Integrity issue follows fired researcher
Heidi Ledford
Published online 5 October 2011 | Nature | doi:10.1038/news.2011.574
Paper linking chronic fatigue syndrome to a virus suffers another blow
as duplicate figures surface.
The scientist behind a study1 that linked chronic fatigue syndrome to
a virus has lost her job and is now facing accusations that she has
misrepresented data.
Judy Mikovits, formerly research director at the Whittemore Peterson
Institute for Neuro-Immune Disease in Reno, Nevada, was fired on 29
September after she clashed with the institute's president and
co-founder, Annette Whittemore, over the work of another researcher.
The following day, in what seems to be a separate development, a
blogger posted a figure from a 2009 paper1 that Mikovits co-authored
in Science alongside one that Mitkovits used in a recent presentation.
The two figures, which are used to describe different results, look
identical, except for the labelling.
No known cause
The paper in Science raised hopes among those who have chronic fatigue
syndrome, because it identified a possible cause of the mysterious
debilitating condition. The researchers reported that a retrovirus
called XMRV, which stands for xenotropic murine leukaemia
virus-related virus, was present in 68 out of 101 people with chronic
fatigue syndrome, compared with only 8 out of 218 healthy
controls1(see Nature 471, 282=96285; 2011).
But attempts to reproduce the results in other laboratories have
failed. On 22 September, the authors took the unusual step of
retracting only part of the paper, including the first figure, after
learning that some of the samples were contaminated2. On the same day,
Science published a large study conducted by nine independent
laboratories, including Mikovits', that failed to confirm the presence
of XMRV in patients with chronic fatigue syndrome3.
Mikovits has since acknowledged that XMRV may not be behind the
syndrome, but says that another related retrovirus is likely to be
responsible.
Despite the growing criticism over her work, Mikovits seemed to enjoy
the support of Whittemore and her institute. According to a
termination letter that Whittemore sent to Mikovits it was a
laboratory power struggle unrelated to the XMRV paper that soured the
relationship. Whittemore wrote that she had ordered Mikovits to allow
another researcher in the lab to work with a particular cell line but
Mikovits refused. "Your actions have shown a complete lack of respect
for your colleague and for my authority," Whittemore wrote.
Mikovits counters that the experiments would have been beyond the
scope of the federal grants that funded the work. Whittemore could not
be reached for comment on the matter but the Institute released a
statement that it would, in the wake of Mikovits' departure,
re-evaluate its research projects.
Double trouble
Mikovits also came under fire when an apparent duplication of data was
brought to light by Abbie Smith, a graduate student in virology at the
University of Oklahoma in Norman and author of the blog ERV. In a post
on 30 September, Smith overlayed a figure from the 2009 Science paper
and a figure presented by Mikovits at a meeting of the The
International Association for Chronic Fatigue Syndrome/Myalgic
Encephalomyelitis in Ottawa, Canada, last month.
The image, Figure 2c in the paper, tracks the expression of a viral
protein called p30 Gag in people with and without chronic fatigue
syndrome. The corresponding slide shown at the meeting was said to
show activation of the protein's expression following treatment by a
compound called azacytidine. Furthermore, some samples labelled as
'normal' in the Science paper were given patient numbers in the
presentation. And the patient sample numbers differed between the two
figures.
Commenters on the blog also pointed out that the cropped figure used
in the presentation can be expanded to show more of the gel, including
the original handwritten labelling. The labels on that original image
differed from how the slide was described in the paper and the
presentation.
Such discrepancies are difficult to cast as unintentional errors,
argues Jonathan Stoye, head of virology at the MRC National Institute
for Medical Research in London. "There is no consistency in the way
these things are labelled," he says.
Mikovits says that the Science paper didn't mention the azacytidine
treatment because that detail was not necessary for the publication.
Instead, the authors referred to the samples as being 'activated'. But
for her presentation, she wanted to emphasize that the addition of
methyl groups to viral nucleic acids may have prevented the virus from
being detected using standard assays. Azacytidine strips off those
methyl groups and, Mikovits argues, can boost viral gene expression.
Patient anonymity
As for the variability in patent sample numbers, she says it was
common practice for her to change the numbers before any public
presentation to prevent patients from identifying their own samples.
Mikovits maintains a database of the original numbers and their
corresponding new labels. But in the rush to prepare for her talk in
Ottawa, she says she neglected to switch the numbers on the slide in
question.
And she chose to relabel a 'normal, untreated' portion of the image
with a patient number because the data were the same. "It simplified
the slide primarily for a patient audience," she says. "This is not in
anyway inappropriate for a presentation as long as the data are
correct, and they are."
The Whittemore Institute responded to the allegations by saying: "It
is our understanding that some patient ID numbers may have been
changed to a new set of coded numbers during the research to protect
their privacy before publication." The institute says it has requested
information from Mikovits and that it will work with Science "to gain
a full understanding of the cause of any potential discrepancies".
Critics have also argued that the original, handwritten labels, which
include the letters 'RT' suggest that the blot had been stained for
reverse transcriptase, another viral protein altogether. But Mikovits
says the 'RT' on the blot simply meant 'room temperature'.
Mikovits' collaborator, Frank Ruscetti of the National Cancer
Institute's Center for Cancer Research in Frederick, Maryland, whose
lab prepared the blot, offers an alternative explanation: The antibody
used to detect p30 was originally made to detect reverse
transcriptase, he says, but instead recognizes p30 and its precursor
so it was used for this purpose.
"This is the problem of people trying to interpret lab jargon," says Ruscet=
ti.
Science says it is reviewing the allegations. The journal has
requested the original images used to make the published figure;
Mikovits says the data were sent on 4 October.
Those who have been critical of the Science article1 say all of this
simply strengthens the argument in favour of retracting the entire
paper. "I have a copy of that paper on my desk," says Stoye. "It has a
line through Fig 1. It has a line through Fig 2c. Where is the next
line going to be? Is there going to be anything left?"
References
1.Lombardi, V. C. et al. Science 326, 585-589 (2009).
2.Silverman, R. H. et al. Science advance online publication
http://dx.doi.org/10.1126/science.1212182 (2011).
3.Simmons, G. et al. Science advance online publication
10.1126/science.1213841 (2011).
Mikovits used this published figure in a later presentation but
changed the labels. (Click to compare the two figures.)
Science, Lombardi et al. 2009;326:585-589Mikovits also came under fire
when an apparent duplication of data was brought to light by Abbie
Smith, a graduate student in virology at the University of Oklahoma in
Norman and author of the blog ERV. In a post on 30 September, Smith
overlayed a figure from the 2009 Science paper and a figure presented
by Mikovits at a meeting of the The International Association for
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis in Ottawa, Canada,
last month.
The image, Figure 2c in the paper, tracks the expression of a viral
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