Headway, Headlines and Healthy Skepticism

xmrv-structure

Mid-December gave the study of XMRV and other murine leukemia virus-related viruses (MLVs) an extended run on center stage, with the Dec. 14, 2010, meeting of the Food and Drug Administration (FDA) Blood Products Advisory Committee (BPAC) focused on XMRV/MLVs, a follow-up webinar to present the Department of Health and Human Services Blood XMRV Scientific Research Working Group’s latest results on Dec. 17, and publication of a total of eight new studies between Dec. 20 and 26. Each of these events on its own was noteworthy, adding important information to future studies of this family of retroviruses and CFS, and the public health response they warrant.

Of these events, the one that garnered the most media attention was one of the five papers published in Retrovirology on Dec. 20. A group of investigators led by Stéphane Hué and Gregory Towers from three U.K. research institutions examined XMRV sequences amplified from human cell lines and 12 mouse strains using polymerase chain reaction (PCR). They analyzed the genetic diversity and relationships of the resulting sequences to assess evolutionary history, a study referred to as “phylogeny,” similar to the study of family trees and human ancestry. The authors concluded that, “XMRV in patient samples is likely to be derived from PCR contamination from either mouse DNA or cell lines infected with XMRV, and that XMRV is unlikely to be a human pathogen.”

Three other papers published in the same journal on the same date presented data about other possible sources of contamination in studies of XMRV/MLVs, including a brand-name kit used in PCR reactions and from other laboratory reagents. A highly sensitive test for detecting contamination was described as a means of guarding against falsely positive results. These three studies from groups in the U.S., the U.K. and Japan, and the accompanying perspective article, were largely overlooked by the media. Wall Street Journal reporter Amy Dockser-Marcus provided the most complete coverage and has established herself as the journalist of record on XMRV.

Two days later, a summary of the First International XMRV Workshop written by members of the workshop’s organizing committee was published in Retrovirology. And in the journal Public Library of Science One (PLoS One), a group of investigators in Germany published results of a negative study of XMRV in two patient groups, one with CFS and another with MS. The German group had presented its findings at the XMRV Workshop and its negative results were covered in earlier reports of that meeting. On Dec. 26, 2010, a paper hypothesizing the origin of XMRV was published in Frontiers in Virology. None of these three papers generated any new media coverage.

Analyzing the media attention paid to these events, it’s clear that the focus on the Hué study was generated by a press release that accompanied the paper, issued by Wellcome Trust Sanger Institute, the funding agency for that study. The first articles about the package of studies came from U.K. media (BBC, The Guardian and The Independent) and were essentially rewrites of the press release, with little depth or analysis of the actual data presented in either the Hué paper or the other studies. Quotations were limited to those contained in the press release. Later coverage, from outlets that have published other stories about the XMRV-CFS connection, took more care with the data and included perspectives on the other studies and from other authors and experts, including a statement issued by the Whittemore Peterson Institute and comments like this one from John Coffin, PhD: “The argument for lab contamination as a source of XMRV is subtle and indirect, and not, in my opinion, conclusive.” (See the Wall Street Journal, Nature.com and MedPage Today.)

Coverage-enhancing press releases have been issued by groups with positive and negative findings: the Whittemore Peterson Institute added new data to its Oct. 8, 2009, Science paper in its press release issued the same day; the first negative U.K. study from Imperial and King’s universities in U.K. was accompanied by a press release; and the National Institutes of Health hosted a press briefing about data published in in the Proceedings of the National Academy of Sciences (PNAS) on Aug. 23, 2010. Funding institutions often use press releases as a means to establish their own scientistists as the experts (especially in multi-site collaborations) and to promote opinions that may not have survived peer review of the paper or consensus among collaborators. Journalists are supposed to sort out fact from opinion, but too often these days, that process is cut short by the rapid news cycle and media agencies’ interest in being first rather than careful. (See “Calling Science to Account” from Nature, Feb. 17, 2010.)

For those who dig deeper than the surface, a bundle of five complex papers, on a charged topic like contamination, is tough for even experienced virologists to absorb in the fast-turnaround media cycle. Columbia virology professor Vincent Racaniello, PhD, who hosts the popular science podcast “This Week in Virology,” (TWiV) provided an immediate assessment of the papers to the Chicago Tribune that he retracted after closer analysis of the data. He blogged about why he retracted the statement; he also secured a guest, Dr. Alan Rein of the National Cancer Institute, for TWiV episode 113 to discuss the papers and the current state of XMRV study, recorded on Christmas Eve and posted on Dec. 26.

There are plenty of examples of media coverage that fails to examine source material and challenge sound-bite-ready quotes provided in press releases. In the first quarter of 2010, with the close succession of three negative studies of XMRV from groups in the U.K. and the Netherlands, media outlets were quick to report a three-to-one score and to characterize the competing data sets as a war being fought across the Atlantic. There were several “case closed” headlines at that time, too; headlines about the Hué study should be viewed against this background. The news cycle is short and public attention even shorter, particularly with the distraction of the holidays. For those of us paying closer attention to these studies (no matter what time of year), it is worth repeating Dr. Anthony Komaroff’s perspective that he offered after publication of data linking CFS to MLV sequences in PNAS:

“Our study does not and should not settle the question as to whether mouse retroviruses may be associated with CFS. It is one study, one piece of evidence. Scientific conclusions require multiple studies, and multiple types of evidence. More work needs to be done, particularly among those laboratories already engaged in the study of this question, to understand why their results are different. Even if it is concluded that these viruses are often present in patients with CFS, that will not prove that the viruses are a cause of CFS. So we are a long way from the finish line in getting solid answers to these important questions.”

Our top priority in the wake of these papers was to ensure that the studies under way would not be deterred or delayed by either the data or the headlines. NIH has commissioned a multi-lab study being coordinated by Ian Lipkin, MD, at Columbia’s Center for Immunity and Infection. The HHS Blood XMRV Scientific Working Group is set to commence its third phase of a four-phase study. FDA has just received guidance from its Blood Products Advisory Committee that a question should be added to blood donor screening questionnaires about CFS. We reached out to experts in the field.

Dr. Lipkin provided this statement to the media and he was quoted by Nature.com:

“These papers emphasize the pitfalls of molecular assays and raise concerns. Nonetheless, it is premature to rule out XMRV or related viruses as factors in prostate cancer or CFS. Links have also been made based on serology and the presence of viral proteins as well as of viral sequences. Thus, we still need appropriately powered, rigorous blinded studies of well characterized patients and controls. One such study is underway under the auspices of the National Institutes of Health.”

In response to our request, the Blood XMRV Scientific Research Working Group issued this statement:

“The Blood XMRV Scientific Research Working Group has discussed the findings from the four studies published in Retrovirology on December 20, 2010. These studies confirmed the importance of carefully checking XMRV/MLV related-positive results for any evidence of contamination with mouse genetic materials. The Working Group is proceeding with phase III which will evaluate the clinical sensitivity and specificity of multiple laboratory assays that test for the RNA and/or DNA of XMRV/MLVs or antibodies to these viruses. All laboratories have and will continue to apply best practices and check to the best of their ability that no contamination with mouse DNA is present before reporting any positive results. These reports also substantiate the importance of employing tests that not only detect viral DNA and/or RNA but can also detect the virus itself (culture) and/or an immunological reaction to the virus. These tests are reflected in the Working Group planned phase III study.” (Dec. 27, 2010)

Other researchers involved in the study of XMRV affirmed plans to continue studies and/or preparation of manuscripts of data already collected, with some adding that they will take even more steps to reduce the possibility of contamination by routes elucidated in these papers and/or to test samples in additional ways for mouse DNA. All were sensitive to the fact that these papers likely raise review standards for future study applications and results.

So, in spite of headlines last week, researchers and institutions engaged in the study of XMRV/MLVs remain committed. The timeline for arriving at definitive answers about the relationship(s) of these agents to human disease and how to test for and treat them has defied accurate prediction. If the history of retroviruses associated with CFS is any guide, it’s more likely to be a marathon than a sprint. In the 1990s, CFS was associated with three different retroviral agents (an HTLV-II-like retrovirus, JHK virus and spumavirus) by Elaine DeFreitas, PhD, Sidney Grossberg, MD, and John Martin, MD, respectively, over a period of about six years, and many believe those investigations ended prematurely.

At 15 months from the time of the first publication associating XMRV with CFS, we’ve really just begun. Having read a great deal of the formal and informal reaction to the latest studies, it seems timely to repeat a few lines of an article I wrote in March 2010 (under the title “We’ve Just Begun”):

“There are other studies to come and, as we have counseled many times over the past five months, studies don’t always yield the result one hopes for or expects. We continue pressing for appropriately designed replication and validation efforts and studies that inform about the unique characteristics of XMRV that may help make sense of all the data collected so far. In the meantime, scientists have an obligation to publish new data and to submit their conclusions to close inspection and genuine debate.

“This process used to be confined to peers, speaking within the fairly closed confines of scientific conferences and professional meetings; now, largely due to the Internet and social networking tools, it extends to interested communities and the general public. But science isn’t American Idol and we can’t simply vote off the researchers whose results we don’t like.

“Four studies are not enough to answer the questions about the role of XMRV in CFS, or resolve other complicated issues in science. The science has to move forward, even if the process isn’t as direct or straightforward as any of us would like. While patience is in short supply after long years of suffering and searching for answers, it’s important to remember that all of the developments related to XMRV have come in a relatively short period of time. We simply don’t have solid answers yet.”

There are now more than 85 articles in the peer-reviewed literature about XMRV and 2011 promises to add greatly to this total. It may be hard to reach agreement on what constitutes “definitive” evidence, but it’s clear – on the basis of all the studies published so far and the differing interpretations of that body of evidence – that it doesn’t yet exist. As the studies continue to unfold, a constant on which you can rely is that the Solve ME/CFS Initiative will steadfastly advocate for and support robust research that leads to early detection, objective diagnosis and effective treatment of CFS.

Kim McCleary
President & CEO
The Solve ME/CFS Initiative
December 28, 2010

(Revised by author on Jan. 4, 2010)

December 28, 2010