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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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July 7, 2010

XMRV and Chronic Fatigue: You Thought You Were Confused Before

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Posted by Derek

Time to revisit the chronic fatigue/XMRV controversy, because it's become even crazier. To catch up, there was a 2009 report in Science that this little-known virus correlated strongly with patients showing the clinical syndrome. Criticism was immediate, with several technical comments and rebuttals coming out in the journal. Then researchers from the UK and Holland strongly challenged the original paper's data and said that they could not reproduce anything like it.

Recently I (and a lot of other people who write about science) received an e-mail claiming that a paper was about to come out from a group at the NIH that confirmed the first report. I let that one go by, since I thought I'd wait for, you know, the actual paper (for one thing, that would let me be sure that there really was one). Now Science reports that yes, there is such a manuscript. But. . .

Science has learned that a paper describing the new findings, already accepted by the Proceedings of the National Academy of Sciences (PNAS), has been put on hold because it directly contradicts another as-yet-unpublished study by a third government agency, the U.S. Centers for Disease Control and Prevention (CDC). That paper, a retrovirus scientist says, has been submitted to Retrovirology and is also on hold; it fails to find a link between the xenotropic murine leukemia virus-related virus (XMRV) and CFS. The contradiction has caused "nervousness" both at PNAS and among senior officials within the Department of Health and Human Services, of which all three agencies are part, says one scientist with inside knowledge.

I'll bet it has! It looks like the positive findings are from Harvey Alter at NIH, and the negative ones are from William Switzer at the CDC. Having two separate government labs blatantly contradict each other - simultaneously, yet - is what everyone seems to be trying to avoid. Sounds to me like each lab is going to have to try the other's protocols before this one gets ironed out. I wouldn't be expecting either paper to appear any time soon, if that's the case.

Update: Well, as it turns out, the Retrovirology paper has been published - so what's holding up PNAS? Might as well get them both out so everyone can compare. . .

Comments (33) + TrackBacks (0) | Category: Biological News | Infectious Diseases


COMMENTS

1. HelicalZz on July 7, 2010 11:02 AM writes...

Shame, as it would be great to have them both published in the same place back to back, along with plenty of commentary on each (means, methods, potential issues, etc.). Something is wrong somewhere, and having it come to light (hopefully) in a good solid scientific discussion would be a good thing. [I am of course assuming that such an issue is one of scientific interpretation and/or methods only.] What I don't see is how avoiding such a controversy accomplishes anything (maybe reputation protection for whoever is mistaken).

And since when does the government have to agree on things?

Permalink to Comment

2. Carlos Gonzalez on July 7, 2010 11:08 AM writes...

Well, you did not expect "either paper to appear any time soon", but you were wrong, the CDC paper has already been published, but the FDA & NIH positive paper has been pulled out!
http://ireport.cnn.com/docs/DOC-469366

Permalink to Comment

3. Rhenium on July 7, 2010 11:20 AM writes...

It strikes me as a little odd, that Derek and apparently quite a few others received an email announcing the soon to be published "positive" results. Was this a preemptive email from some one with a disclosed or undisclosed interest, or just science gossip?

Permalink to Comment

4. Judson on July 7, 2010 12:15 PM writes...

@Rhenium. Dr. Alter, the man who discovered Hep C virus, gave a presentation in the Netherlands - a closed door presentation for other infection control officials in the country. He had an entire slide denoted to XMRV that read
" Comments on the Agent Du Jour - XMRV
• The data in the Lombardi, et al Science manuscript are
extremely strong and likely true, despite the controversy.
Not only have they detected gag and envelope XMRV
sequences, but they have infected prostate cell lines and
recovered gamma retrovirus particles and have transmitted
XMRV to rhesus macaques by the IV route and demonstrated
infectivity
• Although blood transmission to humans has not been
proved, it is probable
•The association with CFS is very strong, but causality not
proved
• XMRV and related MLVs are in the donor supply with an
early
prevalence estimate of 3%‐7%.
• We (FDA & NIH) have independently confirmed the Lombardi
group findings"

According to the wall street journal, and several other news sources, the NIH was willing to confirm that the slides were authentic, and that (at the time) the study was being published.

It was then announced several days later that the study was not going to be published.

If your interested there is a petition (with a link to several respected news sources) containing more information. Its the link on my name.

Permalink to Comment

5. Eric Johnson on July 7, 2010 12:41 PM writes...

Rhenium,
Like you I'm a cui bono? asker in many situations. I'm also a typical patient, in being livid that politicians are toying with MY already-peer-reviewed paper, and consequently with my sweet hide's remaining years. So yes, there are self-interested parties out there - primarily a legion of apoplectic patients.

We have a long antagonistic history with CDC, which I won't bore you with. There is reason to suspect that highly-placed people at CDC and NIH may feel somewhat embarrassed by the new results, because of their history of not necessarily considering CFS to be a grave matter, and certainly not a research priority. CDC has a history of outspoken support for a psychoneurotic etiology for CFS.

All we want is fair play, period. I realize that it is quite likely that the research community will reach the correct consensus even if the process is somewhat tampered with. But if there's even a small chance that a false consensus will be reached, even for only a few years, am I not right to be seeing red? Needless to say, every university biomed researcher in this country works for HSS (via NIH grants), so there is a possibility that this interference could have a very broad chilling effect. And yet precious, precious few of them are complaining about what's happening. Reason? Again, that they work for HHS.

I'm sure many industry people are also running replications of the Lombardi et al paper in Science, but obviously they aren't making noise about what they are learning.

Permalink to Comment

6. Eric Johnson on July 7, 2010 1:03 PM writes...

Derek is correct, it is repletely confirmed that the PI on the PNAS paper is Harvey Alter, an intramural NIH guy who was critically involved not only in discovering hep C, but also hep B. The blood supply was lousy with both prior to intercession by Alter et al, and as you might expect, infected blood is highly effective at transmitting things (90-100% effective at transmitting HIV, per contaminated transfusion, whereas the efficiency of sex or accidental needlestick is far lower).

If you want to see for yourself Alter's slides from a recent conference in Zagreb, well, you can. Don't worry about this being a compromise of collegial decorum (confidentiality). It was such a compromise, but it no longer is -- the slides were leaked weeks ago. They are already quoted and linked to on hundreds or thousands of pages on the web. Slide ten concerns XMRV:

http://www.ipfa.nl/ipfa/Upcoming_Events.nsf/0/cbfb86b6bbdcc818c125706600483652/$FILE/1%20-%20Alter.pdf

As stated by Judson, the blood supply is a big concern here. Large numbers of Westerners recieve blood transfusion -- I believe the point prevalence for having ever had one is about 20%. So if 5% of blood units are potentially XMRV+ according to Alter, and ~10% of XMRV+ individuals develop CFS (point prevalence).......

Of course we have no idea what the transmission efficiency by transfusion is. It could be 0%. We don't know whether 5% of normals are really XMRV+, or whether XMRV causes or is even associated with CFS -- the literature is highly discordant on those points at present. But apparently Secretary Sebelius wants to decide all that for herself, and then tell the research community what the answer is.

Permalink to Comment

7. Eric Johnson on July 7, 2010 1:15 PM writes...

Let me underline one thing, before I finally break off my hypnogogic speechification.

567 people have signed the petition linked above by Judson. At least dozens, but probably hundreds of people have emailed HHS, the Director of the Office of Science and Technology Policy (in charge of implementing a "scientific integrity" policy of the current administration). And so on.

In response, they have *not* made any statement that the Alter paper will *ever* be released from the DHHS bar on its publication. They have made *no* statement pledging that none of the data found in it when it was peer-reviewed and then accepted by PNAS, will be suppressed. Why?

Permalink to Comment

8. Sili on July 7, 2010 1:26 PM writes...

According to ERV (who's my goto grad for all things virology):

... the journal's editor-in-chief, cell biologist Randy Schekman of the University of California, Berkeley, sent the paper out for further review after government agencies requested the publication delay. That review came back with requests for additional studies, the scientist says.

So this seems to be a case of PNAS trying to avoid another butterfly/velvet worm interspecies orgy scandal.

Permalink to Comment

9. Eric Johnson on July 7, 2010 2:04 PM writes...

Rhenium,
I shouldn't have given the impression that it's solely patients that are angry. There have also been indications -- all from unattributed sources -- that some of the scientists involved in XMRV are distressed about this, and feeling uncertain about whether these data are ever going to be "liberated" by HHS. They may also be worried about a broad chilling effect on all NIH-funded researchers, as I am.

Permalink to Comment

10. Anonymous on July 7, 2010 2:44 PM writes...

Is science free from political interference? Clearly it is not.

I have also heard that the NIH/FDA study had undergone extensive peer review before the HHS asked for more. The question is, why wasn't the CDC study required to also undergo extensive and then extra peer review?

Permalink to Comment

11. Anonymous on July 7, 2010 2:47 PM writes...

ERV has limited knowledge of this subject. She states that the CDC paper used the Fukuda criteria, they did not, they used the revised Fukuda criteria.

Permalink to Comment

12. john on July 7, 2010 3:03 PM writes...

So just curious but when I look at the total numbers of donors when reading the abstract they're in the 50's for the control and the disease group. Are these the normal numbers in a study like this, it's out of my field but I feel it's a little low.

Permalink to Comment

13. Eric Johnson on July 7, 2010 3:25 PM writes...

John, the CDC study has good numbers for its intended purpose: to test the claims about XMRV being present in 66-98% of CFS patients.

When it comes to the rate of XMRV infection in healthy normals, the literature to date is highly discordant - just as discordant as it is on the question of XMRV in CFS patients. One paper claims that the rate in healthies is 0.1%. Clearly the CDC study lacks the statistical power to dispute the latter claim, but surely it never intended to dispute it.

Permalink to Comment

14. Today's World on July 7, 2010 5:57 PM writes...

It's pathetic that Science is discussing unpublished manuscripts submitted to other journals which the general community cannot read. What ever happened to the appearance of confidentiality upon submission of manuscripts? simply pathetic.

If the two groups have decided to try to reconcile their differing results, then that is to their credit.

Permalink to Comment

15. retread on July 7, 2010 7:24 PM writes...

So sad and so unnecessary. The goings on besmirch all concerned, just the way climategate did -- the only difference is that this is all being conducted in public, but to the same ill effect.

Given the fact that the CDC and NIH are reputable institutions (so far), hopefully they will exchange samples, subject them to the other's protocols and see if the data hold up.

Can this be so hard to do? Nearly 50 years ago I worked as a medical student on the National Collaborative Perinatal Project. Serum obtained in the study was frozen and kept in storage for years, and then unfrozen and studied again as new hypotheses were generated (or new organisms discovered).

Permalink to Comment

16. Kati on July 7, 2010 8:51 PM writes...

I am afraid that the CDC CFS division has made a habit of screwing patients' lives. it started in the mid 80's when 2 investigators from the said institution went to Incline Village, Nevada to research an EPIDEMICS of what seemed like Epstein Barr Virus. About 200 people were affected, many severely and they also got an alarming rate of mantle cell lymphoma. The 2 guys came back to the CDC and said that it was a case of mass hysteria. (www.oslersweb.com and Hillary Johnson's Osler's web).
The CDC keeps saying CFS is a psychiatric disease. The doctors that have seen patients for a very long time (Dr Daniel Peterson, Dr Cheney, Dr Nancy Klimas) say it is a disabling disease that can be compared to a late stage AIDS patient before death, and has biological markors.
For the last many years, the CDC has spent all of the CFS budget (4 millions, compared to 3 billions for AIDS) studying a cohort that has been found through random calling of inhabitant of Wichita and Georgia and asking if the occupants of the house were tired. Dr Reeves, who is a co-author of the XMRV CDC paper, also researched the correlation between CFS and sexual abuse and emotional trauma in childhood. dr Reeves also said on October 9th 2009, the day the Lombardi paper came out, that them, the CDC would not find XMRV. Interestingly enough, Dr Reeves has been demoted from the CFS program on February 14 2009.

This is extremely political science, and there are people at the receiving end of this, patients that have been denied care, respect, disability benefits because some people at the CDC decided that CFS was not a real illness. Other countries turn to the CDC for answers, including my family doctor.

We, patients with CFS want the truth to prevail. We already know XMRV is in the blood, in prostate tissues and in respiratory tract of immunosupressed patients (german study). The CDC did not want to find XMRV.

Let science be true, and let the truth be uncovered.

Permalink to Comment

17. Damaris on July 7, 2010 9:12 PM writes...

Thank you for writing about this.

For the sake of accuracy, would you please make sure to call it "chronic fatigue syndrome" instead of merely "chronic fatigue"? Chronic fatigue is characteristic of many long-term conditions, in contrast to chronic fatigue syndrome which is an individual disorder that has a very specific set of criteria as well as many other symptoms besides fatigue such as neuro-congenitive impairment, memory problems, orthostatic intolerance, non-inflammatory pain, unrefreshing sleep, sensory overload, and immune system dysfunction. Thus calling CFS "chronic fatigue" is inaccurate.

More information can be found at: http://www.cfids-cab.org/MESA/AU_CFS.pdf

The WPI used the Canadian clinical criteria of CFS for their study, which is much more precise for the syndrome than the CDC's overly loose definition and may have largely contributed to the discrepancy in results.

Permalink to Comment

18. dearieme on July 8, 2010 8:44 AM writes...

Jesus, is science dying before our very eyes? If you have a paper you publish it and then argument ensues; that's the deal. If an arm of government contacts an editor and asks him to suppress a paper, his bounden duty is to reply "Fuck off". That's true in spades if the government in question is as notoriously corrupt as the US federal government.

Permalink to Comment

19. katieann on July 8, 2010 9:33 AM writes...

see

http://toadlily-gamer.blogspot.com/2010/07/cdc-boilerplating-101_02.html

for a hypothesis why this is curretnly happeneing, and imo, some things we may yet see form the CDC/NIH in the future.

Permalink to Comment

20. oerganix on July 8, 2010 11:43 AM writes...

Read about the previous attempts at obfuscation by the CDC regarding CFS: www.oslersweb.com Click on "CDC Scandal"

When WPI revealed their findings last October, Bill Reeves immediately told the NYT they would look for XMRV but he didn't think they'd find it. That's called "confirmation bias" in scientific circles. Then he used collection tubes with the wrong chemicals for preserving the blood, IF you're looking for a virus or retrovirus. Guaranteed to NOT find ANY.

If I didn't know his history, I'd simply think he had a closed mind or was incompetent. But the fake research he's already done on this illness, trying to "prove" it's caused by inappropriate response to stress, the newest code phrase for "hysteria", is just bogus.

For an independent virologists take on this see: http://www.virology.ws/2010/06/22/fda-and-nih-confirm-wpi-xmrv-findings/

For 2 trailers of a documentary on how the US and UK have tried to disappear this illness see: http://www.whataboutme.biz/

Permalink to Comment

21. Eric Johnson on July 8, 2010 12:45 PM writes...

Retread,
The CDC paper does not have a true positive control for either the serologies or the PCR. It describes using spiked DNA preps and animal sera as positive controls. This imperfection is not a trifling one, under the circumstances, but that's not quite the end of the story.

WPI (the authors who published in Science last year) stated that they sent CDC positive samples last year, something which is not acknowledged in the CDC paper.
http://wpinstitute.org/news/docs/XMRV-CDC%20Statementrevisedawfinalawfinal.pdf

Permalink to Comment

22. Eric Johnson on July 8, 2010 12:48 PM writes...

Mindy Kitei reported being told by an anonymous source that CDC had run the samples and gotten negatives across the board.
http://www.cfscentral.com/2010/06/embargoed-studies-redux.html

Kitei raised this question with the CDC paper's PI, William Switzer, during an exchange of emails, and didn't get a straight answer (see her July 3 post at the above site).

Permalink to Comment

23. Eric Johnson on July 8, 2010 11:31 PM writes...

Sili,
Journalist/activist Hillary Johnson (no relation to me) wrote that "a cabal of top government administrators decided to suppress [the paper] by demanding it be sent out for yet more peer review."

Johnson has a number of well-placed sources. All are anonymous, for which reason I'll not ask that you take her word as gospel: it remains conceivable that Scheckman desired another round of review on his own account, and was not forced. But you should give serious consideration to the possibility that H. Johnson's version of events is true.

Permalink to Comment

24. Eric Johnson on July 9, 2010 11:06 AM writes...

Allegedly the Alter paper is now "expected" to be published "within weeks"... in PNAS. That's news as of this morning.

Permalink to Comment

25. Eric Johnson on July 9, 2010 12:28 PM writes...

While it is not stated officially so far, Those Who Would Know say the conclusions of the paper are unchanged.

I'll believe it when I see it!

The paper stated that it was held in "stress positions" for up to ninety minutes, but it was not waterboarded. Huzzah!

Permalink to Comment

26. Joachim Denner on July 13, 2010 9:57 AM writes...

I hope the following will be of interest to everybody:
http://www.ncbi.nlm.nih.gov/pubmed/20219088

Best regards

Permalink to Comment

27. Barbara Moore on July 14, 2010 5:10 AM writes...

Why can't the scientists get it right? M.E sufferers have waited long enough for the cause & propper treatment of this horrible syndrome!! Myself being a sufferer myself for many years on & off, it completely messes your life up, infact it takes it away from you!! We are getting desparate, i can fully understand why people with CSF take their own lives, especially when we are not believed, that it is not a psychiatric disorder but a real physical one!!!

Permalink to Comment

28. Patricia Carter on August 15, 2010 7:44 PM writes...

It seems incredible that the NIH/FDA (Alter) paper has still not been published. This is definitely government interference with science.

Patricia Carter
www.mecfsforums.com

Permalink to Comment

29. aidan walsh on August 26, 2010 2:04 PM writes...

garth nicolson found in gulf war illness and chronic fatigue syndrome 45% of the hiv aids virus inside the bacteria mycoplasma which was made in a u.s. lab! that was 10 years or more ago and to this day the cdc/nih/fda have done nothing! garth nicolson has published over 800 scientific papers and he probably has more experience combined than all these so called government scientists as far as any published materials! these institutions will never tell the whole truth and the clear reason for all of this is they would have to admit to where these viruse and the other epidemics came from and the hiv deaths not counting the gwi/cfs deaths already from neglect! "HIV IS A SYNTHETIC VIRUS"! for now well over 20+ years they have on purpose dragged their feet and stuck with their idiotic phyco-babble "all in your head" theories! the only thing i want now from my life is these criminals brought to justice and serve very serious life sentences! CRIMINALS ARE EXACTLY WHAT THEY ARE AND JUSTICE WILL BE SERVED, SO HELP ME GOD! TO ALL OF YOU WHO ARE SUFFERING DO NOT EVER STOP SEEKING THE REAL TRUTH! MAKE THEM REPLICATE GARTH'S HIV VIRUS ENVELOPE INSERTED INSIDE MYCOPLASMAS!! SINCERELY AIDAN WALSH SOUTHAMPTON U.K.

Permalink to Comment

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