The CFIDS Association started off what’s going to be an exciting week for XMRV with a CFIDLINKs devoted to asking the experts about XMRV. Fittingly enough Dr. Lo and Alter were first. After noting that both groups, the Alter/Lo and WPI/NCI/Cleveland Clinic groups had found a similar ‘strong association’ between murine Leukemia retroviruses (in one case polytropic and the other xenotropic MLV’s) the CAA asked about ‘blinding’ – a question we have not heard before – but the kind of question researchers ask all the time; were the samples ‘blinded’? That is, were they coded and then mixed and run together in the PCR?
Dr. Alter stated that that the samples were run in ‘parallel’ and then mentioned a key strength of the study – that all the positive samples were sequenced; that is, once they picked up a signal that the sequences they were looking for was present, they went to the trouble of sequencing each of them to insure that that was what they found. Since the MLV’s found passed this test the only way that ‘blinding’ could have altered the results (that I can think of) would be if more controls tested positive. Dr. Alter was careful in the first answer to state that they really had no chit in this game – they had no expectations one or another – they simply wanted to see if XMRV was present.
Those CDC samples and Those CDC Patients – the FDA reported Alter/Lo did not found any XMRV in the samples the CDC sent to them. Since Alter/Lo weren’t able to find XMRV in their own samples we’d hardly expect to find them in the CDC’s samples but what about those four MLV’s they found? Did they show up? If they did this would suggest that the CDC made a mistake somewhere. Given Alter and Lo’s findings of about 8% positives in their healthy controls it was reasonable to expect at least some samples to turn up positive.
Dr’s Lo and Alter reported they had not found any MLV’s at all although they did pick up three samples with ‘weak positive signals’ which were not confirmed by sequence analysis; that is, they did not appear at this time to be MLV’s.
Cohort Differences or Methodology Problems or Both? – It was a small sample set (34 samples). If those 3 samples turn out positive, that will indicate CDC made a mistake somewhere (sample preparation?). Even if the samples do not turn out to positive its clear (assuming that Alter/Lo are correct) that the CDC has been studying a very different group of CFS patients than ME/CFS physicians are seeing. (Their samples were provided by Drs. Komaroff, Bell and Cheney.). This is something we always expected but this is the first real evidence that it is so. The CDC’s patients do have some broad similarities to other CFS patients; they tend to have low cortisol and low heart rate variability readings – but no one suggests that these rather mild abnormalities define ME/CFS.
The FDA’s suggestion that problems with ‘sample preparation’ may have compromised the CDC studies results a bell after Dr. Vernon’s statement a month or so asserting they used the wrong test tubes and then cited the CDC study as a study in how ‘not to find XMRV’.
If ‘sample preparation’ or other methodological problems turn out not to be an issue then the only other conclusion to be drawn is that the CDC has been looking at not just a ‘strange group’ but a very strange group indeed. Tom Kindlon pointed out that, the group tested may be a subset of a subset. He noted that while a significant number of the samples came from people diagnosed with CFS using the Fukuda definition (at least at one point) that everybody passed the Empirical Definition as well. The presence of this additional filter – the need to pass the Empirical Definition – could have further altered the cohort.
In any case, even in the best case scenario, with the indeterminate samples turning out to be MLV’s – finding MLV’s at just a bit higher percentages than would have been expected in healthy controls would be an astonishing indictment of the population the CDC has been studying for over 10 years.
Dr. Komaroff on Viruses, XMRV and CFS – the CAA then asked Dr. Komaroff a nice, open ended question. Dr. Komaroff was one of first ‘believers’ and he’s been at this a long time. The CAA, to paraphrase the question, basically asked him what does he think about this study (which he was intimately involved in) and XMRV given all the infectious agents that have been proposed to cause ME/CFS over time?
Dr. Komaroff’s support of ME/CFS has probably made him like a wild-eyed-radical to his peers but he’s always been quite conservative within the ME/CFS field. He doesn’t jump at the latest discovery, which, of course, makes it all the more notable when he does jump. His answer was too long to include here but he basically endorsed a viral cause of CFS stating that the ‘most likely explanation’ of the disorder is a ‘chronic infection’ that ‘very plausibly’ either occurs in the brain or affects the brain. (Definitely hope for the later….it’s so much easier to get at an infection in the body…)
Given his generally careful and conservative approach to issues it wasn’t surprising to see him take a step back and state that while results of the Alter study he was involved in were very strong, and while the group had identified possible reasons why the other studies might have failed – that more work (multiple studies) needed to be done to determine which labs were doing what incorrectly. It’ll be interesting to see how he feels after the XMRV Workshop if, as we expect, several more positive results are announced.
The next question went to Dr. Cheney – who is sure, given his answer, to be providing positive results at the workshop. He stated his poster would contain ‘extraordinary’ data on 48 CFS patients not only from 27 states but from 7 countries as well (!).
(Just how many positive reports are we going to get at the Workshop? The Hanson, WPI/Invest in ME UK, De Meirleir and Cheney studies seem to be locks and the Blomberg study from Sweden is being presented, as well. (De Meirlier and Cheney will be presenting posters – they are not on the program.) The Hanson study appears to have impressive enough for the NIH to give her a large grant to expand on it. She will be speaking at the Workshop). Could 4 or more positive studies be presented there?
The XMRV/MLV Question – Dr. Alter found MLV’s and the WPI found XMRV and much has been made in some quarters of the disparate findings. The CAA, citing a Cold Spring Harbor abstract the WPI submitted March of this year, questioned just how disparate these findings really are and Dr. Mikovit’s answer was that they really weren’t all that different. She stated that not only has the WPI has been finding XMRV variants from the beginning but they have been finding “the exact ones” found in the Alter/Lo study. Most patients tested in fact display a ‘swarm” (my words) of both polytropic (Alter) and xenotropic (WPI) retroviruses. Indeed, she noted that a close look at the antibody evidence in the Science paper suggested that this was so way back in October.
In fact, Dr. Mikovits believes that a swarm is necessary for some of these viruses to survive – that they simply don’t ‘live alone’ – and, indeed, this is what they have find in CFS patients. They now have almost 500 isolates of XMRV they would love to sequence and trying to raise funds to do so.
Dr. Mikovits has no doubt about the provenance of their original discovery. Her answer indicated that she feels the issue was settled with publication of the Alter/Lo paper and that its time to move on. With the WPI’s multiple checks on their PCR evidence (culturing, growing the virus, proving it infects cells, sequencing it) she has not been happy with the ‘push-back’ from some quarters of the scientific establishment and the continuing focus (despite what appears, at least to me, a laymen, to be incontrovertible evidence to the contrary) on contamination. (Welcome to CFS!). It brings to mind, actually, the default ‘psychology’ card some parts of the medical establishment automatically plays when it comes to ME/CFS; if they can’t explain it – then it must be psychological! Or if they can’t duplicate the PCR results…it must be contamination. It couldn’t, after all, that the little lab no one ever heard of it got it right about CFS when these other labs failed…
Of course, not everybody feels this way; the WPI has some strong friends in the research establishment and, if the Workshop goes as we imagine it will, it’s hard to imagine they won’t have more after the 8th. Still it’s clearly been in Dr. Mikovit’s mind a long uphill climb.
Location, Location, Location? Dr Alter has suggested that his inability to find XMRV could be due to it not being present in New England which suggests that different swarms of MLV’s could be present in different parts of the country. The CAA asked the Blood Working Group if their study will be able to pick up any geographic variations in MLV infection? It turns out that this study – which is quite intense – but also not particularly large – will not.
The geographic variation argument could, and in fact seems likely, to fall apart with the introduction of more positive papers that we believe will find XMRV in more parts of the country and, indeed, across the world.
More questions….did XMRV jump from mice to humans? At some point it apparently did. Who names viruses? An International Community on the Taxonomy of Viruses and it looks like it could be awhile before they get around to this, which would be a shame, since XMRV research could explode over the next year.
A question about infectious agents in the blood supply yielded the fascinating information that improved molecular techniques are identifying many more viruses that are present in humans and can be transmitted through the blood but which do not appear, at this point, to cause disease. (The difference with MLV’s and XMRV being that they are retroviruses with a high potential for damage and appear at this point to be sequestered in a specific disorder – ie CFS – not spread randomly throughout the population in otherwise healthy individuals). Indeed, the presence of approximately 4,000 chopped up and (hopefully) inactive ‘proviruses’ in our DNA indicates that viruses are ever present in our environment. American Red Cross officials stated that they fully expect more viruses will emerge that are associated with currently unexplainable disorders.