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ME/CFS: A disease at war with itself
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Xenotropic MLV's can infect many mammals and also (wild) mice

Discussion in 'XMRV Research and Replication Studies' started by Jemal, Nov 30, 2010.

  1. Mark

    Mark Acting CEO

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    "This symposium will ...reveal recent advances in the testing and screening of the blood supply"

    Safe to assume those advances have now been made.

    And what George describes of this paper does seem to take the lid off the fact that the X/P factors have been resolved.

    I'm curious about the "about 80 years ago" bit, George. How accurate do you think that's likely to be? Any guess as to margin of error with that?

    Because 80 years ago would be 1930 or so, around about the time of a candidate for the first documented outbreak of ME, I think?
  2. Mark

    Mark Acting CEO

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    "The Los Angeles Outbreak (1934) occurred at Los Angeles General Hospital and was the 1st ME/CFS/CFIDS outbreak ever officially recorded. 200 members of the hospital staff contracted the disease and over 50% of them remained unable to work 6 months later."

    76 years ago.
  3. George

    George waitin' fer rabbits

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    Hey Mark

    Yes she pretty much follows the MLV virus from around 8 to 12 million years ago or MYA to the present and shows how XMRV arrived in it's present form. The three things that this paper does and it's like the holy grail as far as I'm concerned. Christine Kozak goes on the refrigerator "ABOVE" Dr. Signh and Dr. Mikovits. Now why would I elevator her over Dr. Signh who is so much cuter? (grins)

    1-She puts the "contamination question to bed". Period, end of story, any scientist who can read will know this is the end of the line for contamination silliness.

    2-She shows that this virus originated around 80 to 100 years ago. Which I blogged about and she has confirmed (grins) and my ego is just big enough to really enjoy that. (HUGE GRINS)

    3-She's produced a solid primer for researchers about what the potential problems are in regards to this virus. She shows what paths researchers need to follow up on. She shows that this virus has all the markers to produce pathogenesis in lymphocytic leukemia, erythroleukemia, immunodeficiencies, and neurological diseases.

    I blogged it if anyone wants to slog through the blog couse it beats the full paper I guess, but I thought it was worth reading. I posted some of what I wrote below but feel free to delete it if you think it takes up too much of the thread.


    I've laid it out with some quotes and page numbers for anybody that wants to slog through this instead of the 30 or so pages of the paper. Any misinterpretations are mine and mine alone and maybe the result of stupidly, brain fog, or lack of working brain cells. Any mistakes that you find please let me know and I'll correct them.

    The paper really does start from the beginning, not as far back as the primordial ooze but close in human terms, (grins) She follows the rise of "XMRV" from 12 Million Years Ago (MYA) to present.

    She starts out showing how the receptor (the old XPR1) arose within the species of mice. You have to get to that receptor in order to have XMRV. She knocks out an entire range of mice right out of the gate.

    Meaning there are three types of MLV's that have developed in mice. They can be grouped according to the receptors or their ability to bind to cells their RBD's. E-MLV's or ecotropic MLV'S just infect mice and sometimes only the species of mice that they come from. These have an mCAT-1 receptor and are not a problem for humans since we don't have cells that would allow this to bind.

    Both PMLV's and XMLV's CAN have the XPR1 receptor that would allow it to bind to human cells and to a range of animal cells but it turns out it's not that easy. There are other factors. First of all many of the virus's are Endogenous so they are bound into the DNA of the mice they are in and don't produce any infectious virus.



    However it turns that the nice quite little viruses can, when they come into contacts with other Ecotropic or mouse only virus's, wake up and get busy making a working virus that has the ability to by pass certain restrictive mechanisms and produce a variant [B ]infectious virus
    . This possibility was discussed in the science community early on regarding XMRV however, it looks like "recombination" is not an issue for the XMRV virus. It looks like it evolved over time to be a straight up novel Exogenous virus.

    The XMLV's break out further into groups and are a bit newer on the phylogenetic tree. These virus's break out into three "clades" or subgroupings. Most do not produce infectious virus however within the clades or subgroups there are two that do produce infectious virus the NZB and the F/ST. It is interesting to note however that if certain chemical or bacterial events occur that there are among the non infectious clades or subgroups the ability to produce infectious virus. It doesn't say particularly what these event's might be but the paper treats these as of no importance to the development of XMRV itself.

    I'm not sure if it is only in the laboratory or if events of this nature can occur in the wild. (oh, goody more bed time reading) So far all of the virus types that have been discussed can be found in both wild and laboratory mice and have been studied in the laboratory since the 1950's.

    I think that's why she sort of stops on page 9 and discusses the problem of contamination. She sites several cell lines that are used to produce a variety of products that have mouse DNA in them and so have virus wrapped up in the DNA. As discussed above some of the quite XMLV can become active if you introduce certain chemicals or bacteria into them. (Note: This is speculation on my part but it appears that many scientist who were not necessarily working with XMRV experiments themselves remembered this bit of information from school days and so jumped on the "could it be contamination" bandwagon, possibly because the ideal of a mouse based endogenous virus being able to infect humans seemed a little 'world is round' to them, grins)

    However the above being said she goes on to complete the tracing of the phylogenetic tree of the very unique XMRV and puts the potential of contamination completely to rest. Read on. (if you're not bored, grins)

    At this point she looks at the wild mouse and it's origin in the Indian subcontinent 8 to 12 MYA (million years ago) and that the MUS split off from other murinea animals like the hampster and the mink shortly after, around 7 MYA. MUS Then split into 40 subspecies of mice and 3 of those became house mice around 1MYA to 1/2 MYA (I'm gettin' there Mark I swear, grins) from there "fancy mice" or pet mice strains were breed by humans (Note: this goes back to around 1500 C.E. in China and spread to Victorian England where pet mice were very popular, that's just my reading and is not included in the paper) and from "fancy mice" laboratory mice were breed starting in 1905. It turns out that wild mice don't carry the particular type of MLV's that are found in house mice so the phylogenetic tree splits at 1 to 1/2 million years ago and begins to develop in the house mouse strain. Turns out that's why the wild type mouse mus pharia which is being brought into the laboratory in order to study lab virus's is susceptible to the XMRV virus. Note: mus pharia like to play dead and bite. I like these guys already!)

    So the MLV's that gave birth to XMRV turn out to be a from house mice rather than wild mice. (no mouse hate for the local field mice please.)

    She next notes that Asian mice tend to carry many of the XMLV's while the western European Mus domesticus carries the multiple PMLV's and at the time when M. domesticus was brought to America there does not seem to be an indication of the X/P hybrid that would give rise to XMRV yet. This would indicate that XMRV's developed well after the settling of America or after 1500 to 1600 C.E.

    Then it get's interesting. . .

    Turns out there is one wild type mouse that produces both Pmv's as well as Xmv's and this is a cross breed found in California (hmmmmm, where was that first out break? Oh yeah in California, grins) This mouse is a cross between M. domesticus with it's multiple PMLV's and Japanese fancy mice which produce XMLV's. These mice where most likely brought over by Chineese and Japanese laborers to the West coast where they hooked up and produced the Lake Casitas, California mouse So we finally have a mouse that has the ability to make an XMRV type virus in the Lake Casitas or LC mouse. However these mice don't produce virus with the correct receptor but with a variation of the receptor called BXV1. Rather than the XPR1 which can get into a lot more cells in a lot more animals.

    So far we've gotten our mouse to the west coast of America sometime between 1800 and 1875.

    The paper then narrows the field to look at 4 types of things that must be in play for a virus to infect humans and are unique to each MLV.

    So you not only have to have and XPR1 host range but a specific type of host range like XPR1n or XPR1(sxv) that seperates where a virus comes from and what it can do. (page 15) Also what "restriction factors" come into play like does your virus get smacked down by APOBEC3G but slide by Trim5 (alpha) then it could only arise from a cross of these viruses. Also a what type of proteins that your virus codes for since they are all different and are there deletions that can pick up junk on the envelope of the virus allowing it to hide. So starting at page 12 Ms. Kozak breaks down how the various mice in the laboratory stack up to produce the XMRV virus.

    Two known virus strains have been isolated that produce virus that have shared characteristics of both P and X MLV's however looking at the isolates neither produced XMRV because neither produced the correct receptor to bind with human cells.

    The importance of the fact that Christine runs through just about every lab mouse strain over the next few pages and very carefully shows that while a variety of laboratory mice have the ability to produce XMRV which is a cross between XMLV and PMLV none have produced the strain of XMRV that we are seeing in humans. This puts the question of contamination to rest. You could say that this paper is what we have been waiting for. This is the paper we could/can toss into Dr. McClure's face and say "HA". Indeed anybody who want's to shout "contamination" could be effectively extinguished with this paper.

    The paper goes on to the next level of XPR1 receptor alleles that are defined by the ability of a particular portion of the receptor ELC's 1 to 4. Turns out you have to have a very specific one in order to infect a range of animals.

    In separating out XMRV from the herd Ms. Kozak shows that while XMRV shares specifics with both known X/P MLV's the overall sequence identity to known viruses that have been studies for years does not reach beyond 94%. When comparing the current copy of XMRV VP62 it has similarities to some X type, some P type and some E types virus's. This shows that it absolutely is not one of the laboratory derived virus's but may have passed through another/other animal(s) before making it's way back to humans. However she qualifies this as saying it's a possibility not a certainty and this is where the rubber pretty much leaves the road.

    What makes her think that it is possible that the virus has more than one host is that the receptors XPR1 (sxv), shows up in areas where there are a lot of cases of prostate cancer like the US and Western areas of Europe while the XPR1 (m) group is found in the areas where there is lower incidents of Prostate cancer like Asia, Japan, India and China. She makes a good point but this could be as much about the genetics of the people living in those regions as the receptors on the virus.

    She could have a good point in that ME/CFS also shows up more prevalent in Western Europe, America and Australia so there may be some genetic typing much like HTLV which tends to only be pathogenic in the Pacific Rim and Africa.

    So that's pretty much it. Nothing that we didn't really know but some really solid science.
  4. Mark

    Mark Acting CEO

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    Hey George, do I remember rightly that way back when you were interested in mouse labs near Los Angeles and mice that may have made it to Royal Free Hospital...can't remember the details of what you found but it's sounding like an interesting line of inquiry right now. If that 80 years thing is solid...

    Somebody has emailed me to ask what happened to John Coffin's comment at CFSAC 2009 that the early estimated age of XMRV was about 40 years, which sounds right to me that he did say that but my recollection is a little hazy. Anyway, I have been asked what has become of that comment because the person can't reference it and says it appears to have been removed from the video. Would be nice if somebody out there could track that one down and confirm or deny that...

    Anyway, while the forum's been down I couldn't wait to hear back from George about the Los Angeles 1934 mouse connections so I thought I'd do some digging around myself. I found something that sounds rather exciting to me...is the following all well known already, and is it as suggestive as it looks to me?


    Experimental Studies on Encephalitis:
    Specific Inactivation of Virus by Sera from persons exposed to encephalitis, St Louis Type, 1933
    With a note on the evaluation of the results of mouse tests of sera
    (Webster, Fite, Clow)
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2133312/pdf/827.pdf

    Note 1 (p 835):
    p 837:
    p 846:
    I haven't yet perused the following two papers, which also came up via google search for terms like 'Los Angeles 1934 mice virus', but they too seem worthy of re-examination now:

    Observations on the Epidemic of Polioencephalitis in Los Angeles, 1934:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751857/

    A virus recovered from the feces of "poliomyelitis" patients pathogenic for suckling mice (1949):
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2135891/

    In summary:
    - George reports here that Kozak's paper is saying that "X/P" XMRV was born from a 'mating' of X and P MLVs in mice about 80 years ago.

    - The first documented outbreak of a disease resembling myalgic encephalomyelitis was in Los Angeles general hospital, 1934

    - There were sporadic cases documented of 'atypical primary encephalitis' in the previous 2 years

    - In 1932-1933 Muckenfuss, Armstrong, and McCordock, and Webster, Fite and Clow gathered specimens of sera from cases across the US - too many of them to mention them all - and during their experimentation they "obtained a virus" by inoculating brain tissue from the fatal cases into monkeys and mice

    Is it too much of a leap to now speculate that X/P XMRV may be the cause of ME, and may have been born in the early 1930s, when the first documented outbreak of ME occurred in Los Angeles, and when sporadic cases of a new type of virus and a new type of encephalitis were observed across the US?

    Is it then a leap too far to further speculate that the mating of two different types of X/P MLVs that gave rise to X/P XMRV may have occurred when researchers gathered specimens from around the US and injected brain tissue from fatal cases into mice and monkeys?
  5. George

    George waitin' fer rabbits

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    You're saying that XMRV is actually a cross between X/P MLV that in mice and then got crossed with St. Louis Encephalitis during an experiment in which somehow the two items got injected into monkey brains and then got out into the population??? Well, it's not 100% impossible but I would think it a little improbable but who knows. (shrug) There was some crazy stuff going on at the time and nothing to stop the monsters (doctors) from creating some Frankenstein stuff in the name of progress.

    There is an indication that ME did not show up in Europe until well after the 33/34 outbreak at Los Angeles County Hospital so it could have been brought over via soldiers from America during the war. (Grins) Our gift to the world? I'm wondering now if prevalence rates of ME will be highest in the UK because of soldiers stationed there and Germany, France and Spain and Japan. It will be really interesting to watch it all unfold.
  6. Mark

    Mark Acting CEO

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    Hi George,

    We posted just about the same time; guess we've both been at this for the last few hours. Yours is informed comment and mine just speculation of course - as you know, I just throw these things out there and hope you may find something in them...

    Sounds like my idea isn't the explanation of how the X and P came together if there was already X and P in those Californian mice. But where I was coming from was basically the combination of your "80 years ago" and the first outbreak 1934 in LA.

    I read you earlier as saying (in very rough shorthand because I don't fully understand the depth behind what you're saying) that (P/X) XMRV arises as a combination of X and P variants. ie. that XMRV is a cross between X and P MLVs in mice. And that this happened about 80 years ago.

    Sounds like you're saying the X and P variants were already present in the Californian mice well before that so in that case maybe my premise was wrong...but the arrival of those Californian mice was somewhat more than 80 years ago so as I understand it, after that arrival you're still looking for another event that can explain the birth of XMRV, possibly via another species. If so, the sort of experimentation going on at that time seems like a possibility. But I'm certainly not saying that it is, just raising the question/speculation and asking whether it makes sense.

    I wasn't meaning to imply anything about how St Louis Encephalitis may be involved, but rather suggesting that the gathering of samples from fatal human encephalitis cases from around the US, and the injection of brain tissue from infected humans who died of encephalitis into mice and monkeys may have been an opportunity for the different X and P variants to get together. (We both may have got confused about what was injected into what, sorry if that was my fault, the way I just described it is how I understand it). One of the teams injected into monkeys the other into mice so I was wondering if the X/P combination could have happened when sera and brain tissue from people from the other side of the US were injected into a mouse. From my reading of it, some kind of MLV has been via humans and caused encephalitis, and then the brain tissue from those humans who died was injected into mice. You were talking about some kind of passage through some other host, perhaps another animal, so could this be the type of event we're looking for?

    By the way I think maybe the mice used in the paper I cited weren't what we'd now call laboratory mice? I seem to remember mention of fancy mice from that paper.

    The more significant part of what I wrote seems to me to be that prior to the 1934 outbreak there had been sporadic outbreaks of a novel encephalitis during the previous 2 years. I didn't know that before, but if we're now tracing the history of XMRV to be born 80 years ago and we trace the history of ME to these outbreaks of a then-novel encephalitis in the early 1930s, then it does seem to fit rather well.

    Just throwing it out there to see what you make of it; I guess you've looked at all this stuff before anyway. Had you explored the particular paper I'm citing here before?

    I seem to remember you talking some time ago about a lab near LA County Hospital, and mice that could have been in a lab attached to Royal Free, and I also seem to remember your epidemiological calculations based on WPI percentages and growing rates of ME and other conditions led you to the 1930s as well. All coming together 'nicely'?

    By the way I want to stress that I'm not at all wedded to the idea that XMRV was born in the lab. It does seem to me an interesting coincidence that all this wild science with mice and encephalitis was going on around the time that ME was born, but it totally could be a coincidence. Have to bear in mind that they were already observing novel cases of encephalitis and that's why they were doing these experiments in the first place, so I may well have the cart before the horse.

    Aside:
    Also I'd like to just note that I'm not pushing some anti-science or anti-mouse-experiment agenda by suggesting all this here either, just following a trail and seeing where it leads. I often find it interesting though how some people (not you George and not other members here especially) often jump on any merest hint of such speculation and reach wild conclusions that I am saying things definitively, and that I have an anti-science agenda; I've seen consistently hysterical reactions of that sort from Bad Scientists attributing all kinds of motives and beliefs to me that I don't actually hold, just because I raise a certain possibility and ask if it's feasible - and my views, and the nature of Phoenix Rising, have been completely and wildly misrepresented over on BS pretty frequently; I find it almost comical to read sometimes.

    I find those reactions really interesting. Since I know what I believe of course, and I know when I'm being misrepresented, it seems to tell me a lot about those other people. What it suggests to me is that there are certain ideas or concepts that are simply taboo and will provoke hysteria amongst many scientists, often to the bafflement of the person suggesting the idea (I've seen it happen to others, plenty; it's a fundamental pattern). It even happens when it's merely the implications of the idea that are troubling to the scientist, and not the idea itself. It's as if they process it and say "well if that were true, that would mean x, which would imply y, which would imply z, and....oh no! that would be horrific! No, no, no!", and then they decide that's exactly the chain of reasoning that the person is trying to set up, so they launch into the person suggesting the idea and bully them into shutting up. If that person isn't even aware of this x,y,z that the scientist has apparently worked out, it can be baffling.

    It's hard for me to understand, because I don't reason towards a desired conclusion (perhaps the people I'm talking about do, or automatically assume that others do), I just keep a totally open mind and try to be as neutral as possible, follow where the connections seem to be heading, and throw out suggestions that occur to me. But I've seen that sort of thing happen enough times for it to be worrying, because if there are questions that scientists (in general) tend to be uncomfortable about asking - anything that may lead to scrutiny of science itself, for example - then that is a troubling systematic distortion of the balance and open-mindedness one would expect from scientists. Indeed I would go so far as to say, having read some Martin J. Walker, that when people talk about "conspiracies" that what they are really referring to is this phenomenon I've just described, and to organisations of skeptics (often allied to industrial interests just because that's where they work) who are mostly quite unconscious of their own biases. Here's a couple of free books that seem to me to be highly relevant to us:

    http://www.scribd.com/doc/8401751/C...n-Goldacre-Quackbusting-and-Corporate-Science
    http://www.satori-5.co.uk/downloads/dlf_168.pdf


    Sorry to digress...back to those mice now...
  7. Mark

    Mark Acting CEO

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    To highlight the key bit more briefly:

    The former workers obtained a virus by inoculating brain tissue from fatal cases into Macacus rhesus monkeys; the latter recovered a similar virus by inoculating the brain tissue into special mice.

    ie: it was the brain tissue of humans who died from encephalitis that was injected into mice, and a virus was then recovered from them. And the mice were 'special mice' by the way...what does that mean I wonder?
  8. urbantravels

    urbantravels disjecta membra

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    Don't mind me, I'm still stuck on the Lake Casitas mice, since Lake Casitas (in Ventura County, close enough to LA for a day trip) didn't exist until a dam was built in 1959. Evidently the mice were named at some later date but the strain of mouse was shown to exist much earlier.

    You know, we are really pretty damn lucky that the trail seems to be leading to mice and retroviruses, considering how heavily studied all this has been in the past. Starting on third base with regard to a lot of this science.

    Mark, I get what you're saying: what I often find myself trying to argue against here is what seems to be a perception that lab accidents and/or intentional lab experiments are *more likely* causes for disease origins than just natural accident. I think this is a fallacy that the human mind falls into because we don't directly see, and can't directly apprehend, the scale on which nature does this all the time - viruses evolve crazy fast and jump from species to species all the time. It's happened millions upon millions of times in the history of the world and untold thousands of times in human history. But our bias is to look at patterns that our brains are better designed to understand, which are human activities on the small and immediate scale, and attribute outcomes to those actions.

    If you want to point the finger at the real technological villain in the development of viral diseases that jump into humans from other animals, you will find that agriculture, and the development of dense settlements that agriculture made possible, is the real Dr. Frankenstein. (Followed by industrialization and the furious pace of urbanization which it made possible.) People live closely together with one another and with domestic animals all over the world, and ever-expanding human settlements encroach on previously uninhabited areas, bringing people and their domestic animals into contact with wild animals of all kinds. So we get bird flus and pig flus and weird tropical diseases making their way into the human population all the time. And we have mouses in our houses. And cats, and rats, and...

    So when you're talking about what's possible, you also have to keep in mind what's likely. An event that has already happened thousands and thousands of times happening once again (although perhaps with some characteristics that are novel to our current understanding of infectious disease), or a very rare and idiosyncratic event that is theoretically *possible*, but that we are naturally biased to assign causality to over the much more common events that are invisible to us.

    I think we have *plenty* to blame the scientific, governmental, and medical establishments for in the way they've mishandled our disease, but thinking it was created in the lab has never been very high on my list of things to be angry about.
  9. George

    George waitin' fer rabbits

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    Wow, two really good posts. First UT is correct about the fact that zoonosis is happening faster these days because we are removing species in between original host species and humans. For instance if a virus would normally be restricted or kept from becoming a provirus in say beetles and you use a lot of pesticides then you have a much better chance of the virus making a leap into say house cats where normally the chance of a house cat getting the beetle based virus would be very slim. So in a way humans are responsible for some of the pressure in the environment that leads to modern illnesses but not so directly. We push on nature and nature pushes back to keep things from running amok.

    I hadn't read the article you cited Mark, thank you for turning me on to it. It sounds like it may have bearing on what's going on. I apologize for not reading it before commenting. I think my comments sounded much rougher than intended. I wasn't thinking that you were saying it definitively but trying to wrap my mind around the possibility without reading the facts. Never a good choice. (big grins) I'll take a look at it and then comment how's that?

    As for the points that you remember me making back when I was just a wee pup and first on the forums I did repost my "old mouse theory" on the blogs. But yeah, C.C. Little first breed "lab mice" in 1907 and sent mice out to the LA County General Hospital in 1922 which would have given the virus (if it came from this batch of mice) an opportunity to infect as many as 20 to 50 people who would have worked with them at the University of California Medical School which was attached to the Los Angeles County General Hospital. So the entire thing fits kinda nice and the Christine Kozac paper. She lays the development out in such a way that it's possible. Since all "lab mice" have the basis for the XMRV virus but no Lab mouse currently has the exact XMRV virus (VP62) then the virus capability had to cross paths in California since the LC mouse is first mouse strain that had the capability to produce a cross X/P XMRV type virus. So did the LC mice cross with the University of California Medical School mice or were the "fancy mice" that later got out into the LC area establish the original Lab mouse lines?? That's not clear in her paper only that the capability didn't exists until the Asian fancy mice crossed with the European fancy mice producing the lab mouse with the X/P - XMRV producing capabilities. Which would have been after 1875 and before 1917. The reason for the 1917 date is that all of the C.C. Little mice except a few dozen that he had at home were killed in a fire in 1917 all subsequent "lab mice" are breed from those few dozen mice called the "DBA" strain. So all the mice that came after which all have the capability to produce and XMRV virus are breed from that group of mice.

    The original C6BLK mice which is all that's left from the DBA strain are the mice that carry the 94% identical XMRV virus no lab mouse has the exact strain. Variants on the strain exist within the PV62 group much like HIV or HTLV there are mutations but all within the context of the PV62 strain.

    Dang I went off again and forgot the original question but I think it's yes, if you read the "old mouse theory" blog it uses the HIV calculator to figure out how many people had to be infected originally and when to come out with the current numbers. I'm just not sure what the "current numbers" really are these days!???
  10. urbantravels

    urbantravels disjecta membra

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    You can tell my mind's on urbanization (as it so often is, note my user name) as I'm reading "Hungry City." But soon I'm going to have another go at Laurie Garrett's "The Coming Plague," which I've never managed to read much of.
  11. jenbooks

    jenbooks Guest

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    Good work, you guys. Thanks, Georgie. Still think you should go easier on Lipkin, tho:)
  12. George

    George waitin' fer rabbits

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    He got Judy on his dance card so I can't be far behind. (big grins)
  13. Mark

    Mark Acting CEO

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    Ready for me to throw you a load more sticks and balls to fetch George?

    Ah, now I get the bit I had misunderstood: the LC mouse is the strain that had the capability to produce it, not that it had already produced it some years earlier. So the actual birth of X/P XMRV in the early 1930s, based on that "80 years ago", is back on.

    So then the next step is when did both X and P get into a mouse capable of producing X/P XMRV, yes? The birth of X/P XMRV was an event estimated about 80 years ago where both X and P were present in an LC mouse, or in a lab mouse descended from the DBA strain, and created X/P XMRV, correct?

    What's involved with both X and P getting into a mouse capable of producing X/P XMRV? Would X and P normally be expected to be present in the same mouse, or not?

    Also there was the suggestion that the virus had to do something like passing through some other host in order to get into the form that infects humans, right?

    So that experiment where brain tissue from humans who died of encephalitis was injected into 'special mice' (?) seems to potentially fit that pattern, because whatever virus caused that encephalitis had then passed through humans, infected their brains, and then that infected brain tissue went back into mice in the lab, and a virus from those mice was then extracted by the researchers.

    And btw where did that "80 years ago" bit come from and how accurate/reliable is it?

    And could these "frighteningly elegant and subtle experiments" have anything to do with it?
  14. Cort

    Cort Phoenix Rising Founder

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    Raleigh, NC
    Where does the 80 years come from? I can't find that in the paper - which may not be that surprising given how dense that paper is.

    I see that the VP62 isolate shares 94% sequence identity but does that mean that XMRV is not found in lab mice? Some of them can produce X MLV's.....
  15. Mark

    Mark Acting CEO

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    I've been reading through this one and there are some intriguing observations in there:

    Observations on the Epidemic of Polio-Encephalitis in Los Angeles, 1934:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751857/pdf/calwestmed00415-0071.pdf

    One of the first things that strikes me about these 1930s papers is the difference in their style from modern scientific work. I find them qute refreshing: the style seems more literary and human-readable, to me, but also there seems to be more space for somewhat more personal observations: historical detail and interesting observations that may prove to be significant. The science is still there as well of course, but I can't help wondering whether researchers back in the day received a more rounded, balanced, less specialised education.

    Some of the things that seemed interesting to me:

    The observations place a great deal of evidence on the "pleomorphic streptococci" found consistently in nasopharyngeal swabs, findings "obtained in Rochester and reproduced and greatly extended in Los Angeles". Intriguingly, the paper states:

    I had to look up "pleomorphism" and the wiki entry is also intriguing:

    http://en.wikipedia.org/wiki/Pleomorphism

    This seems to me to be suggesting that the idea that certain bacteria can change shape dramatically during their lifecycle was popular when this paper was written, fell completely out of fashion, but now turns out to have some truth in it after all.

    What seems suggestive about this to me is the analogy to the proposed recombinant properties of the X/P MLV family: the idea that the X/P XMRV family may overlap and recombine with each other and may modify each other during their lifecycle. With retroviruses having the ability to alter DNA, it seems to make some sense that this sort of thing will be going on. RNA transcription by a retrovirus, perhaps, might not just be able to alter the structure of host DNA, but perhaps also to alter the structure of other retroviruses from its own family!

    I'm perhaps expressing this poorly and by analogy, and maybe it is already well-known: the HIV viruses are so complex because they change in a dynamic fashion too. I'm coming at all this more from a computer science perspective, and there is a highly suggestive analogy there for me.

    Normal computer code runs by modifying data that is external to it, in some separate area of memory. The logic and the data on which it operates are kept very separate. However, some really wild and extreme programming code - extremely bad practice and traditionally the stuff of fun and challenging competitions for geeks rather than conventional software engineering - is actually written in such a way as to act upon itself: manipulating its own code as if it were data. I remember seeing some C code many years ago that did exactly this, and it boggled my mind. Incredibly short C functions were able to produce far more in terms of output, relative to the actual length of the code, than would be possible in conventional computer programming. My memory is a little hazy, but I seem to remember one very short sequence of code that won a competition for the shortest sequence of code able to write out the Lord's Prayer. The textual content of the prayer was not present in the original code at all - it was way, way shorter - but the way that the program itself evolved as it changed itself caused the correct sequence of letters to be written out.

    Such self-modifying computer code strikes me as an analogy that should inevitably hold good in the biological realm as well, and since XMRV is a very short sequence of genetic code with apparently powerful effects, that too seems suggestive. Finally, it also makes me wonder about all those empty and unused bits of DNA within genetic code: long stretches of genetic code that seems to do nothing. We assume that those blank and unused sections of the genome are merely background noise, the legacy of the randomness of the evolutionary process. But could it be that all that space is used during the lifecycle as a kind of 'data store'? Such processes might create interim states of the genetic sequences that perhaps exist only for an instant, as one genome acts upon itself and transforms itself into another. Just like a computer program, this could all happen so fast that it's over in the blink of an eye, and we might never have seen this happening. And perhaps this sort of behaviour - maximally efficient code - could explain puzzles like why the number of genes in the human genome turned out to be so small, yet capable of producing the extraordinary complexity of human life.

    Self-modifying genetic code. Maybe this is all well known and nothing new here, but anyway these are the thoughts sparked in me by this comment about pleomorphism.

    I was also very interested by these observations: again, appearing to be general observations and impressions of the kind one might not expect to see in a modern paper...but which I find refreshing...and also highly suggestive because there is something unusual about the epidemiology of ME/CFS and these observations seem like they might speak to those peculiarities - here are the extracts that struck me most:

    Again, fascinating!

    The whole "yuppie flu" business and the claim that CFS affects the middle class more than the poor, is of course part of the history of ME/CFS, and is generally disputed as a prejudice, a myth, and explained by psychologists with ideas such as "they read it in the papers and convinced themselves they had it". But these observations of a disproportionate distribution of ME/CFS amongst the middle classes are surely subject to none of these factors and can't be explained away by any of the theories from either side. What on earth could be going on here? Genetic susceptibility is an obvious idea that comes to mind, but again, this seems to me to be a hypothesis driven more by our assumptions than anything else. I suspect that the answer lies in some environmental factor, and in the means of transmission. The observation about upper stories and high sides of hillsides looks like a massive and overlooked clue. All these observations, both in this paper and historically, seem to be pointing at some environmental factor that is present in what we might think of as clean, sanitary, desirable environments, where the air is, theoretically, somewhat cleaner - or perhaps the heat, or some other aspect of environment - were the middle classes more likely to have something like central heating for example?

    There is much more in the paper that is intriguing. The section on clinical observations emphasises muscle weakness, gastro-enteritis, sore throat and respiratory tract infection during the early stages, involvement of the nervous system, recurrence of fever and other symptoms during convalescence, malaise, headache, tingling sensations in the extremities, lower back pain, photophobia, lethargy, and extreme variations in type of disease and severity...anything here sound familiar?

    So I'll try to pull all this together and summarise what it suggests to me:

    - there is something unusual about the lifecycle of the pathogen
    - the pathogen may have various states and may have self-modifying genetic behaviour and thus be hidden or latent except when in an infectious state and causing outbreaks
    - the agent mediating the infections may only be infectious or pathogenic under certain very specific conditions
    - the unusual heat may be significant; maybe a set of conditions including a precise temperature is required for the 'pleomorphic' transformation
    - greater rates of infection by those with apparently clean air, and unusual environmental conditions (early May heat) might suggest that the absence of some other bacteria or insanitory condition, which might normally restrict the pathogen, enables the pathogen to thrive.
    - there is something which is proportionately more likely in middle class environments which is necessary for the pathogen to thrive - heating? clean air? pets? absence of mice or infestation?
    - those observations about high-up living environments: could the pathogen change state when moving from a high-temperature environment into a much cooler upper room?

    And finally, I'll indicate the hypothesis I appear to be reasoning towards (and I'll admit that maybe my pre-existing hypothesis may be biasing my reasoning):

    X/P XMRV can infect mold. It becomes active and infectious, perhaps modifying itself by acting upon its own genetic structure, under certain conditions perhaps related to changes of temperature and other environmental factors. Inhalation of mold is one of the primary means of infection, particularly during outbreaks, through infection of the respiratory tract.

    (As an alternative, it may be that the above factors point instead towards tick-born infection; perhaps ticks fly into cool upper rooms under certain conditions. But there's no mention of tick bites in the impressions of the researchers, which I might have expected to see given the nature of their other quite careful and open-minded observations.)

    Please bear in mind that all the above speculation is a vague and approximate sketch: it's more of a "discussion document" intended to spark ideas in those more specialised in the relevant disciplines than myself. I look forward to the thoughts of George and others on the above...may be it's time to call in the mold warriors...:D
  16. Mark

    Mark Acting CEO

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    George says in #23 in this thread:

  17. Mark

    Mark Acting CEO

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    This all seems so significant folks, but hidden deep in the technicalities and so most forum members won't have read the key headlines. Any chance somebody can summarise the implications of all this stuff for the benefit of the less scientific minds? (I'm looking at you, Cort and George :D)

    Amongst the key messages seem to be:

    - Contamination theory buried at last
    - XMRV was born from a combination of XMLVs and PMLVs 80-100 years ago
    - This new genetic information about X and P MLVs explains the apparent discrepancy between WPI finding XMRV and Lo/Alter finding PMRV sequences
    - Thus this means that Lo/Alter is now shown to be a confirmation of WPI findings
    - Only Californian mice and lab mice are able to produce the X/P XMRV hybrid
    - This ties in very neatly to the Los Angeles 1934 outbreak, the first documented outbreak of ME

    I think those messages deserve a wider audience...:D
  18. alex3619

    alex3619 Senior Member

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    Logan, Queensland, Australia
    Hi George

    This is interesting, you quoted this bit in the paper (post 23):
    two strains, NZB and F/St, have a high virus phenotype, producing high titers of X-MLV throughout most of their lives. Other strains rarely produce infectious virus, but cells from many common strains can produce virus following chemical induction or stimulation of spleen cells by bacterial lipopolysaccharide (LPS) or in a graft versus host reaction

    LPS is what de Meirleir was tracking, and it correlated with CFS severity. It is also the PRIMARY toxin that attacks the body from a leaky gut.

    I may have more to say later. I am too tired now.

    Bye
    Alex
  19. George

    George waitin' fer rabbits

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    Hey Mark,

    I read the article and I'm sorry, there just is not enough information here for me to make any kind of inference at all. I've read most of the work regarding the early outbreak's including the one in 1934. The thing that has always struck me about the 1934 outbreak is that it affected 198 nurses and doctors but not patients. Two things that the doctors and nurses had access to in the years prior to 1934 (remember it would take time for a retro-virus to spread) The first is lab mice from the CC Little, that were part of the University of Southern California Medical Teaching College which is part of the Hospital Complex and was built in 1934 around the time of the first outbreaks and second one is some of the first versions of the polio virus vaccine. One of the reasons this was considered an abortive polio is because of early efforts to create a polio vaccine at that time.

    Another theory, since we are tossing some of them out there (grins), is that rather than being an abortive polio that the polio triggered a different virus which caused the symptoms. All of it's just guess work right now and a lot of detective work has yet to be done. Dr. Coffin first speculated that XMRV entered the population around 40 years ago but with the work of Christine Kozac, we can see that his original estimate might well be wrong. About the only real solids that we have is the knowledge that after 1800 the ability of mice in America to produce a cross X and P type MLV became a reality. And we know that it entered into to lab mice since all lab mice have the potential but are not currently or in the recent past producing this particular virus XMRV with XPR1(sfx or x)receptor.

    We also know from this paper that ability to produce XMRV type virus's is part of all "Lab Mice" However, only three strains of mice the C6BLK, the DC-75 and 129 produce XMRV with the XPR1 (x) allele, all of the other species of Lab mice produce XMRV with either the XPR1(p), (m) or (n) type receptors. So Ms. Kozac demonstrates that XMRV came from mice and either mutated after zoonosis to humans or past through a different host, dogs, cats, rats, sheep, pigs who knows and then came back to humans in this form or mutated in humans themselves. The question hasn't and isn't answered in this paper. Lab mice do not have the (x) type XPR1 receptor so other than the mus pharia which is a wild mouse that is being introduced into life as a lab mouse that are not able to become infected with this particular brand of XMRV.

    (Note: Speculation and Questions on my part)
    The next question is when did it pass to humans specifically? We know after 1800 for sure but then it get's fuzzy. We also can extrapolate that you would need 20 to 50 originally infected individuals by 1925 in order to reach the current numbers of infected, taking into account at least a 3% of the world population. (less in Japan and India, more in the US and Western Europe) Fewer individuals would be needed the farther back you go but most virologist think that a minimum of 10 infections events are needed for a zoonosis to occur.

    We know that XMRV itself is a cross of not only X and P type but Christine states that it has some Ecotropic features as well. So this virus came from mice and then mutated into a Virus that is not only able to infect humans and monkeys but it looks like may be able to infect other animals as well. It is as likely that humans mutated the virus in vivo and have passed it to a variety of animals rather than the other way around.

    I know some folks like to extrapolate that it's a really bad experiment gone wrong some where but the time line doesn't really suggest that unless you toss in lies and covers ups as well, in which case I think I'll dye my hair red and join the FBI. (big grins) I'm of the personal opinion and it's just an opinion you don't even have to read it, that most likely the mutation occurred with the 1910 or early mouse strains that were shipped to University of Southern California's Medical School. USC had opened in 1898 but closed for a period between 1910 and 1921. It's possible that the mice that were part of the USC labs were used by the hospital or housed by the hospital during the years the Medical School was closed. The mutation could have occurred during this time. This would provide a division from the original lab mice developed by CC Little. and the early events that are considered to be ME/CFS outbreaks in 1934. Another note is that CC Little lost all but a few mice in a fire and started over breeding lab mice in 1917. Little went on to create Jackson Laboratories which is the worlds largest Lab Mouse distributor. Jackson Laboratory mice have the potential to produce this virus but have not produced this particular virus with the exception of the strains cited above that harbor close cousins of the VP62 virus.

    The above scenario is the only one I can come up with that would make the division and allow both paths to develop. But who knows. As for possible vectors for infection. I'm sticking with tried and true until someone proves otherwise cause there is just no telling. For now as far as I'm concerned you have horizontal via sex and blood or vertical from mother to child via breast milk.

    Hopefully the path will be worked out over the next year. There are good trails for people like Christine to follow up on but it will take some time to figure it all out. The only thing I'm really interested in at this point is the fact that lab mice don't make the virus there fore

    a) the virus can not be in the mouse DNA so it can not be contamination of samples. If your primers are set to find XMRV/XPR1 (x) then you will find it if it's there.

    b) by the same token it's pretty hard to make a case for a government experiment gone wrong. Since the government would have to have infected mice that they used (knowingly or unknowingly) to produce vaccines, or other products that where then transferred to people. The virus didn't develop in it current form in mice so that argument doesn't fly either.

    c)The important thing is to push for funding into how to treat the virus if you have it and how to look deeper for those who don't.
  20. urbantravels

    urbantravels disjecta membra

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    Los Angeles County Hospital is affiliated with USC (University of Southern California), not the University of California - Los Angeles. The USC medical campus is not in the same place as the rest of USC and it is pretty far from the UCLA campus.

    And, while I don't follow these activities where people throw balls around, there is a significant proportion of the population here in Los Angeles that considers loyalty to one or the other a matter of life or death, so you might get in serious trouble for confusing UCLA with USC... :cool:

    Is there a good link to a more detailed history of the 1934 outbreak at Los Angeles County Hospital? I'm little use with virology but I know a lot of local history.

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