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By John Timmer, Ars Technica
In 2006, scientists announced a provocative finding: A retrovirus called XMRV, closely related to a known virus from mice, was associated with cases of prostate cancer. But other labs, using different sets of patients, found no evidence of a viral infection. Before the controversy could be sorted out, another research group published a 2009 paper containing an even more intriguing claim. XMRV, it said, was associated with chronic fatigue syndrome (CFS), a disorder that some had claimed was purely psychosomatic.
[partner id="arstechnica" align="right"]Reaction came quickly. The CFS community, viewing a viral cause as a validation of their malady, embraced the finding. One author of the XMRV/CFS paper, Judy Mikovits, landed a position as research director of a private foundation dedicated to CFS. A company associated with the foundation started offering tests for infections.
Then the story took a strange turn. A long chain of events led not only to the collapse of the XMRV hypothesis, but it landed Mikovits in jail — and brought death threats upon some of the researchers who debunked her ideas.
The science falls apart
As reports of XMRV findings appeared in the scientific literature, the federal government grew alarmed. It organized a special team tasked with trying to figure out whether XMRV represented a real threat to the nation's blood supply. At the same time, a number of labs were already working on CFS patients and quickly used their existing samples to look for the virus. The hunt was on.
The first results weren't promising. Retroviruses, as ably demonstrated by HIV, can be notoriously difficult to detect. The immune system does not efficiently generate antibodies against them and infections often persist at extremely low levels, making other forms of detection technically challenging. So it wasn't a huge shock that some labs quickly reported having trouble finding XMRV in other CFS patients, just as they had trouble finding it in prostate cancer patients.
Repeated failure to detect the virus eventually prompted some researchers to consider alternate explanations for the original findings. The resulting work, summarized here, effectively ended most worries about the virus. Two studies showed that samples which had tested positive for XMRV also showed signs of being contaminated with genetic material from mice — remember, XMRV looks like a mouse virus. Another showed that some commercial kit suppliers had also allowed their materials to be contaminated by material derived from mice. This made a strong case that XMRV's presence was a mere matter of contamination (though possibly one that was entirely outside the researchers' control).
>'Even a charitable interpretation of Mikovits' attempts to explain the discrepancy indicates a serious lapse of research ethics.'
The key piece of evidence came in an evolutionary analysis of XMRV origins. Researchers found that the most diverse group of XMRV sequences come from a single prostate cancer cell line called 22Rv1 that was grown in lab dishes. All of the XMRV sequences isolated from patients clustered within the evolutionary tree derived from the cancer cell line, meaning the ancestors of the viruses supposedly found in patients had all come from a single lab-grown cancer cell line. The clear implication is that the sequences came from the cell lines rather than patients.
How did a mouse virus get into this cell line in the first place? It turns out that 22Rv1 cells are commonly implanted into immune-compromised mice in order to test various approaches to detecting and controlling cancer. The cells probably picked up the XMRV virus during one of these procedures.
In parallel to this work, the federal government's Blood XMRV Scientific Research Working Group continued under the auspices of the National Institutes of Health and the Department of Health and Human services. It organized the distribution of samples to nine separate labs, with the labs blinded to the disease status of the samples. The results, published in the same journal where the CFS paper first appeared, were definitive. The concluded that "current assays do not reproducibly detect XMRV/MLV in blood samples and that blood donor screening is not warranted."
The state of play was now settled: XMRV detection was an artifact, the product of various forms of contamination, and it was derived from a cell line that had picked up the virus during experiments involving mice. At this point, there was no indication that the people who had associated the virus with any disease had done anything wrong. The appropriate response would be to accept the weight of the evidence and move on to other projects; several of the researchers did exactly that.
Judy Mikovits, however, did not.
Unscientific behavior
Even as the evidence against XMRV began to build, Mikovits dismissed the failure of other labs to replicate her work as technical shortcomings, while defending her own research and continuing to suggest that patients with CFS should be tested for XMRV. Many of her former collaborators parted ways at various points as more evidence rolled in.
Some portion of the CFS patient community, elated by the original virus finding, also refused to abandon the idea. The same account that described Mikovits' tenacity describes how a talk about her research received a glowing reception from patients and advocates; some left gifts for her, or even had bumper stickers printed saying, "It's the virus/XMRV."
In some cases, boosters of Mikovits and her ideas have allegedly taken a darker turn, one focused on bringing down the researchers who produced contrary findings. Indeed, many of the tactics sound similar to the ones employed against climate scientists: As the Guardian noted, activists have "bombarded researchers with freedom of information requests, made rounds of complaints to university ethical committees about scientists' behavior, and sent letters falsely alleging that individual scientists are in the pay of drug and insurance companies." Other researchers have reportedly faced death threats.
This sort of behavior is in no way linked to Mikovits, and there is no reason to think she would condone it. It is, however, enough to discourage people from entering the field, which could skew future research on the causes of CFS or prevent a better understanding of the spread of XMRV.
Although Mikovits wasn't condoning the antiscientific behavior of some CFS advocates, there were indications that she engaged in erratic behavior of her own.
From bad news to surreal events
Some of the data in Mikovits' original Science paper turned out to be a result of the contamination identified by other labs; a partial retraction of that paper was issued in September, in the same edition that contained the nine-lab, government-backed study.
About a week later, Mikovits was out of a job. One of her former collaborators had requested a cell line used in her work, and she refused. The Whittemore Peterson Institute for Neuro-Immune Disease a private institute associated with the University of Nevada's medical school in Reno, and where Mikovits was director — became involved. Mikovits was apparently asked by the Institute to provide the cells. Again she refused, and was fired for insubordination.
That wasn't even the worst part of her week. A science blogger who does research on retroviruses obtained a copy of a slide used in a talk by Mikovits. It showed some of the same data used in the original Science paper, but the data had been relabeled and was then described as part of a very different experiment. Even a charitable interpretation of Mikovits' attempts to explain the discrepancy indicates a serious lapse of research ethics. (Oddly, Mikovits claims that she had a dispute with the Institute that was focused on its partnership in producing the tests for XMRV. As noted above, an earlier article quotes her as endorsing those tests.)
By the beginning of November, her situation was completely unravelling. Not only was Mikovits unwilling to turn over a cell line to other researchers, but she took her lab notebooks and various computer files with her when she was fired from Whittemore Peterson. These were the property of the institute, which responded by filing a lawsuit demanding their return and receiving a temporary restraining order that required Mikovits to preserve the materials.
Although Mikovits retained a lawyer who contested the charges, within a week she was arrested in California. The charge: possession of stolen property. Apparently, the Whittemore Peterson Institute was taking no chances when it came getting its notebooks back. In yet another surreal twist, ScienceInsider was told that the charges were related to a break-in that occurred on Nov. 9—several days after the lawsuit was filed.
The science worked like it should, even when people didn't
There's no shortage of human frailty on display in this story. Mikovits was clearly wedded to her idea long after the evidence supporting it should have been convinced her otherwise. At best, she clearly had a lax attitude toward accurately presenting research results; moreover, she felt possessive of her data and resources. Even if the charges about the lab notebooks and computer files end up being overblown, the fact that she was refusing to send cells to former collaborators is itself a significant breach of scientific ethics.
It's no surprise that patients who frequently had their disorder treated with dismissiveness would respond positively to indications that it had a concrete, biological cause. But demonizing scientists who don't support something that appeals to you is never going to end well, especially when all indications are that the scientists are being careful and thorough. Unfortunately, we're now seeing more of this sort of behavior in areas as diverse as climate change, vaccine safety, and animal research.
If individual humans come out looking badly here, some of their institutions performed remarkably. Most journals, funding bodies, and research institutions have requirements for the sharing of published reagents precisely to block the sort of behaviors that Mikovits allegedly engaged in. For the same reason, research materials are the property of the institution where research is performed, rather than the property of individual researchers (although this is also a bit of self-interest, as the institutions get to keep intellectual property).
The Department of Health and Human Services, part of a government that's often derided as a paragon of inefficiency, managed to recognize a potential threat to the nation's blood supply, organize a consortium of research groups with relevant expertise at nine different institutions, arrange to give them all blinded samples, and get the resulting publication out. Interim results were also published along the way. Anyone who has experienced how difficult it can be to get academics to agree on anything will be doubly impressed with all that the working group accomplished.
The publishing system also seems to have acquitted itself well. Even though XMRV detection was clearly somewhat iffy in the prostate cancer studies, Science was willing to publish the original paper provided that its reviewers said the data looked solid. Other researchers weren't automatically convinced by publication in a high-profile journal, and they quickly set about trying to replicate it in different sample populations. The results, even though they were published in a lower-profile, open access journal called Retrovirology, proved persuasive and helped build a scientific consensus against the XMRV/CFS link.
These features are all necessary parts of scientific self-correction. Frequently, non-scientists view the corrective process as one where people question some results and attempt to perform an exact reproduction of the experiments that generated them. That's not what usually happens. Instead, the best questions usually focus on the consequences of the result — what should we be seeing if this is right?
In this case, various researchers looked at the initial XMRV results and determined that, if they were correct, we should see similar things using different assays and with samples from different patients. When we didn't, the results raised questions about the whole hypothesis. If evidence in the idea's favor couldn't be found by anyone else, it would look shaky even if we assume that the original experiments had all been done properly.
Those sorts of questions, which focus on the consequences and prompt an inexact form of replication, are essential to ensuring that the scientific record remains robust over the long term.
Image: Courtney Potter
