Could this be an early XMRV? The JHK virus

[xrayspex]

Hey interesting thread. I decided to wander over because I noticed out of my peripheral vision that this thread just keeps on keepin on....I've been busy over in the treatment sections, cus I'm a patient. So wait, there are people writing frequently at this forum, mostly about xmrv, that are not cfs patients? That does seem odd to me, man, if I didn't have some sort of bogus pain and "fatigue" crap going on I sure wouldnt be spending my time here. and if I was a scientist I would guess I would go to forums designed specifically for scientific colleagues to share ideas....it seems bizarre to go a support forum for an illness and argue with the patients, if that is what is going on. I have to say though, I am impressed with how knowledgeable some of you m.e. sufferers are! Wow, reading this thread, I feel more convinced by currer and bob's approach than the naysayers. And honestly, I don't feel an investment in xmrv having to be our "thing" or not, I just want to get to bottom of these similar illnesses (fm, cfs, sjogrens, connective tissue etc) as something epidemic does seem to be going on. Anyway, thanks to you guys who do understand the science and can hold the fort and who care about what happens to us.

 

[alex3619]

Warning: Philosophy Alert

Statement 1 - From RRM, post 54: "However, this is how science works: first you hypotheisize, and then you observe if the data backs up your hypothesis. If it does, then you conclude that the hypothesis must be right. When you read back this part, you'll see that the authors did exactly this."

Statement 2 - From RRM, post 57: "In science, no conclusions are really 100% absolute and I am fully aware of this."

Hi RRM, which is it? I agree with statement 2. I seriously disagree with statement 1. The implication used by many arguing as you do is an absolutist position. Its been iterated time and again, as in statement 1. This is one of the main reasons I have rejected the reasoning behind your arguments. Could you be right: yes. Are you right: thats a probabilistic assessment (though I will argue it is no more than a guesstimation) at this point. It translates to somewhere in the range of possibly to probably, about which people will disagree. Although according to Popper a correct probabilistic assessment is that the probability approaches zero, a technical point that I am not sure I agree with.

You cannot rationally conclude that the hypothesis must be right. If this were one instance I could accept it were a slip of the tongue (metaphorically speaking). This is a pattern in your arguments though, and I invite you to rethink them.

Statement 1 is a very simplistic inductivist viewpoint. It is not rationally defensible. Most of the debate on the philosophy of science in the last half of last century has been about rejecting this viewpoint, but it still lives on.

A more accurate claim, much more defensible, would be: "However, this is how science works: first you hypothesize, and then you observe if the data backs up your hypothesis. If it does, then you conclude that the hypothesis may be right due to evidentiary substantiation. This however requires rigorous testing to ensure that it is a probable conclusion."

Your (and Paprotka et. al.'s) conclusion is however a valid scientific hypothesis. It can be falsified. In time if it is not falsified your conclusion will look much stronger. There has however not been enough time for this. Hence your reasoning, and conclusions, can only be viewed as no more than tentative.

Much of the problem I have with many arguments on this and similar threads, and not just by you RRM, is they are too absolutist. They give the impression that they must be fact, or unassailable logic. Neither position is correct. While I overlook this in patients time and again, because I have an understanding of their (and my) cognitive issues, I am more critical of people who have a scientific background and are outside the ME and CFS community - I am not disputing that.

There would be far less disagreement if the conclusions were couched different: very improbable ... possible ... very probable. There would be far less disagreement if some of your statements were couched as hypotheses, because most of them are valid as hypotheses.

From RRM - Statement 3, post 59:"All of science essentialy builds upon the existing accumulaton of knowledge."

What is your position on philosophy of science? I am presuming you are not a positivist, I regard that as dead and buried. So are you eclectic, an inductivist (this can include statistical variants) or rationalist? I am not aware (broadly speaking) of more than one other view (though there are variations of each view), and that view is new and not widely discussed in the scientific literature, I am currently investigating it (a systems theoretic view).

Your statement 3 is very much a positivist view, which concerns me. We do build on the past, but we do it as much by challenging, refuting and reorganizing (including paradigm shifts) as just adding knowledge. Science is more like an exploration of the probable than the building of a structure. I suspect you know this though and this instance is just a slip or oversight.

In case there is any doubt (and I think most are aware of this now) I am a critical rationalist with leanings toward pragmatic and systems theoretic variants. I have forgotten most of my philosophy of science and training in reason, despite many years of it at a tertiary and postgraduate level. I am relearning it now. I do regard inductivism as valid, but only for formulating hypotheses and collections of interacting hypotheses (models). I see major problems in scientific methodology in ME related matters, most of which are not in virology but psychology, which is why I have started writing a book on it. They need to be challenged, as too many things on which our lives depend are presented as fact whereas they are merely hypotheses. The medical and scientific professions should know better.

In particular I am very concerned about the trend toward accepting consensus viewpoints as facts when the evidence may be distorted as in the phenomenon called Zombie Science. This is why the language used is so important. Its not just a semantic argument, but one of the few things we can do to prevent becoming Zombies.

Bye, Alex

PS I have yet to decide where the philosophy of Kuhn and similar thinkers lie: I would call that eclectic in my simplified view. Feel free to give a more detailed and not simplified account if anyone thinks differently.

 

[RRM]

Also, as Paprotka et al say, XMRV could be an undiscovered endogenous mouse virus.

Yes but, even then, it would still be formed as the obvious results of a recombination between preXMRV1 and preXMRV2. In fact, because no wild mice seem to carry both viruses and the three lab strains that do also carry the Xpr1(n) receptor variant nonpermissive to XMRV infection, it is now considered to be even more remote than before that this could have happened.

A paper has been published which demonstrates XMRV variation consistent with evolutionary changes.

No. Like I said, if this were true, you would not expect to find the very same sequences in seperate patient samples. Switzer basically found what Lo et al. found, closely related but apparently distinct sequences. In his phylogenetic analysis, you can actually see that these sequence were not derived from, nor ancestral to XMRV or any other know patient sequence (the blue "boxes" reflect Switzer's sequences):

But Switzer has detected other variants, thus making the Paprotka paper irrelevant with respect to possible human infection.

You are right in saying that the Paprotka findings do not affect Switzer's findings. The whole body of recently accumulated knowledge does, though. Just like Lo retracted his findings (despite not being affected by Paprotka et al.), these Switzer's results fail on another level.

Because we now know that contamination is potentially coming from several sources, it is not good evidence to "just" report different (but disctinct) sequences, by the way.

VP-62 could have jumped from a cell-line (possibly 22RV1), into humans, and then evolved into the sequences that Switzer has detected. Or it could have arrived in humans via another route. Nothing you have said or shown me, RRM, contradicts that.

Giraffes could have evolved on Antartica and then traveled to places where their necks give them an advantage in eating food. However, the fact that I can think of an alternative possibility (I can think of a thousand) does not mean it should be considered with serious thought.

Yes, everyting is possible, but the scenario proposed by Paprotka is, all things considered, extremely likely to have happened.

So, I'm glad that we agree with most of the issues then RRM.

Indeed.

 

[currer]

Nonsense, RRM!

 

[RRM]

Hi RRM, which is it? I agree with statement 2. I seriously disagree with statement 1

This implies that the statements are contradicting each other. They are not.

There would be far less disagreement if the conclusions were couched different: very improbable ... possible ... very probable.

Yet I do exactly this.

The problem with most of the language of science, is that it would make things incomprehensible to specifify this time and time again. For instance, like I stated earlier, Lombardi et al. did not "absolutely" show an association. To "really" show an association, they'd had to sample millions of samples.

To make a stop in between - I take it that you fully agree with this? After all, these authors (just like any other scientists) could have accidentally selected more infected patients than controls. You agree that this is unlikely yet possible?

However, in science, it is accepted to say that there is an association if your results are statistically significant. Everyone who reads these papers understands the limitations of the "absolute" sounding conclusion that they've found an association, and specifying time and time again the limitations of your conclusions would only lead to an unreadable paper.

Nothing is certain, some things are more certain than other things, but in the context of these inherent limitations, the data and conclusions in the Paprotka et al. paper are very robust. They show this throughout their entire paper, just as Lombardi et al. showed and explained that their results were statistically significant. Thus, when at the end the authors conclude things (just as Lombardi et al. conclude that they found an association), the targeted reader should be fully aware of the strengths and limitations of such statements.

Much of the problem I have with many arguments on this and similar threads, and not just by you RRM, is they are too absolutist. They give the impression that they must be fact, or unassailable logic. Neither position is correct.

Strictly speaking, of course this last bit is true. However, the same really goes for the theory of evolution, the theory that HIV is causing AIDS or even the theory of gravity. Knowledge is not absolute, yet this is no excuse to only fall back to this rather semantic argument when the available evidence strongly rejects a personal pet theory.

I have said time and time again that it is impossible to prove that an unknown murine retrovirus of unknown sequence diversity is infecting an unknown part of you with a viral load that is below the level of detection. I can only tell you that there is no evidence to support this notion.

What is your position on philosophy of science?

I view myself as a crtitical rationalist too and I cannot see how you can view my statement as positivistic. I any case, what I was trying to convey with this "statement 3" you critize is essentially the following:

We, as society, send people to prison, (largely) on the basis of fingerprint evidence. We basically assume that the view that is shared by most if not all scientists, that it is incredibly unlikely for two persons to have identical fingerprints, to be true. We don't have to invent the wheel each time - we just build on that knowledge when making future decisons. And any suspect/lawyer that tries to attack this notion, not by real evidence but with a general remark that science is not absolute and therefore this fingerprint evidence should be thrown out of court, will be laughed out of court (and into jail) him/herself.

However, it is entirely possible that someday, someone proves the mainstream view wrong. For instance, if tomorrow someone presents 10 persons from the same city with the exact same fingerprints, we would have to review a lot of past criminal cases. However, until it is actually falsified, we can consider it to be part of our body of knowledge and "safely" send people to prison based on fingerprint evidence.

The same applies here. Based on our current understanding of "how things work", there is really no way of two exactly indentical organisms emerging independently of each other. Of course someone can prove this entire body of knowledge to be wrong and collect his or her well deserved Nobel prize, but until that day, we can consider this knowledge to be as true as the things we know about fingerprints, based on what we know of things like random mutations and recombination patterns.

It rather seems that you are wrongly applying the critical rationalistic view on science. The fact that fingerprint analysis could be falsified tomorrow does not mean that the alternative hypothesis automatically deserves serious consideration. Likewise, the fact that all that we know about evolution could be falified does not mean that the view that two identical organisms could emerge independently should be seriously considered. Many use the inherent falsifiability of proper scientific hypotheses/theories as a weakness (although this is really a strength), and you seem to be doing exactly that.

 

[Bob]

A more accurate claim, much more defensible, would be: "However, this is how science works: first you hypothesize, and then you observe if the data backs up your hypothesis. If it does, then you conclude that the hypothesis may be right due to evidentiary substantiation. This however requires rigorous testing to ensure that it is a probable conclusion."

Your (and Paprotka et. al.'s) conclusion is however a valid scientific hypothesis. It can be falsified. In time if it is not falsified your conclusion will look much stronger. There has however not been enough time for this. Hence your reasoning, and conclusions, can only be viewed as no more than tentative.

That seems like common sense to me! Thanks Alex.

I see major problems in scientific methodology in ME related matters, most of which are not in virology but psychology, which is why I have started writing a book on it. They need to be challenged, as too many things on which our lives depend are presented as fact whereas they are merely hypotheses. The medical and scientific professions should know better.

In particular I am very concerned about the trend toward accepting consensus viewpoints as facts when the evidence may be distorted as in the phenomenon called Zombie Science. This is why the language used is so important. Its not just a semantic argument, but one of the few things we can do to prevent becoming Zombies.

Talking about 'facts', it was interesting to read the recent article on ADHD which I posted on the forum.
I've always assumed that Ritalin had a long-term benefit for people with ADHD.
But the article says that all of the past research was based on short-term outcomes.
When they finally carried a long-term trial on children with ADHD, it seems that Ritalin etc., had no long term benefits for the children. They weren't any better off on Ritalin than they would have been without it. In fact, due to side effects etc., they might have been worse off.

So 'facts' were presented to us for years, which turned out to be untrue. Well, that's according to the article anyway.
And doctors continue to prescribe Ritalin etc based on the short-term research.
(I don't know anything about ADHD, or about the research in the article, so I'm just dicussing this to highlight the issues, and not as a commentary on ADHD)

So we must always remember that research is not absolute, even when it seems very convincing.
In the case of Paprotka et al., it's not conclusive at all.

 

[Bob]

Yes but, even then, it would still be formed as the obvious results of a recombination between preXMRV1 and preXMRV2. In fact, because no wild mice seem to carry both viruses and the three lab strains that do also carry the Xpr1(n) receptor variant nonpermissive to XMRV infection, it is now considered to be even more remote than before that this could have happened.

Why single out and highlight that part of my argument? That wasn't a central part of my argument. I was using it as an example to highlight that there are alternative possibilities. Some of which may not have been considered by the researchers. You seem to think that they have covered all alternate possibilities, when we have no guarantee of that at all. And as I said, the Paprotka research only applies to VP-62, so it is very limited in its scope.

No. Like I said, if this were true, you would not expect to find the very same sequences in seperate patient samples. Switzer basically found what Lo et al. found, closely related but apparently distinct sequences. In his phylogenetic analysis, you can actually see that these sequence were not derived from, nor ancestral to XMRV or any other know patient sequence (the blue "boxes" reflect Switzer's sequences):

You are right in saying that the Paprotka findings do not affect Switzer's findings. The whole body of recently accumulated knowledge does, though. Just like Lo retracted his findings (despite not being affected by Paprotka et al.), these Switzer's results fail on another level.

So you know more about it than Switzer then? How convenient.

Switzer clearly concluded that they are XMRV strains, although I accept that he may or may not be correct"

"Sequence analysis showed that patients 5935, 5956 and 6203 are infected with variant XMRV strains.

"Sequence analysis of the PCR-positive specimens was highly informative because it confirmed that all three specimens were XMRV-related."

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

Because we now know that contamination is potentially coming from several sources, it is not good evidence to "just" report different (but disctinct) sequences, by the way.

Yes, that's right, Switzer only detected contamination because of the genetic variability in his samples, whereas Mikovits only detected contamination because of the (alleged) lack of genetic variability in her samples. How very convenient again.



RRM, you have taken an absolute, and absolutist, position, which has been shown to be very weak, and flawed, which you are promoting forcefully on a patient forum.
Why don't you just accept that this is not a black and white field of research, and that our understanding of MLVs is limited?

 

[Bob]

Switzer basically found what Lo et al. found, closely related but apparently distinct sequences. In his phylogenetic analysis, you can actually see that these sequence were not derived from, nor ancestral to XMRV or any other know patient sequence (the blue "boxes" reflect Switzer's sequences):

Hmm, it's interesting that you only showed us the tree for the pol sequences, RRM.
If we look at the trees for the env and gag sequences, then they are closely related to XMRV.
See trees 'A' and 'C' in this link:
http://www.plosone.org/article/show...ournal.pone.0019065.g002&representation=PNG_L
You weren't cherry picking by any chance were you?

It's a complex analysis, and I don't think it's easy to come to any conclusions (either way) based on Switzer's research. Further research is needed.


Switzer detected gag, pol and env genes in one of his patients, so they weren't just fragments he was detecting.

Like you say, RRM, some of his sequences, from different patients, are identical, suggesting possible contamination, but others have enough variety to suggest evolution.
One of his sequences was identical to a known mERVs (suggesting possible contamination), but the others are not known mERVs, which raises lots of questions.

With regards to some sequences being identical in different patients, here is further info, quoted from the paper:

"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]. The env sequences from both persons were highly divergent from EMLVs sharing only about 46% nucleotide identity. "

This opens up a lot of questions and possibilities, and certainly can't just be dismissed as contamination without further investigation.

These two sequences were identical to each other and similar to (but not the same as) XMRV VP62.
But they are not endogenous MLVs. So what are they?

Yes, possibly they are hitherto unknown MLVs, or are they novel human viruses (as Switzer concludes), or are they novel viruses that are breeding in other cell lines?
We don't have the answers. Further research is needed.


Note that the pol genes, although similar to MoMLVs, were not identical to existing recorded sequences. So the presence of MoMLV-like pol genes could be suggestive of contamination, or they could be as a result of recombined viruses (a recombination of XMRV and MoMLV genes), resulting in a novel virus, which is what Switzer concludes. These novel viruses could be from contaminated cell lines, they could be unknown mouse viruses or they could be novel human viruses. Switzer concludes that they are human viruses, although I personally think we need to wait for further research to confirm that. I can't see how he can rule out the possibility of contamination.

If anyone wants to read further about the env and pol genes, click on the following link, and read the second paragraph under the heading "Identification of XMRV diversity in prostate cancer patients":
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0019065#abstract0

 

[alex3619]

Warning: Philosophy Alert

Hi RRM, thank you for replying to my post. I will try to answer the points in-line, as mass quotes make it difficult to sort out issues.

RRM: "This implies that the statements are contradicting each other. They are not."

"Must be" implies certainty. Its a misleading claim. Saying it is most probably right assists in the conclusions that people might draw. The two statements are inconsistent at a superficial level, and only by explaining the context in which you say it does your understanding of the deeper issues show. You might well see this, but others might not reading your statements. Hence its misleading. We (as a community) are not, for the most part, scientists.

RRM: "To make a stop in between - I take it that you fully agree with this? After all, these authors (just like any other scientists) could have accidentally selected more infected patients than controls. You agree that this is unlikely yet possible?"

Yes, I agree with this, and also I agree that they may have gotten erroneous results for a variety of reasons. Its why I like the Lipkin study. This study gives maximum chance for a successful validation of the hypothesis, and if it fails will give us a very good probability estimate of that failure being the correct conclusion.

RRM: "However, in science, it is accepted to say that there is an association if your results are statistically significant. Everyone who reads these papers understands the limitations of the "absolute" sounding conclusion that they've found an association, and specifying time and time again the limitations of your conclusions would only lead to an unreadable paper."

I agree with you here RRM. However, in discussing outside of a paper too many scientists slip into less careful statements. This is, I admit, apparently less common for virologists than the main offenders, but it still happens.

RRM: "Nothing is certain, some things are more certain than other things, but in the context of these inherent limitations, the data and conclusions in the Paprotka et al. paper are very robust. They show this throughout their entire paper, just as Lombardi et al. showed and explained that their results were statistically significant. Thus, when at the end the authors conclude things (just as Lombardi et al. conclude that they found an association), the targeted reader should be fully aware of the strengths and limitations of such statements."

As an hypothesis with some data to back it up, I have no problems with Paprotka et. al.. My concern is that discussion is overstating certainty for the hypothesis.

RRM: "Strictly speaking, of course this last bit is true. However, the same really goes for the theory of evolution, the theory that HIV is causing AIDS or even the theory of gravity. Knowledge is not absolute, yet this is no excuse to only fall back to this rather semantic argument when the available evidence strongly rejects a personal pet theory."

Again I agree with you in the first sentence. The problem with this second sentence is as I have stated earlier: statements that imply certainty are subject to misinterpretation. In the case of patients, we may realize its implication is wrong, and this generates hostility and controversy. In the case of the media, these days they tend to take everything at face value. The media (for the most part, and I am thankful there are exceptions) will just accept the certainty and report it as such. So the misunderstanding spreads and becomes common knowledge.

RRM: "I view myself as a crtitical rationalist too and I cannot see how you can view my statement as positivistic. I any case, what I was trying to convey with this "statement 3" you critize is essentially the following:

We, as society, send people to prison, (largely) on the basis of fingerprint evidence. We basically assume that the view that is shared by most if not all scientists, that it is incredibly unlikely for two persons to have identical fingerprints, to be true. We don't have to invent the wheel each time - we just build on that knowledge when making future decisons. And any suspect/lawyer that tries to attack this notion, not by real evidence but with a general remark that science is not absolute and therefore this fingerprint evidence should be thrown out of court, will be laughed out of court (and into jail) him/herself."

Thank you for this clarification RRM. In the first half I agree with you. In the second half there is a difference between a courtroom and a blog, or a media piece. You have also shifted from a theoretical comment about truth, to a practical comment based on sound probability estimates. The two are not equivalent. Even the argument raised in Paprotka et. al. though involving probability, is not the same.

RRM: "The same applies here. Based on our current understanding of "how things work", there is really no way of two exactly indentical organisms emerging independently of each other. Of course someone can prove this entire body of knowledge to be wrong and collect his or her well deserved Nobel prize, but until that day, we can consider this knowledge to be as true as the things we know about fingerprints, based on what we know of things like random mutations and recombination patterns."

There is an implication here I do not agree with. Any given similar strain of virus will recombine over enough time and enough hosts. Old viruses can resurrect this way, because their components still exist. Viral swarms are different than say a European rodent and an Australian marsupial mouse. The host range is huge, some of it is incorporated in the genome (in the case of retroviruses and some non-retroviruses). So old viruses can indeed resurface in my view, and I have seen this concern expressed by many scientists over the years. So any individual resurfacing of an old virus in this way is highly improbable in any specific host, host population, geographic region or time-frame. However in the long run the probability shifts to highly probable unless all closely related viruses become extinct or the host range becomes tiny or isolated - its a question of the available host range, the available genetic sequences, and time.

RRM: "It rather seems that you are wrongly applying the critical rationalistic view on science. The fact that fingerprint analysis could be falsified tomorrow does not mean that the alternative hypothesis automatically deserves serious consideration. Likewise, the fact that all that we know about evolution could be falified does not mean that the view that two identical organisms could emerge independently should be seriously considered. Many use the inherent falsifiability of proper scientific hypotheses/theories as a weakness (although this is really a strength), and you seem to be doing exactly that."

On this I partly disagree. I have already addressed the issue with old viruses re-emerging, so I shall not revisit it. Alternative hypotheses should not be automatically considered of equivalent potential truth, on this I agree. Falsifiability is a strength in my view. However, prematurely treating an hypothesis as though it is adequately tested in not a virtue. Its only an hypothesis. Over time the value of the hypothesis can be more accurately assessed as more research is done, and implications of the hypothesis are tested. That is when its possible to make stronger claims about the hypothesis. The fact that a hypothesis has some data backing it, and some reason to think it is right, is only the beginning. Most hypotheses have that. Lombardi et. al. had that, and it was supported by Lo and Alter as well. My guesstimate is that at least half of the hypotheses we actually hear about are probably at least partly wrong, but I am probably underestimating - I suspect it might be most hypotheses are at least partly wrong.

Again, the main problem is not how scientists view this, its how the public and media view this. The days when the scientists only had to worry about what other scientists thought are gone.

To clarify, I consider the Lipkin et. al. XMRV study to be the first good study that is testing an implication of the Paprotka et. al. hypothesis, even if that is not its goal. If this confirms an association, its some evidence against Paprotka et. al.. If on the other hand it refutes an association, its some additional evidence that Paprotka et. al. might be correct. This evidence is based on a double blinded trial and with enough numbers to provide a good probability estimate. Thats very different from using other negative studies which are not much more than suggestive in my view. With the accumulation of such evidence over time, the strength of the Paprotka et. al. hypothesis could grow.

So, to reiterate, I consider the Paprotka et. al. XMRV hypothesis to be a valid hypothesis with some supporting data. Over time I will probably re-evaluate that as evidence accumulates.

Bye, Alex

 

[Bob]

Other interesting little snippets from the Switzer paper:

"Phylogenetic analysis of the env sequences inferred three distinct clusters with strong bootstrap support based on viral tropism as expected, since this region includes a portion of the viral surface membrane involved in cellular tropism..."

"...the gag and pol regions showed less clustering by tropism indicating viral recombination in these regions..."

"One prototypical PMLV (MCF1233) clustered with all EMLVs and two XMRVs, suggesting it is a recombinant in this region..."

"These results confirm the presence of XMRV in both patients and demonstrate that XMRV diversity is greater than currently appreciated."

"...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"

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

 

[currer]

Thanks for all your work on this thread, Bob. It is a while since I reread the Switzer paper, and it is surprising how rapidly the arguments and details are forgotten.

Switzer also had the advantage of looking in prostate tissue for his retrovirus, if I remember correctly, and there are arguments going round the internet that tissue is the best place to look.

 

[RRM]

If we look at the trees for the env and gag sequences, then they are closely related to XMRV.
See trees 'A' and 'C' in this link:
http://www.plosone.org/article/showI...entation=PNG_L
You weren't cherry picking by any chance were you?

No, I was not cherry picking by any chance.

The two env sequences from the tree you posted are identical to each other, which I pointed out is not consistent with evolution but with contamination. They are also exactly identical to other known partial mouse DNA sequences (you can verify this with a BLAST in Genbank). Again, this is not evidence of, or even consistent with evolution at all. Which leaves us with the single gag sequence, which is 100% identical to a mouse mERV (which you yourself acknowledge). Again, this is not consistent with XMRV evolution (unless you want to believe that XMRV evolved into an already existing mERV).

So, I only posted the sequences that were relevant to the discussion because these were at least not all identical to known sequences and/or each other.

By the way, it only takes part of a full viral sequence to show that evolution from/to another sequence is not realistically possible. You could try to "save" this by hypothesizing that these partial sequences reflect seperate infections in a single patient and that some are evolving and that some are not. While this of course is *possible*, it seems highly unlikely to me in light of other things.

So you know more about it than Switzer then? How convenient.

I don't know more about it than Switzer, but it is pretty clear that this research has been outdated by more recent findings.

And you know more than Coffin, Stoye and Hohn all other scientists that agree with the conclusions of Paprotka et al. and/or are convinced it's game over for the association of MRV's with ME/CFS? At least the person I disagree with doesn't have an actual PhD in the field.

Yes, that's right, Switzer only detected contamination because of the genetic variability in his samples, whereas Mikovits only detected contamination because of the (alleged) lack of genetic variability in her samples. How very convenient again.

This is not convenient but just plain logical.

With a genuine infection, you would expect variability of a specific kind, i.e. sequences that are distinct from each other but still cluster together and/or are derived from one another.

It is wrong to assume that, because someone expects to see sequence diversity, that then *any* sequence diversity is perfectly fine.

- When you contaminate samples with 22Rv1/VP62, you would really expect to see the reported XMRV sequences.
- When you contaminate your samples with mouse DNA, you would really expect to see the kind of diversity that is reported by Lo and Switzer.

Why don't you just accept that this is not a black and white field of research, and that our understanding of MLVs is limited?

I never said it was a black and white field of research.

The proposed association with human disease and with ME/CFS in particular has only been totally discredited. It is really up to any left proponents to prove everybody wrong, just like with any other claim that is not (or no longer) backed by any credible evidence.

 

[RRM]

"Must be" implies certainty. Its a misleading claim. Saying it is most probably right assists in the conclusions that people might draw.

Like I said, this is gettig purely semantical. I think that it was clear that I didn't mean that this made the conclusion absolutely right and impossible to falsify, or something to this effect.

To give you an example of bad, much too absolute scientific wording that remains too absolute even when read in its full and proper context, I supply this bit from Lombardi et al. 2011, in which the authors state:

Taken together, this work clearly rules out any possibility of gross contamination

In any case, I don't feel Paprotka's (or my) wording doesn't even come close to this.

Its why I like the Lipkin study. This study gives maximum chance for a successful validation of the hypothesis, and if it fails will give us a very good probability estimate of that failure being the correct conclusion.

I can certainly agree with this, although I might add that the same really applied to the BWG study. In both studies, scientists were(/are) basically free to choose their own methods on a collection of samples. The only real difference is that the BWG used a (rather small, but still statistically significant) panel of "known positives" while Lipkin uses a panel of "fresh" patients that is expected to include many "known positives" (if they exist).

You have also shifted from a theoretical comment about truth, to a practical comment based on sound probability estimates. The two are not equivalent

I have given a example of a theory being applied in pratice. You don't absolutely know if fingerprint analysis is based on 'sound probability estimates'. You assume it is because, like I said, you "build" on the knowledge that you accept as being true (but can be proven false tomorrow).

So old viruses can indeed resurface in my view, and I have seen this concern expressed by many scientists over the years.

Resurfacing is not the same as emerging. And if XMRV really emerged twice in exactly the same form, you would also expect to observe many almost-XMRV's to emerge (but I've already argued this before).

However, prematurely treating an hypothesis as though it is adequately tested in not a virtue. Its only an hypothesis

Yet, this totally depends on the context of the experiment and the evidence which it generates. Scientists feel confident that the data in Paprotka et al. is true, because they have weighed the evidence and placed it into the context of other findings.

Of couse, any follow-up study could make the data even stronger (or weaker) but this is always the case. Like I said, the study was more or less part of a puzzle and now many scientists feel confident that they can see the picture. Of course, someone could always come along and destroy this piece of the puzzle, but the interest in solving the puzzle has largely disappeared as for now (and for good reason, in my opinion).

To clarify, I consider the Lipkin et. al. XMRV study to be the first good study that is testing an implication of the Paprotka et. al. hypothesis, even if that is not its goal.

I don't understand how you think the Lipkin study is really testing an implication of the Paprotka et al study. How exactly do you feel this is happening in Lipkin's study?

I also genuinely wonder why you then think the BWG study did apparently not succeed at this. Can you explain to me why you find this?

 

[Bob]

No, I was not cherry picking by any chance.

The two env sequences from the tree you posted are identical to each other, which I pointed out is not consistent with evolution but with contamination.

They are also exactly identical to other known partial mouse DNA sequences (you can verify this with a BLAST in Genbank). Again, this is not evidence of, or even consistent with evolution at all.

OK, these are fair points, thank you for explaining.

Which leaves us with the single gag sequence, which is 100% identical to a mouse mERV (which you yourself acknowledge). Again, this is not consistent with XMRV evolution (unless you want to believe that XMRV evolved into an already existing mERV).

So, I only posted the sequences that were relevant to the discussion because these were at least not all identical to known sequences and/or each other.

OK, fair points.

And you know more than Coffin, Stoye and Hohn all other scientists that agree with the conclusions of Paprotka et al. and/or are convinced it's game over for the association of MRV's with ME/CFS? At least the person I disagree with doesn't have an actual PhD in the field.

OK, fair point, I shouldn't have said that cos it was unhelpful.

This is not convenient but just plain logical.

With a genuine infection, you would expect variability of a specific kind, i.e. sequences that are distinct from each other but still cluster together and/or are derived from one another.

Fair point.

However, with regards to contamination, Switzer does say the following:

"Importantly, in all three specimens we were unable to detect mouse mtDNA despite the use of a highly sensitive assay, which suggests that the source of XMRV is unlikely the result of contamination with mouse DNA. These results are important since mouse DNA contamination was reported to be the source of XMRV in a recent study of prostate cancer tissues."

And he was aware of the Paprotka et al study because he mentions it in the paper, and then he concludes:

"Nonetheless, more work is needed to better understand the prevalence of XMRV and MLVs in humans and their role in human disease."

I never said it was a black and white field of research.

The proposed association with human disease and with ME/CFS in particular has only been totally discredited. It is really up to any left proponents to prove everybody wrong, just like with any other claim that is not (or no longer) backed by any credible evidence.

And thank you for proving my point... It's black and white... No grey areas... No disease association.

I was not aware that Dr Singh's work had been discredited.

I agree that the ME related research is very weak at the moment, but not all the ME work has been discredited.

Maureen Hanson, for example, says she has found the same antibodies, although she isn't publishing yet.

Even Coffin says ME could be caused by a retrovirus infection, just not VP-62, and that it warrants further investigation.


[On a side note, it's interesting that Switzer's study has not been retracted, if it is a result of contamination (I'm not saying that it is a result of contamination, but I do acknowledge the possibility.) Only Mikovits seems to have been targeted by the establishment for retraction.]


Whatever the case with ME, and prostate cancer, these MLVs (and/or MLV-like viruses) clearly need investigating further, as they seem to be ubiquitous in reagents, cell-lines and labs.

MLV (and/or MLV-like) 'contamination' seems to be a major problem, because it is present in so many labs and reagents.
Isn't this a rather perturbing state of affairs?
No further research required though.
Nothing to see here, move along.

 

[natasa778]

RRM, you have taken an absolute, and absolutist, position, which has been shown to be very weak, and flawed, which you are promoting forcefully on a patient forum.

And which increasingly sounds like a hard-sell pitch.

 

[Ecoclimber]

Whatever the case with ME, and prostate cancer, these MLVs (and/or MLV-like viruses) clearly need investigating further, as they seem to be ubiquitous in reagents, cell-lines and labs.

MLV and/or MLV-like 'contamination' seems to be a major problem, because it is present in so many labs and reagents.
Isn't this a rather perturbing state of affairs? No further research required though. Nothing to see here, move along.

I want you to know Bob, as well as everyone else out there, that this is not the end of the world for the association of ME/CFS with a retrovirus. Because of past accusations within an extreme vitriolic atmosphere of heated debate between certain members of the ME/CFS forums and blogs with world renown retrovirologists, there is a general consensus within the scientific community to pull back within the public arena and quietly go about researching the cause and possible cure for ME/CFS. Whether this is justified or unjustified is not the issue at point.

However, I do wish to convey the message to all parties concern, that they have not given up on the ME/CFS patient community nor are they as closed minded as many here would think. You will probably not hear the results of their research studies until they are published. These studies include both private and public grant funds both inside and outside this country so the research may not show up in various databases until completed.

As RRM pointed out here on many occasions, it is the scientific evidence gathered collectively that formulates their consensus and they are well qualified to discern the difference between incomplete or fatally flawed research and robust research. They do not have the resources to research ad infinitum into every minutiae alternative explanation that is raised by conjecture. If a researcher finds a compelling argument to the contrary, they will consider it. As a caveat, I want to make this clear. I am speaking here of researchers in the U.S. and Canada only and not other countries.

The bottom line is that there are individuals behind the scenes maintaining oversight in the sense of observation only, over the broad base research currently ongoing at this time. I believe everyone is taking a collective breath until the results of the two major research studies that Dr. Lipkin is currently conducting, are published.

I would be optimistic at this point and no I will not reveal my confidential sources for those that insist on knowing more.

However here is something that may be of interest to some. If posted elsewhere ignore. This is a Canadian study.
http://okeefe-lab.blogspot.com/2011/12/next-gen-sequencing-provides-evidence.html

http://www.ncbi.nlm.nih.gov/pubmed/22162557

Eco

 

[Bob]

I want you to know Bob, as well as everyone else out there, that this is not the end of the world for the association of ME/CFS with a retrovirus. Because of past accusations within an extreme vitriolic atmosphere of heated debate between certain members of the ME/CFS forums and blogs with world renown retrovirologists, there is a general consensus within the scientific community to pull back within the public arena and quietly go about researching the cause and possible cure for ME/CFS. Whether this is justified or unjustified is not the issue at point.

However, I do wish to convey the message to all parties concern, that they have not given up on the ME/CFS patient community nor are they as closed minded as many here would think. You will probably not hear the results of their research studies until they are published. These studies include both private and public grant funds both inside and outside this country so the research may not show up in various databases until completed.

Thank you for that Ecoclimber. It's nice to know.

 

[Bob]

...here is something that may be of interest to some. If posted elsewhere ignore. This is a Canadian study.
http://okeefe-lab.blogspot.com/2011/12/next-gen-sequencing-provides-evidence.html

http://www.ncbi.nlm.nih.gov/pubmed/22162557

Eco

Well, I don't understand much of the blog, on first reading... I'd like to read the actual paper... But this is the conclusion in the blog:

"So what to make of all this? I don't know right now...it looks like there are MLV and even XMRV transcriptomes present in some prostate cancer tissues. There might not have been the sensitivity to detect the viruses at the DNA level."

 

[markmc20001]

I want you to know Bob, as well as everyone else out there, that this is not the end of the world for the association of ME/CFS with a retrovirus. Because of past accusations within an extreme vitriolic atmosphere of heated debate between certain members of the ME/CFS forums and blogs with world renown retrovirologists, there is a general consensus within the scientific community to pull back within the public arena and quietly go about researching the cause and possible cure for ME/CFS. Whether this is justified or unjustified is not the issue at point.

However, I do wish to convey the message to all parties concern, that they have not given up on the ME/CFS patient community nor are they as closed minded as many here would think. You will probably not hear the results of their research studies until they are published. These studies include both private and public grant funds both inside and outside this country so the research may not show up in various databases until completed.

As RRM pointed out here on many occasions, it is the scientific evidence gathered collectively that formulates their consensus and they are well qualified to discern the difference between incomplete or fatally flawed research and robust research. They do not have the resources to research ad infinitum into every minutiae alternative explanation that is raised by conjecture. If a researcher finds a compelling argument to the contrary, they will consider it. As a caveat, I want to make this clear. I am speaking here of researchers in the U.S. and Canada only and not other countries.

The bottom line is that there are individuals behind the scenes maintaining oversight in the sense of observation only, over the broad base research currently ongoing at this time. I believe everyone is taking a collective breath until the results of the two major research studies that Dr. Lipkin is currently conducting, are published.

I would be optimistic at this point and no I will not reveal my confidential sources for those that insist on knowing more.

However here is something that may be of interest to some. If posted elsewhere ignore. This is a Canadian study.
http://okeefe-lab.blogspot.com/2011/12/next-gen-sequencing-provides-evidence.html

http://www.ncbi.nlm.nih.gov/pubmed/22162557

Eco

Heya ECO,

I always assumed research was kind of a free market where researchers could go and try to raise funds to do whatever research they want. Either that or government agencies like the NIH, CDC, and FDA would decide. It Never occurred to me there would be kind of a spokesman that would speak for the scientific community as what their research intent is, or how they intend to disseminate information to the public.

Are you aware of some kind of research concensus board that decides who/who doesn't get research dollars for ME or something?

I would really like to know how this process works so maybe the research efforts could possibly be influenced in a way that gets results now, in my lifetime. It seems that most research efforts don't get any tangible answers.

For instance, wouldn't it be great if a study was done to improve the understanding of methylation? That would be a good research effort that could potentially benefit many in the near future.

Thanks,
Markmc

 

[Bob]

Heya ECO,

I always assumed research was kind of a free market where researchers could go and try to raise funds to do whatever research they want. Either that or government agencies like the NIH, CDC, and FDA would decide. It Never occurred to me there would be kind of a spokesman that would speak for the scientific community as what their research intent is, or how they intend to disseminate information to the public.

Are you aware of some kind of research concensus board that decides who/who doesn't get research dollars for ME or something?

I would really like to know how this process works so maybe the research efforts could possibly be influenced in a way that gets results now, in my lifetime. It seems that most research efforts don't get any tangible answers.

For instance, wouldn't it be great if a study was done to improve the understanding of methylation? That would be a good research effort that could potentially benefit many in the near future.

Thanks,
Markmc

Hi Mark,

I understand your point, but I had also thought that many of the retrovirus researchers might be behaving in the way that Eco describes, for reasons as follows...

There's been such a lot of controversy, and false hopes raised, that it seems like a sensible time for researchers to quietly buckle down, and get on with some hard graft, and also to wait to see how things settle down before publishing.

It's probably a sensible idea, under the current climate, to only release results when it's time to officially publish all the results.

It's a bad time to raise funds for ME/MLV research, and it's a bad time to try to get published. And no one sensible would want to stick their heads above the parapet right now, for obvious reasons.

Maureen Hanson, for example, has got some preliminary results with antibodies, but I get the feeling that she wants to come to a fuller understanding about them, and do more thorough research before publishing. And possibly even allow the field to settle down a bit before publishing. But that's just my guess... I don't have any knowledge.

It also seems quite sensible to wait until Lipkin publishes his results before anyone else publishes, because his results will have a massive effect on the field, and will have a profound effect on the consensus point of view.

I think that Eco is in touch with at least one scientist (I don't know the details), so he does get some feedback from the scientific community, or at least a section of it. And the scientists obviously talk to each other about what's going on.

So Eco isn't describing a conspiracy here, but probably just a general feeling about the general situation among colleagues.

I might be wrong about all of this, but that's my perception.

Bob