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New Paper by Dr Ruscetti

Discussion in 'XMRV Research and Replication Studies' started by VillageLife, Jan 4, 2012.

  1. currer

    currer Senior Member

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    There is no explanation for the sudden rise in some cancers since the 1970s.

    Of course, there could be any number of reasons for this. But I find the Snyderman study (on lymphoma and CFS) and his successful self treatment with antiretrovirals exciting and important.
    http://treatingxmrv.blogspot.com/2011/09/reason-for-hope.html?spref=fb

    Read the articles on lymphoma. See how concerned the lymphoma charities are about the growth in lymphoma cases. Should we shut down a promising medical investigation out of cowardice?
    Many people are dying of lymphoma.

    http://www.retrovirology.com/content/8/S1/A230
    This is the Ruscetti/Mikovits paper showing that B cells in a lymphoma patient contain a gammaretrovirus.

    So what if the establishment are afraid of discovering that retroviruses are capable of causing lymphoma. Why is this idea so disturbing? It has been suspected for years. Why try to stop the investigation of gammaretroviruses and lymphoma?
  2. RRM

    RRM

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    Alex,

    First, I am aware of the differences between a virus and the human genome and that the odds for human DNA are much, much lower. With this example I really wanted to also illustrate the following: I have seen people arguing that, because of Paprotka et al.'s calculations that something like this is unlikely to happen twice, it must also be very unlikely that this freak accident happened once, while xenografting human tissue. I believe that everyone understands that the freak accident that is the generation of one's DNA does not mean it is unlikely to happen - it really only comes into play when thinking about something like this happening twice. Thus, by using this even much more unlikely but very concrete example, I think I've illustrated that the frame of thought mentioned above is without merit.

    Second, I understand your points about probabilities and evolutionary convergence but they really have little to do with the argument. If your argument is that the odds predict that XMRV is likely to have been generated multiple times, then you must also accept that there should be many (as in a multitude of) occurences of near-XMRV being generated in independent events. Convergence doesn't come into play as many differences in all of those independently generated near-XMRV's would be silent.

    There is just no logical way that it would be perfectly normal for a 8000+ bp virus to be generated by independent recombination events multiple times, given the fact that we are not also observing these near-identical recombination events.

    Finally, your point about conserved areas does not apply here, as we are not talking about point mutations but recombinations. In fact, recombination breakpoints are much more likely to occur in those areas where the two recombining viruses share a short continuous stretch of identical base pairs. Thus, the number of identical stretches between the two viruses rather increase the recombination options there are. In any case, the authors (naturally) included this into their calculations.
  3. currer

    currer Senior Member

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  4. currer

    currer Senior Member

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    RRM

    Please do not obsess about the XMRV sequence.

    The debate has moved on. Obviously the odds make it impossible that XMRV would be exactly created more than once.

    There are MANY SIMILAR gammaretroviruses being found in cell lines, all replication competent and able to infect human cells. They are potential pathogens.

    Dr Mikovits has repeatedly stated that she is finding a wide range of gammaretroviruses in ME patients, not just the XMRV sequence. These gammaretroviruses need to be researched to see whether they have a causal relationship to ME/CFS.

    The attempt to restrict the debate to just the XMRV sequence is artificial and designed to close the door on research in this field.

    What is it about this you dont understand ?
    ukxmrv and Wildcat like this.
  5. RRM

    RRM

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    I don't. I am just arguing about your assertion that this finding (which was basically already reported in 2010) "destroys the Paprotka argument that "XMRV" was a unique event".

    In the sense that Paprotka argued that "22Rv1 XMRV" was a unique event this study does not refute that (and you seemingly agree). In the sense that Paprotka argued that that the generation of "an" X-MLV in a cell line was a unique event it is a strawman, because the Paprotka et al. paper clearly does not argue that at all.

    Please also note that this Ruscetti paper does not address any possible recombination event at all but proposes that this X-MLV infected the cell line because of the "activation of an endogenous virus". Thus, even if Paprotka had argued the pratical impossibility of any recombination event you'd still be incorrect (in the sense that this paper would then refute that). In fact, Paprotka et al. already acknowledge Ruscetti's proposition by saying that "[e]ndogenous xenotropic MLVs can infect human tumors during passage through nude mice".

    Yet, Mikovits's argument still somewhat hinges on this. Remember, all of the partial gag sequences deposited in Genbank by WPI, are still identical to Paprotka's recombinant or essentially identical (i.e. the difference is expected to occur through a sequencing error or culturing).


    The finding of gammaretroviruses in cell lines rather indicates that xenografting sometimes leads to the "breeding" of viruses that are able to infect the human cell line in question, either through the cell line "picking up" already existing MLV's, through random mutations, or recombination. The fact that this is inherent to the xenografting procedure is indeed a (relatively small) cause for concern, but the fact that this happens now and then also suggests that there are just many lab artifacts out there that can easily contaminate experimental samples.

    Like prof Racienello explained quite well in his latest TWiV (in my opinion) there is really no reason to assume that a contaminant has lead you in the right direction. It is really the same argument as the thought that perhaps we should look in tissue instead of blood. If the results in blood cannot be reproduced, there is really no result anymore to base hope on. The same really goes here. If we accept that XMRV is a lab artifact that contaminated Silverman's lab, then it would be incredibly unlikely that it would lead to other scientists finding an almost identical virus that independently evolved.

    Now, of course, it would still warrant one or more follow up studies if this other scientist would produce a compelling paper but, when reproduction of the initial study fails, there is just no reason to still hinge on the initial results because of this reason. On the contrary, really.

    Yes, and many labs have also searched for more these diverse sequences, ever since Lo et al. published their findings.

    Remarkably, regarding the Lo sequences, Mikovits has clearly stated that they didn't find the MLV-like sequences reported by Lo but "genuine" XMRV. Also, in the BWG study, the PCR positives Mikovits reported were sequenced and these partial sequences were basically identical to "22Rv1 XMRV".

    There is no evidence or other reason to base, or at least fund, research on. Of course, everybody is still free to look where they want and I wish Mikovits and Ruscetti the best of luck if they continue to think this will lead somewhere, although I am afraid that they then will be retweaking their assays for the rest of their lives, in search of this virus of barely detectable intensity (and producing antibodies of barely detectable intensity to boot).

    Now, if Mikovits (and/or others) can suddenly discriminate between patients and controls in Lipkin's study, then at least there would be something to follow-up again for other researchers.

    It is not artificial. The sequences reported by Lo are perhaps closely related, but still clearly distinct. There is really no way that one sequence could have evolved into the other.

    Moreover, even if we just rename the virus to "something" (to keep it as broad as possible), then still none of the original scientists was able to reproduce their "something" results in the BWG study, and still none of the original scientists have been able to map integration sites of this "something" in their ME/CFS patients. That (and many other "stills") is the reason the debate has basically settled, not because of some restriction of the discussion to just XMRV.
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  6. alex3619

    alex3619 Senior Member

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    Hi RRM, as I have said before you could be right, but its still not very convincing. XMRV may or may not have generated elsewhere. It has been found many times and nobody knows for sure it all comes from the Silverman lab. It is only recently that the Silverman issue was even recognized. In addition, my argument extends to the entire host range. I would not expect to see XMRV appear thousands of times spontaneously, only that it could arise several times a century (this featured in an earlier argument of mine). As such there should, if my calculations are even remotely correct, exist XMRV in a few cell cultures and or natural hosts on the planet. It would not be ubiquitous. The point I wanted to make, the reason for this line of argument, is that it is possible that the Paprotka cell line was contaminated rather than it having arisen spontaneously. This puts doubt on the hypothesis, but can't disprove it by itself.

    On XMRV and ME, I hope the Lipkin et. al. study will put an end to most of the remaining debate, one way or another. An earlier comment was made in this thread that existing RT assays were insufficiently sensitive for some reason. Yet these were a key player in finding HIV and I think HTLV but I am less sure about that. So while RT assays may fail to find an MLV at low copy number with a slow replication cycle, it might still be able to pick up on another retrovirus. If nothing else it will help to put the RV hypotheses in context, and mean that we will know that future RV research will require better RT assays if they are to be validly pursued.

    To be honest, I have always wondered why Lombardi et. al. never seems to really address this issue. I am not a retrovirologist or virologist, but reverse transcriptase would seem an obvious assay to do. Does anyone have any more thoughts on this?

    Bye
    Alex
  7. asleep

    asleep Senior Member

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    Even if one grants that VP62 was created only once and that Paprotka et al sufficiently demonstrated that it wasn't introduced to the 22Rv1 cell line via the original prostate tumor (an arguably major concession), there is still the question of where and when the recombination took place. It could have occurred in the creation of this cell line or it could have occurred at another time and place and, as Alex alludes to, been introduced to the cell line during its creation as de novo contamination.

    Paprotka et al and those who uncritically support it would have you believe that it obviously occurred within this cell line (and therefore "XMRV" post-dates incidence of ME, implying it cannot be a factor in the disease--a rather clean exit for an inconvenient finding). The probability of a "second event," which the authors conjure up through a ritual exercise in hand-waving, is purported to demonstrate that it could not have occurred elsewhere. But this is a red herring because the recombination need not have occurred twice for it not to have occurred in 22Rv1.

    The use of probabilistic argument to refute the possibility of single recombination having occurred elsewhere is a classic example of begging the question. Applying probabilities to undesirable alternative explanations (de novo contamination) while holding one's desired explanation (creation within 22Rv1) as a given in order to support one's argument is intellectually vacant, if not actively deceptive. Consider the following comparable scenario:

    Alice and Bob both buy the same type of scratch-off lottery ticket with a 1 in 1 million chance of winning. The tickets are indistinguishable prior to being scratched off. Both of them give their tickets to Charles, who does not know which is which. After scratching both cards, Charles reveals that one of them is a winner. Bob then proclaims himself the winner because, after all, Alice only had a 1 in 1 million chance of winning!

    Bob's reasoning is flawed because he does not know that it was his card that won. Without being able to conclusively trace the source of the winning card to his own purchase (because card owners were obscured in giving them to Charles), he cannot assume his is the winning card. Rather he too had only a 1 in 1 million chance of winning, making both he and Alice equally likely to be owners of the winning card.

    The argument being put forth in Paprotak et al (and swallowed whole by many vocal virologists) is flawed in essentially the same way as Bob's claim above. The mere observation of VP62 in this cell line does not privilege the "created in 22Rv1" argument over alternative explanations (de novo contamination). Nor does it mean that probabilities can be applied selectively to these explanations--as Bob applies probabilities only to Alice and not himself--to rule favorably for one over the other.

    (It's also worth noting that the presence of the PreXMRVs and the generously conceded elimination of the original prostate tumor as a potential means of VP62 introduction do not affect this logic because they merely establish necessary, not sufficient, conditions. They at best establish that the recombination could have happened in 22Rv1, but do not prove that it did, just as the fact that Bob gave a card to Charles means he could be the winner but does not ensure it.)

    But of course, as currer aptly pointed out, none of this matters: VP62 can no longer be claimed as the only game in town when it comes to gammaretroviruses capable of infecting human cells. This thread's eponymous study may not say much directly about Paprotka et al--the scope of which was always scientifically narrow, though it suited political ends--but it certainly renders it (and the entire anti-HGRV narrative built upon it) moot.
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  8. currer

    currer Senior Member

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    @ RRM,

    What you seem to forget in all this careful rationalisation is that the original virochip studies showed the presence of murine gammaretroviruses before XMRV was introduced into the argument.

    So the murine gammaretroviruses predate XMRV.
  9. RRM

    RRM

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    The probaliatic argument is actually not used at all in relation to the finding that the recombination itself happened in 22Rv1 and not elsewhere. It is being used in support of the assertion that the recombination event could realistically not have happened twice.

    While that simple observation basically refutes your arguments and example, I'll add that authors actually provide compelling evidence for the notion that XMRV arose in 22Rv1 (oe rather, one of its "ancestors"). It is the combination of the findings that a) XMRV arose in 22Rv1 and b) 'it' is unlikely to have happened twice, that makes for a convincing argument it not being a genuine human pathogen.

    In other words, when Bob has shown that a) he has the winning lottery ticket in his hand and b) that there is really only one winner, we can throw Alice's ticket away without scratching, and on very solid probabilistic grounds.


    Actually, from Paprotka et al.:

    And even more actually, from Hue et al. (the infamous Towers/Welcome Trust paper):

    If you find that this paper renders Paprotka et al. moot, then Paprotka et al. already rendered its own concluisons moot in its introduction, and the Hue paper (that didn't recieve much love from within the community) basically did the same.

    I can only say that it is then quite bizarre that this wasn't picked up by the critical followers of Paprotka et al. then, and it equally strange that it also didn't get picked up when Hue et al. published this very same finding in December of 2010. However, with this paper, it gets almost immediately picked up that finding an X-MLV in a cell line completely renders Paprotka et al. moot?

    This of course all while being completely ignored by the whole retrvirological community. Yes, it is very obviously these retrovirologists who are really 'uncritically supporting' certain findings they desire to be true, and not others.
  10. justinreilly

    justinreilly Stop the IoM & P2P! Adopt CCC!

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    correction: I had said in a previous post that there were about 10 cases of Burkitt's Lymphoma in California in 1982 (which is correct) but I had instead meant to say there was only an average of one case per year reported in California up until 1982 (Osler's Web, p.92, footnote) before it started appearing at stratospherically increased incidence in ME and AIDS patients.
  11. ukxmrv

    ukxmrv Senior Member

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    Alex, I did ask some of the UK investigators by email why they didn't do a search for RT and I did ask the WPI. Don't want to name names here as I do not have permission to do so.

    In the UK I was told that either it wasn't included in the original proposal or in one case that no one connected to the study had experience in setting up tests to do this.

    At the time this struck me as particuarly important and an oversight. Particularly when it has been done here for ALS by a team in London.


    Detection of serum reverse transcriptase activity in patients with ALS and unaffected blood relatives.

    Steele AJ, Al-Chalabi A, Ferrante K, Cudkowicz ME, Brown RH Jr, Garson JA.


    http://www.ncbi.nlm.nih.gov/pubmed/15699374

    Centre of Virology, epartment of Infection, University College London, UK.


    When I did ask the WPI I was told that after the inital paper they thought that the virus might not replicate the same as HIV so searching for RT might not be high enough to search for and before the original science paper that they wanted to identify the virus instead.

    I couldn't remember anyone checking CFS for RT but after looking found this. Mike Holmes was the NZ researcher for the Tapanui Flu in the late 80's.

    Immunocytology and in vitro reverse-transcriptase activity in CFS

    AuthorsM.I. Holmes, R. Easingwood, J. Cross, and J. Faed

    http://www.cfids-me.org/aacfs/poster3.html#holmes


    Objective: This paper describes two blind clinical trials of paired, age, sex and ethnically matched patients with CFS; 24 pairs of patients and controls in the first, and 18 in the second. In the first, the range of duration of symptoms was 1 to 3.5 (mean 1.5) years and in the second 1 to 5 (mean 1.7) years. Peripheral blood lymphocyte (PBL) cultures were assayed in triplicate for reverse-tran scriptase (RT) activity, and examined by EM for the presence of virus-like structures at days 0 and 12 and CD2, 3, 4, 8, 16, 20, and 31, and B1 phenotypes were counted at day 0 by FACScan.

    Methods: A single dose of 1 g ml-Concanavilin A (Con A) was given to all cultures at day 0. At days 4, 8 and 10 they were given 4.5 ng ml- human recombinant IL-2. Cells were harvested at day 12 for EM studies, and ultracentrifuged supernatants and cells for RT assay using a poly rA:eek:ligo dT template-primer and measuring RT activity by uptake of tritiated thymidine triphosphate.

    Results: In Trial 1, RT activity up to 3 times background was observed in 9, and virus-like structures in 7 of 24 patients, and not in controls. Group means showed a significant CD4 cytopenia. In Trial 2, RT activity at levels of 2 to 4 times background were observed in 5 patients, and virus-like structures were observed in 4 of these, and not in controls. Group means showed significantly reduced CD4/CD8 ratios and an NK cytopenia. RT activity and EM virus-like structures were seen almost exclusively in the cohort of patients who identified the onset of their condition with a non-specific, acute febrile illness and whose duration of symptoms was 2 years or less.

    Conclusion: These studies suggest the in vitro RT activity and the presence of virus-like structures in PBLs may correlate in CFS with patients who relate the onset of their condition to a non-specific, acute febrile illness.
  12. alex3619

    alex3619 Senior Member

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    Thank you ukxmrv, I think I had come across this before but forgotten it, my memory is heading in the direction of a pureed squash. Its nice to see what I so vaguely thought was important was indeed important. This kind of study should have been followed up on in a large cohort, especially at the WPI.

    The only negative are these:
    1. Has it ever been replicated? It is important to do this with blinded controls.
    2. Is it causal or yet another virus that we have because our immune system is fubar? After all, we typically carry ten times more species of active virus than a healthy control - why wouldn't this apply to retroviruses too?

    To asleep, thank you for explaining my point more eloquently than I did.

    Bye, Alex
  13. asleep

    asleep Senior Member

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    But that's essentially my point. Their probabilistic analysis is a red herring that obscures a gaping assumption in their conclusion. If we grant (generously) that they established the necessary conditions for recombination in 22Rv1 and that VP62 definitively "appeared" between two time-points in the cell line creation, there are at least three mutually exclusive explanations that account entirely for their observations and data:

    1) VP62 only arose due to recombination within this cell line. Hence, it was temporally created between 19931996. This is the conclusion and talking point of the authors and their acolytes as it conveniently airlifts "XMRV" from culpability in ME.
    2) VP62 only arose elsewhere (recombination, mutation, etc) and infected the progenitor xenografts between these time points as de novo external contamination. Hence its time and place of creation is not known and not constrained to 19931996.
    3) Both #1 and #2 occurred. Hence VP62 arose more than once.

    The authors provide no evidence to suggest that #1 actually occurred, merely that it might have occurred (from their paper, emphasis mine: "there were opportunities for this recombinant to form and spread in the tumor cells that were the progenitors of the 22Rv1 and CWR-R1 cell lines"). In this context, #1 is an inherently probabilistic claim, as are #2 and #3, yet the authors provide no evidence that #1 is a more likely explanation (just as Bob has no evidence that the winning ticket is more likely his than Alice's).

    Rather, they simply presume that #1 is the explanation. They don't even mention #2 (or #3) in their paper, much less provide evidence against them! That they then go through the pedantic motions of computing the probability of a "second recombination"--all while implicitly assuming #1 is the "first recombination"--is irrelevant to the fact that they merely assumed their way past alternative explanations.

    In this regard, my example is perfectly appropriate, as Bob's proclamation is conceptually equivalent to assuming #1 (he wins) over #2 (Alice wins), though he actually goes above and beyond Paprotka et al by at least offering a fallaciously probabilistic argument against #2 directly (as opposed to simply overlooking it and making an obliquely fallacious argument against #3).

    In terms of begging the question (i.e. assuming the very thing you are trying to prove), you've made a rather obvious display of it as I've emphasized above. You, like the authors, are arguing that XMRV arose in 22Rv1 because XMRV arose in 22Rv1.

    Furthermore, the unlikelihood of it having arisen twice says nothing about when and where it arose the one time it's guaranteed to have happened: hence, it says nothing about #1 being more likely than #2.

    Well in truth people have picked up on and discussed these before. The reason that Paprotka et al is being brought up in reference to this paper (and why I suspect you are here giving this discussion the old carousel treatment) is because this paper further undercuts the (scientifically untenable) political narrative that HGRVs=VP62 and that Paprotka et al, by it's biased conclusion, "proves" that "XMRV" is not a human pathogen.
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  14. RRM

    RRM

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    Yet you fail to explain how this is. Their probabilistic analysis shows (and only shows) that it is extremely unlikely that two recombination events that are exactly the same occur multiple times, independently. They don't use this analysis for other purposes, as you previously implied (and which is also implied by your lottery example by the way).


    While the three possibilities are of course strictly true, by putting them side to side it appears that they are also equally likely, which is not backed by the evidence. For instance, option 1 is billions (!) of times more likely to have happened than option 3 (see the probabilistic analysis, which was (solely) used for testing this hypothesis).

    Actually, the authors do address option 2, but they (understandably) restrict themselves to the possibility of mice being the source of the contamination. However, their arguments/evidence apply equally. In short (and without trying to be exhaustive), you'd expect to find some (reproducible!) source of the thing (or one of its descendants) that has infected your cell line. Since no one has found this source, it is highly unlikely that this other source existed before "22Rv1 XMRV", managed to infect humans and many years later managed to infect the 22Rv1 cell line.

    Moreover, all found strains that are almost identical to 22Rv1 XMRV can be subjected to phylogenetic analyses, which could provide evidence that 22Rv1 XMRV is not ancestral to these other found strains. Again, the faillure of obtaining data in support of this after analyzing countless XMRV sequences, is supportive of the notion that the XMRV in 22Rv1 is the source.

    Finally, the fact that the lab where they did the xenograting was one of not many places where a "human" environment and both preXMRV-1 and preXMRV-2 'were brought together on a regular basis' (so to say), is also a pretty strong indication that it happened "there" instead of from some other source (after which it had to first infect people and then travel to the lab where they were doing the xenografting to boot many years later).


    No, I am not at all. Would you care to explain how you think I have done this?

    I specifically stated that the "authors actually provide compelling evidence for the notion that XMRV arose in 22Rv1". You could actually dispute that there is "compelling evidence" or that I have failed to provide it (I just don't want my posts to get any longer than they already are), but I have not asserted or argued that "XMRV arose in 22Rv1 because it did".

    After I asserted that the authors had provided compelling evidence for the above notion, I used this notion as a (partial) argument in favor of the position that XMRV is not a genuine human pathogen. Again, you can disagree with the conclusion because you don't agree with the supporting argument or because you don't agree that the supporting argument, while perhaps true, is unable to carry the conclusion.

    However, I completely fail to see why my argument "commits" the fallacy of begging the question, and I would be very happy to hear why you would (still?) think this is the case.

    You are right about this, but like I said, the authors really only use the probabilistic analysis in the context of the same event happening twice. You are therefore refuting a strawman, i.e. an argument that the authors haven't made in the first place.

    As I've laid out above, there is actually compelling evidence in support of the notion that this event happened in 22Rv1 and not somewhere else.

    Actually, not only does this finding fail to undercut Paprotka et al. in any way, it even supports the notion that current and future detections of related but clearly distinct "HGRV's" (that are always at the limit of detection I might add), are the result of contamination.

    After all, not only XMRV has been quietly hiding in in 22Rv1 cell lines in many labs, possibly contaminating experimental samples. We know now that there are actually many more X-MLV's that have been quietly and unknowingly "living" in many other cell lines that have been handled in many labs with experimental samples.

    It was/is only a matter of time before one of these other X-MLV's from one of these cell lines did/will actually contaminate some samples in some labs.

    Because of these dangers, it is important that any study that proposes an association of X-MLV viruses with any disease and that wants to be taken seriously, not only blinds their samples, but also only uses patient and control samples that were treated in the exact same way from start (collection) to finish (testing).
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  15. alex3619

    alex3619 Senior Member

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    On this point, RRM, we agree. However since many laboratory materials are used that are now shown to be contaminated by RRM, the range of testing necessary is much larger - every reagent that might be contaminated needs to be tested.

    On the basis of probabilities, I find it much more likely that XMRV arose elsewhere and contaminated the cell line, than that it arose sponataneously. We know this virus and others like it can circumvent the usual precautions, we know it is widely distributed, what we don't have is lots of testing of very early samples and reagents in storage. Which is more likely: that it arose sometime in history over a long time frame with many potential sources, or once in a particular cell line?

    Now I know that this unfairly focusses on the cell line in question, which has a probability of containing the virus of 1, but that is exactly the problem I have with their argument. Why this cell line? Sure they found it might be the source. Great. No great reason to dispute that. Just because it might be doesn't mean it is. If it was then I think we may never know the answer for sure, although if they can find the hypothetical partial recombinations in a sample that would help their case immensely. If it wasnt it is only a matter of time before earlier XMRV samples are found, presuming that storage of enough samples from that time still exist. As an hypothesis I have no great problems with the recombination idea, as an almost proven event I have major problems indeed. Its a question of perspective. If its almost proven then other data, other experiments, may not be critically assessed. If its an open question, a possible or probable answer only, then others may look more closely at future data and we have a better chance of noticing anything amiss.

    Bye, Alex
  16. ukxmrv

    ukxmrv Senior Member

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    Alex, Mike Holmes in New Zealand couldn't get funding to continue his work so I don't know if this was ever replicated. After Defreitas the whole RV theory got buried. It was a mess.

    One of the doctors who worked with him told me that in New Zealand their research was blocked in the 90's and the researchers involved in that work are still wanting to follow up what they were unable to do at the time.

    A while back it was announced that Dr Warren Tate in NZ was going to look at XMRV

    http://biochem.otago.ac.nz/professor-warren-tate/
  17. RRM

    RRM

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    Must be the first time I ever get mistaken for a retrovirus. ;)

    This is nonsensical. Exactly because many cell lines have been propagated through many mice during their respective devolpments, it was only a matter of time until one random recombination event (that happened to be XMRV) in one particular cell line of these many potential sources (that happened to be 22Rv1) lead to the generation of a recombinant virus that was able to infect human cells.

    Your "alternative" hypothesis is really a (good but unintended) interpretation of the original hypothesis.

    This is not how this works at all.

    If you mean that a succession of multiple partial recombinations lead eventually to the "final" recombination, then it is simply factually wrong. This is not hypothesized by the authors, and for very good reasons by the way.

    You could also mean that the hypothesis that XMRV was generated in 22Rv1 implies that a lot of other, independent recombinations must also have occured in that same cell line. While this is of course factually true, the argument derived drom this contains a fundamental error of evolutionary principles: you would expect all of these "partial recombinations" that occur to "die" immediately if they didn't have the ability to survive their human environments. Only when, by chance, a recombinant is generated that can survive its human environment (like XMRV), it will stay to live and replicate in the cell line in question.
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  18. Purple

    Purple Bundle of purpliness

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    Just to add information about Prof Warren Tate: he was the recipient of the Rutherford Medal in 2010. This is probably 'the' most prestigious award in science in New Zealand and this would bring lots of general awareness to who he is in the country, with public lectures/talks traditionally given by the recipients throughout the year. The medal/prize is named after Ernest Rutherford, a Nobel Prize winner from New Zealand (who with Sir Edmund Hilary is one of the most well-known New Zealanders).

    http://en.wikipedia.org/wiki/Rutherford_Medal_(RSNZ)

    Also, Prof Warren-Tate's daughter is an ME/CFS sufferer:
    http://www.radionz.co.nz/national/programmes/ourchangingworld/20110714
  19. asleep

    asleep Senior Member

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    Referencing the explanations I enumerated above (and ignoring #3, which was included for completeness and is largely inconsequential to the main point), we have two competing, possible explanations: #1 and #2. As possible explanations--neither is certain, as the first recombination in question was not (nor likely could have been) witnessed directly--both explanations have some implied a posteriori probability (p1 and p2 respectively) of explaining the observed phenomenon: the "appearance" of VP62 in 22Rv1 between two time points.

    Because these are mutually exclusive explanations, any claim of relative likelihood requires consideration of the relative probabilities p1 and p2. Hence, my lottery example. As presented, the probabilities of Alice and Bob winning are are both 1 in 1 million. Because their relative probabilities are equal, both Alice and Bob have a 50% chance of being the owner of the winning ticket (i.e. comprising the source of the observed phenomenon of winning), despite the observed event being extremely improbable a priori. If instead Charles had been given tickets from an additional 98 individuals (for a total of 100), then the probability of Bob owning the winning ticket drops to 1% because the relative probability of Bob not being the winner is 99 times higher (again, despite the a priori odds of any of the 100 people winning being extremely small).

    In the context of Paprotka et al, this matters because the authors made no attempt whatsoever to determine p2. Hence, any claims that #1 is more likely than #2 constitute pure, unfounded supposition. In the lottery example, this would be akin to Charles scratching off Bob's ticket and some unknown number of other tickets. Maybe he only has Bob's ticket, or maybe he has 10 thousand other tickets. Without knowing, any claim to victory by Bob is, by definition, nothing more than speculation rooted in his biased desire to be the winner.

    What about your points quoted above? In a nutshell, such specific exclusionary claims (to the extent they are supported by evidence) might have some effect on p2, but p2 remains unknown. This is because p2 comprises all imaginable pathways that VP62 could have arrived in 22Rv1, minus the singular, mutually exclusive possibility of recombination taking place within the cell line as proposed by the authors (#1). These pathways include, but are not limited to, an identical external recombination event, as well as other means of forming VP62 (mutation, deletion, other recombinations) and having it arrive at this cell line. Going back to the lottery example (with the unknown number of tickets), your claims are akin to Bob knowing that Danny, Emily, and Fred did not give tickets to Charles. Even with this knowledge, Bob still does not know how many tickets Charles had and therefore his claims of victory are just as unfounded. (It is true that this knowledge constrains the scope of p2, but in the context of Paprotka this scope is indefinitely large, implying that elimination/reduction of a fixed set of elucidated pathways still leaves an unknown probability: ? - X = ?).

    Ironically, the probability of a second event calculated by the authors (1.3 10[SUP]?12[/SUP]), must also serve as an estimate for p1 (the probability of their choice recombination having occurred). This is because, in making their calculation, they assume the exact same preconditions that they purport to have led to #1 (the presence of the PreXMRVs). They offer no evidence that the PreXMRVs were more likely to recombine inside this cell line than in some theoretical situation outside the cell line where both of them are present. (One should argue that these probabilities are tempered by the relative number of chances, but you've already rejected this line of reasoning when presented by Alex to support #2. Furthermore, any concrete attempt would simply be speculation). So, within reason, we can estimate that p1 = 1.3 10[SUP]?12[/SUP].

    If it were true that p2 >= 1.3 10[SUP]?12[/SUP], then as demonstrated by the lottery example the authors have essentially sold something no better than a coin toss as a certainty (this is comparable to the original scenario with only Bob and Alice). Furthermore, it must be noted that p2 encompasses the possibility that VP62 was introduced via the original prostate tumor and simply not detected in the earlier samples by the authors (hence the "appearance" is an illusion as it was there all along). If there is any truth to the finding of XMRV in ~20% of PC tumors, it is certainly not unreasonable to suspect that this possibility alone (serving as a lower bound on p2) is > 1.3 10[SUP]?12[/SUP]. Of course this is simply speculation, but when put in this light it should be clear just how spectacularly implausible and speculative the authors' conclusion really is.

    Apologies on that. I originally misread your points a and b as being offered in support of your prior sentence.

    From what I wrote above, it can be seen that their probabilistic analysis applies equally to their proposed recombination event as it does to a second identical event under identical circumstances (and this can be proven mathematically very simply). That they only care to apply it to the latter is merely sleight of hand (which they "get away with" by simply ignoring the relative probability p2 in its totality).

    As for this being a strawman, it's hard to see how discussing a perfectly viable alternative explanation (#2)--the elimination of which constitutes the backbone of the scientific endeavor--is a strawman. Such a claim amounts to embracing "science by bias" where one just accepts their preferred explanation and classifies the remainder as unworthy of discussion.

    Or one could ask: how many X-MLV's are quietly and unknowingly "living" within human hosts? After all, if our esteemed virologists have failed to notice these X-MLV's directly under their noses for decades, it's certainly plausible that they continue to miss variants residing in the far more complex environment of the human body.

    The existence of multiple variants capable of infecting human cells further establishes the importance of continued study. The only argument made against further study is that we don't need to worry about them infecting humans (if they haven't already) because APOBEC and complement, purportedly, crush these viruses in the blood. Of course, as others have pointed out, these defenses are themselves merely probabilistic (one virion breaching the fold could be sufficient in establishing infection) and only relevant to blood-based modes of infection.
    Lou and currer like this.
  20. alex3619

    alex3619 Senior Member

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    Logan, Queensland, Australia
    Sorry RRM, my mistake. Meet brain fog in action. :oops:

    Bye, Alex

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