Switzer now finds (some) XMRV in Prostate Cancer

[Bob]

But Switzer earlier on has published studies concluding there is no association between XMRV and ME/CFS.
For Ila Singh it's the same, prostate cancer (+), ME/CFS (-).

Ila Singh now says, as you can read in the article on CFS Central, that she believes there is XMRV in prostate cancer, but not in ME/CFS.
Who tells you Switzer will not do the same. It seems a real risk to me. And he's from the CDC. What they say matters.

I agree about it being positive news, but not necessarily because of what Switzer is going to make of it, but because it hints the 0/0 studies might not allow to draw any conclusion.

Switzer is now admitting that absence of virus in the blood does not mean that there is no virus.
He mentions the monkey studies to give an explanation of the absense of virus in the blood, and explains how the virus quickly disappeared from the blood of the monkeys.
So this is a really important development, along with his other findings.

I believe that any advance in the science of XMRV is good news for the ME community, because it means we have more knowledge about XMRV and how to detect it.
The main thing stopping the ME/CFS research advancing is a lack of knowledge about how to successfully detect XMRV in the blood.

If Switzer's research advances the knowledge, then this can be used by all scientists, even Judy.
So if Switzer is genuinely interested in the science of XMRV, then I personally believe this is good news for us.

In the end I believe that the science will win over the politics (But then I do seem to have a very optimistic nature in relation to this subject!)

 

[Cort]

In some ways this was not a positive finding for XMRV at all. Look at the last paragraph

We found a very low prevalence of XMRV in prostate cancer patients. Infection was confirmed by phylogenetic analysis and absence of contaminating mouse DNA. The finding of undetectable antibodies and viremia in all three patients may reflect latent infection. Our results do not support an association of XMRV or MLV variants with prostate cancer

Later on Switzer notes

In the three specimens with detectable sequences, we noted that the copy number was very low as nested PCR and replicate testing was often needed for detection.

The problem is that XMRV was found in so few samples and in such low numbers. I get the feeling researchers want to find pathogens in a substantial percentage of patients and in high enough numbers to indicate the virus is causing harm. The original XMRV paper triggered just a little research because the bug was found in a small percentage of samples (but much larger than this one) and didn't appear to be causing the cancer. Research into XMRV only exploded when it was found in the blood of CFS patients.

However Switzer does hold open the possibility that XMRV could contribute to prostate cancer in some cases

Although our data do not support an association of prostate cancer with XMRV, it is important to understand whether XMRV has any causal role in prostate cancer when it is infrequently detected. In general, gammaretroviruses like XMRV induce malignant transformation by insertional mutagenesis, so that malignant cells in a tumor are all clonally infected.

But that

Therefore, the low-frequency of XMRV-infected cells found in all three patients are inconsistent with a direct role of XMRV in the prostate carcinogenesis in these patients.

but there is the startling genetic variability data (see post below). He concludes that more studies are

needed to better understand the prevalence of XMRV and MLVs in humans and their role in human disease.

So, yes - it sounds like it should spur more research

 

[currer]

Cort, I can't agree with you on this one.

The complete paper is MUCH more interesting and positive than you suggest.
Dont just read the conclusion but think about the implications of the whole paper.
They admit they found a highly variable mutating virus that infects human cells. All the lines of reasoning from the contamination side are out at a stroke.

To me it seems we could still be very much at the beginning of understanding XMRV and its potential.

 

[Cort]

Cort, I can't agree with you on this one.

The complete paper is MUCH more interesting and positive than you suggest.
Dont just read the conclusion but think about the implications of the whole paper.
They admit they found a highly variable mutating virus that infects human cells. All the lines of reasoning from the contamination side are out at a stroke.

To me it seems we could still be very much at the beginning of understanding XMRV and its potential.

After reading the paper I can't agree with me either . There is alot more to it than my first quick read suggested....Switzer clearly states that the genetics in the XMRV found suggests it was from a natural infection..

This is why the gene variability data from the WPI is so important.....If XMRV can be shown to have more variability then the pieces that look like they were related to 22RV1 may not look like that in the future.

We'll have to see; the data showing XMRV appear in Cleveland prostate cancer cell line as it was being passaged through mice was really startling but....XMRV could be both; it could be a lab creation that slipped out into the population and then started infecting people and therefore increased its genetic variation...

Science is full of twists and turns.....this could be a big twist (and coming from the CDC )

 

[Bob]

Science is full of twists and turns.....this could be a big twist (and coming from the CDC )

Yes, it seems like a weird and unexpected turn of events, for the CDC to apparently be taking XMRV seriously, doesn't it?!

I mean, this is Switzer's own research, so he must surely now believe and follow up what he has discovered and discussed in this research paper.

 

[eric_s]

We'll have to see; the data showing XMRV appear in Cleveland prostate cancer cell line as it was being passaged through mice was really startling but....XMRV could be both; it could be a lab creation that slipped out into the population and then started infecting people and therefore increased its genetic variation...

And Coffin tells us to leave XMRV behind. Does this seem like an intelligent and responsible idea?

What's wrong with those people? I'm really a peaceful and calm person normally, but now i'm just angry.

 

[Bob]

And Coffin tells us to leave XMRV behind. Does this seem like an intelligent and responsible idea?

No it doesn't... I agree with you eric... Coffin's statements always seemed to be more about the politics of science rather than an honest scientific curiosity about finding out the facts about XMRV.

Switzer has taken me completely by surprise with this study. I think Switzer's study blows the previous negative studies out of the water.

What's wrong with those people? I'm really a peaceful and calm person normally, but now i'm just angry.

I'm not surprised.

I'm hoping the scientific process will get us the facts eventually. Science has always been like this, for centuries.

 

[Bob]

Another significant quote from the paper:

In the three specimens with detectable sequences, we noted that the copy number was very low as nested PCR and replicate testing was often needed for detection.

So the paper explains that the copy number of XMRV was very low in the prostate cancer tissue, and that there was even less virus in the blood of the infected patients, so that it was undetectable in the blood.

Surely this is a good evidence to explain why no one can find XMRV in the blood (except Mikovits of course, who is using specialised techniques).

It seems quite pointless to continuously publish negative papers where they've only looked for XMRV in the blood.
Switzer confirms what the monkey studies discovered, that XMRV is found in very low copy numbers, if at all, in the blood.

 

[eric_s]

Yes, but this of course casts doubt on the positive ME/CFS studies. On the other hand, i don't think studies that are unable to find XMRV in the blood are more credible than the WPI's and Alter/Lo's work, that was at least in some parts blinded and didn't produce positives in the negative controls (according to what they tell us).

I'm no virologist, biologist or something like that, so i can't answer this question, but would it be possible that a virus is in tissue, like the prostate, for example, but absolutely not present in the blood?

They have analyzed blood samples of hundreds of healthy controls and hundreds of people with ME/CFS and also with other illnesses that should have a higher prevalence of XMRV rather than a lower one, compared to healthy controls, in all those negative blood studies so far.

So would it be possible that in all those positive cases that must have been in those hundreds of samples (asuming a background rate of XMRV in the population of some percent, 2% - 7%) there was absolutely no XMRV in the blood? Or are they just not good enough at finding these low levels yet?

Can a virus be somewhere in the body but the blood is absolutely free of virus in every case?

 

[eric_s]

And then there was also the German study (Fischer et al.) that found XMRV in respiratory secretions. Can it be there and not in the blood at all? I mean it must travel through the body somehow... How does it do that, if not through the blood? Unless at some point after the original infection it settles in some places and then does not move at all anymore. Would this be possible?

 

[lansbergen]

And then there was also the German study (Fischer et al.) that found XMRV in respiratory secretions. Can it be there and not in the blood at all? I mean it must travel through the body somehow... How does it do that, if not through the blood? Unless at some point after the original infection it settles in some places and then does not move at all anymore. Would this be possible?

My guess is that after the first viremia it settles in tissue. When it is reactivated and/or reinfection occurs viremia's will be present again. Between the viremia's it can spread to surouding cells without going trough the blood. It only needs close contact.

When virions bud from bloodvessel endothelium/epithelium it will be in the blood but whether it circulates or quickly go hide in the bloodvessel cells is not clear to me.

 

[Bob]

Yes, but this of course casts doubt on the positive ME/CFS studies. On the other hand, i don't think studies that are unable to find XMRV in the blood are more credible than the WPI's and Alter/Lo's work, that was at least in some parts blinded and didn't produce positives in the negative controls (according to what they tell us).

I'm no virologist, biologist or something like that, so i can't answer this question, but would it be possible that a virus is in tissue, like the prostate, for example, but absolutely not present in the blood?

They have analyzed blood samples of hundreds of healthy controls and hundreds of people with ME/CFS and also with other illnesses that should have a higher prevalence of XMRV rather than a lower one, compared to healthy controls, in all those negative blood studies so far.

So would it be possible that in all those positive cases that must have been in those hundreds of samples (asuming a background rate of XMRV in the population of some percent, 2% - 7%) there was absolutely no XMRV in the blood? Or are they just not good enough at finding these low levels yet?

Can a virus be somewhere in the body but the blood is absolutely free of virus in every case?

And then there was also the German study (Fischer et al.) that found XMRV in respiratory secretions. Can it be there and not in the blood at all? I mean it must travel through the body somehow... How does it do that, if not through the blood? Unless at some point after the original infection it settles in some places and then does not move at all anymore. Would this be possible?

Hi eric,

I have exactly the same problem with XMRV... So many questions and no answers!

My own personal opinion is that the ability to detect XMRV is based on unestablished and innovative science...
I believe that something might be different about XMRV from other viruses that means that it can't be detected with well known and established scientific procedures.
I also believe that the virus is probably only found in the blood in extremely tiny numbers (at the limits of current detection technology), and that there may well be reservoirs of XMRV in certain tissues that haven't yet been identified.

That's a good question about the respiratory secretions... Maybe it is possible that XMRV exists and replicates most happily in the tissue of the mucous membranes... But I don't know enough about retroviruses to know if that is possible or likely.

I think that it is possible for some viruses to settle in some places in the body, and then not move about the body significantly.
For example, I believe that one of the Herpes viruses is supposed to retreat to the spinal cord where it only comes to the surface to cause symptoms at times of stress. (I think it's a Herpes viruses that I'm thinking of - sorry that i can't be more specific about that.)

Theoretically, it could be possible that the entire population is infected with XMRV, but that it is only detectable in ME patients, and prostate cancer patients, because of a faulty immune system.

I'm inclined to think that Judy can detect XMRV in the blood because of her specific methodology, and that XMRV in the blood is at the limits of current detection technology, and that there might be reservoirs of XMRV in certain tissues.

Interesting questions eric.
I don't think I've answered them very well.
Maybe someone else can give us some better answers?

Bob

 

[eric_s]

But i think the other researchers are very experienced and capable as well. So the most likely reason i can think of that they're not able to find the virus if it's there would then be that the autors of the positive studies have chosen not to share all the necessary details with them. Or they did not exactly apply them, for whatever reason (as people on ME/CFS Forums suggest).

 

[August59]

Couldn't xmrv go latent in B-cells ust like the EBV. There have been people test way above normal for EBV only to be retested at a later date and come back negative. The EBNA infects b-cells and keeps them alive for its own purpose and thus remains undetectable in serum samples. I wonder if xmrv couldn't do the same thing and it may be possible for it to piggyback on ebv?

I really wish Dr. Singh would release her autopsy study that has to complete by now. It is possible however that she will have to go back and look at everything due to the contamination issue. Hopefully we will her from this study before too long.

 

[Bob]

But i think the other researchers are very experienced and capable as well. So the most likely reason i can think of that they're not able to find the virus if it's there would then be that the autors of the positive studies have chosen not to share all the necessary details with them. Or they did not exactly apply them, for whatever reason (as people on ME/CFS Forums suggest).

Yes, I think that's likely. Scientists can have very big egos, and I think that established successful scientists might rely on their own past techniques and assume that these are the best, and therefore not be very willing to adopt other scientists' practises and methodologies.

It was notable that Alter did not actually do the research that found the PMRV's, as far as I understand, but it was Lo who seemed to be doing the research. I don't know what role Alter had in the project. But Lo is a younger scientist and was therefore possibly more willing to adopt novel research techniques.

I don't know the answers. These are just my thoughts.

 

[eric_s]

Alter is an author nevertheless, participated in the phone conference after the release of the study etc. So i assume he was aware of how Lo was doing the lab work and backing it.

I don't think Lo is so young (maybe compared to Dr. Alter ). He worked for the armed forces for 20 years or so, if i remeber correctly.

It's funny, because Alter in German means "old man". It can also be used like "dude"...

 

[ixchelkali]

I thought this part was interesting:

DNA from only two (5956 and 6203) of 162 patients (1.23%) tested positive for XMRV sequences in the initial screening. Of the 77 DNA specimens that were additionally tested in triplicate by the pol PCR assay, only one patient (5935) (1.3%) was found positive. This specimen was positive in only one of three replicates. Thus, the overall PCR prevalence was 3/162 or 1.85%. Patient 5956 was positive for gag and pol sequences in 3/5 and 4/6 repeat tests, respectively, and env sequences were also detected in 1/3 repeat tests. Specimen 5956 was also positive in all three replicate pol PCR tests. Only XMRV pol and env sequences were detected in patient 6203 prostate tissue DNA in 1/4 and 1/1 repeat tests, respectively. Additional testing of DNA extracted from another prostate tissue section of 6203 was repeatedly negative, likely reflecting an uneven distribution of low copy XMRV in this tissue. DNA from all three patients repeatedly tested negative for murine mtDNA demonstrating the absence of contaminating mouse DNAs. To test for viremia we analyzed RNA extracts from plasma specimens from all three patients. All samples had undetectable sequences by the qRT-PCR and nRT-PCR tests.

So even in the three samples that tested positive, they repeatedly got false negatives. And in those 3 patients whose tissue tested positive, the blood tested negative by PCR. It seems very difficult to find XMRV when its there.

Even though they found such low levels of XMRV infection that it doesn't appear to correlate in a meaningful way with prostate cancer, you can't help but wonder what it does do. Does it behave differently in the presence of another virus, such as herpes? Does it behave differently in a person with a compromised immune system? What if the immune system is hyperactive rather than suppressed? Or is it a relatively benign passenger? Lots of questions to answer...

 

[Bob]

So even in the three samples that tested positive, they repeatedly got false negatives. And in those 3 patients whose tissue tested positive, the blood tested negative by PCR. It seems very difficult to find XMRV when its there.

Even though they found such low levels of XMRV infection that it doesn't appear to correlate in a meaningful way with prostate cancer, you can't help but wonder what it does do. Does it behave differently in the presence of another virus, such as herpes? Does it behave differently in a person with a compromised immune system? What if the immune system is hyperactive rather than suppressed? Or is it a relatively benign passenger? Lots of questions to answer...

I thought that maybe they could only detect XMRV in 3 patients because, as they admit, they are at the limits of their detection technology...
As they have struggled to find XMRV in the patients who they know are positive, then maybe they are struggling to find it in all the other patients.
Hopefully this is just the beginning of their research and it will stimulate a quest for knowledge about XMRV at the CDC ?!?

 

[toddm1960]

It may be only 3 of 162 but this makes it a positive XMRV paper. How does this get published? I thought no positive papers were published due to fears it's all contamination, and publishers reputations would be damaged if it's all over turned? Where are Judy's positive studies? Or is this just good science at work again......some get published, others don't.

 

[eric_s]

I think it makes a difference wheter it's a paper about prostate cancer or ME/CFS. And probably also who the author is. If you're from the CDC, FDA, NIH etc. i guess it's easier.