A Closer Look
XMRV Researchers Discuss the State of the Science
More than 200 researchers from around the world met this month to discuss XMRV, a recently discovered retrovirus that has been linked to prostate cancer and chronic fatigue syndrome in some but not all studies. The striking discrepancies in results among researchers—with some groups consistently finding the virus in patient samples and others not—led to discussions about how to gather basic information about the virus and advance the science.
Everyone who attended the international workshop, held September 7–8 on the NIH campus, agreed that XMRV can infect humans. The virus (xenotropic murine leukemia virus-related virus) was initially discovered in prostate tumors in 2005 and subsequently reported to be present in some patients with chronic fatigue syndrome.
Although XMRV may well be detectable in some prostate cancer and chronic fatigue syndrome patients, there is currently no evidence that the virus causes disease in people. “We don’t know that XMRV causes any human disease,” said Dr. Robert Silverman of the Cleveland Clinic, who was part of the research team that discovered the virus in prostate tumors.
His colleague, Dr. Eric Klein, also a discoverer of XMRV, discussed the possibility that viruses may play a role in prostate cancer as they do in some other cancers. If XMRV were a cause of prostate cancer, then the virus could be a biological marker for identifying specific types of disease as well as a basis for developing a vaccine against the virus, he said.
“What We Know”
NIH Director Dr. Francis Collins noted in his introductory remarks that the science on XMRV was at “a very important juncture.” He stressed that proving an association between a virus and a disease is not the same as proving causation. Urging participants to approach presentations with a healthy skepticism, he said that the workshop would be a chance to discuss “what we know and what we don’t know.”
The workshop included presentations by researchers who have found the virus in patient samples and others who have not. Talks were often followed by questions about the methods used in the experiments and strategies for developing more consistent results across laboratories.
“The good thing about the meeting was that it got people talking to each other who hadn’t had an opportunity to do so, and these exchanges will help us set up collaborations and sharing of techniques and samples,” said Dr. John Coffin of Tufts University, one of the organizers. “I don’t think anyone changed their minds [about the role of the virus in disease], but it was a big step toward helping to get all these discrepancies resolved. It was also helpful to have interactions between scientists and people outside the scientific community, such as advocates.”
Among the potential explanations for why only some groups have found the virus were the selection of patients for the studies, where the patients lived, and laboratory methods, such as how the samples were collected, handled, and processed.
Contamination of patient samples by mouse DNA could also play a role in positive results, some researchers said. Mouse cells contain hundreds of DNA sequences that are similar but not identical to XMRV. Contamination is a particular concern because today’s genetic tools are capable of detecting trace amounts of DNA or RNA from mouse viruses or tissues in patient samples.
To make this point, Dr. Coffin showed a picture of his swimming pool and proposed a thought experiment. He said that if a single drop of mouse blood were added to the pool and allowed to mix well, DNA from virus-related sequences in the mouse cells could be detected in a 1 mL sample of water (20 drops) with the tools commonly used to search for XMRV. “That’s how sensitive the tools are today,” he said.
Dr. Ila Singh of the University of Utah agreed that contamination from mice can occur very easily in the lab and urged researchers to be “ultra careful.” Her group recently reported that XMRV was present in malignant prostate cells and was more commonly found in men with aggressive tumors.
“The discrepancies may come down to the tests, or assays, being used, as well as the storage and processing of samples,” said Dr. Stuart LeGrice of NCI-Frederick, one of the organizers. “With this meeting, the groundwork has been laid for focusing on the role of contamination and whether handling and processing play a role in results.”
Some participants also called for creating reference samples that researchers could use to evaluate how well tools detect XMRV. This could include positive samples from patients as well as appropriate negative controls. As one participant said, the field urgently needs a protocol that would give researchers concordant results—regardless of whether those results are positive or negative.
“I suspect that until we have the technological details sorted out we won’t be able to address the more interesting ideas” about whether the virus is involved in human disease, said Dr. Jonathan Stoye of the National Institute for Medical Research, UK, another member of the organizing committee.
Researchers from the Baylor College of Medicine were among those who presented positive results. Bryan Danielson and his colleagues detected XMRV in 32 of 144 patients (22 percent) with prostate cancer from the southern United States. The virus was present in both normal and prostate tumor tissue, which suggests that infection may precede the onset of cancer, the researchers said.
But another study failed to detect the virus in nearly 800 cases of prostate cancer. Dr. Karen Sfanos of Johns Hopkins University and her colleagues had used two different methods (PCR and immunohistochemistry) to look for XMRV.
“We don’t see the virus in prostate cancer,” said Dr. Alan Rein of NCI-Frederick, who co-led the study with Dr. Angelo M. DeMarzo of Johns Hopkins. “Once we can detect the virus, then we can think about its effects on humans. But first we have to show that the virus is there.”
Reliable, reproducible assays are absolutely essential for moving the field forward, said Dr. Donald Blair of NCI’s Division of Cancer Biology. “The meeting focused people’s attention on the need to collaborate and get to the bottom of why results differ and to understand the biological implications of these differences.”
Dr. Coffin predicted that standard assays for detecting the virus in patient samples should be available within a year. “I’m optimistic,” he said.
With so many scientists working on XMRV, the field could answer basic questions about the virus within months, said Dr. Collins, the NIH director. “Now is a great time to have this meeting, and people should be questioning the data,” he added. “That’s what we’re taught to do as scientists.”
—Edward R. Winstead
A videocast of the final session of the meeting is available online.