I’ve learned my lesson

I made the mistake of writing a post yesterday on a controversial subject while watching a football game. So I may not have been as clear as I would have hoped. Mea culpa. I hope I am clearer today.

I have friends who have Chronic Fatigue Syndrome and I know about the problems trying to get the medical community to even recognize it as a real disease and not a mental illness. That is why I was quite excited by the original report when it came out. It seemed like a very nice model to help explain the disease, as well as possibly implicate a retrovirus in other diseases.

However, subsequent work has muddied the waters and, in my opinion, weakened this model. The recent paper I talked about yesterday seems to provide strong, definitive evidence that contamination is a real problem. This along with the inability of other labs to replicate the work, appears to substantially weaken the model.

All this indicates is that the situation is quite complex – something we all knew anyway. Also, that much more and careful work will have to be done. It is as easy to get too positive about a model and fall in love with it. Researchers and others do this all the time.

And it is easy to be too negative about a model and hate it. Researchers and others do this all the time also. Perhaps I let my initial excitement turn too far to disappointment. I don’t think so but I am human. Perhaps that bled a little over yesterday. Damn football!

What I was trying to state yesterday was that the recent paper did its job – helping us understand why some of the results show XMRV and other results do not. They have now presented a model suggesting that cross-reacting PCR primers could give PCR artifacts from a contaminating virus.

If XMRV is actually involved, then researchers will to take the current results into consideration.

That is what I meant by science doing its job. The new report pretty definitively examined the problem of contamination and demonstrated that previous work may not have properly controlled the correct variables. Others will respond. This is the back and forth of cutting edge research where we have little understanding of all the things going on. I am sure this is not the end of the road.

We will get to the bottom of this. It may be XMRV. It might be another unknown gamma retrovirus. It might be something else entirely. When science does its job right, we eventually discover what it is. Feynman was right when he said that Nature always wins in the end, no matter what we want to believe.

11 thoughts on “I’ve learned my lesson

  1. Indeed you did a bad job yesterday while watching the football, but you have not done a better job today with this shy “retraction” which actually does not retract anything when you say:

    “The new report pretty definitively examined the problem of contamination and demonstrated that previous work may not have properly controlled the correct variables.”

    That is 100% untrue, The Lombardi study did control for contamination, used 4 different detection methods, found immune response and antibodies, and had an extensive peer review of 6 months. PCR as described in Retrovirology was not an issue in the study published in Science. Nor was the case in the NIH study that backed up the same conclusions.

    Lipkin, Coffin, Mikovits, De Meirleir, Racaniello among many others stated that the papers published in Retrovirology DID NOT SHOW that the positive studies were flawed in any extent. Yo seem not to understand that…

    1. From the material I have seen, showing that PCR primers can also react with other viral DNAs does demonstrate that previous work may not have properly controlled the correct variables. And they showed a problem with possible contamination that everyone agrees need to be reckoned with. I do not feel that my statement was 100% false. You might disagree with me on an adjective or two, I expect.

      Antibodies are not definitive either, as they only recognize short regions of proteins and can cross react with other proteins, even assuming that the antibody preparation is not cross-contaminated. Perhaps one reason I find that the model is weakened by this data is because I have been directly involved in research where these problems occurred. We spent lots of time tracking down proteins based on antibodies that turned out to be cross reacting with uninteresting proteins. We PCRed out DNA segments with primers that turned out to also anneal to contaminating sequences. We had cell cultures that were supposedly one type of cell be something else entirely. We had cell cultures cross contaminated with viruses. All this stuff happens at the bleeding edge of science. We get fooled all the time because of it.

      More work needs to be done to clear things up. Some of the comments have suggested that this is all due to a conspiracy of scientists working for National Health in England. I feel the chances of that are very small. Having watched the HIV debacle, I guess it is obvious that proving something causes a disease can take a lot of time and be quite controversial. Satisfying most of Koch’s Postulates can be quite hard, especially with retroviruses.

      I fully expect more papers that will clear things up as we discover what has been happening. After all, I do believe a Nobel waits at the end.

    2. You can not blame it on the football now I am afraid…
      The current lipkin study is designed joining forces in a proper double blind split sample replication study that will answer the scientific question as to the relationship of XMRV to CFS…until that is done you simply CAN NOT CLAIM that there was contamination in the studies published in Science or PNAS based on the PCR results published in Retrovirology.
      Four different methods were used in the Science study, mithochondrial DNA was used to rule out contamination in PNAS, isolation of the virus and an immune response was found in Science, roughly the SAME percentages 85% in CFS vs 4% in healthy controls have been found in every POSITIVE XMRV study: Lombardi (Science), Lo & Alter (PNAS), Irsi Caixa- Clotet et al (Spain), De Meirleir (Belgium), Sweeden…
      Don´t you think that if it was contamination these percentages would not hold consistently in all the studies? and do not tell me that the handling of the samples influence the results and would explain the 85% vs the 4%-7% because that was also taken into account in the Lo-Alter study for instance, and the handling was exactly the same in CFS patients as Healthy controls.

    3. Richard

      I advice you to read the FDA Blood Working Group Advisory meeting, where Coffin (one of the authors of Retrovirology papers) ask Alter questions regarding “contamination” that are fully addressed to rule out that possibility. Indeed Coffin said after the publication in Retrovirology that none of the papers published changed any of the conclusions of former positive papers of Alter & Lo and Lombardi group.

      Have a look please:

  2. I left a comment where I first saw this post. It may have been a site that simply recycles any and all content; I suppose I made a mistake in taking it for an alternate blog of yours. At this point I’m going to assume you have not seen it.


    This is appreciated, but, I’m sorry, questions still linger. Upon publication of Lo et al in PNAS last August, Harvey Alter characterized that paper as being ‘highly confirmatory’ of the WPI study. The paper itself used more cautious wording, stating that it supported the ‘central argument’ of Lombardi et al.

    Four weeks ago at a meeting of the FDA’s Blood Products Advisory Committee meeting, the committee heard a detailed presentation on the argument of the Retroviroogy papers, which were published the following week. Even after this, they chose to recommend that the FDA move to ban donation of blood from persons with CFS. The American Red Cross had gone so far as to actually put a ban in effect two weeks prior.

    Shyh-Ching Lo also presented at this conference, and was challenged substantially on the issue of contamination. Apparently it wasn’t enough to cause the committee to throw caution to the wind, and their vote would indicate that, unlike blogs that have apparently decided that this is now a failed hypothesis, they still believe a threat may exist in the form of MLVs in the blood of CFS patients (which, Ila Singh might suggest, might not be the easiest place to actually detect them).

    It was, however, enough to move Harvey Alter to speak: he stated that the association between MLVs (not specifically XMRV, a distinction which has been used as hair-splitting by those who have claimed that Lo et al did nothing to validate WPI’s hypothesis) and CFS remains strong.

    When a press release was issued based on Hue, the statement from Greg Towers that “XMRV is not the cause of Chronic Fatigue Syndrome” was disseminated widely and, apparently, uncritically.

    It has been pointed out on Forbes that the WPI stated that ‘causality is clearly a reasonable hypothesis.’ A search for that quote with “XMRV” added to it yields 11 results.

    A search for Towers’ quote, along with his name, yields over 7,000.

    You say the model is weakened. Any comment on how the Alter/Lo paper fits into all of this?

    1. Thanks for the comment. It has some information I was not aware of. However, simply because they go forward with a study does not always mean that they fully agree that the proposed model is right. I have worked with colleagues examining HIV vaccines which were approved for a Phase II study for efficacy, even though there was no definitive proof of such or even any proof the experimental model was correct – that cell mediated immunity would be protective. They did know the treatments would be safe so they OKed the study because it was the only way to get the information. The study demonstrated that the vaccine was not effective and that the proposed model may not accurately describe the therapy.

      So, I am not surprised they approved a study. Again, they can make sure no harm comes to the people who, fully informed of the study’s actions, chose to enter it. I really hope that the therapy has an effect that is substantially above placebo. If so, we will then have a much better path to clearing up things.

      Also, after the HIV debacle with blood, the precautionary principle is used much more today. Again, that does not necessarily mean they agree with the model.

      And the last point allows me to state something I’ve said before but not had a chance to here – I agree somewhat with Alter. The data indicate to me that something may be going on with gamma-retroviruses. One of the things the current papers indicate is that there may be other cross-reacting retroviruses present. Perhaps it will turn out that one of these is the actual cause and not XMRV.

      In scientific research it is not really hairsplitting. The original paper suggested a specific virus. They may well be wrong there. But, if their work, and especially their creative insight, started the process that leads to the correct answer, they will most likely get a lot of recognition and at least a part of the Nobel that will come from this work. And the group the shows just what virus it is will also get a part.

      Now that would be a wonderful end for the researchers. And their work would finally have led to a treatment for people.

      But we still have a ways to go.

      And a lot of people will be very grateful, even if the first paper only began our travels down the correct path.

  3. Well, I appreciate that comment. But I would ask you to please understand that for some of us that have been following this, that there is a bitter irony:

    Lay press reports scientific publication

    Science writers and scientists respond with disdain due to perceived faulty interpretation

    Science writers and scientists end up showing as little regard for accuracy as the lay press

    Of course, as a layman not trained to properly read and/or interpret scientific publications, I am perhaps not best qualified to tell scientists that either they’re exposing an obvious bias by conveniently leaving out that with which they disagree, or that they are claiming authority greater than the lay press while revealing that they don’t know as much as they think they do.

    An example of the former would be the aforementioned criticisms of Lombardi, et al by bloggers who are unwilling to mention Lo, et al; an example of the latter would include bloggers who wrote derisively about the WPI paper following the negative studies published in the UK a year ago without knowing anything about the differences in criteria defining Chronic Fatigue Syndrome. Of course, those differences are not exactly subtle, but it is odd to witness the spectacle of people who claim that science always wins out behave in a frankly juvenile manner while pouncing on a hypothesis that has not been disproven despite publications they would like to interpret as definitive proof that the hypothesis is faulty.

    No published study has utilized a patient cohort according to the guidelines that WPI used, not even the Alter/Lo study in PNAS. None.

    Bah! XMRV? Chronic Fatigue Syndrome? Nonsense!

    You had the good sense, and integrity, not to mention common decency, to admit that something had been presented that you were not aware of. The author of the blog you linked to initially has had many of the same concerns brought to his attention, yet he has flatly declared the hypothesis to be failed.

    Does that not strike you as being at least somewhat curious?

    His blog was picked up by Forbes. He has not so much as acknowledged Lo, et al, although it has been brought to his attention by a few commenters. He may know of what I mentioned to you regarding the Red Cross and the FDA.

    If he does, then is it ‘scientific’ to write as he has without mentioning these items?

    If he does not, then, is it ‘scientific’ to write as he has on a topic he does not have all the facts on, let alone to declare the hypothesis to be failed when the appropriate authorities are taking very seriously the idea that there may indeed be a threat to the blood supply that was unknown prior to the publication of Lombardi, et al?

    I have to offer that I find his approach to be, well, arrogant.

    As for comments above relating to scientists in the UK: without engaging in anything resembling conspiracy theory, I will tell you that the vast majority of the research on CFS published in the UK comes from psychiatrists whose views on the matter involve terms like ‘functional somatic syndrome’ and ‘abnormal illness beliefs.’ I can provide references to support that assertion if you are interested.

    I will also tell you that there are issues with some of the negative studies, but I will leave that for now. However, as you might imagine, the WPI’s paper in Science made a lot of news outlets upon publication. The negative papers generated some attention, as well. And it was widely reported when slides from a presentation Harvey Alter gave at a blood products conference in Croatia were leaked. They indicated that his research validated the findings of WPI. At the time of the leak, the paper had been peer-reviewed and was said to have been in galleys at PNAS. One week later, it was reported that the CDC had a paper also about to be published whose findings were in conflict with WPI and Alter/Lo; so both papers, it was reported on June 30th, were being withheld while officials worked on an explanation as to why there was a conflict. However, the CDC’s paper was published the following day; Lo, et al was eventually published towards the end of August. This was all covered in depth, by the way, by Amy Dockser Marcus in the Wall St. Journal.

    When Lo, et al was published, it was barely reported on in the UK. It did not make any of the daily newspapers, with the exception of an online-only piece in the Daily Mail. Eventually comments sections were bombarded in the Guardian, and they ran a brief piece on the controversy a few days later.

    The publication in PNAS made a huge splash internationally, as had the paper in Science. There was a tremendous volume of coverage. Everywhere you’d expect…except for the UK.

    XMRV has been covered and mentioned quite a bit in the US, and elsewhere, over the past six months. Not much in the UK. You’ll be hard-pressed to find any mention of Harvey Alter. However, when the papers were published in Retrovirology a couple of weeks ago, there was quite a bit of coverage.

    As a matter of fact, an article originally appearing on the NHS website that contains the unambiguous quote “XMRV is not the cause of Chronic Fatigue Syndrome” has been reprinted verbatim in no less than 25 UK newspapers. Not national papers, mind you, although the BBC, the Guardian, and the Independent, among others, all covered Hue, et al even though they saw fit to somehow ignore Lo, et al.

    I will not offer any comment on any alleged conspiracy. I will, however, provide any and all links necessary to back up every single statement I have made, upon request. And I will merely ask that you consider what I have offered here and leave you to draw your own conclusions.

  4. Yes, thanks for the re-coverage, Dr. Gale.

    Contamination is a conceivable model for some of the results, but only that much. One would have to explain all the other tests that have been run in the CFS study(s) and the prostate studies, too.. .. Eg. integrated virus .. just how did XMRV get into a human DNA?

    There is more work to be done, and more work to be done.

    I want to watch a football game, too.

  5. I think it’s good to examine the emotional reasons why we can misinterpret scientific data… I think these sorts of distortions are a more normal part of science than many would like to admit.

    I think that a lot of patients are worried that XMRV will be dismissed prematurely, and see some of the exaggerated coverage of the negative reports in that context. The exaggerations of some of the press releases do not help matters either.

    Any correlation between XMRV and CFS is a matter science is well suited to settle. If this turns out not to be the case, it seems rather less clear how science should then progress to help our understanding of CFS.

  6. re your comment: “Some of the comments have suggested that this is all due to a conspiracy of scientists working for National Health in England. I feel the chances of that are very small.”

    With due respect, patients and ME researchers and clinicians are the experts on whether there is bad faith and conspiracy. And let me tell you: there is. What about the statement in the press release that “XMRV does not cause ME” strikes you as not being in bad faith? Such distortion of the science and lying is par for the course in CDC, NIH and the UK govt’s quarter century war on ME science and patients. Why are you covering for these charlatans. I would think a scientist would be outraged that the anti-science, anti-patient ‘scientists’ like Towers are lying about the science in order to defeat scientific progress! I understand that as a scientist you must focus on the details, but it is also important to look at the big picture and the big picture is that the press release has more impact than the actual science and the UK charlatans lied as usual about the science in the press release. This was an intentional tactic in their well orchestrated war on ME science.

    1. I have no evidence that anyone here is a fraud, a charlatan or lying. If you do, I am sure there are some reporters who would love to see the evidence. Look at the wonderful career move Brian Deer made with Andrew Wakefield. They just took Wakefield’s medical license away for fraudulent research.

      That is why most scientific controversies are not based on fraudulent research or grand conspiracies – your career is over in a pretty public way when the truth comes out. Wakefield will only be able to earn a living now by catering to the extremists rather than his scientific peers.

      This is a strong scientific debate – any scientist working at the cutting edge will have been part of many of them – and there are very strong opinions on both sides. It is very likely that one side will be wrong but, from the evidence I have seen, there is still some convincing to do, on both sides.

      I agree that PR science can be faulty and have discussed it a lot, which is why I focus on the science. Simply because the PR is extreme does not mean the science is wrong. Simply because a scientist is personally a jerk does not make the science wrong. One has only to look at the same sorts of controversy with Gallo and HIV/AIDS to see that what is happening is not unique. So far here, I see the intense, sometimes emotional debate often seen at the cutting edge of science, but no evidence of outright fraud or conspiracy.

      Scientists can honestly be mistaken without the need for your epithets. Human disease is incredibly complex, as anyone who has had to deal with CFS knows. The frustration on very slow progress comes from it being complex, not generally from scientists that are part of some anti-patient conspiracy.

      What, to me , gets lost in all this vitriol is that there is a strong testable model for CFS. It may be wrong – most scientific models are, which is why the majority of published papers often end up being wrong, at least in details. But science works by trying to reshape and disallow models. If there is no model, or way too many models, progress is very slow. That is what has plagued CFS for over 20 years.

      Peptic ulcers were a plague on humanity for thousands of years, with no real cure. Then Warren and Marshall proposed that it was caused by bacteria, which was received about as well as XMRV by the other researchers. But they were right and ultimately prevailed, resulting in a simple antibiotic regimen to rid us of the bacteria. And they won the Nobel Prize for their efforts.

      My hope is that the recent work with XRMV, even if not correct, will result in similar results.

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