Article: XMRV at the NIH State Of Knowledge Workshop (SOK): The Mikovits Coffin Debate

Article: XMRV at the NIH State Of Knowledge Workshop (SOK): The Mikovits Coffin Deba

You can view the page at http://forums.phoenixrising.me/content.php?401-XMRV-at-the-SOK-The-Mikovits-Coffin-Debate-CFS-NIH

 

Thanks for the clear analysis of the postion now Cort - though sad we have to wait a little longer for agreements of course.

 

Harvey Alter is awesome isn't he - so levelheaded and unemotional?

 

Dr. Mikovits ...does have two papers coming out; ... and one on an antibody for test for XMRV. (The antibody test will not feature Dr. Bagni at the NCI.)

Interesting that there is an antibody study coming out, but also interesting that it won't feature Dr Bagni, given that we were originally told (by Judy Mikovits, I thought) that the Bagni study was positive and the Bagni/NCI work on antibodies seemed so solid. What happened there? Hopefully Bagni will publish those findings separately, whatever they are.

Presumably Judy Mikovitis is now following the broad-spectrum antibody approach mentioned above, arguing that highly-specific XMRV antibodies (which I think the Bagni ones were) are too narrow and will miss many XMRV variants in the patients population.

And thanks so much, Cort, for all the work in attending the conference and writing these reports to make it all accessible and comprehensible.

 

thanks Cort for writing this up

 

Interesting that there is an antibody study coming out, but also interesting that it won't feature Dr Bagni, given that we were originally told (by Judy Mikovits, I thought) that the Bagni study was positive and the Bagni/NCI work on antibodies seemed so solid. What happened there? Hopefully Bagni will publish those findings separately, whatever they are.

Presumably Judy Mikovitis is now following the broad-spectrum antibody approach mentioned above, arguing that highly-specific XMRV antibodies (which I think the Bagni ones were) are too narrow and will miss many XMRV variants in the patients population.

And thanks so much, Cort, for all the work in attending the conference and writing these reports to make it all accessible and comprehensible.

Dr. Mikovits told me what the problem with the Bagni effort was - something did not hold - but I didn't understand (and forgot to turn on my recorder when I was talking to her....).

I imagine the WPI antibody will focus more on the XMLV's or the XMRV's or HMRV's and will be able to pick the strains Dr. Mikovits believes are in that group of viruses.

 

Harvey Alter is awesome isn't he - so levelheaded and unemotional?

Yes, he was - just a delightful guy, really. I was really taken by the fact that he took lots of notes on most of the presentations. He was engaged throughout.

 

Thanks for the clear analysis of the postion now Cort - though sad we have to wait a little longer for agreements of course.

Thanks Enid...My guess is that the first big study that we know of to come out will be the Singh study and then the NCI one from Coffin's lab. It looks like the BWG study will come out before the Lipkin study. The Lipkin study is using the same labs as the BWG study - which presents another resource problem.

 

I disagree that during moderation Alter was leaning on the that XMRV was a contaminant getting into WPI samples. That is not what he said during moderation at all.
You seem to be taking a lot of liberties in saying that. In fact he said he was having difficulties in the next step in that WPI's patients are testing positive and controls are not and how stingently the Lo lab and himself have contrroled for contamination using Coffins own IAP tests that he gave them. Plus a test 100 times more sensitive than Coffins(NCI's) IAP test. So for Alter the assumption of contamination by Coffin is a step of logic he does not seem to agree with at this time.

 

I disagree that during moderation Alter was leaning on the that XMRV was a contaminant getting into WPI samples. That is not what he said during moderation at all.
You seem to be taking a lot of liberties in saying that. In fact he said he was having difficulties in the next step in that WPI's patients are testing positive and controls are not and how stingently the Lo lab and himself have contrroled for contamination using Coffins own IAP tests that he gave them. Plus a test 100 times more sensitive than Coffins(NCI's) IAP test. So for Alter the assumption of contamination by Coffin is a step of logic he does not seem to agree with at this time.

At one point my recollection is that that he did say on the podium that personally he felt the Coffin arguments to be pretty compelling. You are right as well, though, the pieces do not yet fit together for him. I would say he is leaning in the Coffin direction. I added this to the summary in the Alter section

On the other hand he finds it very difficult to reconcile the contamination theory with the inability of the Lo and Mikovits labs to find any contaminants. The details of the WPI's efforts in that arena aren't all known but the Lo lab devised an extremely sensitive assay and then used two of Coffin's IAP tests and still didn't find anything. The pieces of the puzzle do not match up yet.

On the other hand he finds it very difficult to reconcile the contamination theory with the Lo and Mikovits labs inability to find any contaminants. The details of the WPI's efforts in that arena aren't all known but the Lo lab devised an extremely sensitive assay and then used two of Coffin's IAP tests and still didn't find anything. The pieces of the puzzle do not match up yet.

He wasn't kidding when he said this is more complex than any other issue he's ever faced. He, like many others, is waiting for the results of the tests.

 

I would urge everyone reading this article to read with caution. I do not have the time to go through line by line but there is significant bias and distortion. There is a much larger picture than what has been presented here.

If XMRV/HGRVs were "contaminants" in patients samples, then how would "contaminants" always be absent from negative controls? While Alter/Lo did not find "XMRV", the found Mulv's and Alter has previously stated that their work confirmed the work done by the WPI/NCI/Cleveland Clinic.

The fact that one or more replication competent retroviruses (RCR) have been created, most likely accidentally has huge implications. The FDA and the entire world working with biotechnology has been aware of this possibility for a long time. Until recently, most of us believed all the biotechnology was safe. Much more information is out there if people care to look.

There is a document "Briefing Document Testing for Replication Competent Retrovirus (RCR)/Lentivirus (RCL) in Retroviral and Lentiviral Vector Based Gene Therapy Products Revisiting Current FDA Recommendations" that goes into detail. One quote is below:

Many gammaretroviruses are known to cause tumors in animals (Rosenberg and Jolicoeur 1997). After the reported observation that three of ten Rhesus monkeys developed lymphomas after transplantation with cells transduced with a gammaretroviral vector lot that was inadvertently contaminated with RCR (Donahue et al. 1992), FDA began requesting manufacturers and investigators to test the retroviral vector products at multiple stages in manufacturing to ensure absence of contaminating RCR and to monitor the treated patients for evidence of RCR.

There are MANY such documents. It is also important to understand that the word "contaminant" can be interpreted in different ways. For a retrovirologist, when a cell line has something in it that it is not supposed to, it is a contaminant. Cell lines are created where they know exactly what is in them as much as possible. Dr. Coffin's repeated statements that XMRV is a "contaminant" can be interpreted several ways. If XMRV is a contaminant in the sense that it somehow jumped into ME/CFS patients samples but never the negative control samples, then he needs to prove it. A lot of information is extremely technical so I understand many will stay away from it. It is not sufficient to state something is a contaminant without providing context and detailed information. It was at the CROI in Boston when Switzer finally understood... this "contaminant" could be infective and could be infecting personnel at the CDC. Did you hear that as a headline? Not here.

Did it ever occur to anyone here what would happen if HGRVs (Human Gamma Retro Viruses) like XMRV were the key to the ME/CFS puzzle? Even if it isn't, if XMRV is a recombinant retrovirus that is now out in the general population, how did it get there? Why would the CDC test its own lab personnel for XMRV (when their published studies reported not finding it yet other information shows they can)? If recombinant retroviruses have gotten out of the labs OR are being created in people by the use of biologics (drugs, treatments, and vaccines), the whole biotech industry will be (they already are) on high alert. Large sums of money and careers are at stake. Companies like Abbott Laboratories, Gen-Probe, Roche, have been quite busy researching. Are the willing to spend huge amounts of money on a "contaminant"? I think not.

From the previously mentioned document:

Vectors derived from retroviruses, such as MLV-based gammaretroviral vectors, have been used to introduce therapeutic genes into target cells in various clinical gene transfer applications (Hu and Pathak 2000). The stable integration of the vector provides the theoretical potential for long term therapeutic gene expression and may offer persistent beneficial clinical effects in treated patients.

Another document entitled "Guidance for Industry - Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During
Follow-up of Patients in Clinical Trials Using Retroviral Vectors" gives additional information.

I cannot write any more but I urge people to investigate on your own to the best of your abilities. Don't accept everything you read as truth.

~ JT

 

Dr Harvey Alter agreed with Coffin that XMRV is real and had been created a lab(ie contamination).

The disagreement seemed to be around abandoning research now that everybody agrees XMRV is real! However, that is exactly what Coffin suggested was he wanted to leave XMRV behind.

Coffin also hasn't provided any scientific proof XMRV had not infected humans in the 25 years or so that the man-made virus has been shown to exist in human blood. WPI and Alter show the virus infects humans in their peer reviewed and published studies.

Coffin hasn't published his studies either, so whatever he is saying doesn't hold much credibility since his papers haven't been published or peer reviewed like the other Alter and WPI studies.

 

I highly doubt Dr. Alter would tell a patient that he is leaning towards a contamination side.

 

I would urge everyone reading this article to read with caution. I do not have the time to go through line by line but there is significant bias and distortion. There is a much larger picture than what has been presented here.

If XMRV/HGRVs were "contaminants" in patients samples, then how would "contaminants" always be absent from negative controls? While Alter/Lo did not find "XMRV", the found Mulv's and Alter has previously stated that their work confirmed the work done by the WPI/NCI/Cleveland Clinic.

It is not sufficient to state something is a contaminant without providing context and detailed information.

.

Nobody argues that XMRV is not a real virus - the question is did it get into the patient samples or did it come from the patients themselves? I actually think there is plenty of context for both positions and both were protrayed in the article and the Workshop.

As I noted in the article the two things that Dr. Alter stated got his attention were the mouse tissues used in the prostate cancer cell line and the lack of genetic variability in the samples. Dr. Coffin stated that they have looked for XMRV in 75 or so laboratory and wild mice and they have never found it but they have found the putative precursors to the virus (preXMRV I and II) in only 2 or 3 mouse species, as I remember. One of those mouse species was the nude mice use to grow the prostate cancer cells. The fact that XMRV was not present in the prostate tissue early and then showed up as it was grown in the mice tissue buttressed the idea that it came from those mice.

The other thing that struck him was the lack of genetic variability in all the samples of XMRV to date - from the prostate cancer samples to the 2 1/2 fully sequenced CFS samples and in all the gag and env sequences the WPI reported in the original paper. That and the Hue paper suggests that XMRV came from the 22RV1 cell culture line. Dr. Mikovits argues that she has more variability data but can't get it into print.

The gene variability data is a very, very big component of the contamination theory and its unfortunate that it can't get printed somehow - as it in itself would change the playing field. If Dr. Mikovits could show significantly increased variability that would suggest XMRV does not come from the 22RVI cell line and that basically knocks off the biggest chunk of the contamination theory. Until that is presented in the literature, though, researchers will go off the published evidence - which is that variability is very low in this virus - and that would be unlikely to occur in a virus that infected humans.

None of this is a done deal....and its all inferential. My guess is that its the confluence of circumstantial evidence that has lead Coffin and others to where they are. Dr. Alter is not where Coffin is - he is leaning in Coffin's direction but he is certainly not there yet. He is keeping an open mind and is waiting on the BWG and Lipkin results.

 

An "open mind" until all the research (thank heavens) comes in is science. Long may it live !.

 

Even if it isn't, if XMRV is a recombinant retrovirus that is now out in the general population, how did it get there? Why would the CDC test its own lab personnel for XMRV (when their published studies reported not finding it yet other information shows they can)? If recombinant retroviruses have gotten out of the labs OR are being created in people by the use of biologics (drugs, treatments, and vaccines), the whole biotech industry will be (they already are) on high alert. Large sums of money and careers are at stake. Companies like Abbott Laboratories, Gen-Probe, Roche, have been quite busy researching. Are the willing to spend huge amounts of money on a "contaminant"?

I think you have to look at what you mean by the word 'contaminant' as you pointed out earlier. XMRV can be a virus and a contaminant or it can be a virus that has infected people. Again, no one is arguing that XMRV is not a real virus - they are growing all over the world in labs...several strains have been identified...they have shown that a prostate cancer cell line - pumps out large amounts of XMRV....its a very real virus and even if it does not end up causing CFS or prostate cancer it will continue to be studied in the lab both because of where it comes from (a family of nasty gamma retroviruses) and because it how it may have been created (accidentally in a lab).

The contamination question came up long after the paper was published - so the idea that researchers and companies wouldn't have put money into XMRV if it was a contaminant and therefore its not a contaminant doesn't really hold water. They put money into it probably for the reason Dr. Coffin said they did - because they have alot of history with this family of viruses and the idea that one of them actually infected humans and caused disease really excited them.

 

See your points Cort and feel ME/CFS has opened up a whole new world in retrovirology (theirs as we await their really cutting edge understanding of this thoroughly nasty family of viruses).

 

You are putting words in the mouth of Dr. Alter. He is not leaning in the direction of contamination. What did he also tell you that his and Dr. Lo's study was also contamination? He said there was none in his lab or WPI's lab. He also said he could not understand how the controls didn't also show contamination if that were the problem. Doesn't make sense.

 

Nobody argues that XMRV is not a real virus - the question is did it get into the patient samples or did it come from the patients themselves? I actually think there is plenty of context for both positions and both were protrayed in the article and the Workshop.

Cort.... Do you understand how lab testing is done? Do you understand why controls are run? If a negative control tests positive, the assay is invalid. How many times do you think Drs. Mikovits/Lo/Alter/Ruscetti/Singh etc validated their assays?

As I noted in the article the two things that Dr. Alter stated got his attention were the mouse tissues used in the prostate cancer cell line and the lack of genetic variability in the samples. Dr. Coffin stated that they have looked for XMRV in 75 or so laboratory and wild mice and they have never found it but they have found the putative precursors to the virus (preXMRV I and II) in only 2 or 3 mouse species, as I remember. One of those mouse species was the nude mice use to grow the prostate cancer cells. The fact that XMRV was not present in the prostate tissue early and then showed up as it was grown in the mice tissue buttressed the idea that it came from those mice.

Cort - Do you understand how this works? If there are no cell lines used capable of providing the virus and no reagents with the virus, where would the virus come from?

The other thing that struck him was the lack of genetic variability in all the samples of XMRV to date - from the prostate cancer samples to the 2 1/2 fully sequenced CFS samples and in all the gag and env sequences the WPI reported in the original paper. That and the Hue paper suggests that XMRV came from the 22RV1 cell culture line. Dr. Mikovits argues that she has more variability data but can't get it into print.

Cort.... Do you any idea why this might be? This is not too difficult to ascertain.

The gene variability data is a very, very big component of the contamination theory and its unfortunate that it can't get printed somehow - as it in itself would change the playing field. If Dr. Mikovits could show significantly increased variability that would suggest XMRV does not come from the 22RVI cell line and that basically knocks off the biggest chunk of the contamination theory. Until that is presented in the literature, though, researchers will go off the published evidence - which is that variability is very low in this virus - and that would be unlikely to occur in a virus that infected humans.

Regarding Variability:
From: Mouse viruses and human disease
Gkikas Magiorkinis
Department of Zoology, University of Oxford, Oxford, UK

Once a virus is endogenised, it is forced to follow the evolutionary rate of the host. Since XMRV is integrated in cell-lines the virus evolution is restricted to the hosts pace of evolution, and viral descendants have none or minimum sequence diversity. Thus, if a contaminated product, previously cultured in cell lines, is administered to people then the infections would provide the evolutionary patterns reported
by Hue and colleagues.4 If the immunological data reported by Lombardi and colleagues5 are correct, then we need to trace the common source for these infections to prevent possible public health concerns. Products from cell-lines should be the first candidates.


None of this is a done deal....and its all inferential. My guess is that its the confluence of circumstantial evidence that has lead Coffin and others to where they are. Dr. Alter is not where Coffin is - he is leaning in Coffin's direction but he is certainly not there yet. He is keeping an open mind and is waiting on the BWG and Lipkin results.

Cort, You think Coffin is "The supreme scientist"???? He knows damn well what has gone on. He is quite well aware and that is exactly his motive for wanting to "move beyond XMRV". A lab created recombinant retrovirus is not something anyone wants to hear about never mind contract. Coffin is not the only one with a motive to bury HGRV/RCR research

 

You are putting words in the mouth of Dr. Alter. He is not leaning in the direction of contamination. What did he also tell you that his and Dr. Lo's study was also contamination? He said there was none in his lab or WPI's lab. He also said he could not understand how the controls didn't also show contamination if that were the problem. Doesn't make sense.

Actually I am taking the words out of his mouth and putting them into the paper. That is what he said to me and some reporters and bloggers. One of them specifically asked him about the variability question - whether he felt the MLV's fit into the broad XMRV picture. As I noted he gave several reasons why; the fact that the prostate cancer cell line was grown in mouse tissue and the low variability of the virus seen thus far.

I'm not saying this has to all join together...it doesn't all join together and as I noted Dr. Alter said this is the confusing issue he has ever engaged in. Dr. Alter is mystified by the inability of their lab to find contamination..Regarding his finding - they have not been able to grow the virus and they are awaiting the results of another lab that is looking for DNA integration.

Nor did he say it was over...he said they will know when the BWG and Lipkin test results are in.