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Viral link to Chronic Fatigue Syndrome questioned
May 31, 2011 8:08 AM   Subscribe

Editors of the journal Science have asked the co-authors of a 2009 paper that linked chronic fatigue syndrome to a retrovirus called XMRV to voluntarily retract the paper. Science editor-in-chief Bruce Alberts and executive editor Monica Bradford cited concerns about the validity of the findings, saying other scientists hadn't been able to replicate them, among other reasons.

The 2009 paper (PDF)

MeFi post on the original paper.


Further background from the WSJ on the new research that led to Science's retraction request.
posted by Horace Rumpole (64 comments total) 6 users marked this as a favorite

 
This is unsurprising, but I'm quite disappointed that the positive XMRV results couldn't be verified.
posted by muddgirl at 8:29 AM on May 31, 2011


This seems odd. Aren't retractions usually for egregious errors in methods or fraud? The reagents may have been contaminated, but if it led to the discovery that this was widespread, it is still a valid experiment.
posted by Mental Wimp at 8:30 AM on May 31, 2011


Aren't retractions usually for egregious errors in methods or fraud?

A reagent contaminated with the virus of interest would be an egregious error.
posted by muddgirl at 8:32 AM on May 31, 2011


A reagent contaminated with the virus of interest would be an egregious error.

Yes, on the part of the producers of the reagents. But if this was a widespread problem, as the liniked article suggests, it wasn't an error on the researcher's part. With this additional knowledge, the article actually has scientific value and should stay in the literature. If they had misredcorded data, used the wrong reagents, had mislabeled the tissue samples, or something like that, then I could see retraction. As it stands, the initial paper has been adequately vetted by attempts at replication and that literature serves to adequately refute the misinterpretation.
posted by Mental Wimp at 8:40 AM on May 31, 2011


With this additional knowledge, the article actually has scientific value and should stay in the literature.

If the contamination was known or suspected before-hand (as it appears that it was - a previous study on the links between XMRV and prostate cancer had the same problems), then it was irresponsible for the study authors not to validate the materials before publication.
posted by muddgirl at 8:43 AM on May 31, 2011


The paper doesn't show what it purports to show, because the experiment was faulty. Retraction is the appropriate response to that. There may be another paper here for the researchers to write, about method and faulty reagents, but this is not it.
posted by OmieWise at 8:43 AM on May 31, 2011


This is not a failure of science, folks. This IS science. This is how it works.
posted by Legomancer at 8:46 AM on May 31, 2011 [30 favorites]


The paper doesn't show what it purports to show, because the experiment was faulty. Retraction is the appropriate response to that.

I'm not following that chain of reasoning. By that logic, all papers which are found to describe a faulty experiment should be retracted. That would mean retracting a very large percentage of the papers in the literature.

Legomancer's right: Unless there's fraud, the normal mechanisms should hold, and the finding simply be debunked by further research.
posted by lodurr at 8:54 AM on May 31, 2011


"This seems odd. Aren't retractions usually for egregious errors in methods or fraud? The reagents may have been contaminated, but if it led to the discovery that this was widespread, it is still a valid experiment."

This is a prematurely linked expression of concern (PDF), not a retraction. Essentially the editors were planning on saying that they have concerns they could not ignore about the validity of the paper and we're going to give the authors a way to agree as gracefully as possible.

The Wall Street Journal can go fuck itself
posted by Blasdelb at 8:58 AM on May 31, 2011 [4 favorites]


By that logic, all papers which are found to describe a faulty experiment should be retracted.

Retractions for irreproducible results are very very common. It's just not usually so heavily-reported.
posted by muddgirl at 8:58 AM on May 31, 2011


Retraction Watch is the resource I generally use for this sort of thing.
posted by muddgirl at 9:01 AM on May 31, 2011 [1 favorite]


Retractions for irreproducible results are very very common. It's just not usually so heavily-reported.

Is this true in lab sciences? I wasn't aware. If it were true in epidemiology, the literature would be much thinner (maybe a good thing).
posted by Mental Wimp at 9:02 AM on May 31, 2011 [1 favorite]


For non-scientists who are nonetheless interested in the process, can someone clarify a little why this is seems such an emotional topic? Chronic Fatigue Syndrome - which is the underlying disease this paper was attempting to link to a specific cause - is still at least somewhat controversial as a diagnosis, yes? I remember from the days when "Epstein-Barr" was the catchphrase that there are not insignificant voices in the medical sciences who didn't think it was... what? A "real" disease, or serious enough to be taken seriously, or...

Just some quick background info would be appreciated.
posted by OneMonkeysUncle at 9:03 AM on May 31, 2011


Yeah, uh, isn't that part of research? Are we going to go back and start revising all papers that weren't replicated? Part of good critical thinking skills would be to see there was this *one* paper that was never replicated.
posted by mandymanwasregistered at 9:04 AM on May 31, 2011


For example, the first paper discussed here seems like a very similar retraction
The authors "have recently discovered that the cell lines used in their paper were inadvertently misidentified. The cell lines utilized in the paper have now been found to contain the bcr/abl translocation and most likely represent the K562 CML cell line, instead of MMS1 and RPM1 myeloma cell lines. Due to this issue, the relevance of the findings to myeloma and thus, the conclusions of the paper, are not supported by the data."
Similarly, if the XMRV study used contaminated, then the conclusions of the paper are presumably not supported by the data.
posted by muddgirl at 9:05 AM on May 31, 2011 [1 favorite]


Is this true in lab sciences? I wasn't aware. If it were true in epidemiology, the literature would be much thinner (maybe a good thing).

Well, there's two types of irreproducibility, no? (1) A statistical anomoly causes a freak positive or negative result - this type of study is part of the scientific process and is usually not retracted. (2) would be a experimental error, which is the case here. I believe these papers should be retracted, but I suppose that's up for debate within the scientific community.
posted by muddgirl at 9:08 AM on May 31, 2011


I should say that it appears to be the case here.

The study authors could easily show that this isn't the case by re-comparing their data based not on participant population, but based on reagent batches or whatever material is compromised. If one batch always shows the virus and another batch doesn't, then this would pretty clearly indicate an experimental error.
posted by muddgirl at 9:09 AM on May 31, 2011


I'm not following that chain of reasoning. By that logic, all papers which are found to describe a faulty experiment should be retracted. That would mean retracting a very large percentage of the papers in the literature.

There's a difference between a paper written to describe and elaborate a failed (or faulty) experiment, and one that is written treating the faulty experiment as if it were not faulty. Papers of the former sort serve to elucidate the mechanisms of experimental science, papers of the latter sort serve to mislead (not necessarily purposely). It seems self-evident to me that the two are very different sorts of things.
posted by OmieWise at 9:11 AM on May 31, 2011 [2 favorites]


I couldn't find an official policy for retraction of articles on the Science website, but I found a general article about journal retraction policies here (I think that's open access). Nature, another big scientific journal, does state here that they request retractions for 'invalid results', which would seem to encompass not only deliberate frauds, but any type of incorrect experiment. Sorry if this is a derail
posted by aiglet at 9:29 AM on May 31, 2011


XMRV seemed like such an uncontroversial little bug when it was first discovered. Now, it's become "political". This makes no sense, unless it has to do with the fact that some leading researchers believe that XMRV can be sexually transmitted, combined the the off-kilter discussion that usually surrounds CFS. Now there's a touch of weirdness that accompanies all XMRV news.
posted by Faze at 9:47 AM on May 31, 2011


Non-reproducible epi papers are generally believed to not work because of statistical flukes and validity problems which we all know about and accept as a risk of doing business. They also tend to not make bold causal inference claims the way lab-science is designed to do. As long as you've accurately described your data, there's not much reason to retract. On the other hand if you used the completely wrong biomarker, yeah, that's a retraction.
posted by a robot made out of meat at 9:54 AM on May 31, 2011


Part of good critical thinking skills would be to see there was this *one* paper that was never replicated.

Or random people who don't have much understanding of the way things like this work will reference the one, flawed study up FOREVER. It will be used as justification for random theories, cause people to seek inappropriate medical care or refuse appropriate medical care, foment conspiracy theories, lend legitimacy to quacks peddling alternative treatments...
posted by the young rope-rider at 9:56 AM on May 31, 2011 [3 favorites]


Retraction Watch is the resource I generally use for this sort of thing.

Hmmm. Most seem to be for fraud. Didn't see any for non-replication, but I got bored pretty quickly, so maybe I didn't look at enough.
posted by Mental Wimp at 10:19 AM on May 31, 2011


Or random people who don't have much understanding of the way things like this work will reference the one, flawed study up FOREVER.

Indeed. Who cares what the official retraction policy is -- naive searchers are going to find this paper and go on wild goose chases for years. Flagging non-reproducible and erroneous papers should be done much more aggressively.
posted by benzenedream at 10:25 AM on May 31, 2011


Didn't see any for non-replication

I'm not sure why you're ignoring the fact that this is a very particular type of non-replication, much more akin to fraud than to normal experimental results.
posted by OmieWise at 10:26 AM on May 31, 2011


What OmieWise said. Furthermore, I have already provided a link to a less-famous paper which was voluntarily retracted under similar circumstances.
posted by muddgirl at 10:45 AM on May 31, 2011


Hi! I'm your local bedridden ME/CFS patient. Ill since May 29, 2004 (yes, I just had my seventh sickiversary!), bedridden since December 2007.

I don't have the energy to delineate the whole mess here - I'm still reeling from the Chase Community Giving debacle (that's a self-link to the first of four entries on it) and I just had a bath, so my arms are already failing as I type this, but here's a little bit of inside baseball for those of you who are interested.

If you want to see my illness community's reaction to this, and get a lot more information that would be helpful to your understanding, visit the facebook page XMRV Global Action, and don't miss the comments. We have a lot of very sharp sick people who read a great deal of studies among our group.

Here is a list of all the XMRV studies that have been published. An x in the first column denotes a positive finding. No other study besides Mikovits et al has received a request for retraction.

I am a patient of rockstar doctor Paul Cheney, who has been working on ME/CFS since an epidemic (yes, it has epidemics) emerged around him and his practice partner Daniel Peterson in Incline Village, Nevada in the mid-80s. (Actual quote from Dr. Cheney, "Well, after I finished my PhD in physics, I decided to go to med school to specialize in immunology. I had come to the conclusion that the most interesting parts of physics were in the past, and those of immunology still to come.")

Dr. Cheney tells me that of the thousands of ME/CFS patients he's seen in 25 years, I am among the half-dozen most severely affected. I'm just lucky, I guess.

Part of the difficulty of detecting XMRV is that it has very low copy numbers in peripheral blood, unlike HIV, which basically teems there. Instead, XMRV is hanging out in reservoirs, like macrophages, or the prostate. There was a macques monkey study last year where they infected the monkeys with XMRV and detected only transient viremia in two out of three animals. This thing is a sneaky bugger.

90% of Cheney's patients tested have come back positive for XMRV. But, Dr. Cheney has found, the very sickest patients - like me - come back negative for XMRV. He is certain my negative result is a false negative, and he believes you can triangulate around the difficulty of detecting XMRV with other tests.

Those two tests are IL-8 and nagalase.

IL-8:

Judy Mikovits did a poster presentation on this last August. They studied:
1. Healthy controls who were XMRV negative
2. Healthy controls who were XMRV positive
3. ME/CFS patients with mild cases
4. ME/CFS patients with severe cases.

They found:
1. Normal IL-8 and IL-12
2. & 3. Normal IL-8 and elevated IL-12 ("Winning" against XMRV)
4. Elevated IL-8 and normal or elevated IL-12 ("Losing" against XMRV)

I have elevated IL-8. Mine's 95.3, where normal is less than 14. My IL-12 is normal.

Nagalase is elevated in HIV infection. Dr. Cheney is the first person to be testing for nagalase in ME/CFS patients. He's been doing it since the turn of the year, I think. A normal result for nagalase is a value of zero to 1.0. Thus far in the practice, the results have ranged from 1.1 to 6.5 - higher, in many cases, than what's seen in HIV.

Mine came back just last week, and is 2.3.

As far as what's to come, most patients are awaiting the results of the the Lipkin study, which is supposed to wrap up around the end of the year. What's been going on has not truly been replication - there's been a lack of following the original protocol. I mean, hell, even I did an XMRV study. I used baking soda and vinegar to make a volcano, and I didn't find any evidence of XMRV. So there's that.

I have a ton more information about this, some of it far more convincing than what I've shared here, but much of that knowledge has come from Dr. Cheney's postings to his patients via our Yahoo group. Those posts are, unfortunately, confidential.
posted by jocelmeow at 11:08 AM on May 31, 2011 [7 favorites]


Whoops, just picked up the sheet of results again. My nagalase is actually 2.8.
posted by jocelmeow at 11:14 AM on May 31, 2011


I'm sorry to hear about your struggles with ME/CFS. I'm really not sure if the disease is related to XMRV or not, although I understand that many afflicted people are convinced that it is. Your post here is a strange mix of anecdote and appeals to science. I understand that in the case of emerging science, anecdote sometimes precedes good studies, so I'm sensitive to that, but statements like:
I have a ton more information about this, some of it far more convincing than what I've shared here, but much of that knowledge has come from Dr. Cheney's postings to his patients via our Yahoo group. Those posts are, unfortunately, confidential
make me very very skeptical. You obviously have far more of a vested interest in this than a neutral observer, and relying on and appealing to secret evidence makes your case seem weaker instead of stronger.

In any case, I wish you the best.
posted by OmieWise at 11:20 AM on May 31, 2011 [9 favorites]


FWIW, my father was diagnosed with CFS in the mid-90s.

No other study besides Mikovits et al has received a request for retraction.

Looking just at the CFS studies (I don't follow prostate cancer research vs. XMRV at all) - and admitting that I may be misreading the chart entirely - besides two papers by Lombardi and Mikovits in Science and PNAS, the majority of positive studies were presented at an XMRV conference, or were published in journals which republish conference reports (like "Reviews in Antiviral Therapy"). Conference abstracts generally would not be retracted (AFAIK), because they're not papers and don't really hold the same weight.
posted by muddgirl at 11:28 AM on May 31, 2011 [2 favorites]


Here's WPI's response, if you care to read it.
posted by jocelmeow at 11:32 AM on May 31, 2011 [1 favorite]


Can someone who is familiar with this type of research comment on this?:
Most of the negative studies failed to find any evidence of XMRV in any sample type. This would suggest that the methods and materials used in the non-replication studies are insufficient to use when attempting to detect human gammaretrovirus in the blood of human samples. The methods, processes, and materials of Lombardi et al. need to be followed precisely. The Alter and Lo study is the only study which has attempted a partial replication of the methods and materials of the Lombardi study, which confirmed evidence of MLV related viruses. Studies using multiple different methods are not replication studies, and studies optimized to detect murine gammaretroviruses and not human gammaretroviruses must be seriously
questioned. See, Virulence attachment.
If the main criticism of the study is that the methodology itself is severely flawed, why would studies be done that replicate the exact methodology? Wouldn't more robust findings result from studies with diverse methodologies that all reach the same conclusion? Wouldn't a need to replicate a study with the exact materials in order to get the same results point even more conclusively to a flawed methodology?
posted by the young rope-rider at 11:44 AM on May 31, 2011


Here is the paper upon which Science based their expression of concern:

No Evidence of Murine-Like Gammaretroviruses in CFS Patients Previously Identified as XMRV-Infected
posted by muddgirl at 11:45 AM on May 31, 2011


Well, I don't know anything about these types of studies, but their response essentially argues that other means of detection are not adequate, and that part of the importance of their study is that they were able to detect what others could not. In that case their position is that other studies have not replicated their results because they may have been unable to detect the virus even when it was present, where their method obviously can detect the virus. It's a bit of a Catch-22: our methods must be good because they detected the virus, your's must be bad because they did not. I guess the scientific question becomes whether or not it seems credible that detecting the virus is only viably done in this one way.
posted by OmieWise at 11:51 AM on May 31, 2011


From the WPI response, I don't understand this objection:
and studies optimized to detect murine gammaretroviruses and not human gammaretroviruses must be seriously questioned.
Doesn't the "M" in "XMRV" and "X-MLV" stand for murine?
posted by muddgirl at 11:52 AM on May 31, 2011


why this is seems such an emotional topic?

It's true; until recently it was considered perfectly acceptable to call CFS "the yuppie flu". What causes this kind of emotional reaction? My guess would be a tendency to suspect that sick people are responsible for their illnesses or enjoy the attention -- an attitude that is at least expressed less openly if the condition is known to be caused by something concrete like a virus.
posted by Ralston McTodd at 11:52 AM on May 31, 2011 [2 favorites]


OmieWise: Let me speak a little to that. I can do so on jocelmeow's behalf, and she can't really continue to do by herself at this point. (I know this because I'm her spouse and am sitting a few feet away from her.) Just typing that message really leaves her done for the day, I'm afraid.

By no means is she (or are many people in similar situations, if not all) denying the importance of good science here, or denying that science will be the final court of appeals for what causes the disease, etc. And she and others are well aware that a mix of some science and anecdote does not amount to a scientific case. She writes this way in large part because she's not a scientist, she emphasizes. Having followed this closely, Mikovits et al probably do have a point about the difficulty of detecting this retrovirus and the adequacy of some of the negative studies so far, but that's a point that will have to start yielding results at some point, of course. When she mentions what you refer to as "secret evidence," I don't think she intends that to compel you. That material is still proprietary and forthcoming ("inside baseball" as she says), and when it does, it should be vetted like any other data.

Finally, I think it goes without saying that a lot of people most severely affected by the illness hold out hope for this hypothesis because it would suggest a way forward. There's a well-founded fear that its demise would lead to not just support for XMRV-related research, but a further roll-up of any kind of research into the disease. Not scientific reasons there, obviously, but reasons to keep digging all the same. On a personal note, she (and I) appreciate your measure of compassion.
posted by el_lupino at 11:54 AM on May 31, 2011 [3 favorites]


It's a bit of a Catch-22: our methods must be good because they detected the virus, your's must be bad because they did not.

However, reading more it seems like the other researchers' methods CAN detect the virus...in a commercial laboratory reagent. So the whole "you can't detect the virus" thing doesn't seem to make a whole lot of sense.
posted by the young rope-rider at 11:56 AM on May 31, 2011


Sorry, "not just an *end* to support for XMRV-related research..." Duh.
posted by el_lupino at 11:56 AM on May 31, 2011


I think ultimately, this is the reason why Science decided to ask for a retraction:
Bioreagent contamination, however, does not adequately explain the detection of XMRV by Lombardi et. al. (5). We have found that the DNA sequences of 3 XMRV proviruses they described are identical to that of VP62, which is the prototype XMRV cloned from prostate cancer tissue (4). Long-term passage of VP62 led to proviruses with accumulated multiple point mutations (fig. S3). As suggested by others (30), independently derived XMRV DNA sequences should show increased genetic diversity compared to the VP62 clone sequence. Therefore, the remarkable conservation of the WPI-XRMV sequences is most consistent with laboratory contamination with the original infectious VP62.
but their response essentially argues that other means of detection are not adequate

I am giving WPI the benefit of the doubt - that they did not get a chance to review the recent Science paper before writing their response - because it seems to me that the new paper intentionally tries to match the means of detection used in the Lombardi et al. paper. I'm not a biologist, much less an virologist, so there may be some subtleties that I'm missing.

I absolutely agree that there's a legitimate concern about backlash against physical causes for CFS (since we went so many years with doctors denying the possibility that CFS has a physical cause). But on the other hand, it's undeniable that some agencies will prey on the vulnerabilities of those who are affected by mysterious ailments - the way Andrew Wakefield preyed on children with autism.
posted by muddgirl at 12:03 PM on May 31, 2011


it appears that all reagents/cell lines were screened for contamination initially, but I wonder if negative controls were process side by side with the samples. In a PCR-intensive lab, one could actively contaminate reagents that were initially clean.
posted by haldane at 12:07 PM on May 31, 2011


By no means is she (or are many people in similar situations, if not all) denying the importance of good science here, or denying that science will be the final court of appeals for what causes the disease, etc.

Er, is that why she just tweeted a few hours ago, according to her blog's sidebar, "I cannot *wait* until XMRV is proven beyond a shadow of a doubt and Science's face is thoroughly covered with egg."? Because that is kinda not unbiased.

I mean, I really want a cure for CFS too, but one that has dispassionate, reproducible, and irrefutable science behind it. If XMRV is the culprit, that's fine, if it's some other virus or something else, that's fine too, as long as we get to the truth. (Although I do realize how stupidly blithe it is for a mobile, non-affected person like me to say that without being wrapped up in the daily slog of living with a miserable disease like CFS.)
posted by Asparagirl at 12:16 PM on May 31, 2011 [1 favorite]


I'm less concerned about "the truth" and more concerned about the possibility of needlessly suffering from the often-dangerous side effects of anti-retroviral drugs.
posted by muddgirl at 12:18 PM on May 31, 2011 [1 favorite]


Granted, Asparagirl, but I think that's a projection of a hope, not an attempt to make a scientific case to anyone.
posted by el_lupino at 12:23 PM on May 31, 2011 [1 favorite]


Finally, I think it goes without saying that a lot of people most severely affected by the illness hold out hope for this hypothesis because it would suggest a way forward. There's a well-founded fear that its demise would lead to not just support for XMRV-related research, but a further roll-up of any kind of research into the disease. Not scientific reasons there, obviously, but reasons to keep digging all the same.

I do understand that, and I can only imagine the frustration of living with a debilitating and recalcitrant disease that also leaves you stigmatized by doctors and people who are convinced you’re “faking.” The confirmation of a link with XMRV would be great, if only to provide fruitful new directions and confirmation that it’s not “all in their heads.” For those reasons, of course, I’d love to see some resolution. But, at the same time, we know that diseases that do not have easily identifiable discreet causes serve as magnets for speculative causation that can have substantial unintended consequences. The criminal linking of autism with vaccinations is a case in point, and just last week we had news of the resurgence of measles as a result.

More directly, the danger of mixing anecdote with a bit of science is that when one is strongly hoping for a particular outcome, one will tend to selectively pay attention to the evidence. This is very well proven, and there is a strong feedback loop in communities that believe something to be true and then go looking for the science to support it. I certainly did not mean to suggest that there was something nefarious about jocelmeow's appeal to evidence she could not reveal. I just think that that type of evidence, in all respects, is unconvincing. If it isn’t public and has not been vetted, no one, including jocelmeow, has any real way to determine how valid it is. The appeal to it in a comment meant to convince about the link between XMRV undermines the argument because it highlights the aspirational nature of these arguments for CF sufferers. Given the overall stakes here, more, rather than less, scientific rigor is probably called for.

But, as I said in my response above, I’m not sure what the relationship between XMRV and CF is, and I have nothing but the greatest hope that the causes of CFS can be elucidated before long. From the luxury of my position, relatively unaffected by the disease, this seems like good science being continued, but I understand why it might seem significantly more terrifying than that to someone more directly affected.
posted by OmieWise at 12:23 PM on May 31, 2011 [3 favorites]


I'm having flashbacks to reading the heartbreaking section on ultimately unfruitful (and similarly unreproducible) retrovirus research in Osler's Web. I hope this doesn't end up being a retread of that.
posted by Lentrohamsanin at 12:29 PM on May 31, 2011 [1 favorite]


From the WPI response, I don't understand this objection:

and studies optimized to detect murine gammaretroviruses and not human gammaretroviruses must be seriously questioned.

Doesn't the "M" in "XMRV" and "X-MLV" stand for murine?


Yes, I questioned that, too. There were a number of other puzzling wordings contained in their response. Though I have worked in infectious diseases and molecular epidemiology, I am not of this particular field. However, the more I skim on this topic, the more I agree that this seems to be a result of faulty materials. The paper you (muddgirl) link finds that the commercial reagents are contaminated, a fact that cannot be laid at the feet of the investigators. I'm not entirely convinced that retraction is in order here (as that implies in many people's minds a stigma of wrong-doing, a la Andrew Wakefield), but certainly some sort of extended corrigendum of the original study. Given the original authors' defensiveness, I'm not sure that's going to happen.
posted by Mental Wimp at 1:22 PM on May 31, 2011


Mental Wimp - the same paper notes that there was likely contamination from within the lab - I believe that evidence for this is taken from the other paper that Science editors cited in their note: Recombinant Origin of the Retrovirus XMRV.
We conclude that XMRV was generated as a result of a unique recombination event between two endogenous MLVs that took place around 1993–1996 in a nude mouse carrying the CWR22 PC xenograft. Since the probability that the same recombination event could occur independently by random chance is essentially negligible, any XMRV isolates with the same or nearly the same sequences identified elsewhere originated from this event (23).
In other words, if these were legitimate XMRV infections in human hosts, the viral DNA should show significant mutations, both between hosts and compared to the laboratory cloned sample. There is little evidence of mutations in the WPI and VIPDX samples, therefore we can conclude that they all came from the same source.

If you do not believe that reagent contamination is cause for concern and retraction (which I do), then surely you must admit that in-lab contamination of test articles is a serious enough allegation.
posted by muddgirl at 1:34 PM on May 31, 2011 [2 favorites]


OneMonkeysUncle: "Can someone clarify a little why this is seems such an emotional topic?"

My experience is that quite a lot of CFS patients appear to be uncomfortable with any research that indicates a neuropsychiatric etiology for a large portion of their symptomology, or that many of the symptoms often respond well to standard multidimensional treatments for chronic depression and personality disorders. A lot of people would be more comfortable with a simple, single-agent biological cause (years ago it was Cox B or EBV) that could be targetted by equally simple, straightforward "magic bullet" chemicals/endocrines or treatments and that would avoid the "mental health" stigma. A lot of this comes down to arguments about labelling and categories. CFS is not alone in this - we are now finding so much neurohumoral linkage between some kinds of heart disease and depression that labelling or treating each in isolation is problematic and possibly sub-optimal. Finally, the association between states of depression and the socially mediated "sick role" are also at play here.
posted by meehawl at 1:41 PM on May 31, 2011 [3 favorites]


These types of discussions are difficult because, as seen in this thread, there are people for whom it is very personal, and they have heartfelt and strongly held beliefs on the subject. And they believe strongly that those beliefs are based on solid science.

But there are people who can and do write the same detailed, heartfelt, rational comments as jocelmeow did here with regard to, say, Multiple Sclerosis being caused by a chronic bacterial infection for which the treatment is long-term or permanent antibiotic therapy. There are people who can write the same sort of comments with regard to wheat and virtually any auto-immune disorder. Lyme Disease. Vaccinations. And so on.

They generally have both anecdotal and (some) studies to back them up. Yes, even the vaccine crap. Even beyond Wakefield. But they don't understand how science works in the real world; that because of the way statistics work and because of the way positive results are more likely to be publicized than negative results you're going to find a correlation between almost any two things if you run enough studies. That's why we don't jump to conclusions on the basis of one or a few studies; we conclude things on the basis of long-term studies, repeated results, and meta-analysis.

People who suffer from a debilitating or progressive illness are not in a good position to filter out these things because they have an understandable investment in reaching answers. Believe me, I know. And that's exactly why (in my opinion) results should be pulled for serious errors of this sort and not just for flat-out fraud. This isn't a bad study because it is a statistical outlier; those are part of science. It's bad because it's just plain messed up, to put it in very scientific terms.
posted by Justinian at 1:49 PM on May 31, 2011 [1 favorite]


I think one of the reasons that CFS patients and their family are dissatisfied by studies which point to a psychiatric cause, is because they are used by critics to dismiss the real pain and suffering, all the while ignoring research which points to significant physiological effects. This page has a pretty decent summary. They also assume that CFS patients and their doctors haven't tried psychiatric techniques to alleviate CFS symptoms. My own father uses CBT and has been taking anti-depressants for over 15 years, with some small improvement. But he's not cured.

Personally, I don't believe in any sort of mind-body dichotomy - mental disorders ARE physical disorders, and vice-versa. I'm not surprised that CBT can moderately improve CFS symptoms, because I think CBT can probably moderately improve the experience of most physical disorders. I wouldn't be surprised if there was some neurological basis for the hyper-immune response of many CFS patients - does that make it "all in their heads," as many critics want to claim?
posted by muddgirl at 1:58 PM on May 31, 2011 [1 favorite]


mental disorders ARE physical disorders

I agree with the implications of this, that it is wrong and stupid to dismiss something because it is "only" a neuropsychiatric issue. But it is still important to figure out the basis for a disease or disorder. Because the treatments and such will be radically different if you have serious leg pain because of a conversion disorder (or whatever that would be called now) versus serious leg pain from a hairline fracture.

That's why resistance to the idea of a pyschological component can be problematic. Because it could delay or prevent the development of effective treatment.

Personally, my strong hunch is that what is called CFS is a collection of different disorders. Some are other diseases which have been misdiagnosed or not yet diagnosed properly. Some or probably as yet unidentified diseases we don't have names for. And some, yes, I think are likely purely psychological. All of which should be treated seriously. But all of which would require different treatments.
posted by Justinian at 2:09 PM on May 31, 2011


I knew a prominent scientist who even in the mid-90s believed that HIV didn't cause AIDS, had voluminous data to back it up, and argued that those who thought it did didn't understand how science worked, with the unspoken implication (common from hard scientists, especially then) that the opponents were wooly-minded, self-damaging, and vaguely feminine. I can imagine how painful and frustrating those attitudes must have been in the 80s when they were dominant. I mean this as a sociological, not scientific analogy: unlike HIV and AIDS, XMRV may have nothing to do with CFS and CFS may not even be a well-defined disease. But to the informed sufferers who have read the papers and understand the scientific method, the situation must feel similar, and the appeal of finding that single-source cause must be strong.
posted by chortly at 2:20 PM on May 31, 2011 [3 favorites]


then surely you must admit that in-lab contamination of test articles is a serious enough allegation.

Agreed, muddgirl, agreed.
posted by Mental Wimp at 2:24 PM on May 31, 2011


But it is still important to figure out the basis for a disease or disorder. Because the treatments and such will be radically different if you have serious leg pain because of a conversion disorder (or whatever that would be called now) versus serious leg pain from a hairline fracture.

Won't treatments be different if you have serious leg pain because of a hairline fracture vs. serious leg pain because of blood clots? I agree with your underlying point that "CFS" probably has several different causes, and will not have one single cure, but that doesn't answer my underlying point - that disorders with what is considered to have a "mental" cause are not taken as seriously as diseases that are considered to have a physical cause. Even though our brain is a physical organ and our "mind" exists within our brain.

The problem I have isn't with trying locating the source of a disorder such as blindness - my problem is when blindness caused by retinal injury is considered to be "real" while blindness caused by conversion disorders is considered to be "fake."
posted by muddgirl at 2:25 PM on May 31, 2011 [4 favorites]


Some links for anyone who wanders back by here:

Judy Mikovits's reply to Science, which I'd already linked above.

Annette Whittemore of WPI replies to the May 26 (Thurs before the long weekend) Science letter, (PDF download) from before the embargo was broken. Don't miss the tables at the end that detail the differences between Lombardi et al. and the other studies. The only thing that comes close to replication is Lo, Alter, et al. and that found the P variant of HGRV (human gammaretrovirus).

A fantastic quick history of the disease by Llewellyn King, who is proving to be a great new advocate for those of us with ME/CFS.

Chris Douglas's excellent letter to Science, titled "Why Did You Do It?" and his suggestion of a new way forward. Douglas is a patient advocate for a loved one with ME/CFS.

Caroline T. Anderson's absolutely hilarious blog post "If Wishes Were Retractions,", in which she notes five studies in particular for which she'd like to issue an editorial expression of concern.

The most recent blog entry from Jaimie Deckoff-Jones, who, on anti-retrovirals, has gone from housebound to having enough function to be able to work again. Her new job is as the clinical director of the WPI.
posted by jocelmeow at 7:30 AM on June 5, 2011 [1 favorite]


Oh, and a recent picture of me. Thanks to cachexia and muscle atrophy, I finally have thin legs!
posted by jocelmeow at 7:39 AM on June 5, 2011


Late to the post, but that Caroline T. Anderson post is almost a textbook case of the "true believer" patient advocate, inventing conspiracies to justify an emotional belief:
You expect us to believe that you can nail down the exact years and location where XMRV was created? Then you want us to believe that because CFS and prostate cancer were around before your date, that it can’t possibly be the cause of the illnesses. You also want us to believe that XMRV is not the kind of lab contaminant that would jump into the human population and cause disease. Yeah, OK. I can understand why you may be hesitant to be honest here — the stakes are very high. If the way science is conducted can result in new retroviruses invading the human population then every lab everywhere, from college campuses to drug companies, will have to change the way they do research. You’re right, it’s probably best to just to cover up the dangers. It’s just a couple million whiny women anyway….
I am writing this Editorial Expression of Concern and asking for the voluntary retraction of this study because it’s too much like a bad sci fi movie .
Otherwise I pretty much agree with everything muddgirl said. I hope for relief of CFS suffering, but bet the major causes will turn out to be way stranger than any of our current suspects. I say this as somebody who has a chronic disease of unknown provenance.
posted by benzenedream at 4:57 PM on June 5, 2011 [1 favorite]


Here's a new paper from Lombardi et al, from the International Conference on Human Retroviruses. The paper is titled Xenotropic Murine Leukemia Virus-related Virus-associated Chronic Fatigue Syndrome Reveals a Distinct Inflammatory Signature.

From the paper: The greatest statistical difference was seen in chemotactic factor IL-8, a major mediator of the inflammatory response, with a mean value of 1045±245 pg/mL in patients compared to a mean of only 13.1±1.6 pg/mL as seen for the healthy controls.

Note my IL-8 results in my comment above: 95.3, where normal is <14. Is it possible that all the people in this study that are thought to have XMRV all have something else in common that is causing their IL-8 to be elevated? Yes. But it is still possible that what they all have XMRV.
posted by jocelmeow at 6:17 AM on June 6, 2011


Y'know, benzenedream, I believe Caroline was simply attempting to be humorous there. She was taking the possible events and extrapolating them to a ridiculous degree in the service of being funny.
posted by jocelmeow at 6:22 AM on June 6, 2011


Another one from the current conference, appearing in Retrovirology: Detection of MLV-like gag sequences in blood samples from a New York state CFS cohort.

From the abstract: All gag sequences detected in this cohort were more similar to the MLV-like sequences reported by Lo et al. (2010) than to the XMRV sequences reported by Lombardi et al. (2009).

They also note: Samples were tested for mouse contamination with primers to IAP and/or mouse mitochondrial DNA.
posted by jocelmeow at 6:36 AM on June 6, 2011


Just realized I botched the link to Chris Douglas' letter to Science above. It can be found here.

A couple more interesting abstracts:

XMRV replicates preferentially in mucosal sites in vivo: Relevance to XMRV transmission? This is more from the team that's working with the retrovirus in macaques. Interestingly, one of the places they found it was in the "pulmonary enviroment," which a European group (I can't find the link at the moment) did as well - nasal secretions, if I remember right.

From the abstract: While XMRV seems rapidly cleared from the blood circulation in healthy macaques, XMRV protein positive CD4+ T cells were detected in all lymphoid organs throughout infection.

A prototype RT-PCR assay for detection of XMRV in multiple human sample types. Whatever it is this thing may prove to be, this assay appears to be able to detect it in several different spiked sample types.
posted by jocelmeow at 7:02 AM on June 6, 2011


Here are the rest of the abstracts that were online when I looked this morning.

Development of XMRV producing B Cell lines from lymphomas from patients with Chronic Fatigue Syndrome.

From the abstract: Therefore XMRV infection may accelerate the development of B cell malignancies by either indirect chronic stimulation of the immune system and/or by direct infection of the B-cell lineage . Since viral load in peripheral blood is low, these data suggest that B cells in tissues such as spleen and lymph nodes could be an in vivo reservoir for XMRV.

This is the Blood Research Working Group study.

From the abstract: The Blood XMRV Scientific Research Working Group was formed to facilitate collaborative studies into the impact of XMRV in blood donors. Studies will evaluate XMRV detection assays in terms of sensitivity, specificity and reproducibility; assess performance on specimens represented in existing blood donor repositories, and determine the prevalence of XMRV in donors.

Prevalence of XMRV in blood donors, HTLV and HIV cohorts

From the abstract: XMRV seroprevalence ranged from 0 - 0.6% in US blood donors, HIV-1 infected and HTLV uninfected subjects. Notably, 4.1% of Japanese HTLV-I infected individuals were p15E reactive. Inspection of sequence homology between HTLV and XMRV revealed a high level of conservation within the immunodominant region of HTLV gp21 suggesting increased seroreactivity is due to cross-reactive antibodies.

Immune correlates of XMRV infection

From the abstract: CFS patients often display antiviral enzyme RNase L dysfunction underscoring the importance of the innate immune response in CFS. We reported the XMRV detection in the peripheral blood of 67% of a cohort of CFS patients and 3.4% of controls. (I happen to have this RNase L dysfunction.)

The effects of XMRV gene expression on the mouse prostate

From the abstract: With these XMRV mouse models we seek to address the question that remains unanswered to date as to whether XMRV is capable of causing prostate dysplasia or cancer in vivo.

XMRV: usage of receptors and potential co-receptors

From the abstract: XMRV replication was observed in GHOST cells that express CD4, and each of the chemokine receptors ranging from CCR1- CCR8 and Bob suggesting that infectivity in hematopoietic cells could be mediated by use of these receptors. Infection of Lung epithelial cell A549 lacking XPR1 expression clearly indicates usage of other receptors by XMRV for entry into susceptible cells.

Cell line tropism and replication of XMRV

From the abstract: Viral replication could be identified in primary hematopoietic cells and a variety of epithelial cells in addition to the previously described prostate cancer derived cell lines investigated. Viral replication was considerably lower in primary monocytes, suggesting less efficient replication in these cells. These observations will help to further our understanding of XMRV pathogenesis and provide insights into the modes of transmission involved in XMRV infection.

Structure of the xenotropic murine leukaemia virus-related virus matrix protein

From the abstract: Although the protein sequence of the XMRV-MA is very similar to that of the murine leukaemia virus matrix protein (MLV-MA), it varies in several amino acid residues. We compared the structures of the XMRV-MA and MLV-MA and found that those changes are localized in a few domains, mostly on the surface of the protein.

And there's a Switzer et al. study that starts with "Serologic and PCR testing of persons with chronic fatigue syndrome in the United States shows no ass..." but I can't find an abstract.
posted by jocelmeow at 8:42 AM on June 6, 2011


jovelmeow - the problem with Caroline T's post is in the very first (presumably serious) paragraph:
What Alberts did smacked of science by declaration – even censorship, I thought.
I have yet to see a complete response from WPI to the papers published on Science Express last week (although I presume such a response is forthcoming), which present pretty convincing evidence that the Lombardi paper does not show a legitimate connection between XMRV and CFS or prostate cancer (note that the dissenting researchers were very clear in stating that they have not disproven all viral causes of CFS, so papers which indicate some viral cause without specifically identifying XMRF aren't helpful for this issue).

An expression of concern is NOT "science by declaration" - it is a common tool in a journal editors arsenal to, well, express concern about published results. The important scientific evidence is in the dissenting papers.

I don't even know what to say about Chris Douglas's letter:
Why, therefore, should a retrovirus, akin to HIV, that may be infecting millions worldwide be subject to a process that has controversy, debate and procrastination in-built
Yes, why SHOULD a potentially-dangerous medical treatment be subject to rigorous scientific testing? Why not just dose 'em all up and let God sort the out?
posted by muddgirl at 8:58 AM on June 6, 2011


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