Researchers announced yesterday the results of a study that put the final nail in the coffin on the link between the mouse virus XMRV and chronic fatigue syndrome. The study is a culmination of four years of intensive back and forth about the link between the mouse virus and the poorly understood syndrome. Here’s what you need to know about the last four years of fighting and its ultimate conclusion.
Chronic fatigue syndrome is a somewhat mysterious condition characterized by, well, fatigue. Patients with chronic fatigue report constant tiredness for over six months that persists regardless of how much rest or exercise they get. But because the symptoms can be vague—a general feeling of tiredness could be caused by anything from depression to pneumonia—treatments and research have been slow. Some people claim chronic fatigue isn’t a real diagnosis, much like chronic Lyme disease, but rather a psychological condition like depression.
And because its symptoms are so hard to pin down, research into the causes of chronic fatigue has been slow. The CDC lists all the different viruses that have been investigated as possible causes:
- Epstein-Barr virus infection, also known as mononucleosis
- Human herpesvirus 6 infection, a virus that can cause problems for people with impaired immune systems, such as AIDS patients or organ transplant recipients taking immune-suppressant drugs
- Enterovirus infection, a type of virus that enters through the gastrointestinal track and can have no symptoms, mild flu-like symptoms, or rarely severe and even deadly symptoms
- Rubella, a viral infection also known as German measles
- Candida albicans, a fungus that causes yeast infections
- Bornaviruses, which cause borna disease, an infectious neurological syndrome
- Mycoplasma, a cause of atypical pneumonia
- Ross River virus, which causes Ross River Fever, a mosquito-borne tropical disease
- Coxiella burnetti, the agent that causes Q fever
- Human retrovirus infection, such as HIV, the virus that causes AIDS, or xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus
And yet nothing has been conclusive. Down at the bottom of that list is xenotropic murine leukemia virus-related virus, or XMRV, which is the virus behind yesterday’s announcement. XMRV is a single-stranded RNA virus first described in 2006. After its discovery, it was proposed as the cause everything from autism to fibromyalgia, Parkinson’s disease and prostate cancer. As of today, none of those links have been confirmed.
In 2009, researcher Judy Mikovits published a report in Science that suggested that XMRV might be the cause of chronic fatigue syndrome. Mikovits and her colleagues found XMRV in the blood of two thirds of the patients with CFS that they examined. Of 101 CFS patients, 68 percent of them had the virus in their blood, and of 218 healthy patients 3.7 percent had it. That could mean that something like 10 million healthy people in U.S. were infected with XMRV and therefore at risk of CFS. The samples came from three different places, and the chances of their results happening by random chance was astronomically low: 8.1 x10-35.
The results were so shocking that the first submission of the paper was rejected by Science, who sent it back asking for the authors to take a look at some counter arguments put forth by reviewers. Why, for example, had Daniel Peterson, a doctor who submitted the samples and is one of the best known CFS clinicians in the world, been taken off the paper? Other criticisms included:
“Chronic Fatigue Syndrome is full of false alarms,” wrote one advisory board member,“and the detection of XMRV could be false positive PCR.” An otherwise enthusiastic referee wrote that the “one major caveat I have is that the issue of potential contamination has not been completely dealt with.” A second referee found it odd that the genetic sequence of XMRV derived from CFS patients and the virus earlier discovered in prostate cancer were 99% similar. This “seems very unlikely and may indicate contamination, despite the evidence presented to the contrary,” the referee warned.
So Mikovits and her group reworked the paper, resubmitted and were accepted. It was published in September of 2009.
Soon after publication, however, other scientists suggested that perhaps Mikovits’ lab was contaminated and that the results were a mistake. A study was commissioned to try and reproduce the 2009 results in nine different labs. In May of 2011, that study published its findings. It failed to reproduce the XMRV link a single time.
In response, Science published a partial retraction of the 2009 Mikovits paper. Of course, Mikovits and her team weren’t pleased. She wrote a response letter to the editors at Science, outlining her argument that the retraction was far too hasty:
Therefore, we feel this is an extremely premature action which is not in the best interest of the scientific community human health and again we respectfully request that you allow the scientific process to run its course unhindered by bias.
But, in an odd turn of events, Mikovits acknowledged that the XMRV in the blood that she originally reported on was indeed caused by contamination. Yet she called that contamination a red herring. Science explains:
Mikovits and Ruscetti, who have become increasingly isolated from the broader scientific community, now say their original paper erred by focusing on a single XMRV isolate that turned out to be a contaminant. They say that isolate is but one of many XMRVs, which belong to a still larger family of gammaretroviruses. They also contend that the virus may lurk in tissues, only traveling to the blood occasionally. “We still stand by our data that we isolated gammaretroviruses from patients with CFS and also from healthy controls,” says Mikovits, who has taken a more public role than Ruscetti in battling critics and reaching out to supporters.
What followed was a long, strange and dirty string of interactions between patient groups and competing researchers. In November of 2011, Mikovits was arrested in relation to a lawsuit that claimed she stole laboratory notebooks and kept proprietary information on her laptop after being fired from the Whittemore Peterson Institute for Neuro-Immune Disease (WPI) where she did her XMRV research. In 2011, Mikovits told Science:
“Anyone who says this is a lab contaminant has drawn the wrong conclusion and has done a disservice to the public,” she says. Okay, maybe not as many CFS patients have XMRVs as they initially reported, but she’s still convinced that a gammaretrovirus is in at least 20% or 30% of them. “I know of hundreds if not thousands of people with evidence of this infection, from what we’ve done over the last 3 years,” she says. “I don’t know what it means. And I’m gong to keep looking for in vivo reservoirs like the ones seen in the macaques, and I’m going to try to ﬁgure out mechanisms of pathogenesis, epigenetics, or other things. I’m not going to stop studying it.”
Enter Ian Lipkin, one of the world’s most famous, and most successful virus hunters ever. He had no dog in this fight, and if he couldn’t find XMRV, no one could. Yesterday, his team published its findings. The study found no link.
Gene sequences from XMRV and a closely related virus called polytropic murine leukemia virus (pMLV) could not be found in blood samples either from 147 patients with confirmed chronic fatigue syndrome — also known as myalgic encephalitis (ME) — or from 146 healthy volunteers, reported W. Ian Lipkin, MD, PhD, of Columbia University in New York City, and colleagues online in mBio.
So CFS patients are back to square one. Which is a position they’ve been in many times before. In fact, the CFS community might be a big reason that the XMRV debate spiraled out of control for a while. Patients who are often told their illness might not be real cling to hope at every new discovery. Many of them thought the XMRV link would prove treatments and relief. Some of them thought that the studies refuting the link were conspiracies by the FDA or CDC to marginalize their condition. When Mikovits was arrested, one commenter on Retraction Watch wrote:
This shows that big money and political power talk — and sue people and get them arrested if they don’t capitulate. That’s it.
There is nothing that WPI and the Whittemores are doing in this situation that helps people with CFS. Nothing. It’s all about their business and raising money, and lots of it. And pushing aside anyone that stands in their way.
This is really disgusting. No one should support WPI, donate to it, go to it. The Whittemores should just raise disrespect. They brought it on themselves.
If one reads the Wikipedia entry on the Whittemores, their business practices are questionable. They’re tied to casino gambling. They’re tied to lifting of environmental protections and decreasing workers’ rights.
I have never trusted them since I first read about their business backgrounds.
I feel like I’m watching a cops and gangster movie, with them playing the gangsters, and a research scientist caught in the middle.
They have lost the right to have an institute for CFS. They don’t care about CFS sufferers. They have no principles or morality or integrity, that’s it. All out for themselves, not science, not helping cure CFS, nada.
Mikovits’ response to the new study? Surprisingly docile. The Washington Post writes:
“I applaud their courage,” said the study organizer Lipkin on Tuesday at a press conference that was attended by Alter and Mikovits. Lipkin speculated that the disease might be caused by several factors rather than a single agent, something that should be studied with modern methods. “It is simply not there,” said Mikovits of the suspected virus, “it is time to move forward now.”
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