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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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October 13, 2009

Chronic Fatigue - Retroviruses to Blame, or Not?

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Posted by Derek

Chronic fatigue syndrome has long been controversial and mysterious. Is the mystery clearing up, or getting deeper? There have been diagnoses of something like CFS for a long time, under a lot of different names. The common sign is persistent fatigue with no obvious physical cause, often accompanied by joint pain, disrupted sleep, and other symptoms. It's more common in women than in men - but then, so are a lot of autoimmune disorders, which has made some sort of immune syndrome a popular explanation. All sorts of contradictory data have been generated around that idea, but nothing convincing has emerged.

There's a preprint in Science from teams at the National Cancer Institute, the Cleveland Clinic, and Whittemore Peterson Institute that's attracting a lot of interest. It presents evidence for a viral infection which is far more common in patients diagnosed with CFS. What's even more intriguing is that the virus (XMRV, a mouse retrovirus) is already one that's suspected of involvement in some cases of prostate cancer, as shown by analysis of biopsy samples. (Commentary on that work here). About two-thirds of the CFS patients were found to be positive for the virus, as opposed to about three per cent of the control group. The WPI people are now saying that since the manuscript went in that further work has shown 98% of a 300-CFS-patient sample as positive for XMRV. More on that below.

In the case of the prostate patients, there seems to be a link with a deficiency in the RNAse L pathway, which is part of the interferon-induced antiviral response. It may be that patients with this immune system vulnerability are more susceptible to infection by XMRV, which then goes on to cause (or exacerbate) prostate cancer. There may be a link between RNAse L function and a diagnosis of CFS as well. It makes a neat story, and I hope that it's true.

But we're not quite there yet. No one's seen the data yet on that 300-patient cohort mentioned above, and it's not clear if a different diagnostic method was used on them compared to the group in the Science paper. And that paper itself doesn't have enough details on the patients to satisfy some readers - a specialist at the CDC complained about this to the New York Times, and said that his team would try to reproduce the results, but that he wasn't hopeful. (Working on chronic fatigue has not been the sort of thing that breeds a hopeful outlook, to be sure). Other researchers in the field have voiced their doubts to Science (who, to be sure, did accept the original paper).

One of the problems in this area has been defining who's a patient and who isn't. It's a bit of a catch-all diagnosis, or can be, so there's always the suspicion that even if there's a solid underlying cause that the data are hard to dig out of a heterogeneous patient sample. And there's the whole psychological-or-physical question, too, which is a sure route to raised voices and waving fists. My thinking is that there are very likely a number of people with other issues (which I will leave undefined) piled into this area, and that the necessary attempts to draw boundaries will be sure to leave someone upset.

As for this retrovirus angle, there are a number of other steps that need to be taken. Looking over historical blood and tissue samples will be very interesting - could you find that a person showed no sign of the virus when younger, then went positive before showing signs of the disease? Or does it stay latent for a longer period before finally breaking through? Are there animals that are susceptible to infection, and do they show similar symptoms to humans? Can we at least demonstrate infection of cultured cells in vitro? (Update: I see that they've shown that, which is a very good step). Do any of the existing antiretroviral drugs have any effect on either of those processes, and if so, what happens when you give them to patients with CFS? What about the 3% or so of the population that seems to be positive for XMRV but shows no sign of either prostate cancer or CFS - what's different about them, if anything? And so on.

The Whittemore Peterson Institute people are way out in front on these questions, for better or worse. You may have said, as I did, "Who they?", but it turns out that they've only been around since 2004. The institute was set up by the parents of a CFS patient to do research in the field, and they've apparently been quite busy. Their web site gives the impression that the question of CFS as a retroviral infection is basically settled, but I'm not there yet. I have a lot of sympathy for the unidentified-infectious-agent line of thinking, and I believe that there are probably several things out there that will eventually fit into this category, but it can be a hard thing to prove. Let's hope this one is solid, so we can get to work.

Comments (17) + TrackBacks (0) | Category: Infectious Diseases | The Central Nervous System


COMMENTS

1. Chemgeek on October 13, 2009 9:30 AM writes...

They (WPI) are careful enough to say: "Our work suggests, but does not prove, that XMRV may be the underlying cause of ME/CFS. Much additional work needs to be done to understand how XMRV causes disease and what types of diseases it is linked to it."

I think statements like that provide credibility to their research. Especially when an organization like this seems to pop up out of no where.

Permalink to Comment

2. Vader on October 13, 2009 10:52 AM writes...

Is there a decent animal model for this? It strikes me that it would be hard to satisfy Koch's Postulates if the mouse can't tell you that it's feeling tired and run down.

Permalink to Comment

3. NJBiologist on October 13, 2009 11:47 AM writes...

@Vader: Ve haff vays of making ze mouse talk, ja?

I'd start with locomotor activity (measuring how much the mouse runs around a cage rigged with infrared beams). Grip strength might be a good followup. Use one of the interferons as a positive control, look for inoculation dose-dependent effects, look for antagonist effects from antiretrovirals... this could be fun.

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4. df on October 13, 2009 11:54 AM writes...

Yeah, the WPI folks are actually based out of the School of Medicine at the University of Nevada, Reno. They've been doing some good work as a sort of public/private partnership deal. They'll be getting a new home soon: http://www.medicine.nevada.edu/cmm/

Anyway, I've been reading this blog for awhile and it's pretty cool to have a "local" story. Always interested in your take on it.

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5. cynical1 on October 13, 2009 12:08 PM writes...

Koch’s postulates are irrelevant when examining viral links to autoimmune syndromes and diseases. For instance, only ~5% of HTLV-1 infected humans will develop either tropical spastic paraparesis or the associated HTLV-1 associated lymphoma. Similarly, while exposure to EBV is ~90% in the general population, 100% of MS and SLE (lupus) patients are exposed (and they have the patient numbers to make that odds ratio as strong as the association between smoking and lung cancer). There are numerous theories including bystander activation, ‘hit-and-run’ and molecular mimicry which (IMO) renders Koch’s postulates obsolete when investigating viral mechanisms of autoimmunity, assuming CFS is immune-based rather than a direct viral infection of a target tissue/cell ect.

Very interesting post Derek! I spent 10 years trying to convince my former employer (before they layed me off) to invest in an EBV program for treating MS and lupus. I was never successful but the preponderance of epidemiology and supporting immunology linking the virus to these diseases is nothing short of staggering at this point. (One of the stupid arguments that I always heard was that there wasn’t an animal model for EBV.) Your points above are all excellent and relevant to understanding the underlying disease pathology to delineate the viral link to the disease. One of the quick and dirty ones I would suggest would be an identical twin study where the sibs are either concordant or not for both the disease and virus.

I hope this work is either substantiated or debunked rapidly rather than languishing out there in the nether world of scientific research where a lot of good (and bad) work lingers for decades before the research collective pull their heads out of their collective………..well, you get my point.

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6. Janice P. on October 13, 2009 12:29 PM writes...

I HATE your headline! (You forgot the Syndrome!)

Permalink to Comment

7. Retread on October 13, 2009 1:25 PM writes...

"The WPI people are now saying that since the manuscript went in that further work has shown 98% of a 300-CFS-patient sample as positive for XMRV."

This almost certainly does not pass the smell test. Few diagnostic criteria are 98% accurate (particularly those based on symptoms alone), so the group of 300 patients said to have CFS undoubtedly contains more than 2% who don't have the disorder (whatever CFS turns out to be) even though they have the symptoms.

However, classifying illness by symptom complex has a long and excellent history in medicine. Prior to the discovery of micro-organisms, infections were characterized by the type of fever they produced. Now we know that many distinct microOrganisms cause fever. Similarly, it is quite likely that there are multiple distinct causes of CFS (some of which might be one or more microOrganisms). It is very unlikely that 98% of CFS (whatever it is) is caused by one thing.

Permalink to Comment

8. milkshake on October 13, 2009 2:42 PM writes...

I would put some desperate CFS patients on antiretrovirals to see if there is improvement. For example the phosphonate-nucleotide analogs blocking viral transcriptase from Gillead (discovered by Holy group in Prague) have a pretty broad spectrum (working both on HIV, cytomegalovirus and hepatitis, etc) and they are approved for these other indications. I think there is a chance that they might help, regardless whether the recently identified virus is the actual patogen (or just a an associated effect of viral infection with another agent)

Permalink to Comment

9. Sili on October 13, 2009 4:10 PM writes...

How much work has been done to test the placebo effect is CFS sufferers? (All placebo, I mean, as there's no 'cure' in the absence of any real diagnosis.)

ERV wasn't too impressed with the prostate paper.

Permalink to Comment

10. Kelly on October 13, 2009 4:39 PM writes...

Sili,

You are silly indeed. Your comment shows that you have absolutely no comprehension or understanding regarding CFS symptoms or severity.

Some patients have been bedridden for years, sometimes decades. Any placebo is not going to bring them back to life.

There will be no single cure. Retrovirus or no retrovirus, each case has compounding issues: Pesticide or other environmental exposures, mold, heavy metals, etc. Everyone with CFS has different compounding triggers.

Respectfully,

Kelly

Permalink to Comment

11. retread on October 13, 2009 5:12 PM writes...

Milkshake:

What do you pay for malpractice insurance?

Permalink to Comment

12. Sili on October 13, 2009 6:58 PM writes...

I certainly didn't mean to offend anyone (for once), but the question still stands.

I do not doubt that some - even many - people suffer from something, and this does indeed sound like a good case for what can be the issue. So I'm glad that we may now have a good diagnostic criterion to sort people by. That should help to stop this from being a 'catch all' diagnosis.

I don't know to what extent it would have done any good, which is why I ask, but I'd have thought that an anomalous placebo response would have indicated something. Quite likely even that there is more to the syndrome than just 'hypochondria'.

Finally, the fact that someone suffers still doesn't mean that there is necessarily something physically wrong with them. It's just that psychological illnesses still tend to not be taken seriously by PItS.

Permalink to Comment

13. gf on October 13, 2009 7:57 PM writes...

I remembering reading that placebo responses are expecially low for CFS patients, perhaps because they've been offered so many false hopes before.

Permalink to Comment

14. Sili on October 14, 2009 10:08 AM writes...

Thank you. That was the sort of information I thought would be interesting.

Permalink to Comment

15. anone on October 18, 2009 2:08 PM writes...

If someone has XMRV are they infectious to others ? It is passed on through blood, saliva etc. Are sexual partners at risk ? Children ? Is it like having hepatitis or HIV ?

Permalink to Comment

16. Karen on October 22, 2009 12:51 PM writes...

This virus is not airborne.
I have read that this virus is spread through blood,semen,and breastmilk. Have I passed it along to my daughters, both breastfed?

Permalink to Comment

17. Camilla on November 30, 2009 1:39 AM writes...

After reading everywhere how wonderful it is if the cause for CFS is found, finally two people who is concerned with spreading the possible virus. I have CFS or at least symptoms enough for it. After ten years of illness I finally got the diagnosis - but it only made me devastated. Sure I got a name of the cause of my symptoms but I also had to admit defeat. I guess I´d tried everything for so long and been hopeful in vain so many thousands of times that I had to do that anyhow, but still - a disease that doesn't go away by itself is somehow out of my hands.
So I read about research and starts hoping for a cure instead. Naturally I to was glad when I first read the new astonishing results but ... what does it mean?

Please, you medically knowledgeable people writing here, explain to me;
If it is this XMRV or some other retrovirus - does it mean lifelong treatment with antiviral medication or can you somehow be cured for good? Is it likely that anything like huge doses of Cortisone given to people with leukemia or ITP (Idiopathic thrombocytopenic) could cure CFS or remove the retrovirus?

I kind of need to know - can I kiss people and make love to people or is my life gonna suck even more with physical alienation too??

Until we know the cause - where should I draw the line for caution? (having the symptoms I don´t wish anyone to get them, specially not loved ones). So when they say sexually transferred - how cautious should I be. I have come in contact with a lot of sick people via rehab I have attended and via clients of my own. I always differed from all of them - stood out from depressed, stressed and people with pain and so fourth. I work at a Gym with rehab and manage to fix about everyone else but me. They all get better with appropriate exercise and I get worse. So I kind of find it likely that I actually have the damn thing!

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