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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: Twitter: Dereklowe

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June 6, 2011

XMRV and Chronic Fatigue: Down For More Than the Third Time

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Posted by Derek

I meant to blog on this late last week, but (in case you haven't seen it) the whole putative link between XMRV and chronic fatigue syndrome seems now to be falling apart. If you want to see the whole saga via my blog posts and the links in them, then here you go: October 2009 - January 2010 - February 2010 - July 2010 - January 2011. At that last check-in, the whole thing was looking more like an artifact.

And now Science is out with a paper that strongly suggests that the entire XMRV virus is an artifact. It looks like something that's produced by the combination of two proviruses during passaging of the cells where it was detected, and the paper suggests that other human-positive samples are the result of contamination. Another paper is (again) unable to replicate detection of XMRV in dozens of samples which had previously been reported as positive, and finds some low levels of murine virus sequences in commercial reagents, which also fits with the contamination hypothesis.

With these results in print, Science has attached an "Editorial Expression of Concern" to the original 2009 XMRV/CFS paper, which touched off this whole controversy. My take: while there are still some studies ongoing, at this point it's going to take a really miraculous result to bring this hypothesis back to life. It certainly looks dead from here.

There will be also be some people who ask whether Science did the world a favor by publishing the original paper in the first place. But on balance, I'd rather have things like this get published than not, although in hindsight it's always easy to say that more experiments should have been done. The same applies to the arsenic-bacteria paper, another one of Science's recent bombshells. I'm not believing that one, either, at this point - not until I see a lot more supporting data - but in the end, I'm not sad that it was published, either. I think we're better off erring a bit on the wild-ideas end of the scale than clamping down too hard. That said, you do have to wonder if Science in particular is pushing things a bit too hard, itself. While I think that these ideas deserve a hearing, it doesn't necessarily have to be there.

Comments (18) + TrackBacks (0) | Category: Infectious Diseases | The Scientific Literature


1. johnnyboy on June 6, 2011 9:05 AM writes...

PCR is a wonderfully powerful tool, and it's also a real bitch. You add its multiplicative power to potential endogenous viruses/proviruses and the myriad possibilities of contamination, and you can wind up with a whole lot of spuriousness.

On the whole I think it's a good thing it was put out there, if only as a cautionary tale for the next researchers who get a result that seems to good to be true.

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2. newnickname on June 6, 2011 9:23 AM writes...

(Thanks for the links to previous Entries. There are times when I want to find and refer to previous topics. Corante needs to add a decent "Search" function for the rest of us to use. Thank you.)

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3. luysii on June 6, 2011 9:56 AM writes...

Unfortunately, it looks like the title of a post on the subject is correct -- -- Unfortunately, the patients are still there and must be dealt with by practicing docs. Hopefully none of them were placed on antiretrovirals because of the paper (but I'll bet that some of them were).

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4. Henge on June 6, 2011 11:23 AM writes...

Eh?You obviously have not checked out today's issue of Retrovirology to be writing such an article.It does not look like XMRV is out of the game just yet!

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5. guest on June 6, 2011 12:32 PM writes...

I can agree with the statement about publishing first and eventually correcting later. The case of the arsenic bacteria controversy is surely the latest example. This paper brought up a lot of interesting discussions and surely made all of us a bit more careful about controls.

However, when patients are involved it is just different. People desperate for a cure will simply jump on anything, and are too much emotionally involved to be able to judge or listen, for what matters.
So in case of applied -or potentially applied- medical research, scientists should spend a few months more to double check theories before publishing.
Beside patients, this kind of research involve too much money as well, so everything is more complex and uneasy.

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6. Kelly on June 6, 2011 1:19 PM writes...

Good post. The step taken by Science given that there was no fraud involved is rather rare and the decision does need to be looked at overall rather than based on just this one study.

Yes money was spent, but no one would have complained if XMRV had turned out to be the real deal and you don't know if you don't check. (Not to mention no one had a gun to researchers heads forcing them to spend the money. As well the much later studies took more time, but controlled for far more variables.)

Science (the field not the publication) is full of hypotheses that don't pan out the way they are expected to, or where the technology is not sufficient to really get at the answer at the time, but sometimes good science takes what has been learned and moves forward.

Ewen Callaway wrote an excellent "second day" piece for Nature News on where the field should go from here. With the exception of Dr. Wessely's incessant whining the responses were thoughtful and forward looking.

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7. Sili on June 6, 2011 4:30 PM writes...

I think we're better off erring a bit on the wild-ideas end of the scale than clamping down too hard.
I think it's more a case of needing better means of judging when to clamp down hard.

Wakefield never should have been published for instance.

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8. John J on June 6, 2011 5:54 PM writes...

Most people don't understand this disease. While it does leave you alive (suicide aside), the disease claims your job, your health insurance, your family, your hope. You don't recognize yourself anymore. You become "walking dead". It is an infection that goes into your brain, much like HIV does. It's not like being over tired. It's a brain injury caused by a transmissible infection. It's painful and open ended, with no obvious solution yet. I have some doubts of my own but if you look at the Whittemore Peterson Institute website, you will see that the "negative" studies are not using the same techniques as WPI and there are logical explanations for the differing results. The answer is not in yet and some people who are taking antiretroviral drugs ARE doing much better, although, they are in the minority. If you think ARV's are not worth the risk, you probably have no idea what life is like with ME/CFS. The symptoms of the disease DO fit with the known symptoms of other gammaretroviruses (XMRV is one) in other animals. There is still a very good chance that XMRV is the main culprit and to give up now could mean dooming thousands more families to this "might-as-well-be-dead"illness.

John J

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9. Chloe M. Smith on June 6, 2011 5:57 PM writes...

Until one of the "negative result investigations" states that they used the same methods and protocol(s) used by WPI to find XMRV in ME/CFS patients, there is no "down for the third time" nor is there a down for the second or first time, since we already know that different investigative techniques were used in those tests.

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10. gippgig on June 6, 2011 7:30 PM writes...

See amorphous semiconductors for an example of a wild idea that few believed but that turned out to be real.

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11. luysii on June 6, 2011 9:31 PM writes...

#8 John J: One of the oldest adages in medicine is primum non nocere (first do no harm). It's Latin, but it goes back to the Hippocratic oath which contains the injunction to abstain from doing harm.

Antiretrovirals are not a walk in the park. Ask anyone living with AIDS. They are almost guaranteed to have side effects, and if they don't work, which is increasingly likely, will increase suffering rather than decrease it.

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12. Jack on June 6, 2011 11:44 PM writes...

Good article - thanks.

I thought Prof Racaniello's coverage of this has been good, especially, perhaps, his most recent TWiV: Exit XMRV:

The ability to trace the origin of XMRV I think was amazing science.
It is unfortunte that 'XMRV' did not pan out, and as I have been living with this condition for 14 years, I can empathise with those who have been and are clinging to hope.
Because this seemed to 'fit' and was 'science' the hope appeared more realistic and less fuelled by desperate belief.
No doubt the BWG and Lipkin studies will confirm the contamination theory - but we shall have to wait at see.
As was said on Prof. Racaniello's broadcast - the outcome of these trials will help if not completely, remove the idea that this whole saga has been a 'cover-up'.
Then again making hypotheses and seeing them 'fail' is deliberately part of the whole scientific process isn't it?

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13. KAL on June 7, 2011 10:46 AM writes...

Jacqueline over at Laika Spoetnik's medical librarian's blog also gave her usual thorough and well documented take in her post "To Retract or Not to Retract… That’s the Question"

Well done all around.

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14. Jacqueline on June 8, 2011 3:13 AM writes...

Thanks Kal for referring to me and for drawing my attention to this post.

Derek, it seems we largely agree on the topic.

You didn't mention that Science first asked the authors to retract the paper (which the authors refused) before issuing a letter of concern. I don't think a retraction is warranted, since multicenter-studies are still underway to proof or disprove the findings. There is serious doubt, but no proof of error.

I am among those few people who ask whether Science did the world a favor by publishing the original paper in the first place. But not (only) in hindsight. In my first posts I already doubted the robustness of the findings. Strong PCR bands after one round (while the PCR appeared suboptimal)... No good contamination controls, homogeneity of the sequences. I was also flabbergasted that WPI later said the other researchers(finding no XMRV)didn't reproduce their experiments, because they didn't culture the blood cells before PCR-ing. But the Science paper doesn't mention the need for culturing at all (only for other experiments)

I’m not against wild hypotheses, if presented in opinion papers. On the contrary. But original scientific papers, should refrain from wild theories, if not founded upon sound data. The Science papers was flawed for reasons mentioned above and in the post:

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15. Dav on June 8, 2011 1:33 PM writes...

luysii, the issue is not ARVs, although they also give them to healthy people, just in case. Death from ME/CFS or the risk of ARVs is worth a shot for many severe patients. Who has the right to make someone suffer for the remainder of their lives.

The Rancaniello show has turned into a Government mouth piece. False information in that show includes and is not limited to the virus having been created in the 90s. No evidence shows that to have happened, it is only a hypothesis. The show also failed to state that XMRV is not xenotropic and then claimed that two xenotropic viruses could have created this virus. Which of course is not possible. In all the show was a party political broadcast for the Coffin party.

The Laika blog is similar. Choosing not to address the real issues at play, which includes the inability of any negative lab to replicate. This will no doubt be the last we see of such unscientific commentary to poor science, such as that displayed in the Paprotka and Knox papers.

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16. StephanCFS on June 9, 2011 8:36 AM writes...

I really can't believe that some people seem worried that the WPI paper has caused people to take antiretroviral medication.

I mean it's not like you go to the doctor and say:

"Hi doc! There is a paper that supposes that a newly discovered retrovirus is the cause of my CFS. I want to try retrovirals now."
Doctor: "Hell yeah, that seems like a good idea. Here is your prescription."


Anyone who suffers from CFS knows that it's most likely to go something like this:

"There is paper that was published in science that suggests that a retrovirus is connected"
"The internet is full of rubbish. You should do Cognitiv behaviour therapy."

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17. StephanCFS on June 9, 2011 8:55 AM writes...

Sorry that should have been:
"I want to try ANTI-retrovirals now."

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18. Margaret on June 11, 2011 5:15 PM writes...

Actually, that scenario is not all that far-fetched, unfortunately.

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