I did ask about the 'Lipkin Study' detail that Rich had said he found. Will post a link to the NIH Reporter if I receive one. They're usually pretty good at replying to questions.
Will listen to the rest tomorrow too if I can. Arms are in revolt now!! Oh the joys of ME
1 January 2012 (recorded 30th December 2011)
Hosts: Vincent Racaniello, Rich Condit, and Alan Dove
Top ten virology stories of 2011:
XMRV, CFS, and prostate cancer (TWiV 119, 123, 136, 150) 04.56 30 minutes approx.
'Vincent Racaniello: Ok. Ten stories from 2011. First one these are in no particular order I put up a list at the beginning of the week and I put the first one on because it is something we talked about a lot. The retrovirus XMRV, Chronic Fatigue Syndrome and Prostate Cancer. We did four TWiVs on this in 2011, and Rich you say here we first did it in the fall of 09?
Rich: Yeah, I went over the whole archive and the first XMRV episode was TWiV 50 in September 09 on Prostate Cancer. And there have been fourteen episodes total since then, when weve discussed XMRV.
Alan: Well its not everyday someone claims to discover a new human retrovirus.
Vincent: Sure.
Rich: Yeah.
Vincent: So I remember that first episode. It was myself and Jason Rodrigeuz (?) who was, is, a post doc in Goffs lab.
Rich: Right I remember listening to that.
Vincent: And the virus had been discovered already, and they were working on it in the Goff lab and I asked him if he wanted to come and talk about it and so he did. And we talked mainly about Ila Singhs paper showing the presence of antigen, viral antigen, in malignant prostate tissue. And I distinctly remember a week later he came back, and he was just at Coldspring Harbour meeting and hed heard about the group who said that XMRV was also associated with Chronic Fatigue Syndrome [...] 'Wow thats amazing'.
A week after that just a little reminiscence here I went to see Ian Lipkin and I said Hey did you hear about this XMRV and CFS? and he waved his hands and said Im not getting involved in that. [They all laugh] There we go. So, in 2011, he got involved in that. Big time. Yeah well come back to that.
Now the first TWiV was a conversation I had with Dave Tuller who is a journalist professor at Berkley, who writes often for the Times (the New York Times), and he covered the CFS story quite a bit
Alan: And by then we were already having serious doubts about this whole thing.
Vincent: Yeah so by then there were a lot of negative studies right? There had been the original Lombardi et al 2009 Science paper. The Lo and Alter paper had been published. But virtually no-one else was confirming the findings. So there were a lot of doubts.
Alan: And people were looking in places you would really expect to see a human retrovirus and just not finding it.
Vincent: Right. I dont remember how I got in touch with Dave Tuller. Probably emailed me and said he was going to be in New York so I invited him up and we recorded this conversation, which was mainly about science and journalism, but we did touch on CFS and XMRV. And this is interesting.
He did talk a lot about the CDCs role in XMRV and CFS or I should just say in CFS in general and after we recorded I sent it to him. He said Could you cut all the stuff about the CDC out, because I really need to look into it better. Im not sure. So I cut it out and then he wrote this long article of course which I posted in which he did all the research and there it is.
So I thought that was really good that he decided he had better look into it before talking about it publicly. So thats good journalism, right?
Rich: Yes absolutely.
Vincent: So thats TWiV 119. So the next one we did was 123 we looked at a paper or several papers that showed that the published integration sites of XMRV in prostate tumours turned out to be contaminants. Or at least some of them turned out to be contaminants.
Rich: Well the only published integration sites
Vincent: Yes there was one paper from one of the authors was Bob Silverman as he wrote to us he said he doesnt study integration sites, it was a collaboration with another lab and they had sequenced the integration sites and said Aha here we have XMRV integrated into human DNA in a prostate tumour but the paper we talked about on 123 said No. These are contaminants. They are from a cell line.
Rich: Right because you saw exactly the same integration site in the cell line and in multiple patient samples which isridiculous...
Vincent: Right.
Alan: Theres no way that would have happened.
Vincent: So more doubt being sowed by that time. And 123 the title was Contaminated prostates, absolute truth and bleached worms and the contaminated prostates and this was more analysis of integration sites. It was another study which showed more contamination, this was from Greg Towers.
And then, well a number of labs had been published that there were issues with PCR kits, there were contamination issues. And then finally, in my view, a really important paper, which we talked about in 136 which found that XMRV is a recombinant retrovirus that arose during passage of a human prostate tumour in nude mice in the 1990s.
Alan: Right and that was at the same time that phylogenetic analysis showing that all of the sequences of XMRV that had been published were essentially this recombinant it didnt show the kind of diversity that you should see in a retrovirus if it were actually out there infecting people.
Vincent: Right.
Rich: And an expression of concern from Science magazine.
Vincent: Thats right. That was an amazing paper this recombinant origin from Coffin and Patak. Because they were able to track down a lot of the original cell lines that had been made from the prostate tumour and reconstruct both halves of XMRV as they arose from the murine genome.
Alan: That might be one of the most interesting things to come out of this wholeevent.
Vincent: I think youre right because Steve Goff has said the extent to which that happens had been moderately appreciated but this really nailed it. If you pass tumours in nude mice, in various tumours you can probably pull out retroviruses of different sorts that are adapted to the tumour they just pop out of them the mouse genome.
Alan: And it also showed how widespread these things can become in a laboratory environment even when they are supposed to be handled under some degree of containment. Where you have your cell lines multiple cell lines that were then subsequently infected with this thing and now kind of the presumption is if youve worked with cultured cells you probably have XMRV somewhere in your lab because its spread all over the place.
Vincent: Well in fact this prostate cell line was infected but many people who worked with it didnt know it until later. It was during this story that it came out that this prostate cancer cell line was in fact producing XMRV.
Alan: Right but then that spread to other cell lines, quite easily apparently.
Vincent: And then our last episode was 150 called Contaminated which was our recounting of the partial retraction of the Science paper by the authors. They retracted basically, the nucleic acid work because they found it was contaminated with an XMRV plasmid.
Alan: Which pretty much gutted the paper.
Vincent: Right because what was left was serology and some culture which was not specific for XMRV. Now up till now were saying XMRV meaning a very specific virus it is not a generic term. So now you say, or we concluded, XMRV cant infect people because it was generated in the lab in the 1990s so if you want to say it causes CFS its not possible because CFS has been around a lot longer. And then suddenly the discussion turned to Well maybe its a related gamma-retrovirus?.
Alan: Right because the Lo and Alter paper had come out shortly after the original 2009 which found not XMRV but murine-like retroviruses in CFS.
Vincent: But XMRV is out of the question. I see a lot of comments on-line where people say Well, why couldnt it be a related virus? Well it could be a related virus but its not XMRV.
Alan: Right.
Vincent: And theres no evidence that its XMRV or any related virus up until now.
Rich: And this brings up this weird reasoning-thing where you get it into your head that its a retrovirus and you cant get it out [of your head]. I mean if its not XMRV it doesnt mean that its possibly another retrovirus. You are starting over.
Alan: An error does not suggest anything. An error tells you that youve wasted some time. And the only group that had found any other murine-like retroviruses in CFS was Lo and Alter. And I think were going to talk about that in a moment.
Vincent: And the other aspect of number 150 was the Blood Working Group report which was also published, which, basically they had collected some of the original XMRV positive and MLV-like positive samples, blinded them and sent them out to nine different labs. And basically no-one could find any XMRV or serology or virus culture with the exception of I think WPI which had a contamination problem.
Rich: And Ruscettis lab at NIH.
Alan: Right and those labs could not distinguish the CFS from the control samples.
Vincent: Right.
Alan: So the test was a coin-toss which meant that the test which had been marketed and sold to patients for XMRV was meaningless.
Vincent: And that study included some of the samples from the Lo Alter study and those were negative. In Lo Alter the Lo lab which was one of the FDA labs involved in the testing and they were negative as well on their own samples.
Alan: Right and they could not subsequently detect their own virus in their own samples.
Vincent: And so that was our last TWiV and since then in this were a normal TWiV episode wed be talking about the two retractions of the past week I suppose right? Last week Science retracted the 2009 paper. Bruce Alberts the editor-in-chief saying you know the authors have agreed to retract but they cant agree on the language and theres so many problems with this [the agreement of language] that Im retracting it. And one of them of course was that one of those figures was it figure 2, Alan?
Alan: I forget which figure number it was but there was extensive discussion on this. One of the figures in the Science paper subsequently showed up in a presentation that one of the authors gave at a conference but with different labels. Same gel different labels. Which, could be an error but it certainly drew a lot of attention to that Figure and scrutiny to that Figure and it turns out that the authors then came forward and said that in fact what was shown in that Figure in the paper was not exactly the way the experiment was done and that makes a material difference in the conclusions.
Vincent: They never had a good explanation for why it
Rich: I looked at their explanations and it didnt make any sense to me.
Alan: No it really doesnt. Theres noIm not gonna say what this implies but its justerrthings were really fishy with the data.
Vincent: I think when youre doing something this well in all science you have to be careful but if you are going to be doing something that impacts patients directly, you should really, really be careful.
Alan: Especially if you are going to start selling things.
Vincent: In my view it takes all confidence away scientific confidence from that group and that paper. So if anyone has any confidence in it anymore I think its misplaced.
Rich: Yeah.
Alan: Yeah the inability to reproduce the results and all the other findings that XMRV is a contaminant and so on was enough to justify a retraction of this paper I think, but the final straw and the reason I think it was an editorial retraction rather than an authors retraction was this fishiness
Vincent: Now many people on-line are holding onto that Well the authors didnt retract so its still good. But, no. Its not still good.
Alan: No it just means the authors cant get their minds around the fact that the study is completely flawed. And bear in mind you know Andrew Wakefield never retracted his paper.
Vincent: Yeah well he still has many supporters right?
Rich: He still has many supporters and makes a substantial amount of money from promoting this concept and so you know hes never going to retract that even though the concept has been thoroughly disproven and the data have been pretty credibly alleged to have been fraudulent. And that was Brian Deers investigative journalism work. So theres a case where the author is never going to retract the paper but it has been retracted by other authors and by the Journal and we know for a fact that its no longer valid. I dont know that this [Lombardi et al.] rises to that level but certainly this is a report that you know, the authors may be arguing about the wording of a retraction but theres no question that it needs to be retracted that we cant have this sitting in the scientific archives as if it were valid.
Vincent: So you think someone will investigate this like Brian Deer did?
Rich: Oh yeah. We havent heard the last of this. This is its gonna take another year or so but as a matter of fact Brian Deer himself might do it who knows? Hes got a history with this kind of stuff at any rate. No. We havent heard the last of this. Someones got to get to the bottom of this.
Alan: Particularly given the ugliness that has followed it in the discussion.
Vincent: And finally, on Monday the Lo Alter paper was retracted by the authors themselves.
Alan: Yeah you should download the pdf. directly. That was the only way I could get it. PNAS I dont know what it is with their website sometimes they just dont get the links to the table of contents updated properly or somethingbut we have a link in the show notes
Vincent: And this is a retraction by the authors. They say We are retracting the conclusions in our article because And interestingly they say they dont find any mouse DNA in their samples but since no-one else could reproduce the findings
Alan: And they ran out of sample
Vincent: Apparently, they ran out of samples.
Alan: And when they went back to some of the original patients who they had sampled to get more, now they cant detect the viruses.
Vincent: So its a weird retraction because they didnt find contaminating mouse DNA which almost certainly led to their finding these MLV-like sequences because everyone else finds it. They say We retract the conclusions and Ive seen a lot of people asking Well they dont actually retract everything else just the conclusions Well [laughs] thats everything basically.
Alan: Yeah. Thats it. Yeah.
Vincent: Thats the way you say it in science. You dont say Were retracting everything. You say We retract the conclusions.
Alan: I think the significance of the statements they make in the retraction which is open access if you follow the links in the show notes the statements that they are making are just emphasising the point that this was not anybodys fault. There are people whos careers are riding on this. Retracting a paper is a horrible thing to have to do Im sure. So theyre making the point that you know, nobody faked anything, we dont have any evidence that anything was messed with, we just dont have enough sample to get other people to confirm this, we cant confirm it and we didnt find contamination but we cant be sure and so were pulling out of the conclusions we dont believe this anymore.
Vincent: Now what happens with this story? Well, Ian Lipkin is working on something and I have a link to a statement he has put on his lab blog: A message from Directory Ian Lipkin regarding the XMRV/MLV CFS/ME Study. And he says basically, Its not the Lipkin Study its the Alter, Bateman, Klimas, Komaroff, Leven, Lo, Mikovits, Montoya, Peterson, Ruscetti and Switzer Study.
Alan: Trying to distance himself
Vincent: I thought originally Tony Fauci has said Ian sort this out. This was a long time ago now, before all these retractions and clear elimination of XMRV as a human pathogen and I dont know but this seems to have expanded beyond that, but what am I to say?
Alan: Well I think there was some discretion for Ian Lipkin to try and do this and there was a big lump of money dedicated to doing this project and this was, as you say, before all these retractions and the Blood Working Group data and all that came out had everybody waited for the pending data to come out just a couple more months I think this study probably never would have been authorised.
Vincent: Yeah.
Alan: You know its a big expenditure to tell us something that we already know. And if it doesnt match the previous data the burden will be on this new group to explain why it doesnt match what we [laughing] already now. This is not going to disprove or prove anything.
Vincent: So he writes at the end there is criticism in some quarters that this study is unnecessary given the results obtained by other investigators, however the participating clinical lab investigators in our team at Colombia do not agree...
Alan: Obviously
Vincent: we are fully committed to completing the work rapidly and rigorouslyFor those who continue to express concerns is an inappropriate use of resources in a challenging fiscal environment please be assured that more than 85% of the funding associated with this initiative is invested in patient recruitment and characterisation and sample collection, archiving and distribution.
Alan: So were only wasting 15% of the money.
Vincent: I just would like to know exactly whats going on here. I dont think we have a complete description. Do you think thats warranted? Since its NIH money?
Alan: I think that should have gone through the normal grant channels. Theres certainly an argument you could make that we need a set of patients and controls that have been widely agreed on for study of CFS. Because one of the huge issues in this condition as weve all learned here on TWiV recently is case definitions.
This is something that I hadnt really followed, until we started talking about it here, but the case definition for this condition is absolutely crucial to studying it. And there are different case definitions floating about, so to have a whole group get together and say Ok this is what the disease is, now we are going to get 150 patients who unequivocally have it, and 150 controls who are age matched, and all the right stuff, who unequivocally dont have it, and were going to take samples in identical ways with identical equipment and were going to blind them all and were gonna archive them
Thats a useful thing to do but it should have gone through the usual NIH grant review process.
Rich: I just pasted in a I dont know if this is the actual grant but on the NIH Reporter theres a grant to Lipkin, this is actually a supplement, on top of another grant thats in year 8 multi-set blinded analysis of XMRV/MLV in Chronic Fatigue Syndrome and it describesit seems to describe the project.
Vincent: So this is a supplement to this existing this is the north-east bio-defence centre
Alan: Right
Vincent: I didnt know this had to do with Bio-defence
Rich: Its a way of getting a lot of people together
Alan: Its a supplement to an existing grant so they just tacked it on to one that Lipkin presumably already had.
Vincent: I guess thats what Congress does all the time, right?
Alan: Yeah, because it didnt go through the normal grant channels because it was Tony Fauci asking Ian Lipkin Hey can you sort this out? Heres a $1 million. Well tack it on to one of your grants.
Vincent: Well I hear it will be done in 2012. So, I hope we hear about it. I hope its published and well talk about it when its out.
Rich: It would be nice if at least it were structured so that it would generate reagent samples that could be used to look at in different ways to look further into Chronic Fatigue Syndrome.
Alan: Well I think that is what Ian is saying. Is that these samples are being taken in a way that they are going to be archived. Theyre going to be available
Rich: Right. Theyre going to be useful?
Alan: Right. Theyre going to be useful and I would agree that a set like that would be a useful thing to have but I believe it should have gone through the regular grant channels and it should have had to compete with other grants.
And if it won out on its merits then fine. But to have this just you know - $1 million set aside by fiat thatsyou got to have some really good reason to do that and Im not convinced that in this case we did.
Vincent: Do you know whats gonna be done here? Does anyone know for sure?
Rich: I dont know.
Alan: Iall I know is pretty much whats in the blog post and in the earlier descriptions.
Vincent: You see there are some issues with the Science paper as weve discussed. I am just hoping Ian can get around those issues. Do you understand what I am saying?
Alan: Yes. As I understand it these samples are going to be coded and blinded by somebody who has not been involved with any of this XMRV story to date and that that coding system would be kept confidential presumably with robust security because you know there are people that have been involved with this story who are now in Lipkins lab or closely associated with it so this has got to be done very very carefully and hopefully that will be the case.
Vincent: Right. So as you see XMRV and CFS got a lot of our attention this year and I think that was appropriate. You dont always have a chance to follow a new pathogen no matter which way it goes so that was instructive.
Rich: Also got a half an hour of our attention in the top ten. This is going to take us until next week!
Vincent: Yeah sorry about that. Anyway well be visiting it again in 2012. All right. Number 2'
N.B. I wouldn't repost this attempt at least not until I have been back through it all
