Proposition to put the XMRV discussion here on a more profound and scientific basis

[joshualevy]

John Coffin and Illa Singh went from being strongly pro-XMRV at the beginning to being strongly anti-XMRV now. Why ? Because the weight of scientific evidence has led them there. They are excellent scientists who have the balls to change their views when the evidence suggests they were wrong. I'm glad we've finally had scientists of this calibre working on CFS.

The is a very common a normal part of the progress of science which is important, controversial, and wrong. I call it "Collapse of the Middle", which is a phrase I got from Langmuir's lecture on pathological science (I think). Things progress like this:

Right after the first paper is published, different researchers react to the new information differently:
Group 1: Strong supporters. They know with absolute certainty that the new theory is right.
Group 2: Supporters. They think it sounds right, they are excited and positive about it. These guys start doing research in the new area.
Group 3: Neutral. (I call them "uninvolved".) These researchers read the paper, think "sounds OK to me" and think the new idea is right, but don't really care and certainly don't do anything about it.
Group 4: Negative. These guys read the paper, and think "that's wrong". Usually they do something, but sometimes the do a study, just be be sure there's nothing there.
Group 5: Strongly negative. They know with absolute certainty that the new theory is wrong.

Right after the paper is published, groups 1 and 5 are relatively small, group 3 is largest, and groups 2 and 4 are in the middle.

But, what if the new theory is wrong? Then most of the follow up experiments or trials will not work. Those failures will be published. Attempts to build on the research wil fail. Even attempts to replicate it will fail.

Group 2 will be hit hardest by these failures, because they are the guys who are doing most of the new, follow-on research (which is now failing). They start to change their minds about the new theory.

Group 3 will read all the published papers, and shift also ("looks like that first one was wrong, after all. Oh, well."). They will change their mind as well.

Group 4 will harden their position. They never believed it, and all the failed research just reinforces their position.

Finally, groups 1 and 5 don't change their position, because they can't. They are true believers, who's opinions are not going to be changed by results. They are the fringe extremists (both pro and con).

So, a few years later, Group 1 are still strong supporters, but the rest of the research community has moved on. The middle has collapsed, the science is done for. There are a few "true believers" left (who will eventually die of old age, but never change their minds), and that's it.

Joshua (not Jay!) Levy

 

[Jemal]

I thought that post was pretty interesting Joshua. Though I do hope that if group 1 continues the research and presents additional evidence, we see another shift. The minority group of researchers could still be right...

 

[Bob]

The is a very common a normal part of the progress of science which is important, controversial, and wrong. I call it "Collapse of the Middle", which is a phrase I got from Langmuir's lecture on pathological science (I think). Things progress like this:

Right after the first paper is published, different researchers react to the new information differently:
Group 1: Strong supporters. They know with absolute certainty that the new theory is right.
Group 2: Supporters. They think it sounds right, they are excited and positive about it. These guys start doing research in the new area.
Group 3: Neutral. (I call them "uninvolved".) These researchers read the paper, think "sounds OK to me" and think the new idea is right, but don't really care and certainly don't do anything about it.
Group 4: Negative. These guys read the paper, and think "that's wrong". Usually they do something, but sometimes the do a study, just be be sure there's nothing there.
Group 5: Strongly negative. They know with absolute certainty that the new theory is wrong.

Right after the paper is published, groups 1 and 5 are relatively small, group 3 is largest, and groups 2 and 4 are in the middle.

But, what if the new theory is wrong? Then most of the follow up experiments or trials will not work. Those failures will be published. Attempts to build on the research wil fail. Even attempts to replicate it will fail.

Group 2 will be hit hardest by these failures, because they are the guys who are doing most of the new, follow-on research (which is now failing). They start to change their minds about the new theory.

Group 3 will read all the published papers, and shift also ("looks like that first one was wrong, after all. Oh, well."). They will change their mind as well.

Group 4 will harden their position. They never believed it, and all the failed research just reinforces their position.

Finally, groups 1 and 5 don't change their position, because they can't. They are true believers, who's opinions are not going to be changed by results. They are the fringe extremists (both pro and con).

So, a few years later, Group 1 are still strong supporters, but the rest of the research community has moved on. The middle has collapsed, the science is done for. There are a few "true believers" left (who will eventually die of old age, but never change their minds), and that's it.

Joshua (not Jay!) Levy

There's also another scenario to consider...

An innovative researcher makes a discovery, or comes up with a brand new theory out of left-field, that goes so far against the established consensus view that everyone dismisses it as nonsense. The researcher is publicly ridiculed.

Slowly the weight of evidence builds, or a definitive study is carried out that suddenly proves the point. It can take many years to get to that point, and often the researcher works in isolation.

Finally, as the evidence clearly proves the point beyond doubt, everybody has to accept the data.

The discovery that stomach ulcers are caused by bacteria is just one example of this type of scenario.


I would point out that the WPI's XMRV research has been replicated by other researchers, and other interesting XMRV research has been carried out.

There is a growing weight of evidence that supports the WPI's research, as demonstrated at the conference this week.

 

[Bob]

Sorry I have missed many of these comments. But I think Bob's mention of the ulcers/bacteria story is important - that's the scenario that really worries me. It's a great example of someone making a controversial discovery and finding themselves facing enormous opposition - and not for scientific reasons for the most part ( ulcer medicine was huge business and a doc from Australia saying "Hey, a few weeks of antibiotics and you're cured !" was not welcomed by pharmaceutical companies who sold ulcer medicines which had to be taken for life ). It took many years for the initial discovery to be proven correct. I hope we are not seeing a similar scenario. It doesn't seem like it, but then again we do see strange things in the CFS research world...

Perhaps I'm painting too bleak a picture but it seemed to me that given that two of the most enthusiastic early embracers of XMRV ( Coffin and Singh ) had subsequently decided that they were wrong ( on the subject of CFS/XMRV in Singh's case - do we need to nitpick ? ), it makes things look pretty negative at present. If I'm being totally honest, I'd love to see WPI publish a rigorous piece of science which suggests why so many other teams have missed XMRV, and that it causes pathology. This just seems very unlikely at present.

The reason it's up to WPI to cough up more data is because they are still claiming their work is correct, even after having 'Science' magazine request a retraction. This is a really extreme position for WPI to take. Which makes me think they must have some kind of compelling data they haven't had published yet. Why else take such an extreme position which will potentially alienate many other scientists and colleagues ? There is absolutely no shame in saying "We thought we really had something but subsequent data suggests we were wrong". Jonathan Stoye ( I think it was ) had this very experience and moved on. WPI can do the same, but they will make things much more difficult for their future credibility if they are taking such an extreme position without having some new data to back it up. I should mention that I am talking about published data with regard to XMRV. There is no other kind. I have a particular aversion - precisely because I've seen it done several times in CFS "research" over the years - to people who spout "data" or "discoveries" to the media but never publish it. Talk is particularly cheap in the scientific research world. Publish or be quiet, because spouting to the media without publishing is totally meaningless in scientific research terms. Counter-productive in fact.

XMRV may be contamination. In which case things need to move on fast - we're all getting older and our lives have been crap for varying periods of time ( 17 years this year in my case ).

XMRV may be some elusive new pathogen - but for the scientific community to swallow that now will require some compelling new evidence. That's just the reality of the situation. Perhaps Ian Lipkin will give us something definitive. We certainly all need it....

KFG, I think you are not considering a load of details.

1. Alter and Lo have effectively replicated the WPI's research. They found a closely related MLV-like virus, which they consider to be a wild human viral infection. At the very least, this should give us a reason to keep the research into MLV-related viruses alive.

2. The WPI have at the very least found a biomarker, even if it were to turn out that they haven't detected XMRV. The anti-bodies that they have detected in ME patients don't exist in many normal controls. This is a huge step forwards for ME research in itself.

3. The XMRV research is ongoing. There are many researchers who are investigating it, but we only hear from the most vocal ones.

4. XMRV is just as elusive in prostate cancer as it is in ME patients, but there have been at least three positive prostate cancer studies which confirm that XMRV is a human virus. Just as in ME, not all researchers can detect XMRV in prostate cancer. This gives us extra information about the virus, as it supports the theory that XMRV exists in extremely low copy numbers, or is undetectable using established methodologies for some other reason.

5. There are a whole load of researchers who are treating XMRV as a human virus. It isn't just Judy Mikovits. Even the CDC is treating it as a human virus now.

6. Switzer of the CDC detected a small number of XMRV positives in a prostate cancer study that he carried out. Although he concluded that this was a negative study, he did confirm that XMRV is a human virus. He also admitted/confirmed that he couldn't detect XMRV in the blood of the XMRV-positive patients, because, he suggested, of the 'low copy numbers'. In other words, he has admitted that existing technologies are not adequate to detect XMRV in the blood, just as Judy Mikovits predicted people wouldn't be able to, using bog-standard methodologies, especially single-pass PCR.

7. The theories that XMRV is just a contaminant have been continuously challenged by the evolving research. Ever since the Science study was published, the contamination theorists have changed their theories regularly. The latest Coffin paper to be published re the combination event, has now been challenged by both the CDC's latest paper, and by the new sequences published in genbank by both Switzer and the WPI.


Regardless of Coffin, Stoye and Singh's opinions, XMRV research is being carried out by a large number of scientists right now.
This was never going to be an easy ride, or a quick conclusion. Admittedly, it's taking far longer than I expected, but a lot of research is going ahead.

Having followed the research closely, I know that there is far more to the XMRV story than the high profile negative studies. If you want to see some of the ongoing research, then have a look at the abstracts from the retrovirology conference:
http://phoenixrising.me/forums/show...-starts-today!&p=184792&viewfull=1#post184792

 

[joshualevy]

There's also another scenario to consider...

An innovative researcher makes a discovery, or comes up with a brand new theory out of left-field, that goes so far against the established consensus view that everyone dismisses it as nonsense. The researcher is publicly ridiculed.

Slowly the weight of evidence builds, or a definitive study is carried out that suddenly proves the point. It can take many years to get to that point, and often the researcher works in isolation.

Finally, as the evidence clearly proves the point beyond doubt, everybody has to accept the data.

The discovery that stomach ulcers are caused by bacteria is just one example of this type of scenario.

The scenario that you describe is often called "slow acceptance" or sometimes "very slow acceptance". However, it is quite different than the "Collapse of the Middle" scenario that we see with XMRV. In the ulcers-bacteria link, there were very few supporters in the beginning, so group 2 was tiny and group 3 was small. However, there was not a bunch of negative studies, instead there were no studies at all: or very few studies. So groups 2 and 3 never collapsed, they just stayed smaller for longer. Eventually they grew as more evidence came in.

It is very different than what we see with XMRV.

I would point out that the WPI's XMRV research has been replicated by other researchers, and other interesting XMRV research has been carried out.

Of course there is! If you make the same mistake (contamination) then you will replicate their results. But we are now past that. We know how their results were created. If WPI wants to be taken seriously, they need to show that it is not a contaminant, and they have not done that. Indeed their recent genbank uploads, make it look like it was a contaminant.


Joshua (not Jay) Levy

 

[ukxmrv]

Joshua, are you just quoting / blindly trusting someone here on the recent sequences

or have you actually done the BLAST's yourself,

know what to look for

and checked to see if there is any other valid explantion?

 

[Bob]

Of course there is! If you make the same mistake (contamination) then you will replicate their results. But we are now past that. We know how their results were created. If WPI wants to be taken seriously, they need to show that it is not a contaminant, and they have not done that. Indeed their recent genbank uploads, make it look like it was a contaminant.

Well, it looks like you haven't been reading any of the discussions on this thread if you are able to jump to these spurious conclusions with any certainty.
You seem to have a very fixed idea that XMRV is contamination. I can't see how you can be so certain when there is no direct or conclusive evidence for that.
And indeed, much of the evidence points towards XMRV being a real wild human virus.
But you still insist that XMRV is a contaminant, without any doubt at all.
That's an interesting but clearly flawed point of view to take.
Why would you like to see the research shut down at such an early stage in it's evolution?
It doesn't seem very scientific or curious.

 

[Bob]

Indeed their recent genbank uploads, make it look like it was a contaminant.

Not according to the information and analysis that I've seen.

 

[ukxmrv]

KGF, I don't think that it is a bleak picture when you mention that Coffin and Singh have changed their minds. I expect some scientists to do this.

Could I suggest that you get a copy of the HIV book "and the Band played on" and read about the way researchers all fought one another right through that discovery. Then you will get an idea of how "experts" can be wrong, can be dishonest, can change their minds, change them back, make incredible breakthroughs, try to steal anothers work, sabotage and all manner of extraordinary other things.

It really is worth the hassle of ploughing through the book just to read the parts on scientific shenanigans.

 

[Waverunner]

And here we go again. Bob made some good points about XMRV but this is still a layman discussion. I don't know if his 7 arguments are valid and neither do most other people here. I would do anything to have some comments on these arguments from a virologist or people like RRM and drosha who seem to have a scientific background. This is the only way we can advance.

 

[Jemal]

And here we go again. Bob made some good points about XMRV but this is still a layman discussion. I don't know if his 7 arguments are valid and neither do most other people here. I would do anything to have some comments on these arguments from a virologist or people like RRM and drosha who seem to have a scientific background. This is the only way we can advance.

I think Bob made 7 good points and we can verify several of them. There is a lot of evidence for point 1, 3 and 5 for example.

1: Alter has said his research strengthened the case for the WPI and he did finds MLV's that infected humans. Hanson/Bell seem to strenghten Lo/Alters research even more. Of course this point can be targeted by the contaminists as well, saying all detected MLV's are contamination. This hasn't really happened though, there are no published studies that directly attack the Lo/Alter study (like with XMRV and the associated ME/CFS and prostate cancer research).

3: XMRV research is definitely ongoing. Take a look at all the abstracts at the retrovirology conference that just ended. There's still new studies popping up every day. Also the NIH has funded half a dozen more studies, including a study that looks for XMRV in autism. All these studies could eventually prove that XMRV is contamination I guess, but it's definitely true that XMRV research is ongoing and far from dead.

5: Most of the contaminists seem to treat XMRV as a real virus now. I guess the definition of a contaminant is broad. Most of the latest studies definitely treat it as a real virus. I posted a study yesterday that involved using XMRV ("a human gammaretrovirus") as a vector for gene therapy. Obviously it can infect human cells and transcribe itself into human DNA, otherwise it would be useless for gene therapy in humans.

I just picked out these points, because they were the most easy to verify. Yes, as laymen we are groping round in the dark sometimes, especially if we go really deep into the science. It would be nice to have people around with a lot more scientific knowledige. Lots of stuff can be verified by ourselves though.

 

[In Vitro Infidelium]

And here we go again. Bob made some good points about XMRV but this is still a layman discussion. I don't know if his 7 arguments are valid and neither do most other people here. I would do anything to have some comments on these arguments from a virologist or people like RRM and drosha who seem to have a scientific background. This is the only way we can advance.

Unfortunately the discussion of the XMRV saga by M.E/CFS affected people has been underwritten by partialism, where experts have been categorised as either being for us or against us and their results or (even the views of uninvolved commentators who concur with the wrong side) are taken as evidence of either incompetence or malign intent. Its difficult to see why any virologist would now want to engage with M.E/CFS affected people, other than to promote their own research something which given the current controversy looks to be an increasingly dubious practice.

Partialism is a particularly corrosive influence and ultimately it is anti science because it yields a unresolvable contradiction on the one hand it legitimises a notion of empowered citizen whose views are equal to all experts, while on the other it produces the notion of hero scientist, whose position is inviolable. Partialism as a notable influence within the social function of science is a relatively new phenomenon but its antecedence in politics, philosophy and religion is well established with the inevitable outcomes of sectarianism and cultism. Even if we could now attract experts to actually participate in M.E/CFS forums, partialism would militate against any positive outcomes, and IMO until there is a willingness to recognise how far the anti science meme has progressed within the online discourse of M.E/CFS affected people there is very little chance of progress being made.

IVI

 

[ukxmrv]

Waverunner,

Is the problem, that you cannot read the scientific papers, formulate arguments and research for yourself? (Fair enough, most of us are cognitively challenged). Is this possibly leaving you feeling vulnerable and unable to know what to think so you want an expert to tell you what they think?

Have you decided who exactly will be the expert that you would like to comment on this.

Why not send Bob's arguments to them and ask them to comment?

The problem is that no group of retrovirologists and MLV experts is going to agree on everything. Even a single retrovirologist may not be able to explain everything. This is a work in progress as all the knowledge is not there yet.

 

[Esther12]

experts have been categorised as either being for us or against us

It was rather unfortunate that the first negative XMRV study came from Wessely. I think that some researchers can be justifiably viewed as 'against us' - although I never thought he'd be stupid enough to generate an intentionally fraudulent XMRV study.

ME/CFS work is often on the edges of science, rather than founded upon hard, objective evidence. That some try to treat this work and it's ambiguous results with the same confidence one would a chemistry experiment has led to a widespread scepticism of claims of scientific expertise amongst patients. I think that some of this is misplaced with regards to virology and XMRV, but I also think that many people can have too much faith in the claims made by those believed to be operating within the scientific model, and that this has led to a lot of harm for CFS patients.

Sometimes it's good to be 'anti-science' - particularly when much of the work that's commonly presented as 'science' for CFS and has been based largely upon the presumptions of the researchers involved, going far beyond what is shown by the available evidence, and has made life harder to CFS patients. We shouldn't presume that any researcher whose ring brings disappointing results for us is 'against us' - but I think we do need to recognise that some researcher's approach to CFS has been influenced by their own prejudices and distortions of thought, and that the lack of clear evidence around CFS allows these prejudices to affect CFS 'science' in a way that is not the case for most other conditions.

 

[Overstressed]

I have posted this before and will post again: I don't believe the immune system, which served us for so many generations, is now attacking our own bodies, without good reason. I have the feeling many autoimmune diseases might be caused by pathogens we just can't detect. There's also some research going on to see if ERV's are the cause.

Exactly my point too. But on the other hand, our DNA consists of app. 8% of retroviral particles. It means, once our ancestors got infected...but what happened with the viruses ? Did we evolve to inactivate the viruses after generations, i.e. only the ones that could, the others succumded to it ? Maybe that's all evolution, and only the strongest survive ?

Anyway, personally I think that the use of Antibiotics also contribute to a growing number of people with impaired immune function.

OS.

 

[In Vitro Infidelium]

Diagnostic criteria is the most important issue in CFS research. It renders all the debate on lab techniques substantially meaningless.

This is widely accepted amongst M.E/CFS affected people as being an unchallengeable given, IMO however it is a fundamentally flawed proposition. For criteria sets to act as confounding aspects in research designed to identify potential causative agencies, competing sets would have to be so divergent as to produce patient cohorts that were 100% mutually exclusive of one another. None of the proposed sets of diagnostic criteria come anywhere near to doing that; even Reeves, which must be the least satisfactory of all, would allow inclusion of individuals who would meet the Canadian criteria at rates which would be meaningful in anything other than unreasonably small study numbers.

M.E/CFS is of unknown cause, the symptomology is heterogeneous and there are no exclusive sets of symptoms which demand a single common causative agent, therefore the probability is high, that the condition is of heterogeneous causation that is multiple agencies are involved in illness causation across the affected population with potentially multiple disease processes affecting individuals in different combination. Without some definition of causation, it is not possible to arrive at highly exclusive diagnostic criteria sets which meaningfully distinguish between research cohorts that could produce definitively distinct causation evidence i.e its chicken and egg. This circularity may be broken by sub-typing on the basis of symptom type, frequency and severity, but the overall diagnostic criteria would be broadly inclusive.

At this stage we have to acknowledge that there is a large patient population, who are all ill and who suffer multiple and variable levels of disability, whose ill health falls within a description that most of us understand as the illness from which we each suffer. Dividing up that patient population into ever smaller groups based merely on what seems to fit our individual circumstance does nothing to advance the improved health of the patient population as a whole, or even of some small part of it. An inclusive definition should not be of concern, so long as the focus of research is upon organic disease. Where treatment research is concerned there are other issues, however even there sub typing on the basis of symptom type, frequency and severity may ameliorate some the biases PACE expressed in terms of the benefits to the 25% most ill would have given a pretty stark determination of treatment value. Causation research in psychiatry is problematic, it is unlikely that any finessing of diagnostic criteria would dissuade a psychiatric researcher from sourcing evidence of predisposing trauma, attitude or behaviour any chance that theres less child abuse amongst those fitting the CCC than the Oxford criteria, it seems pretty improbable.

What we need is a good enough criteria that allows comparable organic causation research to proceed in countries where there is funding the Fukada definition and the UK NICE guidelines, if not perfect, are good enough and the research that comes from patient cohorts selected on those criteria will not be impaired because of selection choice.

IVI

 

[Alesh]

Basically I agree with IVI but "fatigue" is a sign that never was and never will be pathogonomonic. I suppose most diseases caused by a microorganism start suddenly (like a flu). Why not to start with a definition that would at least define a subgroup of "CFS patients" that began suddenly like an infectious illness (with flu-like symptoms)? In my opinion it is a necessary minimum that must be done if something like "XMRV causes CFS" should be proved.

 

[ukxmrv]

This is just turning into the same old ramble with all the usual people (including me) going off onto tangents and rehashing all the old arguments

I propose that Waverunner (who started this thread) put his questions to some experts. Name who they are, see who is interested and then we can evauluate if is is a worthwhile exercise.

Otherwise this is going to run for pages with nothing potentially new or useful being returned.

 

[Jemal]

This is just turning into the same old ramble with all the usual people (including me) going off onto tangents and rehashing all the old arguments

I propose that Waverunner (who started this thread) put his questions to some experts. Name who they are, see who is interested and then we can evauluate if is is a worthwhile exercise.

Otherwise this is going to run for pages with nothing potentially new or useful being returned.

Not entirely true (I think), I received a message with some information that invalidates one of my arguments. Waiting to see if that person wants to post it here him/herself, otherwise I will do it.
So personally I am learning from these discussions and I am adjusting my views on the evidence presented. I must say I also enjoy the discussions, even if they sometimes rehash old arguments and might even become heated.

 

[Bob]

Unfortunately the discussion of the XMRV saga by M.E/CFS affected people has been underwritten by partialism, where experts have been categorised as either being for us or against us and their results or (even the views of uninvolved commentators who concur with the wrong side) are taken as evidence of either incompetence or malign intent. Its difficult to see why any virologist would now want to engage with M.E/CFS affected people, other than to promote their own research something which given the current controversy looks to be an increasingly dubious practice.

Hmm, that's a very negative view of the ME community. And it's a sweeping generalisation.

It seems that you've completely missed the point in relation to some of our attitudes towards some researchers.

Many of us in the ME community want to see XMRV research continue until enough research has been carried out so that we know the facts. I think this is a very reasonable, scientific and logical position to take.

What I personally don't like seeing is very prominent researchers telling us (patronisingly) that there is no XMRV, and we should all forget about it, based purely on their own biases.