By Dov Michaeli

This post may strike you as “inside the beltway”, some scientists arguing about arcane experimental results that have nothing to do with your life. I don’t think so. This post will show you how science works, and it will tell you why this is important.

In a February 11, 2011 post on this blog site we discussed CFS (Chronic Fatigue Syndrome) and the vexing diagnostic and therapeutic problems associated with it. We have absolutely no idea what causes this syndrome, and without an identified cause it is exceedingly difficult to devise rational therapy; you are basically shooting in the dark.

A momentary ray hope shone when a virus called XMRV was identified in over 60% of patients who were tested. Finally, a “real” cause, a tangible target. The enthusiasm quickly faded when science did what it’s supposed to do –try to replicate and confirm the results. Here is an extended quote from the February 11 post:

XMRV is a mouse virus that causes leukemia in mice. XMRV was first identified in 2006 in patients with prostate cancer.  A study published by Lombardi and colleagues (Science, 2009;326:585) reported finding evidence of XMRV DNA and antibodies in about two-thirds of CFS patients and nearly 4% of healthy persons. Hopes were high that finally, at long last a “real” causative agent for this ill-defined disease was found. Not so fast; a bunch of other papers found no trace of the virus DNA either in patients’ or control blood. So what is the source of the discrepancy? It turns out that it was a simple case of contamination. DNA assay, called PCR, used kits that were contaminated with mouse DNA. Also, the most popular animal in biological laboratories is the mouse, and its DNA is literally everywhere. Consequently, incredible measures need to be taken to ensure lack of contamination. But, we are only human and sometimes we screw up.

The Lombardi paper in Science reports also on anti XMRV antibodies in the patients’ sera, and this assay does not depend on DNA, but on protein. However, a report published by CDC investigators and colleagues in July 2010 found no evidence of antibodies. I cannot think of an easy explanation for this discrepancy.

End of story? Not quite. In the May4, 2011 of the Journal of Virology, Singh and her colleagues published yet another study that refuted the findings that had led to the XMRV theory. They obviously were focused on eliminating any possible post hoc argument that their method of analysis was different from the original paper. They used the PCR technique, which is the most sensitive available for detection of viruses. They worked closely with the team that had carried out the original tests to make sure there were no discrepancies in the execution of the assays. They tested 100 HIV sera, including 14 of the original samples that tested positive in the Science paper. To remove any doubt, these sera were selected by Judy Mikovits, the lead author of the Science paper.

The results? (drum roll):

None of the sera showed any trace of XMRV. As Singh stated to Science: “I’d urge people to move on rather than to keep their hopes hanging on the link between XMRV and CFS,”

I agree. Singh and her colleagues went out of their way to ensure that there was no rational way to question their results. Yet, Mikovits stated to Science “”These people are infected. This study says nothing. We have complete confidence in every bit of the results in the Science paper. We don’t think any of it is wrong.” A surprising attitude from a scientist who is supposed to look unflinchingly at the data, personal bias notwithstanding. In any event, yet two additional studies examining all the original sera by independent groups as well as by Mikovits’ original group should be published in a matter of months. Will this nail it, once and for all?

Why is it important?

This is the way science works. You constantly check and re-check assumptions, theories, methodologies, results, analyses. I was surprised to read a couple of weeks ago that the journal Physical Letters published an experiment that verified, yet again, Einstein’s Theory of Relativity, at a cost of a few hundred million dollars. One may think that it is a bit excessive (as I think is the case with the endless studies refuting the XMRV hypothesis), but it is necessary.

People tend to cling to theories and faux-information that they want to believe in, regardless of the evidence. When it comes to ‘birthers’ and ‘deathers’ (people who don’t believe in Bin Laden’s death), I don’t think we need to waste time and money to persuade them. But when it comes to public health, it is more serious. Mothers who wanted to believe in the theory that vaccination causes autism put their children’s lives at risk. It is imperative that we disabuse them of the idea. Some people with CFS who believe in the virus theory take retroviral medication, used in HIV therapy. This is worse than useless –it is dangerous.

Despite CFS activists’ suspicions of anything that smacks of psychological therapy, there is an excellent study showing that psychotherapy coupled with graded exercise is the most effective of all the therapeutic modalities in clinical use. There is nothing denigrating about it. CFS is not “in your head”, just as rheumatoid arthritis isn’t. Yet, graded exercises coupled with psychological support works wonders for RA patients. Why not for CFS?

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.


  1. Interesting article, but with a few factual inaccuracies. Dr. Michaeli wonders why because exercise is helpful in patients with RA why it wouldn’t be helpful for patients with ME/CFS.

    The answer lies partially in the scientific literature. The first and most important issue is how you define the population being studied. The researchers I will cite below consider post exertional malaise lasting 24-hours or longer unrelieved by rest and upon minimal exertion to be the cardinal symptom of ME/CFS. These are the patients they study. The authors of the PACE trial selected a very different group of people using a rarely used definition – on that perhaps was more likely to produce favorable results.

    Studying peaches and calling them apples and then trying to extrapolate the results to all round fruit is fraught with scientific peril.

    Scientists at the University of the Pacific and the University of Utah, specifically using the International 1994 Fukuda definition, have objectively verified a number of abnormalities in ME/CFS related to exercise.

    The exercise physiologists at the UP have studied the exercise physiology using objective means of measurement whereas the researchers at the University of Utah have looked at genetic expression both on the initial day of exercise and then subsequently.

    Adaptive pacing doesn’t mean you don’t exercise, only that the exercise does not exceed the available energy. The adaptive pacing condition was intended to help patients adjust their activity levels according to their available energy (based on envelope theory).
    The UK researchers didn’t study the same population as the adaptive pacing studies so while it may not have been effective for their population it doesn’t contradict the results for very different groups of patients.

    If you read the PACE study, and as a medical writer I have, the CBT is being used not to be supportive per se, but is predicated on the as yet unproven theory that people have CFS because they are deconditioned and have abnormal illness beliefs – in other words all in their head. The CBT is aimed at convincing the patients that they are not actually ill. Is this how it is used in RA patients? I’ve never seen any scientific evidence that CBT can reverse or cure organic disease – perhaps Dr. Michaeli has.

    No trial is perfect, and all treatment trials regardless of whether they are behavioral or artificial interventions such as drugs, need to have a good dose of healthy skepticism such as that of Bagnalli et al who looked at GET trials in CFS and found as much to criticize as praise. The bottom line as noted by Dr. Fred Friedberg, psychologist and president of the professional (not patients) organization IACFS/ME, is that only an additional15% of patients in the CBT and GET conditions achieved normal functioning in comparison to standard medical care. The critical standard of clinical significance is that a therapy results in restoration of normal function. Was this the case in the RA studies? Skeptics would have a field day with those numbers if this had been a pharmaceutical trial.

    According the New York Times writer David Tuller MPH – “The gold standard for making comparisons across groups of patients identified by three varying case definitions would be a study with three completely separate cohorts.”

    In other words, GET and CBT may work for some patients, which is good, but not those who are the sickest. Without more studies it is too soon to say.

  2. Dear Mr.Michaeli,

    thank you for this article. :-)

    I have one question concerning the mouse contamination. Is there really a study that show that there WAS mouse contamination? I never saw one. The only studies about mouse contamination that I have seen, deal with the high probability that there could be contamination. They never said that there was contamination but they showed how easy contamination could occur. Yet all of these studies were published in a way that on first sight one would read “Ah, it was all contamination”.
    So my question would be, is there really a study that shows that there WAS contamination?

    Concerning the other studies, yeah, xmrv as THE cause for CFS becomes more and more doubtful. I understand that.

    Now I’d like to add my opinion on CBT and graded exercise. ^^

    I sincerely believe that CBT can help you with all chronic diseases and to be honest CBT could help every single person (even healthy ones) on this planet to live his or her life better. I readily admit that CBT helped with with some problems in my life.
    But there are two important things to consider:

    1. As CFS is not “in one’s head” as you say, CBT can only be an addition to a physical treatment, one that has not been discovered yet. Again, I have nothing against prober CBT but it seems that some scientists want to abandon the idea of an underlying physical cause and focus on ONLY CBT. And this seems to be a real problem in my opinion. It often sounds like “we have CBT, why do research on physical causes?”

    2.From my personal experience the biggest problem with CBT seems to be that CFS is not yet really considered as a physical disease. While I think CBT and graded exercise would be great when applied to develop coping strategies and CAREFULLY expand the patient’s limits, I don’t see psychologist do this in real life.
    I was in clinical treatment for five months and I was treated like a person with depression. While I do admit that I indeed developed depressive episodes due to the many losses I experienced because of my severe lack of energy, I can say that at the time of the clinical treatment, i was NOT depressive. It sounds funny, but I am actually happy that I had depressive episodes, so I can really tell the difference between the lack of energy caused by depression and the lack of energy caused by CFS.

    To cut it short, the CBT and its “activation process” (I don’t know if you say that in english, but the doctors at the clinic call it “activation of the patients” which means, to have a depressive person do things and become active again) nearly destroyed me.

    The many conversations and activities and sports therapy I had to do were too much for me and I could only live through the weeks by sleeping 8-9hours at night and 4-6hours during day.

    The problem was that the psychologists, not really familiar with CFs IMMEDIATELY interpreted it as a “retreat strategy”. So they forced me to stay out of bed during daytime. I told them that it was impossible and that I would suffer from that. But they were convinced that my excessive sleep requirement was caused by depression and that staying out of bed would help my health.
    Well I managed to stay out of bed during daytime for about two weeks. And this really DESTROYED me.
    While I considered myself ill before therapy I was far far worse afterwards. It has been six months since then and only in the past weeks has my condition become better and I start to do things again. (like taking showers regularly and even leave the house more than once a week.)

    What I am trying to say it, that I understand that CBT COULD help CFS sufferers but in reality I don’t see that happen, because the psychologists that I know treat CFS patients in exactly the same way as depressive patients.

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