Article: XMRV In the Balance- A Tale of Two Conferences

You can view the page at http://www.forums.aboutmecfs.org/content.php?248-XMRV-at-in-the-balance-A-Tale-of-Two-Conferences-CFS

 

Great job Cort!

In response to the questions raised it is pretty clear who is getting more specific and who continues to make things as vague as possible. In ordinary disputes, this is a good indication of where you find facts and where opinions.

(Question for fred: when Dr. Kerr "decided to withdraw" did he jump or was he pushed?)

Beyond the immediate questions I think we are seeing a paradigm shift in medical research. Most infectious diseases have had characteristics which make it easy to identify them: distinctive pathogens, rapid replication, cell death. We are now seeing a pathogen which is 95% homologous to endogenous sequences in humans and 94% homologous to a foreign endogenous sequence. The disease where this was discovered, prostate cancer, has a very long course, with a great deal of evidence showing years of inflammation prior to onset. If this pathogen is responsible, it must have a very low rate of replication. There is remarkably little evidence of any cell death attributable to XMRV. This has real relevance for detection and immune activation.

All these attributes violate common assumptions about pathogens, but these are not axioms carved in stone. We are getting an education regarding which researchers are actually thinking, and which are operating by conditioned response.

I think that could explain alot of skepticism about it in some quarters from the beginning; if it works out (and no huge tissue reservoir is found) how it works may open some eyes. (It's tough being on the cutting edge!)

 

I just saw this - this paper suggests that laboratory mice can be infected with XMRV. Interestingly it also states that endogenous retroviruses can produce virus in them as well

Common inbred strains of the laboratory mouse that are susceptible to infection by mouse xenotropic gammaretroviruses and the human derived XMRV.

Baliji S, Liu Q, Kozak CA.
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases Bethesda, MD 20892.
Abstract

Laboratory mouse strains carry endogenous copies of the xenotropic leukemia viruses (X-MLVs), named for their inability to infect cells of the laboratory mouse. This resistance to exogenous infection is due to a nonpermissive variant of the XPR1 gammaretrovirus receptor, a resistance that also limits in vivo expression of germline X-MLV proviruses capable of producing infectious virus.

They carry MLV's from way back they they have changed the receptor MLV's need to get in - so they can't infect from the outside

Because laboratory mice vary widely in their proviral content and in virus expression pattern, we screened inbred strains for sequence and functional variants of the XPR1 receptor. We also typed inbred strains and wild mouse species for an endogenous provirus, Bxv1, that is capable of producing infectious X-MLV (!) and that also contributes to the generation of pathogenic recombinant MLVs.

We identified the active Bxv1 provirus in many common inbred strains and in some Japanese M. molossinus mice,

its possible that many mice can produce infectious MLV's - they are carriers

Our screening for Xpr1 variants identified the permissive Xpr1(sxv) allele in 7 strains of laboratory mice including a Bxv1 positive strain, F/St, which is characterized by lifelong X-MLV viremia. Cells from three strains carrying Xpr1(sxv), SWR, SJL and SIM.R, were shown to be infectible by X-MLV and XMRV;

Laboratory mice have a receptor which does allow them to get infected by XMRV and they found which cells can get infected - XMRV can infect these mice (but does it?). Someone apparently looked at a lot of mice and couldn't find it......another XMRV conundrum

 

I would add several more points about contamination:

For contamination:

• 
  They need to identify the contaminant reservoir that is contaminating so many different labs with the same virus. This virus has not been found in ANY mouse yet. If its not coming from humans, where does it come from?
  They need to explain why no mouse mitochondrial DNA is found.
  They need to explain how it is that only the CFS samples get mostly contaminated and not the healthy controls, even for BLIND tests.
  They need to explain why contamination happens consistently in so many different independent labs by a number of different researchers.
  They need to explain why this "contaminant" infects macaque monkeys (a primate closely related to humans) the way it does, but somehow is not infecting humans.

Personally, I would like the researchers move beyond blood tests and start identifying the reservoirs for the virus in humans. The macaque monkeys research demonstrated the problems with using blood tests for XMRV. I think too many researchers are treating this virus like HIV and that is why they are have difficulty with it. Blood happens to be a reservoir for HIV and so its relatively easy to detect with a blood test. Blood is not a reservoir for XMRV and any set of blood tests are likely to prove false negative. In the case of the macaque monkeys even antibodies to XMRV were cleared from the blood within a few months even though the monkeys later showed signs of viral resurgence and continued infection. XMRV gets cleared from the blood fairly quickly and resides in some other tissues in the body. Research needs to quickly identify those infected tissues and develop some alternative tests that can be used to ensure there are no false negatives in identifying individuals infected with XMRV.

 

Great points. It'll be very interesting to see what Dr. Singh's autopsy study turns up.

 

Excellent article, Cort. Thank you.

 

I agree about Weiss - his was a cautionary tale but not a very rigorous appraisal of the facts surrounding XMRV. It was more like an essay than anything and I'm surprised it's been mentioned so much.

The UK appears to be pushing his agenda quite hard but the motives for it are unclear. It could be ignorance, arrogance, disingenuity or deflection. Take your pick. I read somewhere that he was McClure's mentor at one time but I have no evidence myself to support this.

My understanding is that 1.6 m grant from the NIH was produced before XMRV and was devoted to other things. Has Dr. Kerr actually decided to withdraw from ME research? I hope not - he did some pretty compelling research.

Dr Kerr has lost/will lose his job at Georges because of cut-backs, I believe. It is not a popular viewpoint but I don't rate Kerr's work that highly and was quite surprised to see him working with the WPI. In particular, his cohort selection was highly criticised as were certain collaborations with Wessely and the psychiatric contingent.

Thanks for the missed word - it was easy to fill in

Missed word..??

 

Dr Kerr has lost/will lose his job at Georges because of cut-backs, I believe. It is not a popular viewpoint but I don't rate Kerr's work that highly and was quite surprised to see him working with the WPI. In particular, his cohort selection was highly criticised as were certain collaborations with Wessely and the psychiatric contingent.

It would be sad to see him lose his job. The sort of speculative CFS research he was involved in was always high-risk and likely to lead to nothing - but it's also the sort of work that hold the best chance of dramatically developing our understanding of the illness. Having Kerr lose his job will mean even more researchers will see CFS as a career dead end.

 

I thought I read on this board some time back that he'd decided to withdraw from XMRV research, not ME research - can't remember who said it or what made them think so, though.

I was told by a doctor friend of mine who is friendly with Dr. Kerr, that his contract was not renewed!!!! He is going to be out of a job!!!! What a waste of talent. Hi ME/CFS gene expression work was amazing! Can anyone say blacklisted?

The ME/CFS community will sorely miss his research and support

 

Kerr didn't lose his job because he researched ME. He lost his job because of cut backs across the board. And I am not so sure that his work was high risk. The gene expression research he was doing is fairly common in other fields (for instance, in obesity and diabetes) and, indeed, Dr Esther Crawley (prinicipal investigator of the Lightning Process trial on children) is one of a group of researchers which has submitted an application to the Medical Research Council (MRC) for a 2.5 million genome wide association study on 'chronic fatigue'. Personally, I feel that this money would be better spent on XMRV research and that this would yield faster, more cost-effetive results for understanding and treating ME but then the MRC doesn't believe that XMRV (a) exists in the UK or (b) is linked with ME.

 

Kerr didn't lose his job because he researched ME. He lost his job because of cut backs across the board...

Was it chance that losing that job meant it would be impossible for him to collaborate with Dr. Mikovits on work for which there was already an NIH grant? The grant is only useful to someone with a position and a laboratory. It looks very much as if there is an unsubtle effort in progress to isolate WPI and Mikovits, cut off funding, and even make it impossible for them to complete previously-funded research.

 

I honestly believe that people are reading too much into Kerr losing his job. He was not a high profile researcher at Georges and so would have struggled to justify his position given the cuts that many have felt the brunt of, not just his department.

I also don't see why not being at Georges would prevent Kerr working with the WPI. If he was that committed, then he could have worked with them in the US.

There is a tendency in the ME community to assume that every action taken by the authorities is in some way meant to scupper us. Whilst this may on occasions be true, I just don't see it with Kerr. He lost his job because of cost cuts and may even have been relieved to be out of the ME spotlight. He seems like a pretty inoffensive kind of chap but not made of the stuff of Mikovits, and her mettle is the kind that is required to ride the storms we're now going through.

 

I honestly believe that people are reading too much into Kerr losing his job. He was not a high profile researcher at Georges and so would have struggled to justify his position given the cuts that many have felt the brunt of, not just his department.

I also don't see why not being at Georges would prevent Kerr working with the WPI. If he was that committed, then he could have worked with them in the US.

There is a tendency in the ME community to assume that every action taken by the authorities is in some way meant to scupper us. Whilst this may on occasions be true, I just don't see it with Kerr. He lost his job because of cost cuts and may even have been relieved to be out of the ME spotlight. He seems like a pretty inoffensive kind of chap but not made of the stuff of Mikovits, and her mettle is the kind that is required to ride the storms we're now going through.

I appreciate your take Fred...all is not due to trying to marginalize CFS (even if it does!). I think we all have to remember that ALL the efforts on CFS are small and really quite marginal. The NIH and CDC programs are about as small as you can get; the research arm of the WPI consists apparently of Dr. Mikovits and a few assistants...because CFS has been so marginalized all these programs are so small that they are all susceptible to cutbacks when economic circumstances change.......

I looked at a bunch of the other disorders that get little funding at the NIH - its like they just cannot get going. Well established disorders get good increases in funding from time to time but the little marginalized disorders - they just stay stuck at the bottom or decline. Its like they have no good footing.

Love the avatar My Holmes - Brett was my favorite Holmes- he even beat out Basil Rathbone - not an easy thing to do.

 

Still losing Dr. Kerr is a blow when we have so few good researchers. The one thing he did manage to do which no one else was able to do was duplicate his gene expression results - this was the first time that any gene expression results were validated - a big deal in a field that was awash in inconsistency.

I don't know if Dr. Mikovits will work with Kerr again even if they use the WPI's laboratory. Its a shame - the WPI has not been getting its grant proposals funded; whether its because of jealousy, payback to her for her outspokenness, prejudice or whatever, Dr. Kerr appears to know how to write good grants and get them funded. Its a shame they don't appear, at this point, to be not working together - but we shall see.

 

Still losing Dr. Kerr is a blow when we have so few good researchers. The one thing he did manage to do which no one else was able to do was duplicate his gene expression results - this was the first time that any gene expression results were validated - a big deal in a field that was awash in inconsistency.

He didn't exactly duplicate his results. The second round of tests showed slightly different sub-types to the first and, to my knowledge, there has never been a published explanation of the reasons why.

I spent some time recutting the public domain data from Kerr's second study and did not find anything that was startlingly new or overwhelmingly conclusive in terms of a breakthrough finding. Indeed, the results from the cross regional cohorts showed dubious inconsistencies, possibly because of the widely differing sample sizes, possibly because of potential differences in cohort selection, or both.

You could also argue that Kerr's research is downstream of aetiology. For example, if you look at the phenotypes which Dr Esther Crawley is studying in children (musculoskeletal; migraine; sore throat) you could argue that these are simply symptoms of the same aetiology and, whilst they may be useful for researching symptom treatments, they may never shine a light on the underlying cause of these symptoms and why they present so differently across patients.

I don't know if Dr. Mikovits will work with Kerr again even if they use the WPI's laboratory. Its a shame - the WPI has not been getting its grant proposals funded; whether its because of jealousy, payback to her for her outspokenness, prejudice or whatever, Dr. Kerr appears to know how to write good grants and get them funded. Its a shame they don't appear, at this point, to be not working together - but we shall see.

Bear in mind that none of Kerr's grants have come from the UK Medical Research Council, even though he sits on their CFS/ME Expert Group, and so his grant applications to the country's main funding institution have never been successful (if, indeed, he has ever submitted any to them). Most of his funding has come from the CFS Foundation (whose website has been unavailable for months) and ME Research UK (who, it has been suggested, struggles to get researchers to take on ME work).

 

He didn't exactly duplicate his results. The second round of tests showed slightly different sub-types to the first and, to my knowledge, there has never been a published explanation of the reasons why.

I spent some time recutting the public domain data from Kerr's second study and did not find anything that was startlingly new or overwhelmingly conclusive in terms of a breakthrough finding. Indeed, the results from the cross regional cohorts showed dubious inconsistencies, possibly because of the widely differing sample sizes, possibly because of potential differences in cohort selection, or both.

You could also argue that Kerr's research is downstream of aetiology. For example, if you look at the phenotypes which Dr Esther Crawley is studying in children (musculoskeletal; migraine; sore throat) you could argue that these are simply symptoms of the same aetiology and, whilst they may be useful for researching symptom treatments, they may never shine a light on the underlying cause of these symptoms and why they present so differently across patients.



Bear in mind that none of Kerr's grants have come from the UK Medical Research Council, even though he sits on their CFS/ME Expert Group, and so his grant applications to the country's main funding institution have never been successful (if, indeed, he has submitted any at all to them). Most of his funding has come from the CFS Foundation (whose website has been unavailable for months) and ME Research UK (who, it has been suggested, struggles to get researchers to take on ME work).

That was very educational!

Did he have the same genes show up? My understanding that of all the gene expression maybe only one gene or two had showed up in any two of them. I thought he had the same genes show up - which I think was a first - in that very uneven field. Even if the subtypes were slightly different that is fine with me - I was neverwhelmed with the subtyping honestly and gene expression, in general, has been disappointing, for sure.

 

Kerr didn't lose his job because he researched ME. He lost his job because of cut backs across the board.

That's just sad. He was one of the best the british had in ME/CFS.

 

great summary cort! I hope the NIH's rejection of 6 WPI grant proposals since last Oct has more to do with legitimate uncertainty on how to regard the negative studies rather than an agenda to distance themselves from the institute, scandalous history with the CDC notwithstanding.

I'm gonna be on pins and needles until the BWG results come out! It seems like that's really gonna be the tipping point, like you said, for better or worse. It's never good to have our future riding on one bet, but it's seems like things are either really gonna get rolling after that or there will be some major headwinds for researching funding going forward. Yikes.

Well I feel this is in part Dr. Mikovitz fault for not closely watching what she says in public. For example take this statement from the Learning to Live with CFS blog

Rumor is that the National Cancer Institute (NCI) has been told by someone high up in the government to pursue whether XMRV is involved in prostate cancer but should distance themselves from CFS. Though I hate to believe something like this could actually happen, the speaker from NCI at CFSAC last week was the one who suggested that contamination might be responsible for the positive XMRV results in CFS. Dr. Mikovitz said that person has seen all of the data proving contamination is impossible.

This could easily be true but she should never say this in public, it is just stupid. If she wants to respected in the research community, get papers published, and get grants she needs to stop spreading rumors. Don't bite the hand that feeds you, if she is right about XMRV we will all know with time, there are far to many highly respected researchers hard at work in the labs to not get to the bottom of this. Getting funding and researchers interested in CFS is in large part a image problem the illness has, discussing conspiracy theories and rumors in at a large venue is no way to help that image problem.
like this for example:

The prevailing theory seems to be this: if the CDC confirms that XMRV, a new, dangerous, and transmissible retrovirus, is present in people with CFS (and the CDC has estimated the number of adults in the US with CFS to be 4 million), then they have a huge public health crisis on their hands.

 

That's just sad. He was one of the best the british had in ME/CFS.

I'm looking forward to next years Invest in ME conference with zero British researchers (as opposed to last years 1 - Dr Kerr). What a complete and utter embarrassment.

 

A bit overwhelmed by Dr. Weiss's presentation I said "It was mostly about contamination but I thought he did well".

Presumably you mean LeGrice's presentation Cort?

Fred's comments about Weiss are spot on. Very slippery character, who has almost single-handedly kept XMRV off the news agenda in the UK by nefariously linking it to the MMR vaccine & autism. The guy clearly has an agenda. One which we need to examine further and expose.

I'm pretty sure Robin Weiss was Myra McClure's supervisor (remember reading/hearing this). Also her first publication (back in '87) has his name on (as you would expect from a supervisor).

IMHO right now we need to worry less about Wessely & chums and more about the McClure-Weiss axis of misinformation.

 

While in no way downplaying or being ungrateful for what Mikovits has achieved so far (quite the contrary), I still have to agree with LJS that Mikovits could have played a smarter political game.