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Lengthy article on the NCI website about XMRV origin

Jemal

Senior Member
Messages
1,031
There is a lengthy article on the NCI website about their recent research into the origin of XMRV. This is the conclusion:

"The XMRV story is a cautionary tale about contamination," said Dr. Pathak. "And as our technology becomes ever more sensitive [for detecting the presence of mouse and viral DNA in patient samples] this will become an even bigger concern."

The XMRV story is also an interesting story of how science happens. Although Drs. Pathak and Coffin were each aware that the other was chasing down a different XMRV-like virus, they never imagined that the viruses would be the two parents of XMRV.

Good fortune played a role as well. As Dr. Le Grice noted, it is conceivable that the two labs might have discovered the same mouse virus rather than both parents, delaying their progress.

On December 17, when Dr. Coffin made the discovery, Dr. Pathak was too busy racing around to even respond to the e-mail until after he had boarded a plane. If Dr. Pathak had received the news a few days earlier, he might have postponed a 2-week vacation to a place without Internet access.

As it happened, he had a wonderful trip. And in the final moments before the flight, he managed to fire off a short reply to Dr. Coffin: "That's awesome!!"

Also, I think this is a nice quote:

The new reports in Science "are probably not the final word [on XMRV and these diseases], but they are definitive on where we stand at the moment," said Dr. Goff.

Lots more content:
http://www.cancer.gov/ncicancerbulletin/061411/page5
 

eric_s

Senior Member
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Btw, the WPI in the past has gotten some criticism for allegedly being too quick in drawing conclusions, acting in an unscientific way, etc.

Where are those voices now? In regards to the other side?
 

eric_s

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Furthermore, the chance of the virus arising independently in another mouse or in the wild is "vanishingly smallabout one in a trillion," said Dr. Pathak. This virus is unlikely to exist in nature, so the chance that a person would be exposed to a mouse with the virus is also unlikely, he added.
And one more remark...

Who cares if you get exposed to a mouse carrying this virus, if they say it's everywhere in labs, contaminating all these samples? And once it's in lab workers, it could go anywhere from there... I don't believe this is what happened, but i don't think it's mice one would have to worry about, so why mention them and not the much more obvious route?
 

Marty

Senior Member
Messages
118
Excellent article and video, not lengthy. If you read one thing on the Coffin debate, this should be it. It is science and in the language patients can understand, unlike the paranoia and false information often seen on the forums. It is only Coffin's part of the debate and Judy has her contribution to the debate, as will Lipkin, etc.; but it is honest debate.
 

eric_s

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I'm no scientist, but i actually don't think it's scientific to talk as if you know the truth when there are so many question marks still around and so much your hypothesis can't explain (referring to the article mentioned). But i think it's interesting to also hear views like yours, Marty. I would say if you want to read one thing explaining Coffin's view, then read this. But not if you want to read one thing on the entire debate, that would be very one sided then.
 

eric_s

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Less than 2 years later, the field has an answer. With the findings published, Dr. Le Grice said, it is important to remember that "there is still no evidence that this virus was ever in patients."
It's also quite presumtuous to say "the field now has an answer". This means the Drs. Ruscetti and Silverman (and many others) are not part of the field... Hmm... Also i don't see how you can say "there's no evidence that this virus was ever in patients", if you look at all the labs that have found it and the original Lombardi et al. paper. Is that not evidence? It's not absolutely proven yet, but i don't think you can just deny this evidence, because you have found other evidence that contradicts it.
 

Jemal

Senior Member
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1,031
Excellent article and video, not lengthy.

I thought it was pretty lengthy for an article, but I don't see that as negative.

It's also quite presumtuous to say "the field now has an answer". This means the Drs. Ruscetti and Silverman (and many others) are not part of the field... Hmm... Also i don't see how you can say "there's no evidence that this virus was ever in patients", if you look at all the labs that have found it and the original Lombardi et al. paper. Is that not evidence? It's not absolutely proven yet, but i don't think you can just deny this evidence, because you have found other evidence that contradicts it.

Yes, I don't think this answer is final. Dr. Goff said the same in this article:

The new reports in Science "are probably not the final word [on XMRV and these diseases], but they are definitive on where we stand at the moment," said Dr. Goff.

So, the answer is definitive (for some)... at the moment :D
 

justy

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I havent read the link yet, but one thing that keeps bothering me is this: How can it be a contaminant and not in any patients if there is widespread agreement that XMRV IS a real virus in prostate cancer? It seems to me they want to have their cake and eat it. Firstly they say its "just" a contaminant, then that its been "made" from cell lines in labs and could be sort of real (but not in people) then they are lso happy for it to be a real virus in prostate cancer. Almost any expalanation so long as its not in the people with M.E/CFS
Hmm pretty fishy.
 

Marty

Senior Member
Messages
118
You are quite right, Eric; I edited my post to say that if you read only one thing about Coffin's view, this is an excellent review in lay terms. You don't have to be a scientist to understand it.

You really do have to be a scientist to present valid counterarguments, despite the pages of misinformation you read on the internet.
 

eric_s

Senior Member
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Yes, I don't think this answer is final. Dr. Goff said the same in this article:
The new reports in Science "are probably not the final word [on XMRV and these diseases], but they are definitive on where we stand at the moment," said Dr. Goff.
So, the answer is definitive (for some)... at the moment :D
Yes, if "we" means their side then that's ok with me. But if it is supposed to mean "the field", then i don't think it's right to say that.
 

eric_s

Senior Member
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You are quite right, Eric; I edited my post to say that if you read only one thing about Coffin's view, this is an excellent review in lay terms. You don't have to be a scientist to understand it.

You really do have to be a scientist to present valid counterarguments, despite the pages of misinformation you read on the internet.
Thanks, Marty. I agree that this is a problem, that for laypeople it's very difficult to understand these things. I'm a layman myself. And i think it's even dangerous if we try to do the science ourselves. On the other hand, due to the neglect and the aggressive and hard to understand tactics by certain people and organisations, we are to some degree forced to deal with all the stuff ourselves.

So my take is that we should try to find the scientists and doctors we trust (but not blindly) and make sure they have the resources they need to be able to work. And also protect them against attacks, if necessary. Of course we can and should also follow the science, those who feel up to it and like it, but not forget that those of us who are laymen are not really qualified and might misunderstand things (it even happens to scientists :rolleyes:).
 

eric_s

Senior Member
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I havent read the link yet, but one thing that keeps bothering me is this: How can it be a contaminant and not in any patients if there is widespread agreement that XMRV IS a real virus in prostate cancer? It seems to me they want to have their cake and eat it. Firstly they say its "just" a contaminant, then that its been "made" from cell lines in labs and could be sort of real (but not in people) then they are lso happy for it to be a real virus in prostate cancer. Almost any expalanation so long as its not in the people with M.E/CFS
Hmm pretty fishy.
I think there are different groups, with different views. Some say it's always contamination and never in people, others believe it might be associated with pc but not with ME/CFS. I agree about some of it looking fishy...
 

Jemal

Senior Member
Messages
1,031
I think there are different groups, with different views. Some say it's always contamination and never in people, others believe it might be associated with pc but not with ME/CFS. I agree about some of it looking fishy...

I have the feeling they are groping around in the dark. Which is fine, as this might be a new avenue of research. I think it's too premature to close the book on XMRV/MLV's (there are several positive studies and they can't all be explained away) and I don't understand why some scientists say they have the final answer. To me this doesn't look too scientific...
 

Bob

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While the NCI scientists are busy patting themselves on the back, and congratulating themselves, and saying how wonderful they are for conclusively proving (almost) that XMRV is a contaminant, XMRV research and knowledge continues to grow and evolve.

The whole NCI article, and all of the conclusions made, have already been challenged by the CDC in a study by Switzer.
http://www.retrovirology.com/content/8/S1/A235
Conclusion:
"Given the evidence of inter-tropic recombination in MuLV, detection and classification of recombination in XMRV using different MuLV tropism prototypes should be interpreted with caution ... These results suggest that identification of parental strains of the potential recombinants is difficult and that recombination in the highly genetically related MuLV have been occurring for some time."


This CDC study points out that, contrary to Paprotka's, Coffin's and Pathak's conclusions, there are a myriad of ways that XMRV could have been created, and that the prostate cancer cell line might just be one example of many possible recombination events. Switzer draws very different conclusions to Paprotka et al., and directly challenges their study's conclusion of a 'one in a trillion' chance of a recombination event.

The following extract from the NCI article has been directly challenged by Switzer's study:

Furthermore, the chance of the virus arising independently in another mouse or in the wild is "vanishingly smallabout one in a trillion," said Dr. Pathak. This virus is unlikely to exist in nature, so the chance that a person would be exposed to a mouse with the virus is also unlikely, he added.

But even if XMRV is a result of a recombination in that specific prostate cancer cell line, the admission that it has been travelling around as contamination in labs, ever since it was created, gives us a clue to a possible route of transmission into the human population, either via vaccines or a similar route, as this article explains:
http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70081-0/fulltext

Another issue, which flies in the face of the NCI's article, is the evidence that XMRV has indeed infected the human population in at least 5 positive prostate cancer studies.


The 'proof' of contamination given in the following extract from the NCI article, has been challenged by other scientists...

All XMRV isolates reported to date are closely related to the viral sequence found in the prostate cancer cell line known as 22Rv1. If the retrovirus had been replicating in humans, these sequences would contain much more variation, several researchers noted.

The challenges are:
1. The transmission XMRV could be via vaccines or similar contact with lab artifacts.
http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70081-0/fulltext
2. The mutation rate of XMRV could be similar to HTLV, which has extremely low variability.
http://forums.phoenixrising.me/show...it-can-explain-XMRV-s-low-degree-of-mutations


It might also be the case that the original prostate cancer sample had minuscule and undetectable levels of XMRV in it, which then flourished and replicated in the cell line, making it subsequently possible to detect. (The authors assume that they would be able to detect extremelly low copy rates of XMRV.)
The NCI article says: "...XMRV replicates well in culture..." which would confirm this as a possibility.
Some prostate cancer research (Urisman et al. - see quotes below) has found that XMRV is not found in the actual prostate tumour itself (malignant prostatic epithelial cells), but in the surrounding tissue (stromal cells), so could this have led to there only being minuscule amounts of XMRV in the original prostate cancer sample in which no XMRV was detected?

Urisman et al. (Silverman):

"XMRV FISH with concurrent immunostaining for cytokeratin AE1/AE3 to achieve specific labeling of epithelial cells [64] showed no XMRV-infected cells that also had the epithelium-specific staining, confirming their non-epithelial origin"

"Analysis of prostate tissues from XMRV-positive cases by in situ hybridization and immunohistochemistry showed that XMRV nucleic acid and protein can be detected in about 1% of stromal cells, predominantly fibroblasts and hematopoietic elements in regions adjacent to the carcinoma."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1434790/?tool=pubmed


So, yes, this study shows us that XMRV could have been formed from a recombination of mouse viruses. But that's all it tells us. These scientists should do a bit more reading.


Here's another questionable extract from the NCI article:
... it is unlikely that the virus would spread easily from person to person. The reason, Dr. Fan explained in an e-mail, is that humans "have a fairly potent intracellular resistance factor that prevents XMRV infection."

Well, where on earth has this information come from?
XMRV research is only just beginning, so how can he possibly know what the behaviour of XMRV in the wild would be?
What is his evidence on which he is basing this statement?
I thought I had seen evidence of XMRV infecting human cells (1), and of cell lines being created out of XMRV-infected human tissue (2):
(1) http://www.retrovirology.com/content/pdf/1742-4690-8-s1-a208.pdf
(2) http://www.retrovirology.com/content/pdf/1742-4690-8-s1-a230.pdf

I'm afraid that this article get more ridiculous the more I read:

Less than 2 years later, the field has an answer. With the findings published, Dr. Le Grice said, it is important to remember that "there is still no evidence that this virus was ever in patients."

Sorry? Has he not seen the 5 positive prostate cancer studies?

This strikes me as a very unbalanced and unscientific article, based on a single scientific study which has reached flawed conclusions, as demonstrated by Switzer of the CDC, and others.
 

Bob

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Location
England (south coast)
It's also quite presumtuous to say "the field now has an answer". This means the Drs. Ruscetti and Silverman (and many others) are not part of the field... Hmm... Also i don't see how you can say "there's no evidence that this virus was ever in patients", if you look at all the labs that have found it and the original Lombardi et al. paper. Is that not evidence? It's not absolutely proven yet, but i don't think you can just deny this evidence, because you have found other evidence that contradicts it.

Well said eric.
There is contradictory evidence at the moment, but not 'no evidence'.

Thanks, Marty. I agree that this is a problem, that for laypeople it's very difficult to understand these things. I'm a layman myself. And i think it's even dangerous if we try to do the science ourselves. On the other hand, due to the neglect and the aggressive and hard to understand tactics by certain people and organisations, we are to some degree forced to deal with all the stuff ourselves.

So my take is that we should try to find the scientists and doctors we trust (but not blindly) and make sure they have the resources they need to be able to work. And also protect them against attacks, if necessary.

I agree with you eric.

Of course we can and should also follow the science, those who feel up to it and like it, but not forget that those of us who are laymen are not really qualified and might misunderstand things (it even happens to scientists :rolleyes:).

But you seem more far more clued up and informed on the subject than some of the scientists!
 

leela

Senior Member
Messages
3,290
To get a better picture of the NCI (as well as FDA, NIH, state medical boards, Pharma, etc)
watch this sobering documentary. It, like "Under Our Skin", could be a documentary of M.E. and XMRV
if you just substitute the names of some of the players, patents, pathogens, and patients. It is really worth watching,
as it spells out precisely the tactics being used today.
http://vimeo.com/24821365
 

justinreilly

Senior Member
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2,498
Location
NYC (& RI)
I agree with your great comments Bob and Eric.

Also in the latest Switzer article, didn't it say that he had found more variability in XMRV strains than previously reported? Maybe you alluded to this and i missed it.

Marty; some of the overreaching in conclusions are so eggregious, that I don't believe one has to be a scientist to validly argue against them- one has to simply read about the background and be able to think logically.
 

Bob

Senior Member
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Location
England (south coast)
Also in the latest Switzer article, didn't it say that he had found more variability in XMRV strains than previously reported? Maybe you alluded to this and i missed it.

Thanks Justin, that's a good point... Switzer did say that... I had missed out that point... Actually, I'd forgotten all about his significant conclusions in that study.

In his study, Switzer specifically says that the XMRV sequence variation that he has detected is "consistent with virus evolution during spread and persistence." Switzer's evidence and conclusions directly contradicts the NCI's conclusions in relation to there being no variety in any XMRV sequences. Switzer indicates there is evidence of virus evolution expected during normal human infection in the wild.

Switzer study:

Sequence analysis showed that patients 5935, 5956 and 6203 are infected with variant XMRV strains. The 168-bp pol sequences from all three patients showed 90.5100% nucleotide identity to each other, 94100% to XMRV, 91.798.8% to XMLV, 94100% to PMLV, and 91100% to ecotropic MLV (EMLV) in this short region.
164-bp env sequences from persons 5956 and 6203 were identical to each other and shared the highest nucleotide identity (94.9100%) to XMRV and other xenotropic MLV strains, respectively, [25].
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Nearly identical phylogenetic tree topologies for each gene region were obtained with both the NJ and ML methods. The XMRV sequences from both prostate cancer patients were also distinct from the PMLV sequences amplified from the murine cell line (RAW) used for preparing WB antigens demonstrating further that these are not laboratory contaminants (Fig. 2). These results confirm the presence of XMRV in both patients and demonstrate that XMRV diversity is greater than currently appreciated.
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Sequence analysis of the PCR-positive specimens was highly informative because it confirmed that all three specimens were XMRV-related. Also, the finding of a viral strain in three prostate cancer patients that is distinct from the XMRV seen in previous studies is significant and demonstrates a broader viral diversity. This would be an expected result consistent with virus evolution during spread and persistence.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019065#abstract0