New Paper by Dr Ruscetti

Tony Mach said:

1. The argument with pathogens from close relatives is this: If SIV "knows" how to evade the immune system in our close relatives, it stands a big chance to evade the human immune system we share some considerable history and are in some points quite similiar after all. A retrovirus from a mouse, or a pig, knows its ways around its hosts immune defense, but is not so well adapted to other animals.

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Mice share a lot of biological similarity with humans too, which is one reason they are so much used in research. I see your argument more clearly now, but it's just an opinion and an assumption really, not a (dis)proof of anything. If it was completely unfeasible that a virus could come from mice to humans, why was the XMRV theory taken so seriously by so many? Even Dr Coffin took it very seriously for quite a long time. It isn't implausible.

2. Why do you think that ME is a new disease? Correctly recording this kind of disease has been a problem in the last century, what makes you think that the records before that are any good?

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There's very little evidence of such a disease affecting so many people prior to 1934. I also find the early reports, particularly the reports from 1934 and 1955, quite strong evidence - the physicians then were baffled by these outbreaks and had never seen or heard of anything like it before. I think if we weren't looking at a modern phenomenon, there would be better historical evidence. It's hard to imagine that 0.5% of the population have always had this disease and nobody noticed it before.

Remember that this paper is only looking for XMLVs in certain cell lines of the NCI. Other references in this paper show that xenotransmission of XMLVs into human tumors during cancer research is very common.

Mark said:

And this paper does warn of the dangers involved in handling these lab-created viruses, doesn't it? Surely there is at least a 'viable hypothesis' here?

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This is interesting research, just like SV-40, but there is NO connection to ME/CFS whatsoever. None. Nada. Nothing. THIS HAS NOTHING TO DO WITH ME/CFS. If it does, then show me the connection. If this is a "viable" hypothesis that we got this bug through these cell lines, then picking any known pathogen and saying we got it somehow is a viable theory. Well, it could be PERVs, we have been eating pigs, haven't we? So maybe it is PERVs?

Again, I call any connection between this paper (or the gamma-retrovirus group) and our disease BS. You have no evidence, you have just speculation. I call it fearmongering. Show me something at least a bit solid and I will change my mind.

Eating pigs does not bypass normal immune defences (which exist in the gut) So you should be OK.


Deckoff-Jones has expressed concern about early vaccinations as they would have been unable to screen for pathogens at that time (in fact the early vaccinations were probably given before viruses could be isolated) and retroviruses were not discovered until the 1970s.

Mark said:

Mice share a lot of biological similarity with humans too, which is one reason they are so much used in research. I see your argument more clearly now, but it's just an opinion and an assumption really, not a (dis)proof of anything. If it was completely unfeasible that a virus could come from mice to humans, why was the XMRV theory taken so seriously by so many? Even Dr Coffin took it very seriously for quite a long time. It isn't implausible.


There's very little evidence of such a disease affecting so many people prior to 1934. I also find the early reports, particularly the reports from 1934 and 1955, quite strong evidence - the physicians then were baffled by these outbreaks and had never seen or heard of anything like it before. I think if we weren't looking at a modern phenomenon, there would be better historical evidence. It's hard to imagine that 0.5% of the population have always had this disease and nobody noticed it before.

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Yeah, the point was I can speculate too, but first of all I try to say as openly as I can that this is speculation. And secondly, my speculation is better that this HGRV BS speculation that refuses to die a deserved graceful death.

And yes, I was taken in by Mikovits too, wow, after all they pushed their methods to find it in all 101 patients of the Science 2009 cohort! Not a single case of misdiagnose! This must be it! Yeah, too good to be true comes to my mind No, I want evidence and I want the evidence test rigorously by others before I hang my hat on it until then, no evidence of relation to our disease and I call it BS speculation.

And try looking into historical descriptions of a somewhat more substantial disease, like the black death, and you will see that it is almost impossible to rely on historical records to proof that a disease like ME/CFS did or did not exist prior to the 1930ties. If people in the dark ages thought that someone was a malinger, it is doubtful they would connect it to an illness entity like ME/CFS and record it in a way that we would understand it today.

currer said:

Eating pigs does not bypass normal immune defences (which exist in the gut) So you should be OK.

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A vaccine does not bypass normal immune defences (which exist in the blood). So you should be OK.

See, I can generalize too.

And maybe the PERVs mutated recently? A chance recombination event that created xenotropic PERVs? XPRV? I think I will start testing ME/CFS patients for XPRV. And I am sure I will find it. I am going to solve ME/CFS!

currer said:

Deckoff-Jones has expressed concern about early vaccinations as they would have been unable to screen for pathogens at that time (in fact the early vaccinations were probably given before viruses had been shown to exist) and retroviruses were not discovered until the 1970s.

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Oh, retroviruses were know much much earlier, it was just thought that they didn't infect humans. HTLV is just to seldom and HIV wasn't circulating back then. And Jamie Deckhoff-Jones MD interest in vaccine safety is to keep the HGRV theory alive, no matter if there is any connection in reality to ME/CFS.

If you want to speculate properly: IT COULD BE ANYTHING. You could pick ANY virus and say: "But it could be THIS virus!". Yes, it could. But so could any other. We don't know. I hope Lipkin finds something and until then it is baseless speculation. And I am sick and tired that some people still think that Mikovits HGRV pet theory is any better than other speculation. And NO, IT IS MOST LIKELY SOMETHING ELSE. That Ruscetti looked through dozens of cell lines to find one infected does not prove that retro-virology is hiding this problem.

Tony isn't seeing the bigger picture at all here, which is understandable given the cognitive deficits this disease causes. The big picture, for those who can entertain most ideas without knee-jerk hostility, is that there have *unknowingly* been infectious retroviruses being produced in labs for decades. During that same time, the incident rates of several neurological diseases(MS, Autism, ME, Alzheimers) and cancers have risen. No one knows if these retroviruses have been transmitted to humans, or if they cause disease, because little valid research has been done to figure any of this out.

There were many people who said no other planets existed before they discovered the telescope.

Interesting, Christopher.

http://www.nhs.uk/conditions/lymphoma/Pages/Introduction.aspx
http://www.lymphoma.org/site/pp.asp?c=chKOI6PEImE&b=1573333
http://forums.lymphoma.com/showthread.php?t=7821
http://jnci.oxfordjournals.org/content/93/7/494.full

"Lymphoma rate of increase in the UK 4% per year. If the increase continues at this rate it will be as common as breast or lung cancer by 2025."
"Over the 25 year period between 1973 and 1998 new cases of NHL seen each year escalated almost 83%, among the highest increase of any cancer." (from these references)

currer said:

I wonder if this Ruscetti paper has been published by mistake.....surely we are to expect another forced retraction...?

This paper destroys the Paprotka argument that "XMRV" was a unique event. It is clear that XMLVs exist in other cell lines, are continuously created in the lab by xenografting, and are infectious in human tissues.

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This paper is actually perfectly supportive of Paprotka et al.

Remember, Hue et al. already detected the virus in this cell line (see an earlier post by Firestormm), and it was partly based upon this very same finding that those authors then already proposed that "the tumour cell line 22Rv1, [...] was probably infected with XMRV during xenografting in mice."

It appears to me that many people are not quite understanding the meaning/relevance of Paprotka's statistical analysis, so let me illustrate it with a simple example:

- You are basically a recombinant of your father's and mother's DNA. So is every human being in the whole world.

- Now, what are the odds that, when the parents of any child have sex again, a resulting "fertilisation event" would produce the exact same DNA again? You could say there is a tiny chance, but it is really negliable (though I'd love to see a calculation) we all know that this isn't going to happen. You're probably much more likely to win the Powerball lotery ten times in a row, for instance.

- However, what does this say about our own existence? Does this make our own "recombination event" equally unlikely? Of course not. There are almost infinite possibilities each time but, each time, one of those remote possibilities has to occur. That is why we are at almost 7 billion and counting.

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This is basically what Paprotka et al. are saying. The odds of the very same, identical recombinant appearing twice, are alomst impossible (though it is certainly more likely than in the example above, I'll grant anyone that). Does that have any bearing on the unlikeliness of XMRV being "generated" in 22Rv1? No, of course not. This recombination event "just happened" as one of many possibilities, just like your recombination event and mine and everybody else's "just happened" (but we are nevertheless all unique, except of course for identical twins, that were not generated by independent fertilisation events, BTW).

Now, regarding this study: saying that it shows Paprotka to be wrong would be about the same as saying that the birth of another child would prove that your DNA is not unique. But that would of course not be true. After all, Paprotka et al. never argued that recombination events are extremely rare (on the contrary, they knew they weren't rare at all). They only argued that this exact resulting recombination known as XMRV would be extermely likely to be generated twice through independent events, and rightly so.

Hi Tony, you are clearly misinterpreting what I have said, again. It seems it is you who wants to bring everything back to XMRV. I do not believe in HGRVs either. I am doing a risk analysis. You seem to fear that others are trying to promote XMRV as if it were a proven disease, so you see it even when it is not the case. In this case the risk analysis was about MLV contamination with a virus that can infect human cells and in particular lung cells. This virus is known to escape routine anti-contamination measures.. We have NO idea of what its risk profile is. The evidence does point to a low risk factor, but low risk is not zero risk.

If you don't manage risk, dismissing it until proved, its too late. You failed, and you deserve the consequences.

There are indeed other retroviruses in humans, including HTLV. I very much doubt we have discovered them all. One of the first signs of HIV was reverse transcriptase activity. I have wanted reverse transcriptase studies in ME for a long time, they would answer the general retrovirus question very quickly, but somehow these studies never get done. Its time they were, if only to put the retrovirus theory to bed. However, in the case of ME I think it prudent to test patients for RT who are exercise challenged or have another active infection. This would stimulate production of a retrovirus, and hence increase RT activity.

Fear is what keeps people in line - fear of pathogens, fear of prosecution and so on. Nothing else works. Legislation by itself is not a major deterant. Scaremongering though is about emotion. Its about making emotive argument, about mass media hyperbole. I am trying to understand risk.

Risk is not about best case scenarios. If you presume best case scenario, you have already failed risk management. Risk is about probable scenarios, and worst case scenarios.

Its not even a viable hypothesis? Really? Then why have so many scientists looked at it? You like proof, so where is proof of your claim? It doesn't exist. I appreciate that an hypothesis is just that: an hypothesis. A collection of hypotheses are a model. A model is not reality. If models and hypotheses cannot be discussed, rational scientific enquiry is dead, not HGRVs.

The macaque XMRV studies clearly disprove many of your arguments and claims. They too have blood restriction factors. Yet they were infected. More to the point, the virus is cleared from the blood by the restriction factors (including APOBEC) and yet the tissues have a high viral load. This is an animal model of what I am discussing. It is counter-evidence to many of your claims. What it does not show is that the virus is highly infectious, or even pathogenic in primates.

You have no time for disussing of hypotheses and models? I have no time for dogma, and reasoning out of dogma. I wont stand for it either. The evidence refutes your claims, the biochemistry refutes your claims. It is not that you claims cannot be right, its that they are unproven and represent one option in a spectrum of options. I am completely uninterested in restricting my enquiry to one single option, be that HGRV or anti-HGRV. For your claims to be correct there would have to be mitigating, unproven, factors that explain the contrary evidence. I do not dismiss the possibilty of those factors, in fact I would find it interesting if they could be found.

You dislike the extreme HGRV view? So do I, but I also dislike the extreme anit-HGRV view. I want evidence when something is painted as an absolute, not rhetoric. Rhetoric is fine as part of an argument to discuss a possibility or hypothesis though. If you framed your arguments as an alternative hypothesis they would have validity. As an absolute, they are invalid. Alternative hypotheses are important because when new evidence arises it can be more rapidly interpreted.

"I am sick and tired of this BS and I am not going to take it anymore." Ditto - one can debate this rationally or one can decline to debate. Debating from another point of view is not helping scientific enquiry or understanding None of this is a done deal. The science is not there for any view to be certain. When we have an explicit model that leads to a fully effective cure, then we can put most of the models to rest. MOST of them are wrong. We just don't know which ones yet.

For the record, I am interested in models involving cytokines, functional genetics, oxidative stress, biochemical feedback loops and both pathogen and toxin interaction with these. Nobody knows where the answer is. Nobody.

Bye, Alex

Tony Mach said:

Yeah, full ack, if you do this research, you have to check for this and be extra extra extra careful.

But in the context of our disease (or any other disease, like say Autism) running around and crying Wolf about these risks is just scaremongering. Especially after "OMG XMRV is in the blood!!!!" turned out to be BS, then people go around and say "WELL, then it MUST be in the TISSUE!!!!" and "We got it throug VAXXINES!!!!". No, there is no prove, not even a viable hypothesis, just fearmongering BS. You post this as if this were proof that there are retroviruses (other than HIV) circulating in humans - no, there aren't. What do you want? That 100 scientist spent another 10+ Million USD going on a wild goose chase? Again? This time in the tissue? Cutting up patients? Without a clue as to how XMRV/P/MLV/WHATEVER could even establish an infection, not to speak of spreading it? How is trying to hunt down a phantom going to help you? If we don't look like hypochondriac clowns to the medical profession already, two years down the road we will. Let other people give it a try as to the cause(s) of our disease(s) (and there are actually qualified people working at it, who are motivated and qualified to find something), and stop hanging on to retroviruses as if it would solve anything. XMRV is dead as a human pathogen, there never was any "HGRV".

I am sick and tired of this BS and I am not going to take it anymore.

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PS Some instances of the word you do not refer to you personally, they most probably should have be written as "one" but this sounds stilted.

@ RRM

You are trying to put me in a false position, I think. I understand the Paprotka argument.
However, you are disregarding the way the debate has been persistently biased against HGRVs.

The Paprotka paper was used to minimise the significance of MRVs as a human pathogen, to isolate the researchers, to forcibly retract papers investigating this subject, and to deny research funding to this emerging field - and - most importantly to stop the discussion of the hypothesis that new gammaretroviral pathogens could have been lab created and transmitted into the population.

Ruscetti and Mikovits have repeatedly stated that they find PMRVs but the debate is artificially refocused on "XMRV" because "XMRV" and only "XMRV" stood a chance of being denied if the right "facts" could be sought.

The EKVX gammaretrovirus would not be picked up by PCR designed to find XMRV. However there is a retrovirus capable of infecting human cells present, and one of unknown pathogenic potential.

The passaging of human tumor cells through mice has allowed multiple gammaretroviruses (NOT JUST XMRV) to jump species into human tissue in the laboratory. Some may have escaped into the population, especially as knowledge that these gammaretroviruses frequently infected human tumor tissues used in cancer research was disregarded.
This problem needs to be addressed. Isolating and belittling the researchers who are brave enough to publicly discuss this will not do.

This is what the Paprotka paper tried to obscure and deny.
This is what this Ruscetti paper proves.

In support of what currer said, I would like to comment. I have not gone back and reread the argument, so my figures are illustrative only.

The kind of crossover event had a probability of, lets say, one 10 to the 18. What are the chances of it happening twice? Superficially its one in 10 to the 36. This however presumes comparison from two unique samples. How many cells were in each sample? Millions (10^6). How many cultures are out there? Thousands, lets say 10^4. How many natural hosts are there? Millions, lets say 10^7. How many generations of those hosts in the last year? Lets say 10^2, although 10^8 more represents the historical context. How many cells in the hosts? Lets say 10^8. How many recombinatoin events per cell replication? I have heard 4, so lets say its irrelevant. How many closely allied viruses around? Lets say 10^2. The 10^18 argument has to be put in context. It is highly improbable that given the number of potiential recombination events, that it has not occured before, many times, especially in the last century with the rice of nude mice and cell lines that are at high risk of exposure. This argument is clearly only illustrative, and these numbers are likely to be way off.

This also does not take into account that MLVs and XMRV are not equivalent. MLVs do not need a recombination event to exist. The entire recombination argument is deceptive. MLVs get into a good percentage of receptive cell lines, maybe about one in five when a contaminating source is present. MLVs now, they are a good basis for recombining viruses. They might well permit activation of latent viruses. They might allow for recombination with fully functioning MLV. That alone puts the Paprotka paper in doubt. I have no problem with Paprotka as an hypothesis. I do however think it very unlikely to be right.

We still need Lipkin et. al. We also need a reverse transcriptase assay. Failure to find PMLVs in a blinded study using presumed optimal techniques, failure to find RT, failure to find any related virus, that will be much stronger evidence against HGRVs than we have at present. That, if for no other reason, is why we need the Lipkin et. al. study.

Bye, Alex

alex3619 said:

In support of what currer said, I would like to comment. I have not gone back and reread the argument, so my figures are illustrative only.

The kind of crossover event had a probability of, lets say, one 10 to the 18. What are the chances of it happening twice? Superficilally its one in 10 to the 36. This however presumes comparison from two unique samples. How many cells were in each sample? Millions (10^6). How many cultures are out there? Thousands, lets say 10^4. How many natural hosts are there? Millions, lets say 10^7. How many generations of those hosts in the last year? Lets say 10^2, although 10^8 more represents the historical context. How many cells in the hosts? Lets say 10^8. How many recombinatoin events per cell replication? I have heard 4, so lets say its irrelevant. How many closely allied viruses around? Lets say 10^2. The 10^18 argument has to be put in context. It is highly improbable that given the number of potiential recombination events, that it has not occured before, many times, especially in the last century with the rice of nude mice and cell lines that are at high risk of exposure. This argument is clearly only illustrative, and these numbers are likely to be way off.

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I have seen you argue this before and it sounds kind of nice but common sense dictates this is not true.

Although I agree it would be nice to know a quantitative guess at how many time recombinations between two mouse viruses do occur (including the times they instantly "die" of course), we know your scenario can not be true, as then every recombinant virus would also be created with a 1 nucleotide change independently, 2 nucleotide changes independently, etcetera. In other words, there should then be a whole family of closely related viruses (basically all possible recombination results that could survive the cell line in question) that were generated completely independently.

Because there are no observations made to this extent whatsoever, we can conclude with great certainty that exactly equal sequences are not generated through multiple independent recombination events either.

Hi RRM, your argument does not pursuade me. My point was illustrative. Other factors also come into play.

First of all, lets deal with point mutations. For each point mutation to be relevant, it has to be a functional mutation - one that permits viral survival. Most point mutations that do this do not change the amino acid it translates to, or changes it to one that is highly similar. If you want to talk about point mutations, add another 10^6 per year. With such huge numbers of viruses, numerous mutations occur every time it replicates. This is particularly true for reverse transcriptase as opposed to viruses using the host's cellular machinery, but even there I expect to see reasonable numbers of mutation. For point mutations to lead to a final virus, every step in the point mutation chain has to be viable. One failure and that path is pruned.

But I was talking about recombination.

Recombination has nothing to do with point mutations. Well, almost nothing. The source of the genetic material is often from an accumulation of point mutations over evolutionary time, but the recombination itself works by a shuffling optimization strategy. It is hundreds of times more effective than point mutation, at least in artificial mathematical constructs (this was the basis of genetic algorithms in computer science). Recombination exerts evolutionary pressure greatly in advance of any mutational effect. It can give rise, theoretically, to whole new virus types in short order, but the probablity of this is low. What makes it possible is that it is the entire host species that is the breeding ground. Its a numbers game. Not only can it give rise to new viruses, but it can give rise to old viruses that have not been seen in a very long while. This is supported by the math - I was investigating the math behind genetic algorithms in 1992 and 1993, and was considering using them for my thesis. I have since forgotten nearly all of it, but what remained was just how powerful selection and reshuffling can be. It is the real driving force behind evolution, not point mutations, although the source variety does indeed arise from point mutations for the most part.

Common sense is very commonly wrong. In situations that are complicated, involve feedback loops, or phase state changes, common sense lies to us. That is why we have math. However, we have trouble interpreting math. It can lie to us too, largely because we don't understand it (and I am talking about everyone here). Translating from the real world to math and back to the real world is a problematic exercise in any complex situation. However, the single biggest problem with common sense, or any kind of reasoning including formal logic is data (premises in logic): without the right data you cannot draw the right conclusions, and everyone has this problem, including me and you.

There are a whole family of closely related viruses. A virus is not one thing, its a swarm. That is why they talk of percentage similarity, not identity. Even in one person, with one virus type (I have HIV in mind) it is not unknown for upwards of 50 different strains to exist. What is a strain? A stable version of the virus with some point mutations. So I think many viruses are indeed recreated by accumulation of point mutations, very rarely. Recombination is far more powerful, and often ignored because most researchers are completely unaware of this branch of science. Again, this is a numbers game. However once several point mutations exist, recombination events can shuffle sort them into more optimal combinations. The low viability options should exist rarely in a swarm, but there will be many of them, whereas the high survivability mutations should be much more common. Indeed, due to limitations in isolation and sequencing, I suspect the tens of strains they find in patients after a while are only the high survivability strains. The others will be numerous (in total number) and rare (as specific sequences), and there might be many thousands of such strains.

One final point. A particular virus might have ten point mutations from another strain of that virus. It does not mean that that is how the viral strain evolved. Recombination can shuffle mixes of point mutations - so far as I am aware this is not a topic that has had much research in virology, and I regard it as an important open question.

Bye
Alex

PS The recombination argument, all of it including mine, relies heavily on inserted DNA for recombination to occur. When its just regular viruses, I suspect that recombination is more rare, and he nce plays less of a significant role.

Tony Mach said:

To continue my thought:

If the ME/CFS bug were a new virus, it would have probably come from another species. And viruses from other speciecis are either not able to make the jump and then they don't cause disease. Or if they do, they cause massive disease, catastrophic disease (think SARS or HIV/AIDS). Which makes sense, because human immune systems hasn't seen that bug before, so it does not know excactly how to fight it (and a immune system reacting too much is as dangerous as reacting not enough). And the bug itself probably does not show restraint, because it is adopted to another species.

What we see usually in ME/CFS is a flu that won't go away, with results that are definitly devastating for the individual, but no AIDS/SARS/black death like disease so I would suspect a bug that has been around in humans a long time. A bug that "knows" not to overstep the boundaries, so it can keep hanging around in its host, and a immune system that "knows" how to fight it (in most cases).

If you take a look at the polio bug, it causes polio only in half a percent of people it hits, other serious disease problems in one to two percent and maybe slight some kind of flue in some of the rest of the pople. Most people who got the polio bug cleared it. And that is my hypothesis for ME/CFS: some bug hits many people, for most it is just another flu like illness that goes away, for the few unlucky it is ME/CFS.

Well, this is all speculation, I could be completely wrong and I hope we will find the cause(s) within reasonable time. But I want to know the actual cause and not something that fits my confirmation bias. If finding the real thing means showing that I am wrong I gladly take that. And I will not take it anymore if other people think they have to push their fearmongering stories. You have no evidence, no model, no nothing to connect this human disease.

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Tony, what I find annoying is that -when retroviruses come to debate- you accuse people of wild speculations, but your assumptions are also just...speculations.

I don't want to extent this 'debate' on retroviruses with you, because that's not possible. However, I would like to give you some information, not from myself, I'm just the messenger, but from my experiences with lab biologists and retrovirologists:

HTLV: there are far more retroviruses that have adapted, HTLV did in fact adapt very well. It causes immune defieciency by just hanging around in the cell. People infected with HTLV often have some minor symptoms, and develop disease after 30/40 years. Recently, they found HTLV3 and 4. How many more ? A retrovirologist told me recently they find new viruses every day.

Something about testing: commercial HTLV-tests are not the most sensitive ones, if I recollect correctly, it must be something around 96% sensitivity. The same accounts for Hep-C, there is a sensitivity of 96%. A lab biologist told me, by repeating the test, you achieve a 100%.

I hypothise this way: seen the symptoms that goes with this disease, we share a common endogenous retrovirus that sets off by another virus infection, or is activated through vaccines. Or, we share a common exogenous retrovirus that behaves the way HTLV does.
The similarity in just plain symptoms with HTLV are not just coincidence TMHO. My disease started off just like HIV, with flu symptoms(yes). Later on I shared the symptoms of HIV and HTLV.

Of course, I can be wrong, but you can be also, and let's not forget: science doesn't know everything, otherwise we wouldn't be wildy speculating.

OS.

alex3619 said:

We still need Lipkin et. al. We also need a reverse transcriptase assay. Failure to find PMLVs in a blinded study using presumed optimal techniques, failure to find RT, failure to find any related virus, that will be much stronger evidence against HGRVs than we have at present. That, if for no other reason, is why we need the Lipkin et. al. study.

Bye, Alex

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Hi Alex,

I also thought that a reverse transcriptase assay would bring the answer, but it seems the ones available are not sensitive enough. I know a Professor, who does a lot of research into PERT. His name is Prof. Joerg Schupbach, and you can find more info here: http://www.nzr.uzh.ch/

OS.

alex3619 said:

Hi RRM, your argument does not pursuade me. My point was illustrative. Other factors also come into play.

First of all, lets deal with point mutations. For each point mutation to be relevant, it has to be a functional mutation - one that permits viral survival. Most point mutations that do this do not change the amino acid it translates to, or changes it to one that is highly similar. If you want to talk about point mutations, add another 10^6 per year. With such huge numbers of viruses, numerous mutations occur every time it replicates. This is particularly true for reverse transcriptase as opposed to viruses using the host's cellular machinery, but even there I expect to see reasonable numbers of mutation. For point mutations to lead to a final virus, every step in the point mutation chain has to be viable. One failure and that path is pruned.

But I was talking about recombination.

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You are actually perfectly illustrating my point. If you argue that two viruses could recombine multiple times into a single one 8000+ bp virus sequence from independent events, then two independent "almost exactly but not quite the same" recombination events would create (without any need for "point mutations" after this event) two identical sequences that differ from XMRV by just a single nucleotide. And yet other recombination events would lead to other XMRV viruses that would only differ in two, or three, or four or five (non-functional) nucleotide differences from the XMRV we know.

Consider my earlier example about identical DNA. Although I am sure you agree that it is highly likely that no two independent conceptions have ever lead to the exact same DNA profiles, suppose there is someone (and this would probably be a criminal defense lawyer ) that argues that this is not true and that is quite normal for two people to have identical DNA. Logic tells us that it can't be "quite normal" however. Why? Because if this were true, there would also be a bunch of guys (and gals) with a single nucleotide difference (relative to any given reference DNA strain). This alone would already lead to the existence of millions of almost identical persons (i.e. with just a single (silent) nucleotide difference in their DNA). There would be millions with just a two nucleotide difference, or three. Because we know this is not the case, we know that getting identical DNA through independent conceptions is also not a common event.

The same really applies here. There is really no need to bring point mutations into the equation, because you would expect (again, if your theory were to be true) many "almost but not totally identical" recombination events that would lead to these strains that differ by the reference strain by just one nucleotide (or a couple). Thus, if your theory were true, there should be numerous XMRV variants that would have recombined through events that are *almost* identical to the recombination event proposed by Paprotka. But there is no evidence of this whatsoever. This undermines the notion that two identical XMRV's are expected to be the result of independent recombination events.

Hi RRM, this is a numbers game. Viruses are not people. The number of virii is much higher than the human population. The length of the genetic code is much much shorter. The key feature is that they will be viable configuration zones, areas of high survivability for the virus, that leads to evolutionary stability in similar species. These hot zones are an evolutionary convergence. Deviation from that zone is not usuall viable. Sometimes it will be, and this can result in a sudden introduction of another stable viral zone.

For humans there are about three billion base pairs. Each individual nucleotide has four options (discounting U -uracil- for this argument, as its complicated and is really only a substitute). So you have, in reality, six billion base pairs with four options each, or 4^six_billion. It is not so simple though. 99.9% (not sure of the current estimate, I could be out) is identical so can be discounted. So lets say only one part in a thousand is relevant. So the real number is more like 4^six_million. That is a very big number.

I do not know what percentage of the MLV genome is highly conserved. MLVs only have about 8000 nucleotides, so about 4^8000 options. In addition, most can be discounted due to conservatoin, but I have no idea what that number would be, it would be a much wilder guess than I would like.

The problem with arguing strictly from a sngle genome is that there is no such thing as a standard MLV genome, nor any particular strain. Its a swarm as I said. Recombination and mutation tend to keep the swarm on track in a stable evolutionary zone until the conditions change.

Recombination with viruses outside that swarm are what might cause sudden shifts. Altering the landscape, such as jumping species, could also cause big shifts. Evolutionary recombination is NOT random chance, there is a random chance that each event occurs (probably, but maybe not), but the impact of each event is not randomly mixed. Its based on viral viability. This is so much more powerful than random.

I suspect (this is only speculation) that viruses have learnt to use this, and might have an evolved tendency to recombine in specific ways. In other words, the viruses have evolved to direct the evolutionary trend. This is not directed in the sense of purpose, its directed in the sense that evolved mechanisms might have developed that might bias the direction of change. This is an hypothesis that I find interesting.

These non-random biases can trash probability calculations. Probability presumes that each event has equal probability. When that is not the case, probability is at best a rough indicator.

So this is really a very complex situation, which makes me sceptical of most arguments. They might be right, but they might be wrong too. That goes for my arguments as well. Its not over till the science is done, and we are not there yet. I don't want to lock into an argument that is appealing rather than follow the evidence. I prefer to change my interpretations as the evidence becomes available.

With respect to MLV science, we still don't know everything we should. I expect to see more surprises in the coming years, more "Aha!" moments. The bigger issue though is what this says about viral research. I am not convinced that enough care is being taken with viruses that might not be predictable. This is particularly true if they have a propensity to recombine with endogenous viruses or laboratory contaminants like MLV.

With respect to ME patients, a major point I keep coming back to is this: every option has to be looked at till we have a definitive answer for ME. Every option needs to be examined again and again until we are coming back from the doctor's offices in droves with a cure in hand.

Bye, Alex

I agree totally with Mark and currer's posts.

Tony Mach said:

A vaccine does not bypass normal immune defences (which exist in the blood). So you should be OK.

See, I can generalize too.

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It's accepted that injecting a virus, as opposed to eating meat contaminated with the virus, generally causes a higher incidence of disease and that the severity of the disease will be worse.

If you want to speculate properly: IT COULD BE ANYTHING. You could pick ANY virus and say: "But it could be THIS virus!". Yes, it could. But so could any other. We don't know. I hope Lipkin finds something and until then it is baseless speculation.

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I agree with you somewhat on this. There now are multiple lines of evidence against at least XMRV proper as associated with ME. Also there is scant, if any, published evidence (since Lombardi was retracted) that other HGRVs are associated with ME. And I do think that some of the HGRV adherents make the theory sound unwarrantedly certain. I think that's not helpful.

I also think your venom is unhelpful. There are good, at least theoretical reasons, to suspect a retrovirus (and one of the better candidates would be an HGRV) as causative of ME. It's a viable hypothesis, much more likely than pure chance, but yes, with currently little direct evidence. No one, here at least, is saying it's a fact.

In another post you also said that known human retroviruses cause cancer in much higher rates than are associated with ME. HTLV infection is only associated with relatively low levels of blood and lymph cancers, in the low single digit percentages I believe; which is consistent with the rate of such diseases in the case of the Incline Village outbreak.

This study doesn't have to do directly with ME, obviously. To me it was interesting for the reasons others highlighted- that there is pretty good evidence from a number of studies that there are XMLVs besides XMRV in a number of human cell lines that have been passed thru mice and that they are virulently infecting human cell-lines that have not be passed thru mice.

This makes me curious about how accurate Coffin and friends declarations that the XMRV-creation event (which is unquestioned despite the fact that, to my knowledge hasn't been confirmed by any other lab- it seems this is a different standard than is applied to retrovirus/ME association studies) could never have happened more than once.

It IS possible that Mikovits found other HGRVs, though the published evidence base is scant. That was clearly never disproven. Silverman made the mistake, not Mikovits.

If the Lipkin study wasn't going on now, I would say: ok, let's give WPI and Mikovits time to regroup and publish their full sequences for the Lombardi et al paper as they said were immanent (before the Drama). And see what the reaction of the scientists is and what they would need to have this proved. What I really strongly object to is scientists and people like you saying flatly "there is no retrovirus (or HGRV) in ME." That's not correct because WE DON'T KNOW YET! Talk like that is harmful because it closes minds prematurely.

currer said:

Interesting, Christopher.

http://www.nhs.uk/conditions/lymphoma/Pages/Introduction.aspx
http://www.lymphoma.org/site/pp.asp?c=chKOI6PEImE&b=1573333
http://forums.lymphoma.com/showthread.php?t=7821
http://jnci.oxfordjournals.org/content/93/7/494.full

"Lymphoma rate of increase in the UK 4% per year. If the increase continues at this rate it will be as common as breast or lung cancer by 2025."
"Over the 25 year period between 1973 and 1998 new cases of NHL seen each year escalated almost 83%, among the highest increase of any cancer." (from these references)

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According to Osler's Web, burkitt's lymphoma was vanishingly rare in the US (though endemic in Africa in EBV infected people) until the mid 1980s when people with ME and AIDS began getting it. (only one case per year was reported in California up until 1982, which if extrapolated to the US population would give about a 35 million to one chance of contracting it each year; the tahoe cohort has something on the order of a 1,000 to one (very roughly) chance per year)