I opened this thread due to my question here: https://www.s4me.info/index.php?thr...rogress-in-the-past-18-months.741/#post-13549 What happened to the retroviral research line, like e.g. by Mikovits and DeFreitas? The findings seemed contradictory to me (some found something, some didn't). Why was it definitely concluded this is the wrong direction?
Hi @Jonathan Edwards, that's what I understood. BUT I'm not so sure about that, well, I don't get it. Primarily because I don't understand the details. Secondly, I repeatedly read about it, e.g. here: http://meversuscfs.blogspot.de (there's an English version if you scroll down). And I still wonder about deFreitas' findings. She even had a patent about that topic.
Not all the details are clear, but people didn't really want to invest limited research funding into finding all the details once the research indicating XMRV was associated with disease had been debunked. The test for XMRV was unable to distinguish sample from CFS patients and healthy controls under double-blind conditions. We don't know exactly what went wrong to lead to the early false positives. Contamination was an issue but I'm not sure if we know exactly how or why. To me, it also looks like there were some dodgy and undeclared things from the WPI researchers, and personally I'd have liked to have seen that investigated more, but it seems that this is not how science works. It was a duff finding, so people moved on rather than trying to work out who was responsible for messing up. There's much less public info on the DeFreitas work, but again, it sounds as if that failed to replicate, although things were also complicated by DeFreitas developing health problems. Lots of people have patents for things that are worthless, so a patent doesn't really indicate anything.
People clutch at straws and Mikovits's story was told with such conviction that people believed it. But the re-assessment was able to identify a point in the lab where the virus had mutated so it was possible trace back where the problem was almost like having a CCTV recording. Patients with ME improve while taking all sorts of treatment including homeopathic pills with nothing in them - probably because they were going into an improvement phase anyway. I do not remember the precise details but Dr Greg Towers of my own medical school went through them at an IiME conference around 2014 and one could see exactly what had happened. Dr Mikovits was very committed to her task but videos of her talking about immunology indicate that she really did not have a deep understanding of the evidence and tended to make things up as she went along. It is only too common in science - most scientists are more bullshit than brilliance in the end.
I know. This patent was interesting, which I cannot say about all the other patents I read and wrote. Of course, scientifically not very relevant. I have to do some thinking and searching...Thanks for your statements which I use as a starting point.
Just another question that popped up: Would anti-retrovirals work even if no retroviruses are present or not contributing to health issues? Are certain retroviruses common in the population, comparable to EBV or herpes virus families etc.?
I think it would depend entirely on what the mode of action of the anti-retroviral was and what the mechanism of the target illness was. On the other hand, although anything can produce a placebo response it seems relatively unlikely that an anti-retroviral would be effective for ME if it was not based on retroviral infection. There are various bits of virus incorporated into our genome but as far as I know few if any give rise to replicating virus other than HIV viruses.
No probs. Sorry if I over-explained bits. It has been a really long time since I thought about XMRV, so I may well have forgotten important details. Personally, I don't think it's worth even looking into at this point. This was the paper Mikovits co-authored which showed her own earlier work could not be replicated when more care was taken to avoid problems with contamination: http://science.sciencemag.org/content/early/2011/09/21/science.1213841
So, is what you mean that until now we don't know other replicating retroviruses than HIV (in humans)? What about HTLV-II? Sept. 2009: Schlaberg, Singh et al. XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Nov. 2010: Singh et al. "Detecting retroviral sequences in chronic fatigue syndrome." https://www.ncbi.nlm.nih.gov/pubmed/21994623 April 2010: Singh et al Raltegravir is a potent inhibitor of XMRV, a virus implicated in prostate cancer and chronic fatigue syndrome. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009948 Jul. 2011: Absence of XMRV retrovirus and other murine leukemia virus-related viruses in patients with chronic fatigue syndrome. Shin, Singh et al. https://www.ncbi.nlm.nih.gov/pubmed/21543496 Aug. 2014: Retraction for Schlaberg et al., XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143000/ I am still confused. XMRV findings are retracted, especially in ME, at the same time there seems to be something. Something is missing. I admit it's only a feeling that the answer to XMRV/retroviruses is not concluding. Reading about all the PCR methods and possibility of contamination of the reagent, I get the feeling that either our technological knowledge is not sufficient at this time or techniques aren't applied accurately enough; I believe accuracy is major in this, while I think it's very difficult to maintain it in this case. I really don't know much about this, but my feeling is retroviruses are pretty hard to detect and maybe hard to understand.
I'd agree on that. But then it should get worse some time in the future. There ARE people with ME who improved with retrovirals - the one I read of is Tenofovir disoproxil fumarate. I believe the woman whose daughter went from "lying in bed in a dark room" to "getting up, taking a shower and more" (don't know her personally, but from a forum). So there must be a - possibly unknown - mechanism in those people. It wouldn't be the first time that the exact mechanisms of a medical drug in vivo isn't fully understood. OR that in these people there were retroviruses but they cannot be detected. Logical errors somewehere? Would be pleased to be pointed at them! I'm still looking for this talk.
There is no need to assume that people will get worse again after improvement. In young people long term improvement is common. The Dubbo study indicates that there is no precise cut off between people who have post-viral fatigue for six months and then recover and those who have fatigue for longer. Even in well understood immune disorders (lupus, Reiter's, immune thrombocytopenia) full recovery is not rare - the immune system rights itself. And if you happen to take a retroviral around that time it may seem the retroviral caused the improvement. So there will be some people who improve around the time of taking retrovirals, whether or not the retrovirals had anything to do with it. I had post-viral fatigue myself for six months after EBV. I remember complaining at six months that I still could not play sport when all my friends could. And then about a month later I remember suddenly realising that I was OK, and have been ever since. It was as if my physiology had not even realised it had got right and surprised itself. If I had been taking medication I would have sworn it was miraculous. This is the whole point of doing double blind randomised controlled trials. People get better when you are not expecting it. Psychological placebo effects probably wear off within 3-4 weeks in most cases but that does not take into account spontaneous improvement or what is sometimes called 'regression to the mean'. If you study people when they are really bad then a t a later time on average they are likely to be better. In fact I have seen rheumatoid arthritis and several other diseases I used to deal with vanish on their own for ever and I am not sure I know of any drugs that do that for those diseases. Most people who take antiretrovirals for HIV have to go on using treatment for long periods.
There have been a couple studies which use multiple methods to test for a retrovirus. One method indicates there is a retrovirus, but more specific methods indicate there is not. Basically viruses are strings of DNA (or RNA in the case of a retrovirus). We have tons of DNA and RNA in our bodies, since they also form the proteins that we need to exist. If testing for DNA/RNA fragments, or a reaction to them, there can easily be a false positive because different proteins or viruses can have some strings of DNA/RNA in common. Thus if a DNA/RNA string is turning up more often in ME patients it might be relevant, but still not indicate that a retrovirus with that string is present. It's especially possible because humans have evolved in a manner which incorporates retroviral DNA into our own DNA (HERVs). Kenny de Meirleir published such a finding a few years ago, basically saying that while it's technically possible the reaction is due to a retrovirus, indications are that it's more likely a reaction to HERV proteins in some patients. They did GI biopsies and found that plasmacytoid dendritic (innate immune) cells in 8 out the 12 ME patients were immunoreactive to HERV's, but none of the controls were.
I was never very excited about the XMRV research because treating retroviruses is so difficult that it's biggest effect would have been proof we are physically ill. But having said that I found the conclusions really dodgy. PCR is very dependent on conditions and no one was willing to replicate Mikovitz's set up. One researcher said "Oh, and I suppose you want me to stand on one leg and whistle if that's what she did?" which missed the point. She offered to work alongside doubters but no one took up the offer. Then if it was a common contaminant, how come all the other studies were negative? They seemed to say it did not exist because they did not find it, then it did not exist as a clinical entity because of contaminated cell lines. It makes no sense. It was easy to pass into medicine as just another failed retrovirus study but then doctors not involved only know what they were told and did not read all the dodgy papers which had the same dubious statements as the biopsychosocial things we are used to. Plus I find it strange that we do not have an MLV as a species since we have lived in such close proximity to mice for centuries. Even Koalas are infected. Then the big study looked at blood samples yet when they infected baboons (I think it was) the virus was undetectable in the bloodstream after a short time but was concentrated in the lymph glands. Elaine de Freitas studies were also not examined as they should have been. The CDC said they could not visit her lab because they did not have money for the flight! I have read that the study in Glasgow found that the patient blood samples were negative but the controls were positive when the study was unblinded and it was suspected that the samples had been mislabelled, but that could be apocryphal. I am not looking for more retroviral studies but politics were definitely involved not simply medicine.
Do you say this with respect to ME or more generally? Wrt ME my last information was (spontaneous and/or longterm) improvement is very uncommon. Would you be willing to cite that here? I found a Dubbo study, but at first sight that doesn't look like the one you seem to mean. These would be very rare cases, wouldn't they? It's not my impression "success stories" with anti-retrovirals aren't that scarce. But I know in practical life numbers and impressions do not often get together in a correct way. Still, impressions might give an idea. In stochastic/statistic there are many statements (in fact: definitions) for n to infinity. Then people say "the probability for ... is ..." But was this actually verified in reality? I get your point with "regression to the mean". It is really interesting. Didn't know that in fact (we didn't see too many good examples in maths ) I just had these thoughts. I want to say: not models/maths make reality, reality makes models which hopefully mirror reality. Sorry, off-topic...
That's why I asked and from a scientific point of view - as a curious person - I am not entirely happy about stopping research in that direction. I share that. I was wondering these days: How common are contaminations in labs? I guess not very uncommon. How is that being taken care off? How will I know when reading those papers that there is no contamination present? Which led me to HIV and unreliable HIV tests. A pity there's not more from deFreitas.
I found everything that happened then very strange, too. That's one of my motivations to ask. I feel a little the same: once they find something, then again not, then again something, then a partial retraction, and then nothing more. Maybe it's not the XMRV in particular, but the question: What actually was there? It's possible there is nothing, it's also possible it is too complex at this point and scientists can't grab it. Sometimes not the obvious is the answer. Your thoughts on this are indeed very interesting and articulate much better what I ask myself. That's what puzzled me, too. These were interesting findings. Mikovits ended in jail. It's not about sympathy or she didn't understand her search area properly (which is not so rare, what @Jonathan Edwards already said), it's just highly uncommon in science. For me, at least there were politics involved. I feel a little dissatisfied. There was an interesting research line - retroviruses; at least for me. For me it would seem reasonable to follow that line and make a clear, clean statement. I sometimes think that would be more interesting than doing research on the microbiome in ME - which is interesting, definitely. But it seems so unfinished...
