XMRV Study No. 4

[Sasha]

Hi Jspotila - thanks for your response to my question, that's good to know.

I found your post very interesting altogether and that's a good reminder about the CAA biobank - it will be a fanastic resource and should really accelerate research.

 

[bullybeef]

Hi bullyfeef,

I can't get the meaction link to work. Would you mind double-checking?

If it doesn't work this time, I leave the full print: http://www.meactionuk.org.uk/exposing-more-anti-xmrv-spin.htm

In the early 17th century Galileo carried out a piece of groundbreaking scientific research which seemed to show that for years the authorities had been talking gibberish. The establishment tried to quickly replicalte Galileos results but despite their very best efforts were mysteriously unable to do so.

How do you explain the discrepancy between our results and yours? they asked the astronomer.

"That's easy" replied Galileo "When I look through the telescope I always try to ensure one eye remains open"

--------------------------------------------------------------------------------

Comment on the latest anti-XMRV "spin" surrounding the 3rd 0% positive XMRV study from The Netherlands

Stephen Ralph DCR(D) retired

26th February 2010

As many of you here will know, when Lombardi et al was published in Science back in October 2009, two documents were published widely on the Internet simultaneously and are available via the Action for ME website and various websites around the Internet.

http://www.afme.org.uk/news.asp?newsid=649

The first Science Express Report (that appeared in Science) giving details of the study does indeed fail to state that patients were selected using the Canadian Criteria.

However, in the second document entitled Supporting Online Material it does clearly state that patients were selected using the Canadian Criteria and Fukuda.

Taken from the Lombardi et al supporting materials document.

<snip>

Patient samples. Banked samples were selected for this study from patients fulfilling the 1994 CDC Fukuda Criteria for Chronic Fatigue Syndrome (S1) and the 2003 Canadian Consensus Criteria for Chronic Fatigue Syndrome/myalgic encephalomyelitis (CFS/ME) and presenting with severe disability. Samples were selected from several regions of the United States where outbreaks of CFS had been documented (S2). These are patients that have been seen in private medical practices, and their diagnosis of CFS is based upon prolonged disabling fatigue and the presence of cognitive deficits and reproducible immunological abnormalities. These included but were not limited to perturbations of the 2-5A synthetase/RNase L antiviral pathway, low natural killer cell cytotoxicity (as measured by standard diagnostic assays), and elevated cytokines particularly interleukin-6 and interleukin-8. In addition to these immunological abnormalities, the patients characteristically demonstrated impaired exercise performance with extremely low VO2 max measured on stress testing. The patients had been seen over a prolonged period of time and multiple longitudinal observations of the clinical and laboratory abnormalities had been documented.

</snip>

The Kuppeveld et al study failed to give this sort of detailed outline of the patients they chose to use samples from.

In a Statement published today from Dr Charles Shepherd, it was asserted that Kuppeveld et al appeared not to know about the use of the Canadian Criteria because it probably wasn't mentioned in the paper that appeared in Science.

Well, if Kuppeveld et al couldn't be bothered to read all the relevant detail from the Lombardi et al paper including the background information - text that they were supposed to be fully aware of when comparing with their own study; then it would seem to me that there was an element of incompetence on the part of Kuppeveld et al for simply not bothering to read what should have been mandatory reading for the sake of fully understanding the subject..

Further evidence of this assertion could be made because Kuppeveld et al decided not to even bother with selecting their patients using Fukuda et al as per Lombardi et al and instead decided through their own apparent convenience to use the often criticised and even broader UK Oxford Criteria instead.

Over the years it has been pointed out that the Oxford criteria excludes people with ICD-10 G93.3 Myalgic Encephalomyelitis.

From their study, Kuppeveld et al did not validate their test against samples from CFS patients known to be XMRV positive.

This was in spite of the fact that the WPI and Judy Mikovits have been offering to share their work with anyone interested in replication research.

Kuppeveld et al did not carry out their study using at least 100 patients defined using both Fukuda and the Canadian criteria for all their subjects.

A number of 100 patients or more is usually the accepted minimum for decent competent research and anyone with an "A" level in Psychology or indeed an "A" level in any real hard scientific discipline will recognise this as necessary.

Kuppeveld et al only carried out a non-validated PCR test using 25% of the methodology employed by Lombardi et al. The Lombardi et al study took two and a half years to complete as opposed to all three of the recent studies that took just a matter of weeks from start to finish.

In spite of all of this, there have been assertions from the same source (Dr Charles Shepherd at the ME Association) in the same piece that this study from Kuppeveld et al together with the two other UK studies that also had multiple and similarly significant flaws, constitutes the casting of yet more serious doubt on the original Lombardi et al paper.

To reinforce this anti-XMRV "spin" there have have also been assertions that reputable laboratories were used but this curiously is not the issue of concern at all.

What matters is what brief these laboratories were given i.e. not to bother with replication not to bother with validation of their test via the sharing of samples from the initial Lombardi et al study and not bothering with testing *any* *sample* by *any* *other* method than basic PCR a testing method that Judy Mikovits has already stated in various lectures and webcasts is potentially unreliable in relation to finding XMRV in patients with CFS and ME.

Click here for Dr Judy MIkovit's detailed XMRV presentation and Q &A Webcast from January 22nd, 2010

However, if there is an intention to bury any association between XMRV and CFS and ME as appears to be the case then the best way to bury that association would be to "crush" it under multiple quick and dirty non-replication research studies that do not bother *in* *any* *way* to even try to replicate Lombardi et al i.e. to look at the samples as closely and as hard and with the care and precision as the original scientists did scientists who spent two and a half years on their work to make the pioneering findings that they did in three centres of reputed excellence across the USA.

So in closing, we have now had three post Lombardi et al studies 2 in the UK and one in the Netherlands.

None of them bothered at all to replicate Lombardi et al.

None of the three studies used Fukuda *and* Canadian criteria to specifically select *all* their patients using the detailed outline of patient selection given in the Lombardi et al paper (see above).

None of the three null studies validated their test against samples from CFS patients already known to be XMRV positive.

None of these three studies even conceded that there is a growing population of CFS XMRV positive patients across the world including in the United Kingdom.

None of these three studies made any attempt to carry out the full range of testing methods specifically used by the Lombardi et al research i.e.

a) PCR on nucleic acids from un-stimulated and stimulated white blood cells;
b) XMRV protein expression from stimulated white blood cells;
c) Virus isolation on the LNCaP cell line; and
d) A specific antibody response to XMRV.

(Note: It should be emphasised that all four methods were needed for very good reasons and not just for the sake of wasting time and money. You can find out why by reading the Lombardi et al papers cited in this article.)

The simple fact is thus far there is no emphatic or suportable evidence *anywhere* to state that there is no association between XMRV and CFS and ME.

On the other hand there is emphatic evidence of three quick and dirty non-replication studies from teams who decided for whatever reasons not obtain any samples from the Whittemore Peterson Institute from known XMRV positive CFS patients meeting both the Fukuda and Canadian criteria.

All three studies did no precise replication any of the Lombardi et al study.

Yet all three studies obtained significant and totally co-ordinated 0% outcomes and accompanying publicity across the International media within minutes of publication and with the sole intention of casting serious doubt on the original study published in Science during October 2009.

Those in the profession of liaison psychiatry and Governments pursuing CBT/GET agendas (i.e. the PACE Trial in the UK) with vested interests in finding a 0% association between XMRV and CFS are the only people currently benefiting from "quick and dirty" 0% non-replication findings.

The jury is therefore still well and truly out.

For details from the Whittemore Peterson Institute concerning XMRV and CFS and ME go here.....

For all the XMRV News surrounding the October 2009 Lombardi et al Science article visit here.....

Sincerely,

Stephen Ralph DCR(D) Retired.

http://www.meactionuk.org.uk

 

[kurt]

If it doesn't work this time, I leave the full print: http://www.meactionuk.org.uk/exposing-more-anti-xmrv-spin.htm

Stephen Ralph makes a few good points but also I think is not understanding the entire process of replication and validation.

The good points - yes, none of the outside studies have run antibody or culture studies yet, they are relying on PCR testing. In a way that is alright because PCR is the tightest test, it looks for exact matches of DNA sequences, whereas antibody and culture tests using WB can have cross-reactive species giving false positives.

The misunderstanding - he obviously thinks that the tests are worthless because they were not exact replicas of the WPI experiment. This is just false, in fact there is more need for validation studies and less need for replication at this point because WPI has already proven replication with the NCI and CC part of their Science paper study. Replication is doing the test exactly as WPI did it and there is little for an outside lab to benefit from that, particularly when WPI already replicated their work. But a validation study may use different testing methods, the objective is to use the lab's own best tools and most sensitive testing processes to prove that the virus is or is not present. Sort of like finding another wittness to an event being challenged in a courtroom battle, more viewpoints builds a better case. And that is what these labs have done, using their real-time PCR which is highly sensitive, more sensitive than even the original WPI PCR testing. Also, slightly varying the test cohort is common practice in validation studies, that helps narrow down where a pathogen is and is not found. So I realize people are disappointed these are not positive findings but the point is that they are within the parameters of what is expected in this type of consensus-building process. In many research areas hundreds of studies are required to fully characterize a pathogen before there can be a consensus understanding, and they can not all be simple repetitions of the original study or we learn nothing new.

Another misunderstanding - these labs are testing claims made in the Science article, and not any claims that appear in comments Mikovitz or others have made after that article was published. PCR testing was the strongest part of the Science paper, the fact that WPI has altered their testing process and now downplays PCR has no bearing on how these outside labs must test. They are testing a public claim made in Science and must use PCR as part of that testing. They must test the WPI hypothesis based on how they interpret and understand the Science article. If they make mistakes such as in mis-understanding amplification, culturing, or dilution levels, then you have to ask if the Science article was clear enough, or whether the labs simply were not careful enough to make certain they understood.

WPI should put out a new publication if they need to clarify how to actually find the XMRV virus by PCR beyond what was in the Science article. It is not reasonable for them to just say 'call us' because that makes labs rely on unpublished information, and that would make the science a closed process. Science must be an open process so everyone can evaluate claims. Also, if WPI no longer believes PCR is useful, they MUST publish that, it is an ethical requirement in scientific research like this. If they do not do that they may have to live with many failed validation studies, which will cause most researchers and govt agencies to lose interest in XMRV for CFS regardless of anything WPI might say in their defense.

Also, I think one of the reasons this is all so distressing for so many PWC/ME is that there is some confusion here about the consensus-building process, even among some of the researchers involved. There will probably be many positive and many negative findings over several years before the details of XMRV in CFS are known. That is necessary, after all we want to know what is really there and how it all fits in with what we know about CFS.

One last point, where I agree with Ralph, these studies have made ridiculous conclusions. It is like everyone thinks their study answers all the questions, causality and epidemiology. Good grief! Nobody can make any such claims with any amount of credibility at this point. None of the outside studies has put this issue to rest.

 

[Hope123]

omerbasket asked:


One of the reasons that the Association is investing resources in building a national biobank is to meet the needs of researchers by providing patient cohorts that have already been evaluated and sampled. This should save researchers hundreds of thousands of dollars, and as we all know, that kind of money is very very precious in CFS research. It will also save researchers time. It can take months to recruit study subjects that meet a study's criteria. We want to save that time so that studies can move more quickly.

Jspotila, thanks for answering our questions about the CAA. My question about the biobank/ registry is why doesn't the WPI and CAA get together and make a SINGLE registry and biobank? Easier for researchers to find and easier for patients to register/ donate once instead of working with various banks. The politics between various CFS groups always astounds me in comparison to other patient advocacy groups. Let's stop re-inventing the wheel.

 

[Mithriel]

Kurt , in another illness, it might not matter the way the way these studies were done but their conclusions were not a ridiculous add on they were the whole point of the exercise.

While WE may know that science works this way until a concensus is reached it has been broadcast far and wide that CFS is NOT caused by a virus and that people with ME/CFS are desperately grasping for every straw to back up their "false belief" that a virus caused their illness - proof for the weasels that we have a mental need so more proof for their somatisation theory.

These researchers are closely involved with getting CFS redefined as a somatisaton disorder in the DSM handbook and their is a multi million pound study due to be published - we know it will have found that CBT and GET are cures, we knew when they started that they would find this as it was set up to do so. All this would have to be put on hold if they were finding XMRV. If XMRV is found now, by better techniques, these studies will still be used to keep us from tests and treatments.

This research was never about the patients, never about the science, not about XMRV. Wessely said on the 9th October that he would be surprised if it was found and his research made sure it wasn't.

The fact that people on this forum find it hard to believe just how underhand and devious these people are just lets you see how others, not involved in the ME world accept everything they say. I have watched the saga unfold for over thirty years and I have scarcely been able to believe it.

Malcolm Hooper's Magical Medicine document is a place to start.

If XMRV is confirmed in the US, I think it is very possible that they will say that we have just been misdiagnosed and that CFS is still a somatisaiton disorder and their research will be used to back that up becasue in THEIR samples XMRV did not exist. So no payback for all these years and no being brought in front of a court or the Medical Council.

A very nice outcome all round for a few weeks work, and if it costs us more years off our lives, tough.

Mithriel

 

[Advocate]

If it doesn't work this time, I leave the full print: http://www.meactionuk.org.uk/exposin...-xmrv-spin.htm

Thanks, bullybeef,

I thought it was an excellent article.

I've read the three studies that set out to supposedly look for XMRV in groups of patients, and I didn't see anything that remotely resembled the patient cohort described in the WPI Science supplemental information. Did I miss it in these other papers?

These included but were not limited to perturbations of the 2-5A synthetase/RNase L antiviral pathway, low natural killer cell cytotoxicity (as measured by standard diagnostic assays), and elevated cytokines particularly interleukin-6 and interleukin-8.

In addition to these immunological abnormalities, the patients characteristically demonstrated impaired exercise performance with extremely low VO2 max measured on stress testing.

The patients had been seen over a prolonged period of time and multiple longitudinal observations of the clinical and laboratory abnormalities had been documented.

 

[kurt]

Kurt , in another illness, it might not matter the way the way these studies were done but their conclusions were not a ridiculous add on they were the whole point of the exercise.

While WE may know that science works this way until a concensus is reached it has been broadcast far and wide that CFS is NOT caused by a virus and that people with ME/CFS are desperately grasping for every straw to back up their "false belief" that a virus caused their illness - proof for the weasels that we have a mental need so more proof for their somatisation theory.

These researchers are closely involved with getting CFS redefined as a somatisaton disorder in the DSM handbook and their is a multi million pound study due to be published - we know it will have found that CBT and GET are cures, we knew when they started that they would find this as it was set up to do so. All this would have to be put on hold if they were finding XMRV. If XMRV is found now, by better techniques, these studies will still be used to keep us from tests and treatments.

This research was never about the patients, never about the science, not about XMRV. Wessely said on the 9th October that he would be surprised if it was found and his research made sure it wasn't.

The fact that people on this forum find it hard to believe just how underhand and devious these people are just lets you see how others, not involved in the ME world accept everything they say. I have watched the saga unfold for over thirty years and I have scarcely been able to believe it.
Malcolm Hooper's Magical Medicine document is a place to start.

If XMRV is confirmed in the US, I think it is very possible that they will say that we have just been misdiagnosed and that CFS is still a somatisaiton disorder and their research will be used to back that up becasue in THEIR samples XMRV did not exist. So no payback for all these years and no being brought in front of a court or the Medical Council.

Mithriel,
My comments are strictly about the science of what is happening. You obviously know a lot more than I do about the history of the ME advocacy problems and the psychologization of ME in the UK. What I am trying to say is that the science is where one might expect at this point. Attaching so much significance to the XMRV finding has been a mistake in my opinion, a big gamble because of how a consensus process works. And although the feelings are strong, the consensus process still will work the same here as anywhere else, it is a terribly slow process with many twists and turns. The future of ME/CFS definitions should not rest on whether or not XMRV is confirmed, or on hopes that WPI or any one group will find the cure. Even if one or two studies confirm XMRV is present, there will be more negative studies, more methodology questions will emerge, then researchers will have to address whether there are cross reactions or false positives, whethr XMRV is pathogen or passenger, find a reasonable causal model, test that, try various treatments, etc. This will take many years, maybe a few decades. Given the level of research funding and how that will likely drop off when there are more negative findings, a few decades may even be optimistic. And although people will want to short-circuit that process to speed things up, there is a reason for the consensus process and by-passing that can lead to real disaster, dangerous treatment trials before enough is understood, etc.

So I think collectively we need to attach our hopes to something more promising and more stable. I do like the new research directions at CAA, have you seen the early results of the Light study? They have a concrete biomarker and diagnostic for ME/CFS, and there will be more from them. And there is a very promising study at Tufts about HHV6 activating HERV K18 which produces superantigen proteins that definitely could cause serious disease. There are many good research findings already that should be used to accomplish the political goals in the UK and Europe, research that proves many biological problems. If they are all ignored do you really think XMRV will change things even if it were confirmed in the UK? They will just continue playing their little game, say that nothing is proven yet, etc. And that could drag on literally for decades.

I think we have to stand up for our rights, we must learn how to do that, regardless of the outcomes of the XMRV studies. In fact I think XMRV has been good and bad, the increased PR is nice, but XMRV has also been a distraction from the real task of raising the public awareness of the seriousness of ME/CFS and holding public agencies to account. We can't just hope XMRV will make our case for us, we have to do that ourselves. I realize that is not simple, and I am no expert at advocacy, my hat goes off to those who have battled this in the political arena for so long.

 

[anne]

I don't understand why Dr. Vernon's statement turned the CAA facebook page into something out of Thunderdome. But there are some things that seem a little oddly worded to me:

The CFS cases were enrolled from 1991 to 1992, satisfied Oxford Criteria (published in 1991), were severely ill with debilitating fatigue of at least one year, and reported duration of symptoms ranging from 2 to 45 years. The controls were neighbors selected by the CFS subjects, the same sex as and within two years of age of the CFS subject. This study used a well-characterized cohort, well-processed and preserved blood samples and a sensitive technique. Its weakness is the small sample size. Use of the less-restrictive Oxford criteria may be objectionable by current standards, but samples were collected before publication of either the Fukuda research criteria (1994) or the Canadian clinical definition (2003).

I still don't think the fact they they satisfied the Oxford criteria should be taken as a positive, given that criteria rules out neurological problems. It still sounds like she's legitimizing this criteria. The weakness, she says, is the sample size, not anything to do with a flawed criteria. She later says that all studies had a "well-characterized patient cohorts that met accepted and widely used CFS case definition criteria." Again, we don't want to be accepting the Oxford criteria, right? Whether or not cohort had anything to do with the failure of this study, I think its politically sketchy to describe this one as "accepted." And whether or not the criteria was legitimate at the time of selection doesn't make it any more legitimate now, and its odd that she's arguing that it does. If the criteria is objectionable by current standards, no studies should be done on patients under that criteria.

With the third negative study published in just 51 days, it is now harder to explain the negative results based on CFS patient characteristics and methods alone.

This is a really unfortunate statement. The number of studies and the period of time is only significant if you want to make it so. That's the easy interpretation, and the one the media and the Wesslyites are taking. There could be 100 studies tomorrow, and it doesn't make them any more valid. I think it's an error to feed into the meme that the quantity of these studies is proof of something. The CAA is supposed to be encouraging deeper thinking.

The implication is that XMRV is likely to explain a subset of CFS rather than all cases defined as CFS (using any of the seven existing definitions).

But "all cases defined as CFS" doesn't mean anything. Nothing is going to explain all cases defined as CFS. The problem with many of these criteria is that they are too broad, and are bringing in people who don't have actual CFS. Again, we don't want these seven definitions legitimized because some are out of date, some are political, etc. We don't want to confuse "all cases defined as CFS" with "actual CFS." It's imperative that people understand the problems with some of these criteria.

Dr. Vernon's statements have gotten less supportive and more tepid each time. I'm reading that as real frustration, as opposed to anything else--
but I don't want her to be feeding the beast accidentally. This is such a political minefield, and the CAA is treading so carefully. I just wish her statements were as politically astute and careful as they are scientifically so.

I was very critical of the CAA's initial response to XMRV, and I think they've done a very good job since then. I'm not trying to bash Dr. V, but I do think these can be read in ways that can make bigger battles harder.

Anyway, does anyone understand why the WPI is not giving out sample information to the satisfaction of Dr. Vernon and others?

 

[Gerwyn]

I don't understand why Dr. Vernon's statement turned the CAA facebook page into something out of Thunderdome. But there are some things that seem a little oddly worded to me:



I still don't think the fact they they satisfied the Oxford criteria should be taken as a positive, given that criteria rules out neurological problems. It still sounds like she's legitimizing this criteria. The weakness, she says, is the sample size, not anything to do with a flawed criteria. She later says that all studies had a "well-characterized patient cohorts that met accepted and widely used CFS case definition criteria." Again, we don't want to be accepting the Oxford criteria, right? Whether or not cohort had anything to do with the failure of this study, I think its politically sketchy to describe this one as "accepted." And whether or not the criteria was legitimate at the time of selection doesn't make it any more legitimate now, and its odd that she's arguing that it does. If the criteria is objectionable by current standards, no studies should be done on patients under that criteria.



This is a really unfortunate statement. The number of studies and the period of time is only significant if you want to make it so. That's the easy interpretation, and the one the media and the Wesslyites are taking. There could be 100 studies tomorrow, and it doesn't make them any more valid. I think it's an error to feed into the meme that the quantity of these studies is proof of something. The CAA is supposed to be encouraging deeper thinking.



But "all cases defined as CFS" doesn't mean anything. Nothing is going to explain all cases defined as CFS. The problem with many of these criteria is that they are too broad, and are bringing in people who don't have actual CFS. Again, we don't want these seven definitions legitimized because some are out of date, some are political, etc. We don't want to confuse "all cases defined as CFS" with "actual CFS." It's imperative that people understand the problems with some of these criteria.

Dr. Vernon's statements have gotten less supportive and more tepid each time. I'm reading that as real frustration, as opposed to anything else--
but I don't want her to be feeding the beast accidentally. This is such a political minefield, and the CAA is treading so carefully. I just wish her statements were as politically astute and careful as they are scientifically so.

I was very critical of the CAA's initial response to XMRV, and I think they've done a very good job since then. I'm not trying to bash Dr. V, but I do think these can be read in ways that can make bigger battles harder.

Anyway, does anyone understand why the WPI is not giving out sample information to the satisfaction of Dr. Vernon and others?

The strangest thing of all is the decision of said labs not to use the positive blood samples offered by the WPI to validate their assay technique.No replicating virus pcr wont work.

 

[Angela Kennedy]

Mithriel,
My comments are strictly about the science of what is happening. You obviously know a lot more than I do about the history of the ME advocacy problems and the psychologization of ME in the UK. What I am trying to say is that the science is where one might expect at this point. Attaching so much significance to the XMRV finding has been a mistake in my opinion, a big gamble because of how a consensus process works. And although the feelings are strong, the consensus process still will work the same here as anywhere else, it is a terribly slow process with many twists and turns. The future of ME/CFS definitions should not rest on whether or not XMRV is confirmed, or on hopes that WPI or any one group will find the cure. Even if one or two studies confirm XMRV is present, there will be more negative studies, more methodology questions will emerge, then researchers will have to address whether there are cross reactions or false positives, whethr XMRV is pathogen or passenger, find a reasonable causal model, test that, try various treatments, etc. This will take many years, maybe a few decades. Given the level of research funding and how that will likely drop off when there are more negative findings, a few decades may even be optimistic. And although people will want to short-circuit that process to speed things up, there is a reason for the consensus process and by-passing that can lead to real disaster, dangerous treatment trials before enough is understood, etc.

So I think collectively we need to attach our hopes to something more promising and more stable. I do like the new research directions at CAA, have you seen the early results of the Light study? They have a concrete biomarker and diagnostic for ME/CFS, and there will be more from them. And there is a very promising study at Tufts about HHV6 activating HERV K18 which produces superantigen proteins that definitely could cause serious disease. There are many good research findings already that should be used to accomplish the political goals in the UK and Europe, research that proves many biological problems. If they are all ignored do you really think XMRV will change things even if it were confirmed in the UK? They will just continue playing their little game, say that nothing is proven yet, etc. And that could drag on literally for decades.

I think we have to stand up for our rights, we must learn how to do that, regardless of the outcomes of the XMRV studies. In fact I think XMRV has been good and bad, the increased PR is nice, but XMRV has also been a distraction from the real task of raising the public awareness of the seriousness of ME/CFS and holding public agencies to account. We can't just hope XMRV will make our case for us, we have to do that ourselves. I realize that is not simple, and I am no expert at advocacy, my hat goes off to those who have battled this in the political arena for so long.

I agree in principle Kurt that this sort of batting about is common in science, may even follow part of the 'scientific process' (in Kuhnian terms, which I believe you're implying?). However, as should always be repeated, science does not take place in an ethical, moral, ideological or political vacuum. Here, the key problems around ME/CFS and the way it sufferers are treated in ethical, ideological moral and political terms are affecting how the science is being done. In this case, the papers themselves make assertions which are based in ideological belief systems, let alone the editorials from people like McLure and Wessely in the BMJ etc. etc.

Like you, I do think we, the community and its supporters, should NOT see XMRV as a magic bullet (and in fact, the issues around XMRV have similarities to the lyme situation). However, the issue is whether the community is being harmed by unethical and ideologically- informed practices in science, and whether these are making the science flawed, a problem which has been going on for years. In this respect XMRV is just another example of that.

Contrary to what you've said about Stephen Ralph, I believe he well enough understands the process of validation and replication, and most of us probably do. It's not that difficult to understand: to the point that, when we're faced with big discrepancies like, for example, the cohorts used, we do start to worry our pretty little heads about the process. When scientists do not include such a discrepancy in a 'limitations of study' section in their paper, it is rational to be concerned that the science is flawed somewhere, and what is more, that the scientists are either unaware or deliberately suppressing their own knowledge of that flaw. Conflicts of interest are also an elephant in the room here that, in the scientific process, should be addressed, but are not.

We therefore cannot excise the so-called 'scientific process' from the politics and ideological positions of the 'scientists' involved, and its effects on how that science is being done. Nor can advocates afford not to call out 'bad science' when we see it. Hell (Can I say that?) Ben Goldacre gets to do it all the time, and he's not even a 'scientist' as such, just a common or garden medical doctor! (There is a difference). The gay community did it as well around AIDS. THIS is what Ralph (and many of us) are doing.

 

[bullybeef]

I believe fellow sufferers in the States must understand that these three validation studies are misleadingly being quoted by the UK’s very own Department of Health and national government as being fact! They are using these results to advise ME sufferers that XMRV has NOT been found in ME and that there is no concern. This is a lie! I know of two XMRV carriers here in the UK, one is very confused about these misleading comments.

Wessely himself had to explain away a mysterious internet advert to test for XMRV in prostate cancer patients only after publishing this result from his study, and with a fee attached!! Nobody has understood what his motives are here. This is proves a contradiction. How can he say XMRV hasn't been found in ME patients, and yet not mention it maybe in prostate cancer sufferers without publishing this news? It is slight of hand that would make the magician David Copperfield proud.

Also in the second study, they did report XMRV was found in healthy subjects, again this news wasn't reported. XMRV is here in the UK, but no one cares because they are being told otherwise.

The science goes over my head sometimes, but I can see political infighting. I watch a live House of Commons debate last week on TV. A local councillor read a lengthy statement regarding the lack of research funding on ME and went into great detail about the lack of medical services ME sufferers receive here in the UK. A Health minister replied by again quoting (at the time) that two studies have failed to locate XMRV in ME patients and that the Medical Research Council (whom decide were funding goes and how much) claimed that researchers haven’t asked them to fund ME research. Even I know that many researchers have asked on many occasions for funding, and been refused on numerous occasions. In fact the local councillor did state this fact and it was completely ignored.

The purpose of at least the first and third studies are to discredit the WPI, without any shadow of doubt. It is so blatant it is scary. The fact medical professionals and government officials can attempt to bury the third human retrovirus in mankind history is very worrying. Particularly now we know that not only is it happening here in the UK, but in Holland too, and maybe the rest of Europe.

 

[bullybeef]

Here is a response from another UK ME support group: http://www.investinme.org/Article 021-XMRV.htm

 

[garcia]

Here is a response from another UK ME support group: http://www.investinme.org/Article 021-XMRV.htm

That was a brilliant response from one of the only UK ME charities with its eye on the ball.

 

[Advocate]

The strangest thing of all is the decision of said labs to use the positive blood samples offered by the WPI to validate their assay technique.No replicating virus pcr wont work.

Gerwyn, I'm confused. Is that what you meant to say?

 

[fingers2022]

This will take many years, maybe a few decades. Given the level of research funding and how that will likely drop off when there are more negative findings, a few decades may even be optimistic. And although people will want to short-circuit that process to speed things up, there is a reason for the consensus process and by-passing that can lead to real disaster, dangerous treatment trials before enough is understood, etc.

So I think collectively we need to attach our hopes to something more promising and more stable.

Kurt, you are far more learned than I about other research. I stopped watching this game many years ago (after having some magnesium injections in '91 if I remember). Please forgive me if I am missing some of your points.

I cannot agree with your views above. Nobody wants to short-circuit the process, merely to speed it up by getting the researchers to work smarter. Personally, I don't have decades to wait.

Yes, maybe misguidedly, I am still hanging onto XMRV (don't even know my status, if I was confirmed positive, I'd feel even more strongly about it), but it's the best research I've seen to date. It has to be put to bed one way or the other, and as quickly as possible.

To my mind, the first thing that needs to be done is to confirm the validity of the reporting labs testing. If WPI is wrong, end of story. If WPI is right, then we can start talking about cohorts, and start doing some serious research. I know this is very simplistic, but maybe that's what's needed in the first instance.

We need to get the same sample set to (ideally) all four labs, and see the results. The sample set should contain confirmed XMRV +ves and -ves. Cloud cuckoo land - maybe, but that's where all the greatest achievements start.

 

[Gerwyn]

Gerwyn, I'm confused. Is that what you meant to say?

no not to use sorry

 

[Gerwyn]

When the Kerr study came out, I remember that one observer noted:



Given what we're hearing about how XMRV may work, both from the retrovirology conference last week, as well as Dr. Judy's comments about the slow replication rate and the difficulties with finding XMRV using PCR at the ProHealth talk, it sounds like XMRV may work quite differently than what everybody is used to. Thus I can see how it's possible that everybody really is doing everything "right" based on current virological knowledge but still coming up with contradictory results. The fact that the Kerr study and this new Dutch one didn't find XMRV in anybody shows that the problem here goes beyond just the connection to ME/CFS but to how much of a role XMRV plays in humans altogether, something neither study commented on because both were focusing so much on ME/CFS (one for good reason, one malicious).

Dr Vernon does mention the tissue depository issue, suggesting that she too has been reading about the findings at that retrovirology conference (as are people here in this forum) but isn't sure what to make of it yet. Indeed from the way the article summarizing the retrovirology conference ended, it sounds like everybody is still scratching their heads.



Or, I'd add, haven't been looking for it in the right place(s).

Clearly something big is going on with XMRV because there is so much money, so much excitement surrounding it at the moment -- more than anything I've ever seen connected with ME/CFS, even if it's more likely generating the money and excitement because of the cancer connection. The fact that someone like John Coffin, who has been studying retroviruses similar to XMRV for 35 years, is saying "there is no question I think that the virus is real and that the virus is infecting some numbers of people. And it’s VERY important to figure out where it is going as far as all of its disease associations are concerned…" outweighs these three speedy, fairly conventional studies in my mind. The IC and Dutch studies just seem like attempts -- if effective among the general public in the short term -- to shift momentum away from an XMRV-ME/CFS connection in the vain hope that will stop further study (i.e. "waste of valuable resources" B.S.). But as Robin pointed out in the thread about Coffin and Goff, these guys don't know really anything about ME/CFS and don't seem to have a bias about it one way or another. They just see a new human retrovirus to study and people who may well have it. And they seem to be really interested in really looking for it, as do a lot of their friends and competitors (Dr Mikovits said the guy who did the German prostate cancer XMRV study that was negative wants to try again with her techniques to see if then he can find it), especially if it takes them and the field of retrovirology into new places they've never been before. It looks like XMRV may just well be doing that.

Don't forget that it's only been 3 1/2 months since the Lombardi, et. al. paper. It took a few years for the scientific community to reach a consensus about HIV (the fact that so many of these retrovirologists are comparing it to the early days of HIV also feels very promising!). There's going to be a lot of back and forth for awhile.

But many of us are used to vertigo, right?

The Dutch method for extracting RNA was far from right

 

[Gerwyn]

That was a brilliant response from one of the only UK ME charities with its eye on the ball.

Very fair and astute

 

[Gerwyn]

This whole situation gives me vertigo. Everyone has an agenda and an angle here. The retrovirologists have an interest in this for less than charitable purposes, the economy is very tight and a new dangerous retrovirus might pay some of the bills for these labs. WPI is trying to startup and get funding for a CFS research center with a national scope, so they need a lot of media PR right now and a dramatic finding like XMRV is total serendipity for them. CAA has been trying since 2008 to reinvent itself around the idea of using systems biology to redirect research into more productive areas, and they have had some early success with that, actually some amazing new biomarkers have been found, but that is being overlooked right now due to all the attention on WPI and XMRV. The outside labs want to validate XMRV if it is there and some would like to provide testing, although some labs may also lack resources for proper testing (most are not drawing new blood samples). The ME patient community is seeking for biological validation and hopes XMRV can supply that. The US patient community wants better treatments for CFS and some evidence that will make it easier for us to get insurance coverage for CFS treatments, and also easier to get disability (which is very hard to get and keep in the US). And the forum community is suspicious of everyone (with good reason given past experience) and trying to make sense of all this...

And my own angle - I have attempted to find out what is going on behind the scenes and what I see is a lack of understanding between ALL of these groups. We all need to be patient and I think recognize that even if XMRV turns out to be part of CFS we will not have all the answers, and there is still a good chance that XMRV is actually a passenger virus, or only in a small subset of CFS patients.

This is a good place for us to be, one of the reasons we are in 'vertigo' over this is that we have not had an opportunity to argue about something like this before. This should have happened a few decades ago. There may still be critical pieces of the puzzle missing and I think if we can get everyone to agree on SOMETHING we might make some progress.



Gerwyn, this is actually one of the questions I have, why are people saying a retrovirus is an obvious choice for causing CFS? That is just such a blanket statement. Retrovirus is a class of infections, most of which are harmless, there are only a few known to be pathogenic, our DNA is full of retroviruses and remnants of retroviruses. Are people thinking of AIDS perhaps? AIDS does not create CFS, where is the evidence of that? I was acquainted with a man who died of AIDS, and saw him just a few weeks before he died and he did look bad, had lost weight and was pale and a little shaky. But he had more stamina and energy a few weeks before he died than I have had for over a decade with CFS. He could still drive, walk around talk, be in large groups of people, etc. I realize that is only one anecdote but my point is simply, why do you keep saying retrovirus is an obvious cause of CFS? Lowered immune function does not cause CFS, there are many diseases with lowered immune function and to my knowledge they do not create CFS. We may have imbalanced immune function but that is likely part of a more complex pathology. Please enlighten me as to how a retrovirus could cause CFS, and don't forget to explain the outbreaks of CFS, such as the Royal Free outbreak where an entire hospital staff in the UK (and only a few patients) came down with CFS, some recovering and some not.

Mikovitz is a specialist in cancer virology with no background in CFS, and what gave her the idea to look for XMRV was that there was evidence of RNasL problems in XMRV in prostate cancer and CFS. Additionally she learned that some CFS patients have lympatic cancers which obviously suggested to her a retrovirus. Also, apparently some of the Science study samples were from CFS patients with lymphatic cancers. So what I see here is an effort to connect CFS with a suspected cancer-causing retrovirus. That just does not ring true to me as the actual cause of CFS for many reasons. There may be cancer and/or XMRV in some CFS patients, but isn't that an effect of how CFS changes regulatory and immune processes? And not the actual cause of CFS? If it were we would all have cancer which we obviously do not. Therefore, treating a retrovirus under that scenario would do little against the actual CFS pathology.

I am open to new causal models for a retrovirus, but I have not seen one yet. So that is why I wonder why you keep saying this is obvious, it is not obvious to me. So if you have any insight as to why a retrovirus is an obvious cause of ME/CFS, seriously, tell me, what is missing here?




Thanks, that is not something that I have seen discussed here. However, by all appearances the Dutch study was a serious effort to find XMRV, they used the right quantities of blood and had a sensitive test with good positive and negative controls (ie: the test worked). They used the same primers. They could not be expected to know more than what was in the Science article about running the test, yes they did not appear to amplify the samples or run multiple tests for testing older samples such as what they had. However, WPI has brought up those issues since the Science publication. If WPI wants validation for their discovery they have to publish full guidelines that any lab can follow to get the claimed outcome. I am not a biologist but have been told by multiple different researchers that the Science article did not clarify some of the points that WPI now says are important in testing.



Of course WPI could be in the wrong, they are not infallible. These attempted validation studies might not have been perfect but they could detect XMRV in positive control samples, at least one used the correct amount of blood per the Science article and had a more sensitive PCR technique (real-time) than that used by WPI. If XMRV is present in the blood in the quantities indicated by WPI the other studies should have been able to find something. Support of CFS does not mean you are obligated to support WPI or any other lab. I think what is going on here is that people in the CFS world have not seen this before, because this is the farthest we have gotten in public discussion of a hypothesis for CFS. But this is the way discoveries play out, this has happened again and again in other diseases, other disciplines in medicine and science in general. New discoveries are
challenged as they should be. Challenging a scientific position is not an attack on the CFS community, in fact this type of back and forth between researchers and advocates is essential if we are to eventually have a cure.

Kurt



I believe Dr Vernon is reflecting more than CAA's position, it is not just CAA, other labs are also irritated that WPI has not provided more information about how they ran the Science study. This is costing other labs significant amounts of their funding and they just want their questions answered. If WPI can not or will not answer their questions and help those labs rerun their tests successfully I think people should challenge WPI's claim that they are advocating for CFS patients. Every other group here has been challenged, including CAA and the outside labs, and I don't see any reason to protect WPI from some serious questions.

Which human retroviruses are not pathogenic.Aids causes the same spectrum of symptoms so I dont see why you require an explanation as to how a retrovirus could cause CFS Dont you know of the evidence implicating endogenous retroviruses in many previously unexplained disease and acting as pseudogenes.Psuedogenes regulate many body activities. The test in the dutch Sdudies worked because they added fresh porcine RNA They dont know whether they had any viral RNA or not.To say that they used the right sensitive tests is laughable--read the literature on the isolation of viral rna It says clearly that there were no pts with lymphoma in the WPI study.The Dutch tiied to isolate RNA from samples frozen fo i5 years knowing that the previous reports of RNA viability were i5 months in frozen blood even especially taken for virology.Any scientist would have checked the viability of their RNA by known established methods.Despite being in virgin territory they chose not to bother---a serious attempt to find XMRV in its LATENT state.I dont think so--appearences can be deceptive in this game.The WPI is not faultless but these studies are absurd

 

[kurt]

The science goes over my head sometimes, but I can see political infighting. I watch a live House of Commons debate last week on TV. A local councillor read a lengthy statement regarding the lack of research funding on ME and went into great detail about the lack of medical services ME sufferers receive here in the UK. A Health minister replied by again quoting (at the time) that two studies have failed to locate XMRV in ME patients and that the Medical Research Council (whom decide were funding goes and how much) claimed that researchers haven’t asked them to fund ME research. Even I know that many researchers have asked on many occasions for funding, and been refused on numerous occasions. In fact the local councillor did state this fact and it was completely ignored.

This is precisely why I think we should distance ourselves from XMRV until it is better proven. When we hang our hat on a first study of something like this we put our own ability to advocate for ME/CFS at risk. We simply must find a better way to create change, we are here, we are human, we have rights, we are obviously sick. Some of the best research into the biological basis of ME/CFS has occurred right in or near the UK !!! Read Sarah Myhill's work with mitochondria, or Dr Gow's work with WBC abnormalities for example. You already have ammo, with or without XMRV.

Which human retroviruses are not pathogenic.Aids causes the same spectrum of symptoms so I dont see why you require an explanation as to how a retrovirus could cause CFS Dont you know of the evidence implicating endogenous retroviruses in many previously unexplained disease and acting as pseudogenes.Psuedogenes regulate many body activities. The test in the dutch Sdudies worked because they added fresh porcine RNA They dont know whether they had any viral RNA or not.To say that they used the right sensitive tests is laughable--read the literature on the isolation of viral rna It says clearly that there were no pts with lymphoma in the WPI study.The Dutch tiied to isolate RNA from samples frozen fo i5 years knowing that the previous reports of RNA viability were i5 months in frozen blood even especially taken for virology.Any scientist would have checked the viability of their RNA by known established methods.Despite being in virgin territory they chose not to bother---a serious attempt to find XMRV in its LATENT state.I dont think so--appearences can be deceptive in this game.The WPI is not faultless but these studies are absurd

AIDS is not a retrovirus, maybe you are speaking of HIV. And I guess we disagree, HIV does not cause CFS type symptoms although there are a few commonalities. I know that first hand from my acquaintance who died from AIDS. There are over 4000 retroviruses in our DNA and only a few have been identified as pathogenic, which ironically includes HERV K18, found activated by HHV6 in CFS patients and possibly responsible for the reverse transcriptaise found in CFS patients. But yes, I agree about exogenous retroviruses, most of the harmless ones are not found in humans. At least not that we have found yet.

As for the test sensitivity, they relied on the Science article saying 100-250 ul blood sample for PCR with no stated culturing was adequate to find XMRV, which we now hear from WPI may not be correct, but that is too late, they have to be able to stand by the Science article or make a retraction or correction.

And WPI says they found XMRV in 20+ year old blood samples so RNA viability is obviously not at issue, unless they did not actually find that in those old samples and maybe had false positives.

But I agree WPI is not faultless, however I do believe they are doing their best and trying hard and what is happening is typical of the leading edge, you just can not completely predict where this will go.