the experiment. One team found evdience of a different virus in some of their subjects–not XMRV. The other scientists couldn’t find any virus at all that was present in any significant number of people with chronic fatigue and not in people without it.

With remarkable speed, the study and the follow-up research gave rise to a fierce controversy. Critics dismissed Mikovits’s work as nothing more than contamination (the virus is common in mice). Mikovits dismissed her critics becasue they hadn’t replicated her experiment closely enough to really test it. Many people with chronic fatigue syndrome, embittered by years of suffering (and suggestions that it was all in their head) rallied around Mikovits. (To get a sense of the back story, see the comments many people left on a blog post I wrote about this controversy last year.)

A few months into the controversy, I was at Columbia University to interview a scientist named Ian Lipkin for a profile for the New York Times. I focused mainly on his research linking viruses to new diseases. But Lipkin also does the reverse–what he likes to call “de-discovery.” When someone makes a controversial claim that virus X causes condition Y, Lipkin sometimes puts the claim to the test. Lipkin explained to me how it’s important to get everyone on board with such a replication study–both the original scientists and their critics. And he told me that he had launched a big study on XMRV, in collaboration with a team of scientists that included Mikovits, scientists who failed to find a link, and others. (I wrote more generally about de-discovery last year in the Times.)

The study would take a lot of time. The scientists and doctors would examine 147 people with chronic fatigue and 146 normal people, giving them thorough medical exams and a close inspection of their blood. Several labs would use identical methods to search for XMRV. And in that time a lot happened.

More scientists investigated XMRV on their own and found still more evidence that the viruses had likely contaminated Mikovits’s cell cultures. Mikovits wouldn’t budge, even as Science retracted the paper in December 2011. Meanwhile, Mikovits got into a battle royale with her institute, getting locked out of her office, sneaking in a grad student in to get her notebooks (possibly to work on Lipkin’s study), and spending five days in jail.

Today, nearly three years after the start of the XMRV affair, the big study came out in the journal mBio. The scientists found no evidence of XMRV in people with chronic fatigue. Mikovits fully endorsed the conclusion.

I am curious how people with this condition view this finding. I find it pretty depressing. It’s taken up plenty of money along with the valuable time of lots of talented researchers. It’s raised and then dashed hopes. And all we have to show for it is the lack of a link. What causes chronic fatigue syndrome? Your guess is as good as mine.

It would be nice if there was a simple set of instructions for finding the cause, but that’s probably just a fantasy. Perhaps the best we can hope for is to avoid these expensive, time-consuming wrestling matches in the first place. That’s why I find projects like the Reproducibility Intiative so interesting. When scientists make mistakes, let’s find out as fast as possible.

Here’s some more information on the saga:

Nature interview today with Ian Lipkin

Ivan Oransky reporting in Retraction Watch

Martin Enserink reporting in Science

Another team of researchers also published a paper today in PLOS One refuting another proposed link: between XMRV and prostate cancer.

[Apologies for a few typos, now fixed–I hit “publish” instead of “save draft”!]

50 thoughts on “The Slow, Slow Road to De-Discovery

  1. Carl, based on your experience with this story, was there anything that could have been done from the outset to prevent the publication of what we now know to be a false positive? It seems that once that brick was laid, all the rest of it fell into place.

    [CZ: I suspect that if there had been an external Reproducibility Initiative replication from the get-go, it might well have failed to have establish a link, and people would have looked at the original study with skepticism.]

  2. It’s depressing, costly and lengthy, but things are getting better and faster. Lipkin himself will tell you about the amount of time it took him to “de-discover” the link between Borna virus and schizophrenia–I think about 30 years since he first started working on it to good studies showing no links. So, a few years for XMRV is progress, I guess. Now the big question–will patients accept the new research, or will you have holdouts like vaccines/autism?

  3. I am curious how people with this condition view this finding.

    Many of us were cautious from the very beginning, simply from prior experience with (admittedly usually less apparently comprehensive) “breakthroughs” that never seemed to actually go anywhere. Most of us knew better than to get our hopes up — which is probably why the folks who did allow themselves to hope became perhaps overly-invested in the results.

  4. “CZ: I suspect that if there had been an external Reproducibility Initiative replication from the get-go, it might well have failed to have establish a link”

    Carl – I disagree; or at least I certainly don’t think it’s as clear-cut as that. This study shows how hard it is to perform these de-discovery studies. The contamination fooled some very good researchers; it took real specialists to demonstrate where the contamination could be coming from, and that was the work that told further highly skilled people how to avoid that contamination. Check out how careful they were here to avoid the sources of contamination that had previously been shown.

    Would hypothetical Reproducibility Initiative workers have taken the same care to avoid the PCR components now known to be sources of contamination? Would it have been in their mandate to first search multiple commercial sources of PCR enzymes, before testing clinical samples, to see if there was possible contamination?

    I think it’s just as likely that the Reproducibility Initiative workers would have confirmed the initial finding, by reproducing the contamination, and that would have made things even worse.

  5. Now the big question–will patients accept the new research, or will you have holdouts like vaccines/autism?

    I’m sure there will be holdouts — there are always holdouts — but the fact that Mikovits herself has signed off on this study should help keep that to a minimum, I would think.

  6. Bringing my comment from G+ over here because I was finally able to crystallize what I was thinking, after deleting 3 comments here:

    I wonder if “Can we speed up science?” is the right question. I think maybe the question is: shall we manage expectations appropriately? Shall we not hyperventilate from press releases?

  7. As a patient myself, I have learned a lot on how science works from science bloggers like yourself, Vincent Racaniello, ERV, and many others. Thank you all for that.

    Could this have been prevented, of getting so out of hand. No, not this one I think. Scientists and science bloggers have now become aware of the power of social media (for better of for worse) for spreading information (false or true). Keep providing good information, assume that not everyone from your audience understands how science works, so provide context, and maybe make yourselfs available for questions. Science-literate and skeptic patients can then introduce the information in the patient community.

    Was it worth it? Yes. After decades of neglect a lot of the scientists who came into contact with this disease for the first time and started looking things up, got an aha-erlebnis. This is the one from Vincent Racaniello from an interview with David Tuller:

    Dr. Racaniello said that when he used to question colleagues about chronic fatigue syndrome, they would argue that it was an imaginary illness. “Every time I asked someone about it, they would say it doesn’t exist, it isn’t a real disease, even as recently as the past year,” he said. “But once you start paying attention and reading papers, this looks like a chronic or hyper-immune activation. These patients have a lot of signs that their immune systems are firing almost constantly.”

    This disease got a lot more attention in the past 2 years than in the past 2 decades. So, yeah, it was worth it.

    Is it over now? The majority of patients accept the results and a smaller majority already did so for quite some time. A very small but very vocal minority, a couple of people on Twitter, don’t accept it and they will spread the word about conspiracies, …. occasionally getting help from a dozen or so hangers on. Best to make sure good information is available out there and for the rest not to feed the trolls.

  8. Yeah, I want to reiterate along with Ray Radlein that many people in the Chronic Fatigue community were at best cautiously optimistic about this study, and did not hold out against the evidence of multiple failed replications.

  9. Could the original study have been prevented? How can we avoid doing studies like this? I don’t understand these questions. Studies with errors are published all the time. The original study did an extraordinary job of trying the best they could with what they knew at the time, to verify the accuracy before publishing. This was tested in THREE different labs prior to publication.
    Eventually it was apparent that there was an error, but this is kind of normal, isn’t it? We then accept the new information and go on. (Or ideally we do; it seems a lot of medicine is based on outdated studies.)

    The study which came out today was important because none of the other studies had thoroughly addressed whether there might be an association of XMRV/pMLVs to ME or CFS when care was taken with patient selection and when investigators were given a chance to use their best techniques. This is what Dr. Lipkin said today.

    It is essential that we do take the time and funds needed to undertake careful science to examine issues like this.

    Importantly, the first study brought vital attention to a badly neglected disease. Although our hopes of an FDA-approved treatment were dashed, I would not go back. Many scientists are now aware that this is a real and serious disease, who were not aware of it previously.

    To answer what the community thinks, many of us are relieved to not have a retrovirus, but we are very worried that there will not be funding to study other avenues less dramatic than XMRV was. And there are many promising avenues of research.


  10. As a 15 year CFS sufferer, yes it’s disappointing, yes it’s frustrating. But that’s science. Those Eureka breakthroughs don’t happen often which is why we need as many people as we can get following as many possibilities as the funds will allow. And people double-checking the results. Like many of us I try to follow the research as well as my level of knowledge will allow and rule one is don’t get excited about promising results from a small trial group.

  11. “I am curious how people with this condition view this finding. I find it pretty depressing. It’s taken up plenty of money along with the valuable time of lots of talented researchers. It’s raised and then dashed hopes. And all we have to show for it is the lack of a link.”

    The study findings themselves were anticlimactic to most of us. I think most of us had already written off XMRV after the really good studies began to come out. The early, quick-and-dirty studies that followed Lombardi had not been very persuasive. Those of us who even vaguely understand the science rightly said of those early papers, “This is crap; do better.” But when Ila Singh’s paper came out, it was game over for me. The later contamination papers by Silverman et. al. were, or should have been, the final nail in the coffin.

    But the Lipkin study had already been set in motion and needed to be followed through, although many of us winced at the cost, knowing how critically underfunded ME/CFS research has always been. It seemed like a lot to spend to demonstrate something that had already been demonstrated quite well.

    But the fact that such an intensive investigation was even carried out is actually a major step forward for ME/CFS science.

    It is important to remember that decades went by in which ME/CFS research was so benighted that numerous potential leads on biomedical abnormalities were *never* followed up, or barely followed up, because of the lack of funding and interest, the poor handling of the case definition of the disease, and – if we are very honest – the enormous stigma attached to the disease, its victims, and anyone who took their physical complaints seriously.

    Given this history, it is not hard to understand why it was so important to go the extra mile with replication attempts on the Lombardi findings. But those millions were not spent on a purely symbolic effort to calm down a small group of loud patients. (And they *are* a small group: twenty people posting 500 times each on the Internet can make a tiny minority seem unduly significant.) Dr Lipkin may have pulled off a political master stroke in bringing Dr. Mikovits right into the fold from the very beginning, involving her in the study design and making her one of the investigators, and having her fully endorse the results. Dr Lipkin raised an interesting notion in his Nature interview today: If Andrew Wakefield’s initial findings had been quickly and aggressively investigated in a process of equal power and scope to the XMRV study, would the vaccine/autism controversy have evolved quite the way it did?

    I’ve gradually, reluctantly come to agree that the Lombardi paper and all its fallout actually turned out to be an enormous net positive for ME/CFS research. Everybody would rather not have gone through the uglier parts of the controversy, of course. But since October 2009, a great many other interesting things have happened in ME/CFS research. The Lombardi paper got people’s attention; new researchers coming in without the preconceptions and prejudices of the past “chilling effect” generation have been immediately struck by how critically ill this patient population is, how little has been done for them, and what an intriguing challenge their disease actually presents. That’s not what I would call depressing.

    Lipkin: “What I say to [patients] is this: the fact that we did this study means we did take you seriously. We didn’t do a shoddy piece of work. We’re ready to invest in the next phase of research. There are all these samples that will be available. There will be funding opportunities. It’s evidence, I think, of an unprecedented opportunity for people to do basic and applied research into the causes and ways in which one can prevent or mitigate the tragedy that is CFS. People with CFS should actually feel heartened that there’s more energy and effort going into this. It wouldn’t make any sense for us to dwell on something that doesn’t work.”

  12. @Janelle Wiley:

    “Could the original study have been prevented? How can we avoid doing studies like this? I don’t understand these questions.”

    I’m not sure where you got those questions—Carl didn’t ask them, nor did any commenter before you. I did see Carl ask how the negative consequences—viz. the “battle royale” between Mikovits and her institute, the “expensive, time-consuming wrestling matches”—but I’m not sure where you get the impression that this means the study should not have been performed. Rather, perhaps, it would have been better had it not been pushed so hard in the media until after high-quality attempts at replication.

  13. Good piece. In my view a Reproducability Initiative wouldn’t have changed much because we already had one in this case – as soon as the paper came out, a whole bunch of people leapt into action and tried to replicate it – indeed, they did so faster, and better, than almost any other case I can think of.

    I really think that overall this is a success story for science. A claim came out, it was plausible and important if true, it failed to replicate, and we worked out what had gone wrong (mouse dna). And all within about 2 years which is really as fast as science gets.

    However questions remain over the original Science paper that will need to be answered, such as:

    – Why, if XMRV is a lab contaminant, were the CFS samples more contaminated than the controls?
    – Why were Western blots mislabelled in some presentations of the findings? (as proven by erv? Were there further cases we don’t know about?
    – What was the relationship, if any, between the researchers on the Lombardi paper and the people at the WPI responsible for offering XMRV testing ‘clinically’? Was that a commerical conflict of interest?

  14. @Petter Haggholm, my questions were from Carl Zimmer: “Perhaps the best we can hope for is to avoid these expensive, time-consuming wrestling matches in the first place.” (which I interpreted to include doing this last study, which was expensive [debates are not expensive], but as Anne Boyd has rightly pointed out, can be used for other science, so the expense is not solely for a negative XMRV study.

    Certainly some of the quick-and-dirty studies with useless inclusion criteria, for example, were unnecessary, and certainly we’d figured out based on the Singh study that it was more likely than not that this one would be negative, but this study was an important piece of doing thorough science. See the second paragraph in my comment #9 for why.)

    and from Ed Yong: “was there anything that could have been done from the outset to prevent the publication of what we now know to be a false positive?”

    Both are fine people, and I don’t mean to pick on them, but those do seem like odd questions/statements. Perhaps I misinterpreted Zimmer somewhat, but it seems difficult to translate ‘expense’ into something other than this study.

  15. The most depressing thing about htis saga is that:

    a) Lipkin knew that it was important that Mikovits endorsed the results, in order for the patient community to accept the demise of XMRV;

    b) because of this, Lipkin has been very mild end even complimentary towards Mikovits;

    c) the unscientific, unacceptable and sometimes even agressive behavior of Mikovits is the most important reason for this three year long “delay”.

    When the first negative studies were brought up, Mikovits could and should have done what was basically done here, but then on a much smaller scale: simply recollect some patient/control samples (but now under the same conditions!), BLIND them, and them test them internally. Even with a re-sample size of, say, 10 patients and 10 controls, Mikovits could have found out that her first results were crap, with a series of tests, within a few weeks. It is clear that, after the first positive results, Mikovits “knew” that she was right, and basically refused to critically re-examine this position.

    The same applies to a lesser degree to Ruscetti. It baffles my mind how a scientist with such a great track record can be so un-critical towards his own findings. The (very succesful) virus hunter Patrick S. Moore says in this regard:

    “My advice, above all else, is to test samples blindly and randomly. […] Randomized and blinded testing has saved me, on multiple occasions, from appearing to be a bigger idiot than my natural talents for idiocy allow.”

    It’s perfectly okay to be biased, but recognize your bias, or at least recognize that there is a possibility of bias, and create (follow-up) experiments that eliminate this possible bias. Knowing that after the initial “Lombardi” finding, Mikovits and Ruscetti reported (at multiple conferences) on a “positive ” XMRV/autism study and on a “succesful replication” of their initial study by testing 50 British CFS patients, it is laughable to now deem them as ‘courageous’, or as examples for the world of science, for finally doing what every normal scientist should have done much sooner.

  16. I’m an ME/CFS patient, and I applaud Ian Lipkin’s work. I applaud Dr Mikovits too, for her commitment to patients (despite enormous personal sacrifice), and also her ability to accept new data and move on. I think the vast majority of ME/CFS patients are just glad research is being done (perhaps even a bit more research than in the past) and let’s not pay too much attention to any small, vocal minorities who say otherwise. I paid money for an XMRV test, but it’s water under the bridge – I knew it was bleeding edge, it didn’t work out, what’s next?

  17. To pile on RRM’s comment:

    My view is that Mikovits and Ruscetti (and Lombardi) were bloody well aware what went into the lab-results they reported. There were a couple of things they could have done to prevent this – but they didn’t do them, not even when asked to do them. Furthermore much of what Mikovits has said (outside peer-review) seemed to me intentionally misleading.

    Karl Kraus once said (in much more dire times):
    “The unimaginable is happening, because people can not imagine it.”

    We need to imagine that a small minority of scientists are actually frauds.

    So if we consider the possibility of fraud, the question “How could we have prevented this?” becomes: “How can we better check for fraud?”

    Or rather: how can we mitigate the harmful effects of fraud, without crippling the scientific process?

    What needs to be done now? Someone needs to FOIA the lab notebooks and the emails from Ruscetti, and the others involved at the NCI lab.

  18. @neuroskeptic I’ve often wondered how exactly this happened, too. But I don’t think we’ll ever get a better explanation than Vinay Pathak and John Coffin’s “Recombinant origin of XMRV” paper ( Simply, the virus was created when two endogenous mouse retroviruses recombined during the establishment of a prostate cancer cell line (22rv1) in the 1990s.

    It would be time-consuming, costly and probably impossible to determine how individual samples became contaminated, or how certain erroneous data were produced. When I interviewed one of the co-discoverers of XMRV in early 2011, he told me he stayed up at night trying to figure out exactly how his samples were first contaminated. Ultimately he accepted that they were and moved on.

    As to Ed’s question as to whether this could have been prevented, I think it could have. The Lipkin study is proof that the scientific process works — “You put ideas up, you try and knock them down, and then you move on,” he said at the press conference yesterday.

    But you could argue that the original paper represents a failure of the scientific review process. In early 2011, I went over the Lombardi et al paper, figure by figure, with a prominent retrovirologist, and he pointed out obvious flaws with nearly every piece of data supporting XMRV. Also, viruses like XMRV are notorious contaminants in mammalian cell culture, and the possibility of contamination was on reviewers’ minds (see Lastly, Lombardi et al never produced DNA sequences showing the virus genome integrated into the human genome — the gold standard for proving a retroviral infection. Judy Mikovits told me that the reviewers originally asked for that data, but later backed down when she produced other evidence supporting infection. (I have not been able to confirm this point independently.)

    All of this comes with the benefit of hindsight, of course. But given the intense level of discussion surrounding this paper while it was in review [as reported by Nature ( and Science (], I think it’s fair to conlude that this study never should have seen the light of day — at least in a journal as prominent as Science.

  19. Tony Mach: Erm, steady on. I think everyone can ‘imagine’ what may have gone on here. There’s no evidence it was fraud, although that has, I’m sure, crossed many people’s minds.

  20. Ewen Callaway: Interesting… but then hindsight is 20/20. We now know that XMRV is a dud. But imagine it had turned out to be real and a real cause of cancer and CFS, we wouldn’t be worrying about the flaws in the original paper. So when judging whether or not it should have been published, we need to suppress our knowledge of how things turned out in the end (not easy).

  21. I find it hard to let go of all of this.

    I have had close relationship with Dr Mikovits the past few years, I read all the data & ideas from her and Dr Francis Ruscetti. I have seen presentations where they are both speaking.

    and they were on to something…. okay NOT ‘XMRV’…. but they were looking at a connection with mouse retroviruses and the disease M.E.

    Dr Ruscetti and Dr Mikovits were I would say convinced that they were picking up these viruses for many years now and when I saw them yesterday at the Lipkin conference and they basically said.. sorry no its over. I’m sorry I just didn’t understand.

    I don’t think this is the last we will here of Mouse retroviruses being found in various diseases. I just hope it doesn’t take too long for it to surface again for the sake of all of us.

  22. And one more thing: If you go read John Crewdson’s book “Science Fictions”, which is an account of the work of Robert Gallo, and then look into what Judy Mikovits has done, you will see some parallels – Mikovits almost seems like a mini-me copy of the Gallo portrayed by Crewdson. So either Mikovits used “Science Fictions” as an manual, or perhaps she learned the trade from someone who learned from Gallo. I wonder, why is the name Francis Ruscetti suddenly on my mind?

    What Mikovits has done wasn’t a “bolt out of the blue”, it has instead (by now) a rather long history. The XMRV-fraud has been made possible because there hasn’t been a proper investigation into Robert Gallo’s behavior and because Gallo has never been held accountable for his actions. If you want to understand what has happened at the WPI and NCI labs, and if you want to see how long this goes back, you need to revisits history and see what went wrong there.

    And I would be the slightest bit surprised if someone digs into the research of these people and finds more “problematic” papers.

    (And just for the record: It was Luc Montagnier in his sane days together with Françoise Barré-Sinoussi that found HIV, then called LAV, as the cause of AIDS – Gallo’s only contribution to AIDS research was misinformation to push his HTLV.)

  23. @Neuroskeptic:

    Sure, they haven’t been found guilty of fraud (yet), but to use more from the Patrick Moore quote that RRM supplied, there are some indications to consider fraud:

    Patrick Moore
    March 6, 2011, 9:05 pm

    The CFS peripheral blood cells have robust monotonic staining rather than the bimodal peaks that are expected from a mixture of infected and uninfected populations of peripheral blood cells. It is not certain whether this level of viremia for an exogenous retrovirus is medically possible. It may, perhaps, be possible but it seems improbable and is a pattern more consistent with a cross-reactive endogenous retroviral antigen.

    And you do remember the Mikovits slide(s) of shame?

  24. @Neuroskeptic:

    And I invite you to take the 2010 “Addendum” by Mikovits and Ruscetti, take the table 4 from that addendum and put the table in your favorite software (a spreadsheet will do fine, but if you have R or something like that, go right ahead with that). After you’ve done that, you can cross check the content of table 4 with the various other claims made by Mikovits and Ruscetti (e.g. from the 2009 paper of theirs, or even other claims made in the 2010 addendum).

    I’ve done it and posted the results on my blog – but it is far more instructive if you find out yourself how far away from real life processes the results reported by Mikovits and Ruscetti are. And I’m sure I’ve found only the most glaring inconsistencies, and I think that there are more problems to be found in the joint work of Mikovits and Ruscetti.

    Then, when you have done that, I want to know wether you still insist that fraud is not the most likely explanation for the XMRV-mess we have seen over the last three years.

    And as RRM mentioned the autism/XMRV “study” above in passing: the numbers of their unpublished “study” (only the abstract was posted for an conference) on XMRV in autism are not internally consistent, to name only one more problem – don’t believe us, be a skeptic, check it yourself.

  25. I’ve spent the past six years immersed in talking to people in the online ME/CFS community about the things that make a difference in their health. Almost without exception, the people who have made substantial improvements have done so largely or wholly as a result of addressing toxic exposures in general and, for the most part, environmental biotoxin exposures (such as toxic mold) in particular.

    And yet, “experts” in the disease seem to be continuing to take one of two approaches: 1) this disease is caused by pathogens and we need to keep looking for what those might be or 2) we have no clue what causes this disease and shouldn’t even bother to find out.

    Like AIDS patients, ME/CFS patients are riddled with a wide variety of pathogens. That’s why the attention keeps going back to retroviruses: because that’s one possible explanation for the immune problems. But toxins potentially could be doing the same thing to our immune systems.

    I think it’s time for researchers to start thinking about toxins as a possible cause of this disease. Hopefully the firm conclusion that XMRV is not related to the disease and will encourage them to start looking into this.

  26. This is a non-event for me. Once I understood that the initial result was due to contamination I focused on the likely autoimmune nature of the disease. When I was treated for an unrelated cancer, the chemotherapy treatments had an amazing effect. I went from not being able to walk more than half a block to suddenly not knowing WHERE my energy limits were. My nurses at MD Anderson and my doctor who treats my CFS mentioned that this is very common when CFS patients are treated with chemotherapy drugs. When I was diagnosed with cancer, many people helped me with food, errands, etc. The irony was that, in terms of weakness/fatigue, I felt better than I had in over a decade! It’s very frustrating to me that movement on this observation is so slow (but it’s picking up with rituximab).

    So, I moved on from XMRV long ago. I wish the money invested in this study could have been used to focus on a positive causation, and not a negative one, but I do understand why it was done.

  27. The witch hunt against the researchers involved in the Science study will bear as much fruit as the efforts of the XMRV militants still around. I cannot speculate as to the emotional drive behind the obsession with Drs. Mikovits and Ruscetti besides a subconcious fear that they are close to revealing uncomfortable truths. I on the other hand look forward to following future ethically sound research conducted by Drs. Mikovits and Ruscetti.

  28. I feel hopeful. The XMRV issue has been sorted out and now the research community can focus on the promising and intriguing leads in immunology and neurology (immune system abnormalities, differences in protein profiles in spinal fluid, physiological abnormalities after exercise, etc).

    Perhaps some researchers who previously didn’t know very much about ME/CFS have now been made aware of the nature of this disease, how devastating it is, and how crucial it is to map out the biomedical disease mechanisms.

    In Nature interview, Lipkin said: “It’s evidence, I think, of an unprecedented opportunity for people to do basic and applied research into the causes and ways in which one can prevent or mitigate the tragedy that is CFS. People with CFS should actually feel heartened that there’s more energy and effort going into this.”

  29. I feel duped.

    I fully and completely believe Judy Mikovitz and the Whittemores. Heck, Andrea Whittemore had already friended me on Facebook even before the Science article was published. I was so excited to think an explanation of my total dehabilitation that came with my CFS had been found and that treatment , maybe even a cure was right around the corner. I believed every word they said. I contributed my birthday money like they urged. I watched another believer use her last $450.00 in the world to buy an XRMV test and when it showed negative her husband left her saying she was faking it. I continued to believe no matter how many negative results other scientists found. Yep, I was a believer.
    It was all a lie.
    The WPI has a big beautiful building and I remain very sick and home bound with CFS.

    Like I said, I feel duped.

  30. Frankly I was surprised that Judy Mikovits would ever admit that she was wrong. Imagine an alternative scenario where when she found she could not replicate her results in the Lipkin study, Judy abruptly pulled out of the study claiming that there was a conspiracy against her and that she would start her own research institute with direct funding from patients. I’d imagine in that scenario many patients would not know what to think and that a group of “true believers” would become even more convinced of the accuracy of the initial result.

    We are lucky that in the end Judy Mikovits had enough scientific integrity to admit she was wrong. It’s not hard to imagine that some future researcher with less integrity would not do so. Then the gap in perceptions between the patient community and the scientific community would be quite large. There are quite a lot of people out there who are fervently looking for something to believe in (even if that something is not true scientifically speaking). Someone aspiring to fame and adulation might be tempted to play on such appetites. Who knows how much money could be raised by such an individual.

  31. I am very glad that Ian Lipkin conducted a study with Judy Mikovits, Harvey Alter and others, and all were involved with study design, cohort selection and methodology they woulduse. in the end, as a patient, it is clear in my mind that no rocks were left unturned when it comes to XMRV.

    Moreover, Ian Lipkin took the time to organize a press conference and speak to Vincent Racaniello and reassured patients it was not the end of research for ME/CFS. It was a very sensible thing to do for our community.

    ME/CFS have been the butt of the joke and neglected both in the scientific and medical community for way too long. We are in 2012 what HIV patients were in 1981. Mainstream physicians do not recognize our illness, or think our illness is benign. We are sick! We need biomarkers, research, clinical trials and treatments.

    Seabiscuit author Laura Hillenbrand, patient with ME/CFS once said “Fatigue is to chronic fatigue syndrome what a match is to the atomic bomb”

  32. Like some of the other patients that have left replies on this article, I was cautiously optimistic when news broke about the potential XMRV-CFS link. I never got too excited. I knew that even if XMRV was the cause of my suffering it would still take years until some treatment came along that would make me feel better. As a person who is suffering, it really all boils down to one question: when is help coming? Discovery of a cause/causes is just a step in the process, an albeit critical one, but not the end. The end is what is more exciting and is a source of faint hope.

    Its such a relief to have this behind us, and now have the ability to do new explorations with the added benefit of world-wide interest. Im grateful to Dr. Lipkin and all those agencies involved in this finding. The sooner we make new discoveries, the sooner a treatment will be available for us.

  33. Nov 2 2010 – Whittemore Peterson Institute Moving Day.

    I got an email that morning from Dr Judy Mikovits the morning of Nov 2, “Today is the Big Day”.
    The new building is finally completed and it is time to move the lab from its temporary quarters in the Applied Research Facility (ARF building) up to the WPI’s newly finished laboratory wing.
    I showed up for the scheduled 10am move and found…. nothing was boxed up. No signs of any preperation or packing at all.
    The WPI didn’t even have any boxes FOR packing… very strange. So, to “get ‘er done” I scrambled and scrounged around to get as many cardboard boxes as I could, and began boxing up the equipment, to be ready for when the moving truck arrived.
    After several hours, I noticed that I was working completely alone. (Seemed a bit odd) No truck – no help.
    Dr Judy told me why. The brakes on the moving truck had failed, and so, the helpers were dealing with that, and platform lifter was unavailable until they could get it fixed..
    The move would have to be postponed…. or would it?
    I told Dr Judy that I have a cargo trailer. After asking the Whittemores permission, told me to “Go get it”… so I did.
    With occasional help from Max and Dr Lombardi, I continued boxing up the equipment and carried it to my trailer.
    There was a lot of stuff, and it took several trips from the ARF building up to the north end of the University of Nevada Reno campus to the new WPI building, about 3/4’s of a mile away.
    It took two days to complete the move. On the second day, the truck and a team of movers finally showed up for the heavy freezers and large pieces of lab equipment. (Whew!) Still, it’s kind of neat that an original survivor of the Tahoe epidemic had the privilege of moving the WPI into the fabulous new building. (Very impressive.)
    As a result, my cargo trailer has the distinction of being “Home of the WPI”… or at least, the controversial lab equipment… for a few hours, anyway. But that’s not why I brought this crazy story up.
    As I was carrying boxes out of the door of the lab, I almost ran into a girl out in the hallway carrying a tray.
    A tray of lab mice.
    She had just come out of the door directly opposite Dr Judy’s lab, and was headed into Dr Hunters office immediately next door.
    I could look in the open door and see lockers with more trays, and more mice. What the HELL?
    I had heard about the XMRV contamination theories, and in shock, I realized that the entire place must be drenched with lab mouse particles; People, clothing, equipment, supplies.. everything must be coated with parts of mices!
    It may be true that no “mouse work” was done INSIDE Dr Judy’s lab… but that’s kind of a semantic technicality, under the circumstances of being surrounded by them. I asked Dr Judy about it, and she told me that this couldn’t affect a patients serological reaction to the PCR testing. So what do I know? That sounds good enough to me, and if Dr Hunter or none of the others say anything about the place being lousy with mice, they must be satisfied with their reasons.
    And if none of the great geniuses who are implicating contamination think to simply go to the ARF building and look around for mice, they must not be worried about it too much either.
    I would have talked with “CFS advocates” about my mouse particle concerns, but since none of them will speak to an Incline Village survivor and prototype for CFS about anything, that option was totally off the table.
    (How odd that the entire CFS community sees fit to treat someone in my position this way. You’d think it would be the opposite)

    I have no idea if the presence of mice adjacent to Dr Judy’s lab in the ARF building had anything to do with this whole XMRV debacle, but I do know this.
    As with “All things CFS” it strongly appears that people blindly went ahead with
    innumerable hypotheses, concepts, theories and rationalizations from far, far-away places….. and just plain “Never Bothered To Look” where the Xhit actually hits the fan.

  34. I share the concerns expressed by RRM above. I have had the ME diagnosis for 14 years or so now and I find it staggering that any one scientist can seemingly hold the scientific world to ransom like Mikovits has done. And it was always Mikovits and nobody else on that infamous paper. Where was Lombardi throughout all of this for example? Mikovits the ‘maverick’ put herself in front and become the ‘golden girl’ bathing in the limelight who felt she could do not wrong.

    Lipkin almost seemed to be suggesting that the only way to quash the speculation caused by ‘maverick’ scientists who roam the world causing both hope and alarm – is to spend a vast sum of money and time to prove them wrong; and I just felt like throwing up when Lipkin led an applause for Mikovits at the conference.

    All the spin over the last few years that has spawned from the things she has said, and not said but hinted at, have driven desperate patients to distraction. Science itself has to take some responsibility for even publishing the Lombardi et al paper in the first place and then sitting on it for two years despite all the papers that came out.

    Compare Silverman with Mikovits. Both were wrong but look at the behaviour of each. Silverman maintains the integrity in my opinion and I am appalled to learn that I am expected to show similar respect towards a ‘maverick’ like Mikovits.

    Would I also have been required to do so for Wakefield if he had shown such ‘courage’? Give me a break.

    Nobody seems to have mentioned the commercial ‘test’ that was promoted so much to vulnerable patients by WPI and Mikovits. How many times did patients who had received a ‘positive’ result feel justified in claiming their debilitation was the result of a retrovirus and that the treatment was being unjustly denied?

    Damn it. Even a ‘negative’ result was being said by Mikovits to mean a ‘positive’. Why can America allow such ‘tests’ to be sold to the public? What the heck is wrong with you guys? It makes no sense to me and is dangerous. Covering such a thing with the words ‘for research purposes only’ and yet charging for it and then trying to cover yourself by passing responsibility for interpretation on to a physician is inherently wrong.

    There are many answers that need addressing in regard to those ‘tests’ but for me the real debacle was that a rogue scientist was allowed (nay encouraged and applauded) for so heavily engaging with the patient population in the way that she did.

    The distinct lack of self-critique and this sole belief that ‘I am right and you are all wrong’ was never something to engender respect. I do wonder what those folk in Ireland and elsewhere on the whistle-stop tour feel now that all the implied belief has come crashing down.

    And we shouldn’t forget the Whittemore Peterson Institute either in all of this woeful tale. It is so wrong that long-suffering patients should be taken for a ride in the way that they have.

    Mikovits should have been muzzled from the beginning. I am all for scientists engaging with the public and helping us to understand science – but not when it is for purposes of self-promotion of an idea that leads to such fear and anxiety and ridicules the efforts of others in the scientific community.

    Refresh yourselves with a look at the ‘breakthrough’ announcement in 2009. Maybe one can appreciate the excitement but the rest? No. Absolutely not.

  35. As per a suggestion, I’m re-posting (from Facebook commentary) my feelings re this article: “The true “hurt” is when medical professionals don’t take you seriously. Forget that you “look good” most of the time; therefore no one else takes you seriously either! So, you do what you can within your own boundaries of energetic output. It took me a long time to find a wonderful MD/researcher in NYC who “gets” it; who has an open mind regarding conventional/alternative methods, AND who always has a proper treatment/suggestion on tap. If I had a dollar for every tear shed in offices of doctors, before, who DIDN’T take it seriously? Our research would have been extremely well funded (I know many of you can relate)! BUT back to the subject; if this particular research on XMRV didn’t pan out the way we might have liked, at least the issue is more present in the public eye. Being tired all the time because your immune system is on perennial overdrive has a name whether it’s ME, CFS, or CFIDS; a name more recognizable because of research projects. We, who are willing pin cushions and who deal with this everyday, need help. Believe me, I wouldn’t wish this disease on ANYONE…so to the scientists, I say…keep on keepin’ on. It’s only a matter of time and I offer many thanks for your efforts”…Lisa Bernstein

  36. Most CFS sufferers have no idea that mold in their homes is the probable cause of their ongoing illness, a conclusion that is supported by a massive amount of peer-reviewed research on the subject.

    With one of the world’s leading virologists now publicly stating that XMRV plays no role in CFS, and the original supposition of Epstien-Barr virus involvement long discounted, it is obviously now time for alternative etiologies be considered as subjects for research.

    During a recent FDA hearing on CFS, sufferer Jeri Kurre McClure testified her experience in recovering from CFS through avoidance of biotoxin triggers, specifically those from certain specie of toxic molds. A representative from the CFS advocacy organization Pandora can be seen backing Ms. McClure in the video link of this testimony linked below. It is encouraging that a committed advocacy group such as Pandora is willing to take a stance on this controversial and politically charged issue. Pandora’s sister advocacy organizations, CAA and CFSAC are now expected to follow suit with calls for research into the role of biotoxins and mold in Chronic Fatigue Syndrome.

    [CZ: What is the peer-reviewed research that supports mold as the cause of CFS?]

  37. Depressing? A study with an outcome? Probably not. It raised the profile of a highly disrespected disease. What a shame it took drama to get my government’s attention and resources. Disappointing? Sure. I’ve had CFS for ten years, have two children with autism and a husband with an aggressive form of prostate cancer. Just another day in paradise. Thanks for writing about this.

  38. CZ: As a primer for the subject of discussion regarding mold and “CFS”, I would suggest taking a look at the link below from the EPA.

    The commonality of symptoms with CFS/ME and that of Sick Building Syndrome seems to have gone ignored, both by the medical community and the advocate groups involved. Please review the overview provided here, and compare it to what sufferers of CFS/ME report.

    Beyond that, even a cursory investigation by web search should provide you with more than enough citations where “CFS” symptoms are included as a subset of Mold and Biotoxin related illnesses.

  39. Much of the medical world seems to only want to find a profitable cure for ME / CFS / Fibromyalgia.
    By now most of them have heard of ME patients who could lead a normal life while in the Caribbean (or other places). It’s not uncommon. They’ve also mostly heard of patients who were very healthy when they avoided harmful molds. With very very few exceptions, medical people are loudly ignoring these avenues.

  40. If you’re healthy and an onlooker, it may look sad. If you have ever suffered any of these related neuroimmune illnesses (CFS, chronic lyme, etc) then you would have been pleased at Ian Lipkin’s incredibly well designed study, and the fact that the controversy was at last put to rest. A lot of the controversy seems to have been due to the patient community, desperate, feeling ignored for decades, grabbing onto the retroviral hypothesis. A tribute to the power of social media and the internet, I suppose. I appreciate how well Dr. Lipkin designed the study, how the original researcher (Judy Mikovits) was involved, treated with respect, and has now given a firm retraction. It was expensive, but it had to be done.

    Now the samples are there, and top level researchers will be able to sequence them and see what secrets they hold–whereas until recently, these neuroimmune disorders were seen as malingering, as psychosomatic.

    As to the causes, CFS is as much a hodgepodge as cancer. There is no one CFS nor will they discover one pathogen neatly responsible. Certain key pathogens seem to be players, HHV6 in particular is interesting. Toxins play a bigger role than anybody wants to admit, because our world is so permeated with toxins, that it’s almost impossible to point a finger at what and where. Vaccinations may play a role in the 15-20% who get immune derangement from them. The fact we have developed many techniques to save lives that would have never come to pass–my own included, since I was born by Caesarean section and the bicornuate uterus and associated connective tissue abnormalities in both my mother and myself are probably linked to some other immune issues, and not just anomalies–the fact that diabetics live and reproduce, and all kinds of other people living valuable lives, but perhaps perpetuating immune vulnerabilities and a tendency to autoimmune issues–is part of the story. Chronic tickborne illness can be a big player and trigger in certain parts of the country where virulent strains of borrelia, and/or coinfections are common, especially in those with HLA subtypes that don’t handle borrelia well. There is no one answer. Biotoxins such as BMAA are now being demonstrated to increase neurological illness, they may play a role in some cases of CFS for all we know. Toxic mold can definitely trigger or perpetuate CFS, and once you are compromised you really can’t tolerate mold toxins. That’s not depressing, but it’s complex.

    In the cancer genome atlas, they are studying mutated genes and disordered pathways. I think studying the disordered pathways would be the best approach here. The rituximab study is fascinating, not to me because of the drug, but because a portion of very sick people get very well when their antibodies fall away–which points at a place for us to look and research. Perhaps we will find several key pathways commonly disarrayed in CFS/chronic lyme/chronic mold illness. One of the hallmarks seems to be a very narrow bellcurve of tolerance. Whether it’s post exertional malaise from taking a shower (in severe cases, just from standing up, apparently), or extreme reactivity to small amounts of substances normally well tolerated, something must be awry. One area of interest to me is the mitochondrial membrane and whether in CFS and these other disorders it is really compromised.

    So, a blathering answer…I think the study was great, and I was very happy with the results.

  41. Zimmer you know the study was PCR and serology positive, but are refusing to publish comments on that. We know where you stand and will remember in the future.

    These retroviruses are nothing to do with XMRV, and they have been confirmed in 4 other papers. A study using fatigued people wasn’t going to associate them with anything.

    The PCR and serology proved again people are infected. Is it easier to bury your head in the sand then face those people?

    [CZ: I have no idea what you’re talking about. Comments from people who haven’t commented before are placed in a queue for moderation so that I can filter out the huge amount of spam that hits this blog. I do not recall any comments on PCR or serology in the queue. Your accusations are baseless.]

  42. I’d like to agree with Ollie, Kati, Emily, etc. and say thanks to Dr. Lipkin and everyone for sticking with this to carefully complete this high-powered study and work to figure this out. And to Mikovits et al. for being brave enough to stand up and basically say, “there was an error; I was wrong”. And for everyone’s stated committment to stick with ME/CFS and find answers. I hope there’s funding for that.

  43. You don’t recall? Do you know?

    I have posted and those haven’t shown up either.

    This was a fatigue cohort, so who was being tested? How convenient to test a cohort with tired people not those who are likely to have a retroviral infection.

    And how many positive PCR were there? Why is that figure not in the paper?

  44. Mr. Zimmer, I’m 58 and have had ME/CFS for 42 years, and I have a question for you after responding to your query. Back when I was much healthier, I moved to Capitol Hill for over two years starting during the first Gulf War in 1991 because there was no one else volunteering there at the time to do the lobbying and other necessary advocacy. That was during the first retroviral research saga and there is definitely déjà vu now. I was appropriately diplomatic then, but the continued prejudice and abuse of ME/CFS patients since then requires more outspoken advocacy. My closest friend in DC died from ME/CFS this year. She was 52; at least she’s out of her pain and misery now.

    Most of us just want a lot more good science ASAP. The XMRV saga should have at least happened much faster. Ironically it got us much needed recognition and the private funding of research is increasing greatly but it’s still miniscule. The US government funding is outrageously not increasing. The published rituximab studies provide hope now for treatment and a bulwark against the BS from the psychological sophistry brigades.

    Your blog last year had some of the best comments I’ve seen. I was “nonchalant”. Some of the UK press is at the same thing again at present.
    Sonia Poulton wrote a very good piece recently in addition to one last year and got a warm response. A couple writers are recycling last year’s “blame the victim” by “playing the victim” propaganda and are getting criticism. Again, I prefer to be in the USA.
    From elsewhere last year, “Dr. Racaniello said that when he used to question colleagues about chronic fatigue syndrome, they would argue that it was an imaginary illness.” “Every time I asked someone about it, they would say it doesn’t exist, it isn’t a real disease, even as recently as the past year…”
    My question to you is what do you hear? Do you think we are making progress in the broader scientific community, etc.? Any suggestions?
    Thanks, Roy

  45. >Now the big question–will patients accept the new research, or will you have holdouts like vaccines/autism?

    We need to be very, very careful about talking about “patients” as if they’re a monolithic group. ME/CFS patients have widely varying reactions. Some are extremely scientifically savvy, some are naive, some aren’t paying attention to this stuff at all. There may well be a few holdouts, but hopefully few enough that they won’t significantly influence things. But if there are, it does a disservice to allow those few holdouts to characterize the entire patient community. It only serves to give those folks more power, and to further disempower the many patients with different views.

  46. Lipkin said CFS is not one disorder. His study found serology and PCR positives. So why is it not considered that this group represent a different disease and why are the number of PCR positives not recorded in the study?

    The control cohort were not excluded if they had been sick in the last year, and we’re not screened for a number of other diseases.

  47. Julie — You used the term “reactions” as opposed to “symptoms” with what CFS patients experience. I assume this was deliberate on your part. What agent are you inferring is causative?

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