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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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January 11, 2011

XMRV: It's Ugly, But That's Science

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Posted by Derek

How's the XMRV / chronic fatigue syndrome connection holding up? Not real well. Science has a roundup of the latest news in the area, and none of it looks encouraging. There are four studies that have come out in the journal Retrovirology that strongly suggest that earlier positive test results for the virus in CFS samples are just artifacts.

For one thing, when you look closely, it turns out that the sequences from cell-cultured XMRV samples are quite a bit more diverse than the ones taken from widely separated patients at different times. And that's just not right for an infectious agent; it's the opposite of what you should see. A number of supposedly XMRV-specific primers that have been used in such assays also appear to amplify other murine viral sequences as well, and samples that show positive for XMRV also appear to have some mouse DNA in them. Finally, there's reason to believe that some common sources of PCR reagents may have murine viral contaminants that blow up this particular assay.

Taken together, these latest results really have to make you cautious in assigning any role at all to XMRV based on the published data. You can't be sure that any of the numbers are what they're supposed to be, and the most parsimonious explanation is that the whole thing has been a mistake. To illustrate the state of things, you may remember an effort to have several labs (on both sides of the issue) test the same set of samples. Well, according to Science. . .

Some had hoped that a project in which several U.S. labs are testing for XMRV in the same samples would clear up the picture. But so far this effort has been inconclusive. Four CFS patients' blood initially tested positive for XMRV at WPI and the U.S. Centers for Disease Control and Prevention but not at an NCI lab. When all three labs tested new samples from the same patients, none found XMRV—for reasons that aren't yet clear, says Coffin. The group now plans to test blood from several dozen CFS patients and controls.

No, this isn't looking good at all. It's pretty typical, though, of how things are out at the frontiers in this business. There are always more variables than you think, and more reasons to be wrong than you've counted. A theory doesn't hold up until everyone who wants to has had a chance to take some big piñata-shattering swings at it, with weapons of their choice. So, to people outside of research: you're not seeing evidence of bad faith, conspiracy, or stupidity here. You're seeing exactly how science gets done. It isn't pretty, but it gets results in the end. Circumspice.

Comments (70) + TrackBacks (0) | Category: Analytical Chemistry | Infectious Diseases


COMMENTS

1. Anonymous on January 11, 2011 10:32 AM writes...

I guess you are not so updated with the "other" side of the coin, I reccomend you have a look on the studies that did find XMRV and the different than PCR methods they used, and the measures they took to avoid contamination.

Example: FDA Advisory Meeting last December:

DR. ALTER:

"Since Dr. Lo had to leave early, I felt I had to come up and do some defense of him and Judy as well. I think, when a group finds a new agent, they become biased that this agent is real. When another group doesn't find an agent, they become, I think, even more biased that the agent is not real. That leads to this kind of contentiousness.

I think our goal should be not to bring the other side down, but to find the truth. I think the truth will out over the next year, with studies that are already planned.

At this point I concur that we have no evidence for causality. That's going to be very difficult to come by, especially when we are detecting at the limits of detectability and when assay performance is very critical to get equal results.

But I still want to counter by saying I think the current evidence for disease association is very strong, even though not universally confirmed. But it has been confirmed now in at least four studies, two of which were presented today, that either XMRV or a polytropic MLV is associated strongly with chronic fatigue syndrome. A point that I think was misrepresented today: In those labs who do find the agent, it is very reproducible. Judy has found the same patients to be positive by culture year after year. We have found a patient to come back after 15 years and still be positive. So this is not a single, isolated finding. It's confirmed by sequencing. It's reproducible over time.

Dr. Hanson has shown today how critical the assays are. When she tweaked her assay, she went from no findings to findings almost identical to the Lo lab. The diversity is now being confirmed also in the original WPI group. XMRV isn't the only agent even in the WPI lab.

Despite the very legitimate concern for contamination -- I think this is a serious issue -- there have been hundreds of negative controls in the same laboratory that are always consistently negative. An extremely sensitive mouse mitochondrial DNA has always been negative in the Lo laboratory. Lo has done the [IAP] assay that Dr. Coffin recommended. That is also negative. There just has been no evidence for contamination. Although you could say maybe the negatives could be negative somehow and the positives positive for contamination reasons, it really is not logical that that would be so.

I'm not a molecular biologist. I defer to Dr. Stoye, who is world-renowned in that area. But just as a simple doctor, it seems to me that you have used single-case anecdotal evidence to knock down the various possibilities. I just want to make a case to the committee that you can't -- your conclusion is that anything can happen in assays, and therefore it probably has happened this time. I think using that kind of anecdotal probability is not valid to negate reproducible data from four different laboratories. So at least keep that in mind.

Lastly, I'm not a chronic fatigue doctor, but I have learned a lot about chronic fatigue in the last six months and have spoken to a lot of patients. I'm absolutely convinced that when you define this disease by proper criteria, this is a very serious and significant medical disease, and not a psychological disease. It has the characteristics of a viral disease. It usually starts with a viral-like illness. If XMRV is not the causative agent -- and it may well not be -- there is still need by other groups to look for the next agent which may be the case"

Source: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/ucm239304.htm

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2. SonicChronic on January 11, 2011 10:38 AM writes...

I wonder if the homogenity in human titers is representative of some sort of selection process where only a certain sequence can avoid an effective immune challenge. I don't know anything about virology but am just sayin.....

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3. Anonymous on January 11, 2011 10:57 AM writes...

Any serious PCR expert could look at the initial Science paper and in 3 minutes know that it was PCR contamination combined with an insufficiently specific PCR assay. I laughed when I saw it.

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4. xand on January 11, 2011 11:55 AM writes...

Any serious comment should have known that the Science paper did use 4 different methods for detecting XMRV, and never a simple PCR as you suggest, they cultured the virus for 45 days, they found antibodies and an immune response... this virus is NOT contamination.

DR. MIKOVITS:

"These patients in the U.K. have not [had virologic/infectious disease workups]. It is a psychosomatic disease in the U.K., and they can't get those types of medical treatments easily and maintain their benefits. In our study in Science, the answer is yes. These patients have multiple chronic active infections: EBV, HHV-6, CMV, shingles, mycoplasma as I mentioned, We see everything .

It looks to us like an AIDS patient, with an obvious hypothesis being that the retrovirus causes the underlying immune deficiency. But it alone can't cause the disease. It needs the co-pathogens. You can have HIV without having AIDS, but you can't have AIDS without having HIV plus one of 25-odd co-pathogens."

Source: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/ucm239304.htm

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5. AKS on January 11, 2011 12:06 PM writes...

Somewhat generally related to this, but have you seen this interesting article in the New Yorker:

http://www.newyorker.com/reporting/2010/12/13/101213fa_fact_lehrer?currentPage=all

Might make for an interesting blog post and discussion here.

Permalink to Comment

6. Edugreat on January 11, 2011 12:17 PM writes...

Below is part of a paper published on the WPI website in response to the four "negative" papers.
full paper at this link: http://www.wpinstitute.org/news/news_current.html

The main question regarding this issue of "contamination" is how does it explain the integration into the DNA of cancer tissue and the development of an antibody immune response. How can my wife's body have developed antibodies to a lab contaminate 500 miles away?!!!
-----------
XMRV: A Human Retrovirus with Unknown Pathogenic Potential, Not a Lab Contaminant

The recent proclamation that “XMRV is not the cause of CFS,” came from an individual who did
laboratory experiments to show how PCR experiments can become contaminated. These results
have nothing to do with the reality of a disease or the methods used by those who have detected
XMRV in the blood and tissue of patients found to be infected. The positive studies, which
cannot be explained away by PCR experiments, are those which have used multiple methods to
show that XMRV is a live replicating gamma retrovirus in human blood and tissue samples using
the gold standard methods of viral isolation and antibody testing, in addition to PCR.
Unsupported conclusions, such as the one offered by the Wellcome Trust spokesman, often
create sensational headlines but do little to move science forward. Authors of the positive
XMRV studies have been extremely careful not to claim causality, realizing that more scientific
research is required to make such a statement. However, one fact still remains clear. Not one of
the negative studies changes the results of the scientific research done by Lombardi et al., Lo et
al., Urisman et al., and Schlaberg et al.
The WPI-led scientific study, which rigorously ruled out contamination, revealed high
associations of gamma retroviruses with physician-diagnosed CFS patients, using four different
methods of detection. Recent commentary associated with the negative research papers on
XMRV, which used only one testing method, claimed that these studies proved that XMRV was
not the cause of human disease. On the contrary, what the authors of the “contamination studies”
confirmed is something that most experienced scientists already know; there are risks associated
with using PCR if one does not properly control for contamination. They cannot conclude that
other research groups had the same problems or that “XMRV is not the cause of CFS”.
Most significantly, the recent Retrovirology publications failed to address the most
important pieces of scientific evidence of human infection in the previous XMRV studies,
including the fact that XMRV positive patients produce human antibodies to gamma
retroviruses, XMRV integrates into human tissues, and infectious virus has been cultured
from the blood of hundreds of patients with a diagnosis of Chronic Fatigue Syndrome and
M.E. Humans do not make antibody responses to mouse DNA sequences from
contaminated lab experiments. The Retrovirology studies only point out that XMRV
research cannot be done in a mouse laboratory without extreme caution and should not
rely solely on PCR methods.

Permalink to Comment

7. ME/CFS since 2010 on January 11, 2011 1:05 PM writes...

Back in May 5th 2010 i was sexually involved with a girl and when we were doing it i noticed the condom had broken when i withdrew my first thought was "i hope i don't get this girl pregnant" but she told me she was on the pill so i went on with my life,(all these following symptoms i have never seen or felt before in my life) two weeks went by and i had a couple of hot flashes but didn't make a big deal of it, two more weeks went by and i noticed i had many many little pimples on my back right behind my armpits around this same time i started to feel confused but i thought maybe i didn't get enough sleep, around the 5th week i started to get worried because i was feeling nauseated and somewhere around the 6th week i had a "viral spike" i got really sick with all sorts of symptoms, nausea,confusion,weakness, constipation,fatigue, night sweats, lost like 15lbs in a few days, i had a really bad rash on my back.

i thought for sure i had gotten HIV, i went to get tested for HIV on July 21, negative.

i thought mm maybe it's just a stomach flu and it will go away, but the symptoms wouldn't go away if anything i felt like i was getting worse, i kept testing for HIV at many different places, i went to different cities to different health clinics to get tested like every week because the counselor at my local health clinic kept telling me i couldn't get tested anymore because it was negative this went on for about 4 months( by this time i had already been to ER twice because of all the symptoms had been to GI specialist, dermatologist,my primary MD, two infectious disease guys and many different health clinics).

i was sure i had gotten some weird HIV strain that the current test weren't able to pick up, and the funny thing is that all new counselors and doctors i went to see kept suggesting i tested for HIV because my symptoms mimic HIV i told them i had already tested negative and they would say then it's something else.
then i went to the website thebody.com and asked doctor Bob if i had gotten HIV and why my tests kept coming back negative, he suggested i went to see an internist, i went to see an internist at the Northwestern Memorial Hospital in Chicago, i told him what was going on and gave him my binder with all my medical records from the previous months and gave him all my negative HIV results papers, since i had already gotten done head scans,abdomen scans,many CBCs,heart ultrasounds, full panels of stds, he suggested i get a brain MRI(because i kept complaining of weird feelings in my head like it was shrinking and like it was burning and something in there was moving around) he ordered a bunch of test, liver function,kidney function, CBC, HIV 1/2/O and some others and the only thing that was abnormal was the inflammation test it showed that i had inflammation somewhere in the body, i told him it was in the brain i could feel it.

The brain MRI results came back and this was my first big break it showed brain demyelination, i kept telling my doctor that this happens with a viral invasion to the brain, and he said, but what virus, your blood counts are perfect and i can't find this virus, so i suggested he tested me for HTLV 1/2 and it was negative,he sent me to a neurologist she was booked like a month in advance, so in the mean time with no more doctor visits and started to read about XMRV, and at the same time kept testing for HIV at the RUSH university and kept coming back negative, finally i went to see the neurologist, and the very first possible diagnostic was MS, and then i remembered that the girl i was with had told me she was a CFS(later on was diagnosed as atypical MS) sufferer since 2004 and she's always very really tired and faints and has seizures sometimes by then i had read somewhere that XMRV was being linked to CFS, then i had no doubt i had gotten something infectious, the neurologist ordered a spine MRI to confirm MS but it came back as normal and she decided to sent me to another neurologist(i kept calling her and leaving her messages about XMRV and she never responded) i decided instead to go see one of the top infectious disease guys at the Northwestern Memorial Hospital and told her what was going on, she saw my symptoms and she said have you gotten tested for HIV i said yes it's negative, how about HTLV she asked i said yes negative, i told her about the new XMRV virus discovered and was now being linked to CFS and i told her the girl i was with had CFS for 6 years and she said i think you should go see the internist again and have him set you up with a counselor, i was then full with rage i mean who in their right mind would think that having brain demyelination is a mental thing.

My current symptoms are, progressive brain demyelination, major GI problems, i have developed food allergies i can't eat meat anymore makes me puke, extreme fatigue,multiple eruptive dermatofibromas,extreme lower back pain, major cognitive problems, confusion all the time,hands and feet numbness, daily headaches, pain in my spleen, swollen tongue with teethmarks around it, white thrush, pain in my liver and pancreas i have also developed an infection in my urinary tract, pain in my testicles, tingling in my eyes all the time, brain fog and brain inflammation and i feel as if i had a bunch of aunts running around in my brain,(note that i had never in my life seen or felt these before, i didn't even knew what brain demyelination was, i never thought something like that could possibly happen to a human being) and i tested again a month ago for HIV and HTLV, CMV,candida,herpes 6,(just to make sure that wasn't it) and was all negative.

i am really having a hard time understanding how some people think XMRV might not exist i mean isn't the evidence obvious, all they have to do is look at the history of CFS and see how they were these clusters, meaning there's a pathogen infecting people, look at the brain MRI for god sakes, they look like aids MRI but yet these people don't have aids, really the most logical reason for somebody to have a swollen tongue is because you have a virus in your blood that your spleen is trying to clean, white thrush means you have a compromised immune system and something is killing your good bacteria seriously it does not take a genius to figure these things out, it's amazing how some doctors, infectious disease guys,immunologist, virologist have studied for years and years and have spent thousands of dollars in education and yet they keep missing the most obvious things, i mean 30 years and billions of dollars have been spent in HIV research and these brilliant minds haven't figured out that there's something else out there that causes aids like illness and aids like brain MRIs, my five year old nephew could figure this one out really, and to think that some of these brilliant minds think that XMRV a retrovirus might not cause disease, really? when in history has a retrovirus not shown to cause disease when? i wanna know because it seems to be a big puzzle that some people can't figure out, a retrovirus isn't and will never be benign, anyways i just thought i would share this story with you guys because it's really fresh and i still remember every detail like it happened, most CFS and have been sick for years and don't remember what is like to be healthy but i do, 8 months ago i could go to the gym and run 5 miles nonstop, now i can't even get to my third floor condo with out feeling like my heart is gonna blow and nothing in my life is what it used to be this is just a horrible hell.

I really hope that people at the CDC would find it in their hearts to put all politics aside and admit that XMRV is a very dangerous pathogen not only because there are millions of people infected already but because millions more will get infected as well.

The blood supply has been contaminated with XMRV with no doubt and people will get sick from it for sure, when i thought i had gotten HIV i was at both HIV forums poz.com and thebody.com and many many people that had the "worried well" label kept testing negative for HIV for months some even have been in these forums for a couple of years, they reason they kept testing for HIV is because they thought they had gotten HIV exactly like my case specially because they had many many symptoms after having unprotected sex, it turns out that a lot of them were going the Red Cross to donate blood because they thought that Red Cross was screening for all transmissible diseases and it turns out that most of them had their donations approved and later on many many have already tested positive for XMRV and who knows how long this has been going on for.

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8. RRM on January 11, 2011 1:33 PM writes...

Good write up. An additional, revealing piece of information that is not in the report by Science:

In the first round of testing for the "project" (for the Blood Working Group), when two labs found XMRV, the blood was also collected by the scientists that had reported an asociation with XMRV.

For the second round of testing, an independent phlebotomist visited the patients to collect new blood samples, and then all three labs found no XMRV.

Permalink to Comment

9. courtney on January 11, 2011 1:39 PM writes...

ME/CFS since 2010, I feel like it could beneficial for you to consider checking out the HHV-6 foundation (www.hhv-6foundation.org) and consider emailing info@hhv-6foundation.org to get some feedback on your situation. They are incredibly knowledgeable on many of the viruses that result in MS-like lesions (one of them being HHV-6).

Permalink to Comment

10. carlos on January 11, 2011 5:56 PM writes...

RRM...where did you get that information? That is actually relevant, 2 possible lectures:
a)WPI brought contamination in the samples. (although that would not explain that one of the 3 labs was not able to find XMRV)
b)The "independent collector" is not so independent. (But then again they would call me stupid for thinking on conspiracy)
Things are definitly not clear.

Permalink to Comment

11. aidan walsh on January 11, 2011 7:07 PM writes...

i will be very very glad when they make up their minds if it is or it is not xmrv. i read an article recently in huffington post about a percentage of cfs patients testing positive to giardia and the same work was replicated by a huston team. i think it was dr. leo galland and he said an epidemic of cfs in california actually followed a giardia outbreak and if not detected in patients can persists from weeks to years. it is found by stool samples in specialty labs and is curable with flagyl and or other meds. a funny thing with this small intestine parasite is people cannot tolerate antacid medicines, it actually makes them worse. funny thing now is i get extremely ill when they give me calcium d3 and my stomache gets very bad.i believe they are a type of antacids. could be something to this theory. in the meantime i will stick to www.waterure.com www.watercure2.org until these genius scientists make up their minds why we are all slowly dieing....aidan walsh southampton, u.k. god bless all the cfids sufferers... get well soon...cure/peace in 2011....

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12. urbantravels on January 11, 2011 8:37 PM writes...

Where I see evidence of bad faith is not in the published science itself, but in the misrepresentation of the conclusiveness of any one piece of evidence by the researchers themselves, and the subsequent echoing and amplification of those misrepresentations by the press and the Internet.

Such, I believe, was the case with the press release issued by the Wellcome Trust, http://www.wellcome.ac.uk/News/Media-office/Press-releases/2011/WTX064078.htm, which went so staggeringly far beyond the hypothesis presented (and so far unverified by other workers) in the Hue paper (http://www.retrovirology.com/content/7/1/111). To paraphrase Mark Twain, reports of the death of the XMRV/CFS hypothesis have been greatly exaggerated. It would help if the scientists themselves were not so eager to help write the premature obituaries.

Early science is messy and contradictory as hell and can get ugly; scientists, and even some informed laypeople, understand this, and can even see rigorous debate as a good and healthy sign. When information about the messy goings-on get filtered to the outside world via the press, however, either the mess is made to seem like mistakes, confusion and lack of progress (which we ought not to be wasting money on), or the mess is de-emphasized in favor of tidy “conclusions� that are often supported by privileging the claims of one side in a debate that may have multiple sides. (And if conclusions have been reached, we shouldn’t be wasting money on further investigation.)

We have seen how eagerly and uncritically the Wellcome Trust press release was carbon-copied into dozens of press outlets, blogs, Tweets, and spread around the world unchallenged. Why is this a concern, in the particular area of ME/CFS research? Because reporting premature conclusions in this matter serves to reinforce an old and very damaging narrative about CFS: that the cause is impossible to find; that repeated efforts to find the cause have all been blind alleys; that ME/CFS is a ‘vague and ill-defined’ illness, with the implication that an organic cause can never be found – and then we’re back in the “hysteria� wastebasket, with the century-old ideas of Charcot and Freud to weigh us down.

Public opinion affects support for research in very real terms; so does the official stance of the public health agencies. We have already seen several decades in which the NIH officially considered ME/CFS to be a form of depression or conversion disorder - based upon no particular hard evidence - and instructed the press to treat it accordingly. So there were few to protest when ME/CFS research was underfunded, or when funds intended for biological research were diverted elsewhere, or when grant applications for what little money was available were routinely turned down by ‘expert’ panels with no expertise in the disease. The NIH is showing encouraging signs of changing course in recent years, but we have yet to see the result in terms of hard dollars: is there any other disease as serious and disabling as ME/CFS that recieves so little NIH funding?

http://report.nih.gov/rcdc/categories/#bpopup

The recent article that appeared in Science magazine, though reasonably fair overall, ended on a rather sour note, which seems to me a pretty clear indication of how negative perceptions inside and outside the research community can start to lead to a chilling effect on research:

http://www.sciencemag.org/content/331/6013/17.full

“As the new [NIAID/Lipkin XMRV] study gets started, some wonder whether it’s worth the $1.3 million it will cost. Jonathan Stoye of the MRC National Institute for Medical Research in London concedes that the Towers study was “over-hyped.� But he says “it’s pointing people in a certain direction,� away from chasing an elusive link to XMRV. Still, he says, a larger study may be the only way to satisfy [CFS] patients.�

The journalist’s favorite gang of straw men, we all know, is “some.� Who are these “some� people who are already suggesting that $1.3 million is too handsome a sum to spend to get good answers on XMRV, in the face of these supposedly damning recent publications on contamination? Stoye seems to be saying that the only reason to proceed with the study, in his opinion, is to shut up the patients. This implication does a disservice to the NIAID’s motives in ordering and funding the study. If XMRV truly does cause or contribute to human disease, then it’s not just the problem of a group of querulous patients who wants answers – it’s everybody’s problem, and NIH doing due diligence to look for those answers is the proper way to serve the public interest. To suggest otherwise does, indeed, smack to me of bad faith.

Permalink to Comment

13. Warbler512 on January 12, 2011 2:07 AM writes...

OK - Dr. Raciniello proclaimed XMRV done himself, then re-read the four papers, seemed to agree some were overreaching, got the Tribune to retract his worldwide statement, now links his readers to this. Perhaps with a good heart, and Dr. Lowe is welcome to differ, or not. I'm not concerned about Rancaniello's e-mail box melting. I do wonder if a dean at Columbia called him in for a chat about his tenure.

Much as Walter Gunn, the only ally ME/CFS had at CDC in the '80s, was nudged into retirement. Much as John Kerr mysteriously withdrew from one of the negative U.K. XMRV studies, under "academic pressure" as has been put. Kerr's colleague in that study, John Stoye, now NIH spokesman for XMRV (like there's no suitable American) won't disclose why that study never mentioned the samples they received from the U.S., or tell Americans whether their blood was even tested.

Many of us are zoo-fulls of the same pathogens HIV patients get; our blood should have been banned long ago, retrovirus or not. Nonetheless, overlooking Lipkin's shoulder is the same Dr. Fauci who threw and kept ME/CFS under a bus for 25+ years. Patent #WO9205760, the DeFritas retrovirus particles, somehow escaped his attention. NIH didn't just start rejecting grant proposals from WPI either; they've done so since Oct 09, possibly before, as adamantly as in the '80s but for a select few who stayed on-message. CDC, meanwhile, trustworthy Bllod Working Group team-player that they are, keeps producing "results" out of their Atlanta CFS team regarding stress, child abuse, whatever. And we just had to be reminded by some Belgian geniuses in Psychotherapy and Psychosomatics that we "don't live in a vacuum." (We're so stress-maladapted that ARVs wouldn't cure us in any event - just can't read between the lines there.)

From the outside, we may look overly biased, angry, simply unwilling to face "results" that don't suit us. If so, we're not that different from many of our accusers. We're all too aware that scientists don't live in a vacuum either. I don't know what XMRV will turn out to be (is that '06 German respiratory study invalid too?), but I wish a lot more of what I'm watching WAS a conspiracy theory.

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14. Justin Reilly on January 12, 2011 3:00 AM writes...

I am not a scientist, but I have read up on the studies. They don't prove that ME is not caused by XMRV as the press release said. And they don't "strongly suggest" contamination. Some very anecdotal reports of unpublished results and remarks by Rein (?) at NCI and Coffin give me a little bit of pause, particularly Coffin's report of finding XMRV in cereal boxes (you heard me!), but I think that the published data, taken as a whole (particularly the DNA integration site in prostate cancer and the antibody response) strongly suggest that XMRV is strongly associated with ME. It is possible that XMRV isn't a major cause of ME. Dr. Rein thinks it doesn't cause prostate cancer because to be consistent with known viral oncogenesis it would have to be present in every cancer cell and he could find it only in a small percentage or not at all- i forget which.

Anyway, Dr. Alter's statement makes great points and should be read by everyone (along with WPI's and Racianello's blogs and podcasts) before deciding what they think. I think the circumstantial evidence is very strong that this disease is caused by one or more retroviruses, whether XMRV itself is a major cause has yet to be determined.

You say "So, to people outside of research: you're not seeing evidence of bad faith, conspiracy, or stupidity here. You're seeing exactly how science gets done. It isn't pretty, but it gets results in the end." Well, with due respect, patients and ME researchers and clinicians are the experts on whether there is bad faith, conspiracy or stupidity, not you. And let me tell you: there is. What about the statement in the press release that "XMRV does not cause ME" strikes you as not being in bad faith? Such distortion of the science and lying is par for the course in CDC, NIH and the UK govt's quarter century war on ME science and patients.

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15. Jan on January 12, 2011 3:06 AM writes...

Also please note that the CDC study was not done on patients diagnosed with CFS by their physicians. The CDC's participants were decided to have CFS by the Empirical criteria, which judging by the CDC's own research, is not a useful criteria because they have to make comments like "matching was not maintained" between cases and controls (and since research consistently shows a long-term recovery rate of less than 10%, this is not a problem they should be having).

Jason has shown that with the introduction of the Empirical criteria, the incidence of "CFS" has increased tenfold to coincidentally approximate the incidence of mood disorders, and that, for instance, 38% of those with major depressive disorder, can be classified as having CFS by using the Empirical criteria.

Jason LA, Najar N, Porter N, Reh C. "Evaluating the Centers for Disease Control's Empirical Chronic Fatigue Syndrome Case Definition". J Disability Policy Studies. September 2009 vol. 20 no. 2 93-100. full text available at www.cfids-cab.org/MESA/Jason-10.pdf

The CFS inclusion criteria problem is not limited to the Empirical inclusion.

Merz S. [Chronic fatigue syndrome. More and more differential diagnoses suggest a new view of this syndrome]. Lakartidningen. 2002 Aug 22;99(34):3282-7. PMID: 12362846
"Several CFS definitions have been developed over the years, and it is common for investigators to erroneously compare studies based on different definitions, which nevertheless all use the term CFS. Much of our 'understanding' of CFS does not apply to the small group of patients who fulfill the current (1994) CDC definition."

Jason LA, Helgerson J, Torres-Harding SR, et al. “Variability in diagnostic criteria for chronic fatigue syndrome may result in substantial differences in patterns of symptoms and disability.� Eval Health Prof. 2003 Mar;26(1):3-22. PMID: 12629919
"Chronic fatigue syndrome (CFS) is an illness that involves severe, prolonged exhaustion as well as neurologic, immunologic, and endocrine system pathology... The current investigation examined differences between CFS as defined by Fukuda and colleagues and a set of criteria that has been stipulated for myalgic encephalomyelitis (ME). Dependent measures included psychiatric comorbidity, symptom frequency, symptom severity, and functional impairment. The ME and Fukuda et al. (1994) CFS criteria were compared with a group having chronic fatigue due to psychiatric reasons. Significant differences occurred primarily with neurologic, neuropsychiatric, fatigue/weakness, and rheumatological symptoms. These findings suggest that it might be inappropriate to synthesize results from studies of this illness that use different definitions to select study populations."

Although researchers have suggested this is inappropriate, it is standard to compare results from various inclusions when discussing consistency of results (such as XMRV) and even treatments. Although these differences of inclusion are not apparent to most journalists (and even most medical doctors), the problems caused should be easy enough to understand once they have been brought to people's attention.

The Lombardi paper used Canadian criteria for ME/CFS requiring neurological and immunological signs and symptoms, as well as Fukuda (patients meeting Canadian also meet Fukuda).

The CDC paper on XMRV (Switzer et al.) used Empirical criteria and criticized neurological and immunological signs and symptoms, including a diagnostic-supportive symptom of Fukuda and other noted symptoms of Fukuda (the CDC's official definition), saying they might indicate some disease other than CFS.

The patients the term CFS was coined for had neurological and immunological signs and symptoms:
Buchwald D, Cheney PR, Peterson DL, et al. "A chronic illness characterized by fatigue,
neurologic and immunologic disorders, and active human herpesvirus type 6 infection." Ann Intern Med. 1992 Jan 15;116(2):103-13. PMID: 1309285 http://www.ncbi.nlm.nih.gov/pubmed/1309285

The problem with interpreting and reporting on CFS research is that this whole field is unfortunately highly politicised, to the great detriment of the patients.

See also:
http://myalgic-encephalomyelitis.com/definitions_criteria_protocols.html (links to multiple definitions including the ones discussed; Empirical is listed as "CDC revised," a confusing label since that designation is often used in the literature for Fukuda, which was revised from Holmes, the first CDC definition)

Jason et al. “Politics, Science, and the Emergence of a New Disease: The Case of CFS� Am Psychol. 1997 Sep;52(9):973-83. PMID: 9301342 : http://www.cfs-news.org/jason.htm

Editorial. “Frustrating survey of chronic fatigue syndrome.� Lancet 1996; 348:971. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2805%2964917-3/fulltext

Schweitzer M. "Problems continue with U.S. government agencies." 2000. http://www.cfids-me.org/marys/nihprobs.html

Hooper M. "Myalgic encephalomyelitis: a review with emphasis on key findings in biomedical research." J Clin Pathol. 2007 May; 60(5): 466-471. PMC1994528 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994528/

Carruthers et al. "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols" J CFS, Vol. 11(1) 2003, pp. 7-115 (pp 46-49). http://cfids-cab.org/MESA/ccpc-1.html

For well-replicated biological pathologies, see:

Fletcher MA, Zeng XR, Maher K, et al. "Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26." PLoS One. 2010 May 25;5(5):e10817. PMID: 20520837

Jammes Y, Steinberg JG, et al. "Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses," J Intern Med. 2009 Aug;266(2):196-206. PMID: 19457057

Cook DB, Lange G, DeLuca J, Natelson BH. "Relationship of brain MRI abnormalities and physical functional status in chronic fatigue syndrome." Int J Neurosci. 2001 Mar;107(1-2):1-6. PMID: 11328679

Also see:

Light AR, et al, "Moderate Exercise Increases Expression for Sensory, Adrenergic, and Immune Genes in Chronic Fatigue Syndrome Patients But Not in Normal Subjects," J Pain, 2009 Oct;10(10):1099-112. Epub 2009 Jul 31. PMID: 19647494

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16. Jan on January 12, 2011 3:22 AM writes...

evidently I missed something; that the CDC was using the wrong patients cannot account for the varied finding with the 4 patients in the Blood Work Group, but n=4 is not a sufficient amount of data to draw any conclusions with. One of those patients, for example, had begun taking medication which could reduce the amount of virus in the blood. Some researcher also hypothesize that the viral load in the blood may fluctuate with time. As you said, there are a lot of variables. These variables may or may not be related to the presence or absence of XMRV in these 4 patients.

And as I noted, there's also a huge amount of politicization, which is vastly detrimental to the funding and progress of ME/CFS research and to the attitude towards and treatments available for these patients.

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17. RRM on January 12, 2011 7:02 AM writes...

I have to say that quote of Dr. Alter does seem really strange. For instance:

"when a group finds a new agent, they become biased that this agent is real. When another group doesn't find an agent, they become, I think, even more biased that the agent is not real"

Are there many real-life examples where whole groups of scientists were biased agianst a new finding that turned out to be correct? I know there are uncountable examples of scientists that were biased in favor of findings that turned out to be incorrect. Ironically, there seems to be a clear bias in Alter's observation, as the few "successes" (e.g. Helicobacter pylori) are always better remembered than all those "failures" (e.g. Alter and Lo once also "detected" mycoplasmas in patients with AIDS, a finding that has even been "confirmed" by Nobel laureate Luc Montagnier).

"At this point I concur that we have no evidence for causality. That's going to be very difficult to come by, especially when we are detecting at the limits of detectability and when assay performance is very critical to get equal results."

This is really, really strange. His/Lo's own study was not at all detecting MLV related sequences at the limits of detection. It used one of the least sensitive assays of all studies so far and they did PCR only. The Science authors also didn't initially report any problems to detect the virus.

"A point that I think was misrepresented today: In those labs who do find the agent, it is very reproducible."

It apparently is very reproducable in a non-blinded setting and it is at the limit of detection. I am sure I've read that before, and it usually is not a good sign.

"Judy has found the same patients to be positive by culture year after year."

This statement was made like 14 months after the initial study was published. Also, that is exactly what was investigated in Phase IIb of the Blood Working Group: That same Judy (Mikovits) was free to chose her favorite 4 of the patients that were positive "year after year", then they mixed them up with a healthy control, and after that she couldn't tell these self chosen XMRV infected patients from the healthy, pedigreed negative patient (that was also self chosen and thus one of the patients that was "always consistently negative" in a non-blinded setting).

Admittably too little samples were used to draw definite conclusions from these results, but sure they were unlucky.

"We have found a patient to come back after 15 years and still be positive"
How does that argue against contamination in the slightest? Mix this patient up with 10 healthy and pedigreed negative controls (make sure the blood collection, storage and processing is exactly