If past experience is any indication, billions of pixels will be spilled in the coming days as scientists and advocates debate the latest twist in the story of XMRV, or xenotropic murine leukemia-related virus, and chronic fatigue syndrome (CFS). Today’s news is that Science is partially retracting a 2009 paper by Judy Mikovits and colleagues, including Vincent Lombardi, purporting to show a link between the virus and the syndrome — a paper about which they issued an Expression of Concern in May. The retraction is of a table and a figure — more on that in a bit.
In an excellent blow-by-blow account in Science of the nearly 20-year-long saga, also out today, Jon Cohen and Martin Enserink review the unusual circumstances of that Expression of Concern. Science editor-in-chief Bruce
Alberts and Science Executive Editor Monica Bradford had first suggested that Mikovits and her co-authors retract the paper voluntarily. “Science feels it would be in the best interest of the scientific community,” they wrote in a 26 May letter. Mikovits was livid and questioned Alberts’s motives. “Who wrote that letter? I don’t think it was Science,” she says. The co-authors thought the retraction request was premature, too. “What if we walk away from this based on contamination and it’s not contamination?” Lombardi asked. “You’ve got to give us time to figure this out.”
Alberts stresses that they floated the retraction idea because Science already planned to publish the Expression of Concern. “It wasn’t a public call for retraction,” he notes, emphasizing that the recipients shared it with the media. He also does not think it would have been premature, although he says it’s often a tough call whether to retract a paper. “Ultimately, it requires expert judgment and a lot of sensitivity to the issues,” he says. “We had lost confidence in the results.”
As Science noted in May, two studies accompanied the May Expression of Concern
that strongly support the growing view that the association between XMRV and CFS described by Lombardi et al. likely reflects contamination of laboratories and research reagents with the virus.
Today’s partial retraction is also accompanied by a paper casting doubt on the 2009 study, this one by Michael Busch and colleagues — including Mikovits and Lombardi — from the Blood Working Group. The authors took blood samples from 15 people who had been found to be XMRV-positive, 14 of which had CFS, and 15 donors negative for the virus, and had 9 labs test them blindly. As their abstract concludes:
Only two laboratories reported evidence of XMRV/MLVs; however, replicate sample results showed disagreement and reactivity was similar among CFS subjects and negative controls. These results indicate that current assays do not reproducibly detect XMRV/MLV in blood samples and that blood donor screening is not warranted.
In today’s Science feature, Busch is quoted praising Mikovits and her one of her co-authors on the 2009 Science paper, Francis Ruscetti of the National Cancer Institute, as well as the National Institute’s of Health’s Harvey Alter and the FDA’s Shyh-Ching Lo — authors of a 2010 paper in the Proceedings of the National Academy of Sciences linking XMRV and CFS:
Blood Working Group member Michael Busch, head of the Blood Systems Research Institute in San Francisco, California, says Ruscetti, Mikovits, Lo, and Alter deserve kudos for participating fully in the study. “I commend them on their scientific integrity and commitment to the scientific process,” Busch says. “This has been a difficult and disappointing process for them and for CFS patients, but hopefully we have all learned lessons that will guide future research and lead to discovery of the cause and cure of this disease.”
But it turns out that the reason for the partial retraction — an unusual move we’ll have more on in a second — is that not all of the authors of the 2009 Science paper were as forthcoming when that work was being checked. Bradford, Science‘s executive editor, tells Retraction Watch that two of those authors, Robert Silverman and Jaydip Das Gupta of the Cleveland Clinic:
determined that the experimental results contributed by them to the Lombardi, et al. paper were the result of contamination, and they requested that we retract those parts of the paper. While we were aware that other co-authors had tested samples and claimed to not find evidence of plasmid contamination, those co-authors were unwilling to provide their data for examination so we were unable to comment on the validity of the other experiments. Since all of the other co-authors agreed with Silverman’s conclusion that his samples were contaminated, we felt it was in the best interest of our readers and the CFS community to publish this information and to label the notice to make it clear that part of the original paper was not valid.
Here’s the text of today’s partial retraction:
In our 23 October 2009 Report, “Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome” (1), two of the coauthors, Silverman and Das Gupta, analyzed DNA samples from chronic fatigue syndrome (CFS) patients and healthy controls. A reexamination by Silverman and Das Gupta of the samples they used shows that some of the CFS peripheral blood mononuclear cell (PBMC) DNA preparations are contaminated with XMRV plasmid DNA (2). The following figures and table were based on the contaminated data: Figure 1, single-round PCR detection of XMRV sequences in CFS PBMC DNA samples; table S1, XMRV sequences previously attributed to CFS patients; and figure S2, the phylogenetic analysis of those sequences. Therefore, we are retracting those figures and table.
We’ve asked Mikovits to explain the circumstances surrounding the samples, and will update with anything we hear back.
Partial retractions are rare. We haven’t seen any since starting Retraction Watch in August 2010, although comments by a Duke official suggest a number are on the way in the Anil Potti case. The closest we’ve come is a Nature Medicine paper that might have been partially retracted, based on the notice, except that the author told us that particular journal doesn’t do partial retractions.
Partial retractions are rare at Science, too. Bradford tells Retraction Watch this is only the third since she joined the journal’s staff in 1989.
The Committee on Publication Ethics recommends against partial retractions:
Partial retractions are not helpful because they make it difficult for readers to determine the status of the article and which parts may be relied upon.
Still, we can see why Science handled this one the way they did. And as Cohen and Enserink’s feature makes clear, this is unlikely to be the end of this saga.
This is insane. An obvious, schoolboy mistake has led to this entire mess and has wasted millions of dollars as well as falsely raised the hope of thousands of patients with CFS. Everything that is wrong with science is laid to bare in this embarrassing saga. At best, the assay is useless and should not have been used in the first place but, at its worst, this is blatant scientific incompetence on a mass scale. Either way the data is dodgy and not reproducible and it should be retracted IN FULL. No compromises. Even a first year graduate student would know how to check for contamination. The journal Science should also be ashamed of itself for playing such a large part in directing this episode. The journal comes across as a scared little puppy – on the one hand publishing a paper which shows the original paper is tosh, but in the same edition refusing to retract said paper and, worse, publishing a PARTIAL retraction. What a total and utter mess. Show some balls and admit your mistakes.
In retrospect, yes– Silverman should have known something was up when all of the sequences came back VP62. Hindsight is 20/20.
But Im not sure, if given that set of data and the time, whether I would have thought to check the samples for contamination in this way myself. The skew of the data is not indicative of sporadic plasmid contamination or a plasmid contaminating a reagent. The thought didnt occur to me at all when I read the first paper.
I think it is great that a) Silvermans lab *did* do this kind of testing when things started smelling fishy, and b) he took his lab off the paper when they unquestionably determined the positive results were the result of VP62 contamination.
… However, like I said, the data is not indicative of plasmid contamination. I do find it odd that given all of the precautions outlined in the SOM that they still got contamination. I dont do anything even remotely that stringent, and I dont have that kind of trouble.
I also think its odd that the contamination was skewed in such a pronounced manner towards the CFS samples. Plasmid contamination is either evenly distributed (~50/~50-CFS/healthy), or in all your samples because it got in a reagent.
But Silvermans contamination was just a ‘problem’ with the CFS samples he got from the WPI, a company that seems to have ‘difficulty’ finding XMRV when samples are blinded…
Odd…
“Silverman should have known something was up when all of the sequences came back VP62. Hindsight is 20/20.”
That would then have allowed the main authors time to actually fully sequence the MLV-related viruses they have isolated.
“The skew of the data is not indicative of sporadic plasmid contamination or a plasmid contaminating a reagent.”
I’m sure it would not as Silverman only looked at 11 samples and full sequenced 3 strains of VP62/XMRV. The samples from Ruscetti and Mikovits are however VP62 plasmid contamination free as verified by an independent laboratory. That is where the “skew of the data”, as you call it, cannot be explain by anything other than people being infected.
“I think it is great that a) Silvermans lab *did* do this kind of testing when things started smelling fishy, and b) he took his lab off the paper when they unquestionably determined the positive results were the result of VP62 contamination.”
Yes, agreed. The viruses can now be conclusively said to not be VP62/XMRV, as Mikovits and Ruscetti could never get the Silverman assay to work either. In sum we are left with viruses half sequenced and only being polytropic, with much supporting data that they are MLV-related viruses.
“Odd…”
Not when you realise this only applies to 11 samples separate to the 101 on which the results are based.
Thanks for this excellent and layperson-friendly explanation.
From the information given here, it is clear that the paper was partial. A raw research, authors don’t agree with each other, they just spat this piece into the journal. Next, the question of partial retraction. Basically, that’s how you shout “We are working hard on a very important problem”.
How long until the XMRV prostate cancer papers are retracted?
Great post. A sad end to a sad story.
Don’t want to bang my own drum, but I predicted this (kindof) – back in May I commented here on Retraction Watch saying
“My prediction of what’s going to happen is that some of the original authors decide to sign a retraction and move on to other science, while others maintain that there’s something in XMRV and continue to study it. I’ve no idea who’ll fall into each camp, but I’d be very surprised if they all agree to retract it.”
Given the results of this paper the upcoming NIH ME/CFS XMRV study coordinated by Dr. Ian Lipkin may not have much thunder. Negative results can be just as valuable as positive results in terms of knowledge acquired.
Perhaps more importantly it will allow researchers to move on to other more promising pathogen work in ME/CFS such as the recently funded pathogen discovery study being done under the auspices of the Columbia University Center for Infection and Immunity. Under Dr. Lipkin’s guidance his teams have discovered or characterized more than 400 infectious agents including Borna disease virus, West Nile virus, LuJo virus, human rhinovrirus C, piscine reovirus and canine hepacivirus. Perhaps they can crack this nut as well.
There has to be a grad student, tech or postdoc out there that was working in this lab while all of this was going down in Silverman and Mikovits’s lab that knows something that hasn’t been reported. Ivan, go track them down!
I live in the UK and have M.E. I had my blood tested for XMRV by VipDX in the U.S.A. and I tested ‘positive’ for antibodies. This has been so confusing for me. Euphoric highs and now such disappointing lows. I don’t feel fed up with Mikovits et al though. They brought this devastating disease into the public eye and into the sphere of respected scientists. It made a lot of people aware of M.E. as being a serious biological illness. I know that Mikovits won’t abandon the cause and I just hope that the other brilliant scientific brains, go on to continue the search for the cause of an illness that has devastated the lives of more than 250 000 men, women and children in the U.K.
Science journal seems not to accept the mistake it has been doing for the last few years. A similar incident which was posted last week on Nature Immunology retraction – Science journal as guilty as NI for publishing the original paper. They haven’t come up with any judgement yet. There is no decent science yet. Once the papers have been retracted – some one should investigate all his/her papers along with collaborators papers…ultimately, more than 60 % of papers published will be ……disgrace ….
My impression is that most, 90% or more, papers in molecular biology/medicine are needless work. And I am talking about reproducible results. The fault is with the interpretation. The claimed functions of the substances they are studying seem to be imaginary. The specificity claimed seems to be imaginary. The interactions claimed seem to be the authors’ pick from from a multitude of equally possible others and still unknown ones.
I am years behind in the knowledge of biochemistry, moreover – never knew it enough to be a judge. But look at these two examples below.
First. It’s not possible to give the number of works and papers that studied stomack ulcer, biochemically. But a few years ago, Barry Marshall found that it is caused by a bacterial infection. He quickly found the cure. He, during his research, met with organised rejection from other researchers. He called them “acid mafia”. After some ten years of this humiliation, he was given Nobel Prize.
Second example. Being a grad. student in the 80’s, I attended the advanced course on molecular mechanisms of diseases. The prof. (a much respected scientist. I withhold the name) was once asked by another student what he should read to prepare for studying cancer. The prof. answered that this would be needless, cancer will be “beaten” before the student graduates. He said: “I told you that we have now discovered cancer genes.” Well, that was more than twenty years ago. The cancer genes are still being discovered.
It’s only the occasional work of some individuals that discovers what we need to know. The organised attack practically is fruitless. For the molecular studies I can say that a simple control is needed: to see if diluted sulfuric acid produces the same effect you attributed to your newly discovered complex substance. Try then sodium bicarbonate.
Well, I can think of one very prominent paper in Lancet that was published, and one by one authors took their names off of it, and there was a partial retraction followed by a complete retraction over a decade after the original paper was published…
ERV stop trying to draw parallels where there is none.