By K. Kimberly McCleary, President & CEO
There are now at least 170 research studies and thousands of science and general media articles published about XMRV. The novel retrovirus and its controversial association with human disease continues to generate attention-getting headlines and to spur intense debate. Here”s a recap of new research publications from late May, June and early July and the media coverage that followed, in chronological order.
Late May 2011
Two studies published in Science on May 31 (online, ahead of print) cast serious doubt on the association between XMRV, a larger family of murine leukemia virus-related viruses and CFS. The mounting evidence against XMRV as a signficant factor in CFS led Science editor-in-chief Bruce Alberts to issue an Editorial Expression of Concern about the original report by Lombardi et al. in Science (Oct. 8, 2009). The Whittemore Peterson Institute replied to Science in a series of letters, including this one from the senior author of the 2009 paper, Judy Mikovits, PhD. The NIH has updated its website to reflect the findings of these latest studies and to affirm plans to continue with two multicenter studies of XMRV and CFS.
For more than a month, these studies and the charged reaction to them has played out in scores of articles in media outlets geared to scientists, physicians, academics, investors, funders and the general public. Here are some of the articles and the various outlets that covered the publications and latest controversy:
- by Amy Dockser-Marcus, Wall Street Journal (May 31, 2011)
- Scientists now doubt studies linking chronic fatigue syndrome to mouse virus, CBS HealthNews (May 31, 2011)
- The chronic fatigue virus: de-discovered?, Carl Zimmer for DISCOVER (The Loom) (May 31, 2011)
- Science raises questions about XMRV study – updated, Ewen Callaway for Nature (NewsBlog) (May 31, 2011)
- Virus linked to chronic fatigue false alarm, Associated Press (May 31, 2011)
- New data spark retraction request for chronic fatigue virus study, by Jon Cohen, Science Now (May 31, 2011)
- Doubts rise over virus as cause of CFS, by Richard Knox, National Public Radio (May 31, 2011)
- Two studies examine syndrome of fatigue, by David Tuller, New York Times (June 1, 2011)
- Retrovirus no longer thought to be cause of CFS, by Erica Westly, Scientific American (June 1, 2011)
- Mouse virus doesn’t cause CFS, by Brian Vastag, Washington Post (June 1, 2011)
- CFS: virus hypothesis collapses further, by Steven Salzberg, PhD, Forbes (June 2, 2011)
- CFS: life after XMRV, by Ewen Callaway, Nature (June 3, 2011)
- , by Tia Ghose, The Scientist (June 3, 2011)
- Episode 136: Exit XMRV, “This Week in Virology” podcast (June 5, 2011)
- Science asks researchers to withdraw paper on CFS and infectious retrovirus, by Matthew Limb, British Medical Journal (June 6, 2011)
- New research says XMRV not cause of CFS, prostate cancer, by Janis C. Kelly, Medscape (Might require free registration to access) (June 7, 2011)
- PCR testing casts doubt on XMRV link to CFS; reveals reagent contamination, by Ben Butkus, GenomeWeb (Free registration required to access) (June 9, 2011)
- Study undermines XMRV connection to human disease, NIH Research Matters (June 13, 2011)
- Perfect match: Unraveling the origin of XMRV, by Edward Winstead, NCI Bulletin (June 14, 2011)
- Cancer research now: Investigating XMRV, video by Sarah Curry, NCI Bulletin (June 14, 2011)
- Study raises doubts about virus and chronic fatigue, NIH News in Health (July 2011)
- , by Gina Shaw, Neurology Today (July 7, 2011)
A June 2 publication in the journal Oncotarget reached similiar conclusions about the origin of XMRV as did Paprotka et al. In “XMRV in prostate cancer cells likely represents a laboratory artifact,” authors Jiawen Yang, Partho Battacharya, Ruchi Singhal and Eugene S. Kandel conclude, “While the presence of XMRV in 22Rv1 is likely to be an artifact, it may be a significant factor in determining the biological properties of this cell line. This consideration warrants additional caution for the interpretation of the relevance of the studies which utilize this popular cell line as a model. It also invites a closer look at the sources of viral contamination in xenografts and cultured cells, as well as in the experiments that allege the presence of this virus in human cells and populations.”
At the 15th International Conference on Human Retrovirology held June 5-8, eight presentations and 15 posters about XMRV provided some new data and a forum for discussion of the conflicting findings in the field. XMRV-related abstracts, as published in Retrovirology, are compiled here.
The AABB updated its summary of the XMRV (and MLV) studies of the human disease and the general population on June 9 to reflect recent additions.
The open-access journal Advances in Virology published two XMRV-related papers on June 10:
- “Failure to detect XMRV-specific antibodies in the plasma of CFS patients using highly sensitive chemiluminescence immunoassays,” by Brendan Oakes, Xiaoxing Qui, Susan Levine, John Hackett, Jr., and Brigitte Huber. The group tested samples from 112 CFS patients and 36 healthy controls. “Using two novel chemiluminescence immunoassays (CMIAs), we show that none of our samples have any XMRV‐reactive antibodies. Taken together with our previous findings, we conclude that XMRV is not present in any human individual tested by us, regardless of CFS or healthy control.” (June 10, 2011)
- “Testing strategies for detection of XMRV infection,” by Shixing Tang and Indira Hewlett. This review article describes testing methods for XMRV and polytropic MLVs. They conclude, “The use of multiple testing methodologies may be required because of the biology of the viruses, such as transient viremia and relatively low immune response observed in the Macaque model. In order to avoid false positive detection, mouse DNA contamination should be carefully examined and excluded.” (June 10, 2011)
PLoS One published “Identification of replication competent murine gammaretroviruses in commonly used prostate cancer cell lines” on June 17. In this article, authors Karen Sandell Sfanos, Amanda L. Aloia, Jessica L. Hicks, David M. Esopi, Jared P. Steranka, Wei Shao, Silvia Sanchez-Martinez, Srinivasan Yegnasubramanian, Kathleen H. Burns, Alan Rein, Angelo M. De Marzo report that “Prostate cancer cell lines appear to have a propensity for infection with murine gammaretroviruses, and we propose that this may be in part due to cell line establishment by xenograft passage in immunocompromised mice. Our results suggest a need for regular screening of cancer cell lines for retroviral “contamination,” much like routine mycoplasma testing.” Vincent Racaniello, PhD, summarized this paper in a post on Virology Blog.
The Lancet, a top general medical journal, published ”XMRV and CFS—The sad end of a story,” by Frank JM van Kuppeveld and Jos WM van der Meer on June 21. Here are five of the media articles that followed:
- ME “not caused by virus”, scientists announce, by Andy Bloxham, The Telegraph (June 21, 2011)
- Now doctors say M.E. is NOT caused by a virus, but is found in the blood, by Sophie Borlund, Daily Mail (June 21, 2011)
- For chronic fatigue sufferers, another blow, Consumer Reports Health.org (June 22, 2011)
- “Final Nail” for XMRV in chronic fatigue syndrome? by Emma Hitt, PhD, Medscape (free registration required) (July 1, 2011)
- Mouse virus not linked to chronic fatigue, Sleep Review (July 6, 2011)
On June 22, the editors of the Journal of Virology (JVI) selected the XMRV study by Shin et al. as one of the “articles of significant interest” in the July 2011 print edition. The Shin study had been published online ahead of print on May 4, 2011. Here is our summary of that study. Also on June 22, the online edition of Journal of Virology included this study of XMRV:
- “The left half of XMRV is present in an endogenous retrovirus of NIH/3T3 Swiss mouse cells,” by Ramon Mendoza, Andrew E. Vaughan and A. Dusty Miller. “Here we used XMRV-specific PCR to search for a more closely related source of XMRV in mice. While we could not find a complete copy, we did find a 3,600 bp region of XMRV in an endogenous retrovirus present in NIH/3T3 cells. These results show that XMRV has clear ancestors in mice, and highlight another possible source of contamination in PCR assays for XMRV.” Authors Miller and Vaughn discussed this study on several CFS/XMRV blogs and Facebook pages, and the interaction became heated at times.
Also on June 22, the British Medical Journal (BMJ) published a package of four articles about CFS, including aspects of the XMRV controversy and the escalating tension between some researchers and patients:
- Heading for a therapeutic stalemate, Trish Groves (Commentary)
- Ending the stalemate over CFS/ME, Fiona Goodlee (Editor”s Choice)
- Dangers of research into CFS/ME, Nigel Hawkes (Feature)
- Living with CFS/ME, Ollie Cornes (Commentary)
These articles also generated plenty of heat, some of which is reflected in “rapid responses” submitted to BMJ that can be viewed at the end of the article abstracts.
On June 24, Dr. W. Ian Lipkin, director of Columbia University’s Center for Infection and Immunity, gave a presentation at the Whittemore Peterson Institute titled, “Microbe Hunting.” In addition to describing his center’s approach to pathogen discovery, Dr. Lipkin briefly discussed the multicenter study he is coordinating on behalf of the National Institutes of Health to look for evidence of XMRV in CFS patients and matched healthy controls.
Science writer Carl Zimmer included XMRV as one of three examples of the value of careful replication attempts in science in his SundayReview article for the New York Times, “It”s science, but not necessarily right,” published June 26. He described the “large-scale” study of 300 subjects being coordinated by Dr. Ian Lipkin to test the XMRV-CFS link.
The link between CFS, cancer and XMRV was explored through one man”s story by Jo Ciavaglia, a reporter for The Intelligencer (Philadelphia) in “Local man with multiple cancers is part of national study.” Sam Ceccola”s 12 cancer diagnoses, his positive XMRV test and his wife”s fibromyalgia diagnosis are outlined in the July 3 article and accompanying video. The article also describes a study at the National Institutes of Health being led by Frank Maldarelli that is testing 60 people for XMRV, half of whom have tested positive by other labs.
Scientific American has published several articles about XMRV, the most recent of which focused on the issue of blood donation by individuals who have CFS. Published on July 4, “Donor fatigue: Should blood banks reject chronic fatigue sufferers?” brought this issue to the attention of readers of the 166-year-old publication. (The latest information about blood donation and CFS can be found here.)
John Coffin and Oya Cingöz of Tufts University published a review article in Advances in Virology on July 7, “Endogenous murine leukemia viruses: Relationship to XMRV and related sequences detected in human DNA samples.” “Here we review the relationship of the human and mouse virus isolates, and discuss the potential complications associated with detection of MLV-like sequences from clinical samples.” They raise several red flags about possible routes by which “XMRV could have contaminated cultures in many different laboratories” (even those that don”t study retroviruses) and mouse DNA contamination of laboratory reagents and equipment. They urge that future studies heed these cautions and take extreme measures to avoid experimental issues that could lead to false conclusions.
Also on July 7, an editorial in Nature Medicine, “Too soon to translate?” considered the latest evidence about XMRV and the influence of patient advocacy on science. “Patient advocacy can drive the development of new therapies, but it is also essential to consider how scientists and clinicians can communicate with patients to best meet their needs. For example, some people with CFS fear that discrediting of the XMRV connection could adversely affect CFS research. They now need reassurance that other avenues of research will be explored and that their disease is still taken seriously.”
On July 8, a publication in Cancer Biology & Therapy, “Frequent detection of infectious XMLV in human cultures established from mouse xenografts,” described experiments to investigate the frequence of XMLV in human cell lines established from mouse xenografts and to search for evidence of horizontal spread to other cell lines. Yu-An Zhang, Anirban Maitra, Jer-Tsong Hsieh, Charles M. Rudin, Craig Peacock, Collins Karikari, Rolf A. Brekken, Victor Stastny, Boning Gao, Luc Girard, Ignacio Wistuba, Eugene Frenkel, John D. Minna and Adi F. Gazdar conclude, “Our studies demonstrated that several MLV strains were present in over one-fourth of xenograft cell lines. Infected cell lines were identified in most laboratories working with or establishing xenograft cultures, indicating that such contamination was widespread. Infected cultures usually release large numbers of infectious virions, and intra-laboratory spread of MLV virus to other cell lines maintained in the same facilities may occur, confirming the highly infectious nature of MLV virus.” (This study was published online ahead of print in the Oct. 2011 issue.)
In addition to the multicenter studies of XMRV being supported by NIH (the blood safety study and the “Lipkin” study), there are informal reports of forthcoming studies — both positive and negative — from labs that have used various methods to test samples collected from CFS patients. The results of Phase III testing of samples in the blood safety study are expected by late summer. Sample collection for the Lipkin study from six clinical practices has not yet begun, so the timetable for that study remains uncertain. The NIH is also supporting XMRV-related studies at the NIH Clinical Center being led by Frank Maldarelli (see news article of July 3, above) and Harvey Alter, as well as extramural research at Cornell University being led by Maureen Hanson.
The CFIDS Association stands for rigorous research that leads to better care for CFS patients. The results of NIH-supported research into XMRV will provide answers about whether XMRV is a route to better care. We will support the outcome of those studies, whichever way they lead. We will continue to foster the engagement of scientists interested in viral hypotheses and other well-reasoned approaches to improving diagnosis and treatment.
K. Kimberly McCleary has served as the Association’s chief staff executive since 1991.