Thursday, September 20, 2012

Fasification of the CFS/ME retrovirus link

The cause of chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME) has not yet been identified, but a non-cause has been.  A 2009 paper in Science suggested that the disorder might be caused by an infectious retrovirus.  This made sense clinically because many patients report having a viral illness before becoming ill with CFS/ME.  From the 2009 paper:
Chronic fatigue syndrome (CFS) is a debilitating disease of unknown etiology that is estimated to affect 17 million people worldwide. Studying peripheral blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus–related virus (XMRV), in 68 of 101 patients (67%) as compared to 8 of 218 (3.7%) healthy controls. Cell culture experiments revealed that patient-derived XMRV is infectious and that both cell-associated and cell-free transmission of the virus are possible. Secondary viral infections were established in uninfected primary lymphocytes and indicator cell lines after their exposure to activated PBMCs, B cells, T cells, or plasma derived from CFS patients. These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS.
The investiagors also found evidence of pMLV (polytropic murine leukemia virus) in some patients. This work gave many people suffering from this disease hope that now the cause was known, and so a cure might be just on the horizon.  Many began to take anti-retrovirals in the belief that, as for HIV, this could stave off the illness.  Clinics were established to treat CFS/ME with anti-retrovirals, and public health concerns were raised over the safety of the blood supply with respect to XMRV and pMLV. 

But many scientists weren't convinced that XMRV was the explanation, and a number of subsequent studies failed to confirm the finding.  And to make things even more confusing, some labs could readily detect the virus and others couldn't find it at all.  We (and many others) blogged about the confusion at the time, here and here. Indeed, analysis of the complete XMRV genomic sequence suggested that the virus was an artifact of a laboratory recombination event that took place around 1993-1996, and these investigators concluded "that association of XMRV with human disease is due to contamination of human samples with virus originating from this recombination event."

Well, now a new multi-institutional study now proposes a definitive answer.  The investigators who originally found the retroviral association "report that a blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects" finds no evidence of XMRV or pMLV. 

The paper concludes that the original finding was an artifact of the use of sensitive molecular methods, PCR, that can essentially make mountains out of molehills.  Small amounts of contaminant can appear to be causative with these techniques and pose expensive difficulties for public health as laboratories go through the "pathogen dediscovery process."

We have often said here on MT that although one of the cornerstones of the scientific method is falsiability (yes, this can be and has been disputed, but it is certainly still considered by many to be so).  Even so, many scientists cling to their original hypotheses even in light of very well-demonstrated refuting evidence.  Thus, it's good to see this statement now, from the author of the 2009 Science paper that suggested the link between CFS/ME and XMRV, as reported in ScienceDaily
 "I greatly appreciated the opportunity to fully participate in this unprecedented study. Unprecedented because of the level of collaboration, the integrity of the investigators, and the commitment of the NIH to provide its considerable resources to the CFS community for this important study. Although I am disappointed that we found no association of XMRV/pMLV to CFS, the silver lining is that our 2009 Science report resulted in global awareness of this crippling disease and has sparked new interest in CFS research. I am dedicated to continuing to work with leaders in the field of pathogen discovery in theeffort to determine the etiologic agent for CFS."
The problem with falsifiability
Falsifiability was advocated, largely by the philosopher Karl Popper, on the grounds that induction--repeatedly observing the same thing--was not a reliable criterion for inferring something about the world.  The reason is that the next observation could be different and ruin the generalization that had seemed true.

The idea is that one can never show something to be true--indeed, tomorrow the same data could be shown to fit some different idea from the one you had.  But, at least, you could show your idea to be false.  That is, you set up a test and expect the result your generalization would predict....but you get some other result.  That leads you to develop a different idea (hypothesis) about what is going on.  
If one idea after another is falsified in this way, then this is a systematic way to approach knowledge, because whatever explanation remains is more likely to be the true one (this is essentially what Sherlock Holmes said, long before Popper ever came up with the idea!). 

But experiments can fail, studies can be poorly designed, and so on.  As we noted, scientists tend to use those explanations when the result isn't what they want: we need bigger studies!  This negative study was not properly designed!  The methods were not up to date!   And so on...  This makes science a social and political, rather than strictly objective and empirical, form of human endeavor.

That's why falsification is just not a definitive criterion. In this case, the author has given up on the idea  and is just grateful that people are thinking about the problem.  Previous studies that did not confirm the hypothesis, however, were not considered robust enough to actually falsify it. 

The deeper problem is that we have no definitive criteria for making conclusions in science.  We do it by some informal, usually temporary, consensus.  Maybe there will be found some truly definitive way to make inferences.  Or, maybe science as a social and political activity is either the right way, or even the best way we can get.


stevencarlislewalker said...

I find your conclusion very interesting:

"The deeper problem is that we have no definitive criteria for making conclusions in science. We do it by some informal, usually temporary, consensus. Maybe there will be found some truly definitive way to make inferences. Or, maybe science as a social and political activity is either the right way, or even the best way we can get."

I'm curious, how does your perspective differ from Feyerabend's (i.e. 'the only way to describe the scientific method is to say: anything goes')? Do you have any position on him? I'm no expert in the philosophy of science, but like you, I sense that falsification isn't quite right, but I also feel that science is something more than a cultural phenomenon. And I'm also not naive enough to think that those are the only two possibilities.

Ken Weiss said...

A very good question. Even Feyerabend was partly joking. He knew that the real world does exists. But he was willing to take, say, astrology as a legitimate way to view the world, whether or not it happened to satisfy someone else's criterion for knowledge (say, for predictive power). Each culture can have its own ideas of reality and, within that culture, they are legitimate.

Here, the fact is that science is objective up to a point, given the questions being asked at any given time, but subjective in terms of interpretation of data and generalizations (theory) to extend it.

Richard Feynman once famously said that if anyone claims to understand quantum phenomena, they're deluded (or something like that).

After giving a talk in a meeting a few years ago, where I mentioned some of these issues, a woman came up at coffee break and introduced herself to me. She was Feyerabend's wife. She basically wanted to make clear that he didn't literally mean 'anything goes', but as I've said above, that there isn't just one set of criteria for making inference or generalities about the nature of the world.

Popper (I never met or heard him, and have only read bits and pieces of his writing) would not have disagreed with what I've said, I think. He would probably argue that any hypothesis can be advanced, but if a really solid result shows it to be false, it must be abandoned. Neil Armstrong convincingly showed that the Moon is not made of green cheese. The probably that where they landed (and found no cheese) was not representative of Moon matter is trivially small.

But most falsification is not definitive. Most of the views held or that persist in the face of negative evidence, reflect belief not the data themselves. Thus, if you say you use a p=0.05 significance cutoff for your study, and you get p=0.06, you're likely to claim 'suggestive' evidence for your idea (or, before publishing but after seeing this,suggest p=0.1 as the criterion used).

So Feyerabend was tweaking the establishment, as was his wont (he was at Berkeley and was no fool). But there are truths even overstatement. His book, Against Method, gives clear examples of what he means, and is well worth reading (and is very readable).

stevencarlislewalker said...

Thanks for the interesting and thoughtful reply.

When I was much younger I read Against Method, but I don't think I had the appropriate sensitivities to properly appreciate it at the time. Maybe I'll have another crack at it.