ERV readers will absolutely love this paper.
Okay, we all know ERVs are awesome evidence for evolution and common descent. But, imagine we could do classical ERV research one better. Imagine that we had DNA from one of THE common ancestors of humans and chimpanzees-- an ancestor who is the proud owner of a new ERV. Imagine we have its DNA, and the DNA of its parents, and the DNA of their parents. Then imagine we had the DNA of its children, and their children.
Imagine the fun evolutionary research we could do, what we could see, with those kinds of samples! No estimating-- literally watching and recording the event happening, in DNA.
From an HIV-1 perspective-- Imagine what we could do if we had HIV-1 viruses from The Human who got infected with HIV-1 Group M. We had the same SIVcpz viruses from the primate who infected them. And we have all the grandparent viruses and babby viruses too. No estimations of time-lines based on phylogenetic trees-- We would know exactly what happened, while it was happening.
Or, you can think of it *exactly* the same way scientists in HIV vaccine studies
and criminal HIV infection investigations look at the natural history of retroviruses-- Person A was HIV-1 negative, negative, negative, negative, and finally positive at a time-point. You could then look at HIV-1 sequences in putative infectors and determine 'who done it' and almost exactly when it happened.
That is the incredible study that Pathaks group was able to do at the NCI with XMRV.
We have got a cell line in the lab-- 22Rv1. This is a prostate cancer cell line absolutely loaded with XMRV proviruses (>10/cell). The question is, which came first? Did XMRV cause the prostate cancer, and we were just able to detect it in 2006? Or did XMRV come into the picture long after cancer, and is just a laboratory artifact?
Quick summary-- XMRV is a laboratory artifact. It didnt exist until 1993-1996, long after a bunch of folks were diagnosed with CFS, including The Reason for the Whittemore Peterson Institute, The Princess Who Cannot be Named, Andrea 'Fuck all of you and if you don't stop talking about me Im going to sue all of you for defamation of character. I know who you are . I know where you work . Im really Tired of the crap your writing .' Whittemore.
Long summary--
Which came first, the tumor or the XMRV?
To create the 22Rv1 cell line, a prostate tumor, CWR22 was implanted into lab mice.
The tumor grew, it was put into another mouse.
The tumor grew, it was put into another mouse.
And so on and so forth until you get a cell line.
Pathaks group looked at DNA of 'CWR22' at several passage points.
Though they did not have any DNA from the original tumor, they had DNA from early passages of the tumor in mice, and XMRV was not there. Which came first, the tumor or the XMRV? The tumor.
Ummm... so where did XMRV come from?
Started with a tumor in 1992, no XMRV. No XMRV in the third or seventh passages in mice.
However, in 1996, both 22Rv1 and its cousin cell line, CWR-R1, are loaded with XMRV (an average of 20 and 30 copies/cell, respectively). To add another layer of weirdness-- all of the proviruses are identical. That does not happen with retroviruses. Retroviruses dont know the meaning of the word 'identical'. It couldnt happen.
... But it could happen via ERVs. Everyone knows that retroviruses have obscenely high mutation rates, due to their error-prone reverse transcriptase, and recombination via their diploid genome. But once a retrovirus is in a genome as a provirus, it takes on the mutation rate of its host organism.
Pathaks group screened a whole bunch of mouse lines (something like 89?), and found two defective ERVs that match XMRV almost perfectly (like, 1 nucleotide different) 'PreXMRV-1' and 'PreXMRV-2'. Some mice had PreXMRV-1, and some mice had PreXMRV-2, and some had neither... but the mice where the CWR22 prostate cancer tumor was passaged had both.
They then hypothesized that XMRV is the result of six cross-over events between PreXMRV-1 and Pre-XMRV-2.
When they put their 'hypothetical XMRV from ERVs' into a phylogenetic tree with sequences from the 22Rv1 and CWR-R1 cell lines, a handful of 'XMRV' plasmids, and the WPIs 'sequences from patients', they got a tree that showed everyone was identical to everyone else. A hypothetical recombination between mouse ERVs, and sequences supposedly isolated from patients, and are like, TOTALLY NOT contamination, are identical.
An interesting point of this, is that the WPIs super-awesome-gag primers that apparently no one else can use appropriately ALSO target PreXMRV-1. Their super-awesome-env primers target PreXMRV-2. If you have any contaminating mouse DNA, you might find one/the other/both/neither, depending on the strain of contaminating mouse DNA. If you want to exclude detecting mouse 'endogenous XMRVs', you need a forward primer in the 'PreXMRV-1' region, and a reverse in the 'PreXMRV-2'. If your signal is from XMRV, you will have a band of a certain size. If its from contamination, it not be there anymore.
Neato!
Anyway, this lab determined that XMRV as we know it was created in the lab in 1993-1996.
Incline Village was 1985.
Andrea Whittemore was diagnosed 1990-ish.
Kids have had autism for ages.
Gulf War was in 1990-1992.
Ignoring all the hurdles an accidental virus would have to clear to get from our labs, literally into the general population, and all the hurdles of zoonotic transmission, XMRV cannot be The Cause of the illnesses Judy Mikovits is attributing it to, unless we invoke time travel as a very real possibility.
If time travel has to be a current technology in order for your hypothesis to be true, your hypothesis prolly aint true.
And then theres always the defense: "WULL, IF IT HAPPENED IN 1994 IT COULDA HAPPENED IN 1930 TOO AND IS ALL UP IN OUR VACCINES HOMOLOGOUS RECOMBINALTION TINIKERING R VAXXINES!"
That is as statistically likely as HIV-1 was not a regular zoonotic event, but was created in labs for use as a biological weapon. Or, humans and chimpanzees do not actually share a common ancestor, ERVs are really just identical retroviruses that happened to insert in identical locations in two independent, specially created species.
If you want XMRV to be a real, malicious pathogen, pick your poison: time travel or anti-science.
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Check these out:
http://jvi.asm.org/cgi/content/abstract/82/24/12585
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003144
ERV,
Since evoluntionary retrovirology is your niche, you should be able to clear this up for me if anyone can. I know the subject is complicated and hard for non-scientists to understand.
What Lo/Alter found in the small number of CFS patients of Dr. Komaroff was NOT XMRV. They found it in old frozen blood, and also in new blood draws from the same patients. It was basically mouse ERV's, if I recall your comments correctly. Setting aside the issues of external lab or reagent contamination for a moment, is it fair to say that this new Coffin et al paper does not apply to these Lo/Alter mouse ERV's, but only exogenous "Silverman" XMRV as originally published by WPI in Science?
Is it possible in theory that the Nu stain of nude mice used for xenograft research have had similar retroviruses to what Lo/Alter found for a long time, and that these have been inadvertantly passed into some biologicals? I am not an anti-vaxer, and I realise that if there ever was a problem with mouse ERV's in biologicals, it has probably been cleaned up by now by modern safety and testing protocols.
Levi-- This paper does not address the contamination in the Lo/Alter paper. However, I believe the Lo/Alter contamination will be addressed in an upcoming publication. Pure speculation here: XMRV is the result of two previously undescribed ERVs (PreXMRV-1 and-2). Lo/Alters sequences are such obvious ERVs that I doubt there is any virus involved-- Im assuming its straight mouse DNA contamination from reagents, as opposed to XMRV which can be an exogenous virus that is contaminating cell lines.
OT, but what's your take on the man cured of HIV by stem cells?
This was presented at the HIV Dynamics and Evolution meeting in Ireland. As a frequent lurker here, I had struggled to suppress a good lol. Thanks ERV :P
Just to provide a sub-textual update to the WPI passion play....
With 43,000 acres of Coyote Springs looking like the desert and the tortoises will be reclaiming it, Harvey Whittemore, is trying to preserve his political power base and bankroll.
After threatening Sparks with a 100 million dollar lawsuit presumably through his personal attorney who is also Harry Reid's baby boy, the city of Sparks is going to let Harvey proceed with plans for a 100 million dollar casino complex.
Guess what he is going to call it....
Gwan, guess.
After a day of treatment and testing at the world famous WPI the Whittemore's invite you to enjoy fifty dollars of chronically fatigued matchplay at the Lazy 8 Resort and Casino.
Yuck.
ERV,
Thanks for the clarifications. I see WSJ has written about this and has a statement from Alter's representative at NIH.
http://blogs.wsj.com/health/2011/06/01/given-doubt-cast-on-cfs-xmrv-lin…
Looks like folks will be taking a hard look at those polytropic murine leukemia retroviruses he found to figure out exactly where they came from.
I guess we are lucky that retroviruses are mindless, and can't figure out how to be sneaky. Otherwise, they might sort out that the best way to "fly under the radar" would be to look like a mouse ERV since humans would always see them as lab artifacts or contamination. They would not even need to be replication competent if they were given to the host some other way.
But if they were in CFS patients, that would have turned up in the Levy study since they were looking for the larger group of murine gammaretroviruses. It would be interesting to have the Levy group test those Komaroff patients blood.
@Levi Lo and Alter did not find any viruses, they only found PCR products. And all of their PCR products look like murine endogenous MuLVs, some even have frameshifting deletions which would render them nonfunctional.
Humans do not always see anything that looks like a murine virus as a contaminant. The story is a lot more complex than that. If it was that simple, this XMRV business and the Human Mammary Tumor Virus, and dozens of other similar stories, would not take years to sort out.
Fantastic! Papers like this make me love science...even more! Great coverage of the paper, ERV.
Physicalist-- Thats the same guy Ive written about a couple times before. Great luck for him, but probably not very many other people (there have been none since him), and certainly non-viable in the places that need HIV/AIDS treatments the most.
Ben-- I dont think you needed to suppress your lols. We openly loled at XMRV at Keystone :-/
Prom-- I thought Daddy Warbucks was a lawyer. Lawyers have lawyers?? That should be like dividing by zero...
Levi-- In the Levy paper, they studied Group 1 with Mikovits PCR protocol, in Group 2 they used Alters. So, they should have found them in Group 2 at least (and would have probably gone back to look at Group 1 the same way after that). But this paper is just about the mouse ERVs PreXMRV-1 and -2, not the numerous ERV contaminants in Alters paper. Also, what DrDuke said :)
Poodle-- Im actually jealous of the folks on this paper. Sure its cool, but it looks like finding this info out was cool and really fun. lol, ERVs are fun, LOL!!
ERV, keep up the good work. I have learned so much from your blogs.
Let's hope the CFS/ME science moves forward in other directions.
Hopefully, with less drama. :>)
Laurie B.
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0019953
Jonathan Stoye has already found something suspiciously similar to Alter's pMRV contaminating a few reagents.
Thanks ERV even I for a while at least could understand... I think ;) Your blog is a welcome contrast to the multitude out there.
I almost inhaled what I was eating.
Thanks, good summary for us without having to read the paper.
Given Lo's batty history re: mycoplasmas and AIDS (insanely expounded upon here by notorious commenter cooler), it always mystified me that his paper was taken seriously. And it was published in PNAS (aka Probably Needs Another Study).
Well this is the most blatant piece against Dr Mikovits I have read to date:
http://blogs.forbes.com/stevensalzberg/2011/06/02/chronic-fatigue-syndr…
This is a classic tale of a scientist gone bad. Unfortunately for CFS patients, Mikovits is distracting attention from efforts to find the real cause... Itâs pretty clear now that she will never retract her findings, despite the pressure from the editors at Science. I can only hope that CFS patients, who are understandably desperate for a treatment, wonât be fooled into taking ineffective and possibly harmful therapies based on the failed XMRV hypothesis.'
I was actually thinking how cool it must have been to be the one to set the gel with the PCR results on the transilluminator and see the bands for only the later passages light up. Ah, the joys of science!
Another letter from teh crazy to ScienceMag. This one is from Dr. Jamie (and others). They are now playing the autism card again FFS:
"A recently published study found the rate of ASD in South Korean school children to be 1 in 38 children. We are in the process of demonstrating the clear association between these two diseases in our patient group. It is an infectious disease. The world cannot afford another infected generation. This is not just another EEC. Your concern as editors should be for the patients, or in this case, the health of the species. Do not become the journal responsible for shutting down desperately needed research."
https://files.me.com/jdj88/hok3p2
I bet Bruce Alberts is headdesking at this very moment.
Was impressed with this when they presented it at CROI
Urisman et al deserve half as much blame for geting this started in the beginning!
@#17 RRM
So what they say is .... autism is an infection? Caused by what exactly?
Mice rubbing their butts over MMR ampoules?
ZOMG, I just read the whole paper and saw that pre-XMRV2 is found in the 129x1/SvJ strain....I've used those! I must go demand financial compensation to get myself tested! =P
That is just devastatingly clear. A clear case for a "Science. It works, Mikovits" T-shirt.
That is just devastatingly clear. A clear case for a "Science. It works, Mikovits" T-shirt.
I'm a regular commenter on the German ScienceBlogs and just encountered a German XMRV believer who hijacked a thread on HIV to spew her ideas about the medical establishment covering up the true cause of CFS. I tried a lot of angles, including linking her to this blog, but it's like talking to a wall and now my hands hurt from trying to headdesk and facepalm at the same time.
@dt
With XMRV of course. Supposedly vaccines are contaminated with XMRV. It all makes perfect sense. Mikovits has already presented data that conclusively proves the connection. I think she is finding VP62....uh I mean XMRV in 40% of patients...
Regarding the shirt, I'd rather wear a "XMRV: Nevar forget!" or some kind of variation.
Your concern as editors should be for the patients, or in this case, the health of the species
The fate of humanity HANGS IN THE BALANCE!!!
"Prom-- I thought Daddy Warbucks was a lawyer. Lawyers have lawyers?? That should be like dividing by zero..."
They do and should but in this instance Harvey's personal lawyer draws a salary for being Harry Reids' son just like his brothers did whether or not they actually did anything.
It is kind of like paying Vinnie the Torch's son in law to do brickwork...it isn't like he is going to show up with a trowel, he just expects a check and you expect your house will not burn down.
I think that's wrong to hijack an HIV thread, but the medical establishment (especially that of the UK) has been trying to bury CFS for years. And if you disagree with this, it is of my opnion that you are either ill-informed or deluded. I think most are just ill-informed.
You could tell the person that you don't think the science holds up for XMRV, but it very well may be another retrovirus. That way you aren't perceived as some uncaring ignorant jerk (as those people exist too).
as a UIJ I suggest you take your conspiracy theories to prisonplanet or lymebusters, much more receptive audience for it there.
CA, it isn't the medical establishment, it is the government. The reason the UK and the US governments have been trying to bury CFS is because the first well known and well documented group was veterans. Because the government is responsible for the health care of veterans, they want to blame what ever is wrong on them so it can be ignored. That is what they tried to do with shell shock, with PTSD, and with CFS.
They are all essentially the same, and have to do with long term changes in physiology due to chronic stress which persist and produce hysteresis, maintaining the long term chronic stress state. It is purely physiology. The government doesn't want to address it because it means dealing with it as something real, something that happens to veterans. Something that happens to veterans as a consequence of their service.
The medical establishment would be happy to treat it, but the government doesn't want to pay what it would cost. The government doesn't want to admit that a foreseeable consequence of going to war is getting PTSD and CFS. They won't be able to trick as many young and naïve people into enlisting if they do.
Hmm, it doesn't make sense that you were responding to me, but I'll kindly respond anyway.
It's funny how people here know of all these websites I never heard of. Recently somebody made me aware of a website called whale.to, and now I learned of two more!
whale.to and lymebusters look like trash to be honest, but at least prison planet has a good looking design.
But to be quite honest, I get all my news from The Onion. Somebody else told me about that one. It's the most accurate source for anything by far.
"The government doesn't want to admit that a foreseeable consequence of going to war is getting PTSD"
Yes, they freely admit it. I was in the army and we were taught warning signs of PTSD and told to keep an eye out for said signs in out fellow soldiers. Google "army.mil" and "PTSD" and you'll find some of these training modules.
"and CFS."
O.o Is there any evidence that CFS is a result of going to war?
PS, not sure if they have changed the policy yet, but at one time, when people were being discharged, they had the opportunity to be treated for PTSD in theater, or declare themselves to be PTSD-free and be discharged immediately to civilian life back in the US. Some choice.
http://www.fayobserver.com/articles/2010/10/21/1041467?sac=Home
If you look at the prevalence and spectrum of symptoms of veterans who were in the gulf vs those who were not, symptoms associated with CFS are much more common in gulf veterans.
http://www.ncbi.nlm.nih.gov/pubmed/10824302
I am not saying they all have CFS, but what many have is CFS-like and some likely do meet clinical criteria for CFS. That someone has sub-clinical symptoms that are CFS-like does not mean that they are âperfectly healthyâ. The existence of sub-clinical CFS fits perfectly with my conceptualization of CFS.
@ #28.. I like it when the staunch xmrv/wpi/judy lovers post here with their conspiracy theories... (I realize ERV, as the owner of this blog, might not, as they've really flung some abuse at her!) If they are reading this blog, perhaps they are learning something..
or am I giving them too much credit!
"I am not saying they all have CFS, but what many have is CFS-like and some likely do meet clinical criteria for CFS. That someone has sub-clinical symptoms that are CFS-like does not mean that they are âperfectly healthyâ. The existence of sub-clinical CFS fits perfectly with my conceptualization of CFS."
This doesn't show what actually caused the increase in problems observed in the veterans nor does it show that war (or the stress) causes CFS. If I recall correctly (and it's been a while since I've looked into this) the current thought was that problems associated with GWS was linked to exposure to nerve gas, not stress.
If the government requires soldiers to receive treatment for PTSD in theater, this is not unique nor is it an attempt to supposedly suppress the truth. The same has happened for other injuries. One of the soldiers from my unit was held back in theater (at the end of deployment) due to a broken forearm. Another was held back for a similar injury. I don't see how this could be an attempt to hide these occurrences.
Finally, the cause of CFS (again) is not known. To claim otherwise is foolish until such a time that reproducible data indicates the cause(s). You do yourself no service by claiming to know otherwise.
Wait, I thought that the virus was called XMRV when in humans, and something else when in mice?
@Censored Analyst:
I've seen arguments for why the medical insurance industry would want to cover it up, but why would the medical establishment in general want to cover it up?
"
"@ #28.. I like it when the staunch xmrv/wpi/judy lovers post here with their conspiracy theories... (I realize ERV, as the owner of this blog, might not, as they've really flung some abuse at her!) If they are reading this blog, perhaps they are learning something..
or am I giving them too much credit!
Posted by: Mary | June 3, 2011 3:56 PM"
There seems to be a very small group of "staunch xmrv/wpi/judy lovers" who post their opinions as fact on blogs, forums, newspaper, science sites etc-- they hide behind different user names continually posting the same incorrect information. I call them the XMRV spammers.
There are many reasonable people who have been diagnosed with ME/CFS that follow the science not the rantings of the spammers. These people were initially hopeful that Judy had something but over the last two years have realized, it just ain't so. They are disappointed and moving on. The XMRV spammers will believe in XMRV causation forever - even if somebody does an exact replication in front of them.
There is no conspiracy -- every government, every university, every independent medical researcher, every doctor, blah blah blah would have to be working together to undermine ME/CFS -- and just why would they want to do that. In the long run, not looking for the cause and the cure will cost governments billions in increased health care costs. I am sure Big Pharma would love a cause to be found for ME/CFS because I am sure they would develop all sorts of expensive medications to help treat whatever the cause is. Could it be, there isn't just one cause but a combination of factors that result in ME/CFS.
If you look at the science without any emotion, consider just the facts, not the emotional rhetoric, there really is one conclusion that can be drawn.
That it depends on what "science" you are looking at?
I look at good science and I see science.
I look at bad science, and I see corruption.
And why can't I draw two conclusions again?
I look at posts by Censored Analyst and see a complete inability to identify "good science" and "bad science," merely "science I do or do not want to accept". Maybe I'm just missing the post that had an informed critique, though...anyone got a link?
Who was responsible for introducing 'emotive declarations' into the 'science' surrounding 'XMRV'? Hmm.. Sure as hell wasn't the credible scientists or their kling-on 'doctors' if you want my honest opinion.
And yes I am a non-scientist, non-pretend-to-be-knowledgeable-forum-dweller, (though I do benefit from forums that are non-judgemental and prepared to actually debate without personal attacks); AND a person living with a diagnosis for more than 10 years that he would rather was ANY chronic condition other than 'CFS' 'MEs' 'PVFS'.
Now read the latest from Medscape - and if you want you can 'debate' the latest points raised in defence by Dr Mikovits or you can accept these latest studies:
http://www.medscape.com/viewarticle/744158
From the link above: I already knew XMRV didn't cause Cerebral Spinal Fluid.
It seems that people don't care that I say that I don't think XMRV will probably never be associated with CFS (but it would be cool if I were proven wrong). But I guess it bugs people that I still think XMRV and/or related retroviruses may be human pathogens (and evidence outside Mikovits' lab suggests that they may be in the human population). So therefore I worship Mikovits somehow.
I guess I am criticized as well because I don't automatically default to psychosomatic explanations of potentially emerging illnessses like other "skeptics". I see this act as potentially dangerous to the patient community. The modern day skeptics don't practice what they preach.
Oh, and why else am I criticized? Well, I don't consider all alternative medicine quackery like some skeptics. Then the skeptic has their famous line (I think Steve Novella coined this one?): If it works, it's not alternative, it's medicine. This is a weird argument, as I think alternative to the vast majority of the people are things their regular GP can't write on the prescription pad or something the vast majority of GPs know nothing about. So I guess the "skeptics" believe that if your allopathic GP hasn't heard of it, it doesn't work. This idea is ludicrous. These are false ideas perpetuated by influential figures such as Steve Novella. I think he is a very smart and logical, but he flops like a fish when he starts talking about something he really knows nothing about - alternative medicine.
So, yes, I do see many on this blog as unreasonable. That is my bias, so perhaps that's why we don't get along. It is of my opinion that bloggers like ORAC post a bunch of nonsense on a daily basis (I already got bored of the repetitive nature of his blog to be honest). However, I do think ERV posts very compelling arguments and original content. Do I agree with everything? No. I pretty much never completely agree with anybody really and there is no safe haven for me to flock. She obviously hates me, while I really don't have much against her.
And I don't think the contamination studies fit in the bad science category, nor do I think the positive studies fit in the bad science category. Both sides are completely necessary to resolve the XMRV issue.
When I was referring to bad science, nothing about XMRV came to mind. The PACE trial is bad science and is biased and intentionally misleading. Perhaps bad science isn't the right word. Corrupted science fits better.
For an example of a science blog I mostly agree with about the XMRV issue:
http://laikaspoetnik.wordpress.com/2011/06/07/to-retract-or-not-to-retr…
Perhaps this kind of blog is more boring to the layperson as it seems to lack the defamation of character you see some other places.
You're right, it's much better than the mecfsforums.
CA, I disagree. I think that Science was right to issue an editorial expression of concern. I think it relates to the specific details of this specific case and shouldn't be generalized to other cases.
In this XMRV case there is undo weight being put on the WPI results by WPI for commercial purposes. People are being charged for and âtestedâ for XMRV using non-FDA approved tests and being âtreatedâ for XMRV using anti-retrovirals not FDA approved for XMRV infection for which there is no FDA approved test.
These anti-retrovirals have serious side effects relating to mitochondria biogenesis, and mitochondria biogenesis is (very likely) the primary cause of the exercise intolerance exhibited by people with CFS. All the other symptoms of CFS are compatible with insufficient mitochondria biogenesis.
WPI could have done things that would have demonstrated the reliability of the Science paper. They did not do them. They could have sequenced every one of the positive PCR XMRV results that they got and then showed that they were different enough to demonstrate that they were not contamination.
If WPI had been going about this in the normal way, with the normal back-and forth in the literature and with normal patient safety and Declaration of Helsinki protocols being followed, then maybe the Science expression of concern would have been premature.
The Pathak paper on the origin of XMRV really does show that XMRV is contamination and not a cause of any disease of humans. That WPI is unable to accept that because of the egos of the people involved and their narcissistic need to âwinâ a pissing match while patients are being exploited and harmed is unacceptable.
Science screwed up by not doing a more careful peer review of the original paper. They should have mentioned that they screwed up in their expression of concern, but editors have big egos too.
why is it so far-fetched that vaccines would contain retroviruses? wasnt there a recent study that found them in animal vaccines?