The scientist who put the nail in XMRV's coffin

Transcription

1 Nature News: Q&A IACFS/ME Newsletter December 2012 Attachment 5 The scientist who put the nail in XMRV's coffin W. Ian Lipkin tells Nature about his efforts to validate the link between retroviruses and chronic fatigue syndrome. 18 September 2012 W. Ian Lipkin The Center for Infection and Immunity A study published today 1 has found no evidence to support research linking the retroviruses XMRV 2 and pmlv 3 to chronic fatigue syndrome (CFS). The US$2.3-million study, funded by the US National Institutes of Health (NIH), comes three years after a link between XMRV and CFS was first reported in Science 2 (see timeline, below). W. Ian Lipkin, a molecular epidemiologist at Columbia University in New York, was not involved with the initial studies, but he shepherded the effort to replicate them to completion. Three laboratories, including the two that made the original discoveries, tested blood samples from 147 patients with CFS and 146 healthy volunteers, and then reported their results to Lipkin's laboratory for analysis. The veteran scientist, who has debunked other disease links such as that between autism and vaccines, tells Nature about the study including his efforts to keep Judy Mikovits, an XMRV researcher formerly at the Whittemore Peterson Institute for Neuro-Immune Disease (WPI) in Reno, Nevada, out of jail for taking notebooks from her former laboratory and why he hopes that some good will come out of the study. What s the history of this study? When these two papers 2, 3 came out very close together, there was a lot of concern. There was a lot of optimism as well, because now there was a potentially tractable solution for CFS. Many people began trying to replicate the work. Some people were able to do so and some weren t, but there really wasn t any coherence to it. It became clear that it was necessary to have some sort of investigation of this disorder and find out whether or not there was any link. What was really needed was a properly designed study in which the individuals who made these reports could use their own best efforts. I ve come to the conclusion that the most important thing you can do is to design the study, supervise it and then get out of the way. Did everything go as planned? Judy Mikovits, during the middle of all of this, was forced out of her job at the Whittemore Peterson Institute. [She was subsequently accused of stealing her lab notebooks and jailed.] Before she was incarcerated, I tried to negotiate some sort of agreement between her and the institute, so that this would not happen. One of the problems was that she really did need access to her laboratory notebooks so that she could answer questions from other scientists and patients, and she was not given an option to do that. She took these notebooks and I trust that it was true with the notion that she wanted to copy them. Did you find any hint that XMRV is associated with CFS?

2 We did not find any genetic sequences [of XMRV or related viruses] in the people with CFS or the controls. As far as we know, there is no human being that is infected with XMRV. The one wrinkle is that there were patients who were found to be XMRV-positive in serological tests by Francis Ruscetti, [an immunologist at the NIH in Frederick, Maryland,] in 9 cases and 9 controls. Some might say that this is evidence that there are people who are infected with XMRV, even if it isn t associated with CFS. But I have concerns about that interpretation. If you consider this in the context of the work that shows that XMRV originates in the laboratory 4, then I think we can probably close the door on this once and for all. Will we ever have a full explanation of what happened? I think the explanation is that there was contamination. I don t see any reason to invoke anything beyond that. Do you think there are lessons to be learned from this saga? My expectation is that this will be a cautionary note. We will see far more of these sorts of observations coming out over the next few years, as people use ever more sensitive methods for discovering infectious agents. Why was this study necessary, given the failed replication efforts? The only thing that matters is that the people who originally reported the finding had an opportunity to test it with a large, appropriately powered group. This was the definitive study and it was crucial that it be done properly. Had we done this when Andrew Wakefield [the former medical researcher who proposed that autism was caused by vaccines] came out with the initial report 5 about the measles, mumps and rubella (MMR) vaccine and autism, and had something this definitive, there are many more children who would have been vaccinated against measles during the ten years it took us to finally complete the MMR autism work 6. So I think it s crucial that we don t do things in a half-baked fashion, so we can test hypotheses and move on to new ones. Do you think the CFS community and the scientists involved will accept these results? I certainly hope so. I feel very badly for Mikovits, [her co-author] Ruscetti and Harvey Alter [a hematologist at the NIH Clinical Center in Bethesda, Maryland, who led one of the CFS studies]. Mikovits in particular she has lost everything. She can be wrong but she s not a criminal. She has been honest in a respectful, forceful way and said that we have to conclude that we were wrong. You can imagine how difficult it must be, and I think she should be applauded. Lots of people wouldn t have the balls to do that. She has come across as a scientist who really believes in the importance of truth. You have disproved the autism MMR connection and other controversial disease links. Have you dealt with anything quite like the XMRV case?

3 I ve never seen anything like this. To talk to somebody who is running from the law or has been incarcerated, or to try to adjudicate some sort of agreement so she doesn t go to jail, it s a little beyond the pale. I hope I never do anything like this again. Whatever it is we do, we re castigated. My mailbox has been full today with complaints from people in the community saying: You didn t do this, you didn t do that. What do you say to the CFS community to stop them from thinking that scientists will turn their back on CFS when this study is complete? I have to agree with them that they ve not received the attention that other groups have had. They ve tried to take a page from people who work in autism, who looked at HIV/AIDS, breast cancer and so on, and the CFS community has not been as vocal and effective as they might be. What I say to them is this: the fact that we did this study means we did take you seriously. We didn t do a shoddy piece of work. We re ready to invest in the next phase of research. There are all these samples that will be available. There will be funding opportunities. It s evidence, I think, of an unprecedented opportunity for people to do basic and applied research into the causes and ways in which one can prevent or mitigate the tragedy that is CFS. People with CFS should actually feel heartened that there s more energy and effort going into this. It wouldn t make any sense for us to dwell on something that doesn t work. Lipkin study statement by The ME Association The XMRV saga has finally ended 18 September 2012 by Tony Britton on September 19, 2012 Dr Ian Lipkin and his colleagues should be congratulated on the way in which they have cooperated in carrying out a very thorough piece of medical detective work. This has found that there is no link between XMRV (xenotropic murine leukaemia virus-related virus) and pmlv (polytropic murine virus) and ME/CFS. The results come as no surprise given what has happened since researchers at the Whittemore Peterson Institute first linked XMRV to ME/CFS in a paper that was published (but now retracted) in Science back in All the initial hype that surrounded the publication in Science meant that people with ME/CFS were led to believe that a causative infection (ie XMRV) had been discovered, along with a diagnostic blood test, and that effective treatment with antiretroviral drugs would then follow. Sadly, all three claims have turned out to be false hopes based on flawed science with the scientific consensus now being that the original finding was due to laboratory contamination, probably from mouse DNA in the samples. There should now be an apology firstly from the laboratories who persuaded people to spend large sums of money on useless XMRV tests; secondly from those who influenced people with ME/CFS to put their health at risk by taking antiretroviral drugs. ME/CFS is a serious neurological illness and there are many promising lines of biomedical research into the cause that need to be pursued, including the role of viral infections. Contrary to the press headlines that are accompanying this story there is already a substantial amount of sound scientific evidence to show that a variety of viral infections (including enteroviruses, glandular fever, hepatitis and parvovirus) can trigger ME/CFS, that persisting viral infection may play a role in

4 some people, and that reactivated viral infection (eg Epstein Barr virus and HHV-6/human herpes virus type 6) may also be playing a role. Hopefully, we can return to more pressing research priorities now that the final chapter in the XMRV saga has been written. Finally, it is encouraging to note that Dr Ian Lipkin is going to continue working in the area of ME/CFS research. Dr Charles Shepherd Hon Medical Adviser The ME Association September Researchers find no link between XMRV and chronic fatigue syndrome British Medical Journal 19 September 2012 by Tony Britton on September 19, 2012 From the British Medical Journal, 19 September Bob Roehr Washington, DC A study designed to find a definitive answer to the question of whether there is a link between the xenotropic murine leukaemia virus (XMRV) and chronic fatigue syndrome has come up with an unequivocal no. The answer was delivered at an 18 September news conference in New York City, and published in the online journal mbio1. A 2009 paper by Judy Mikovits published in the journal Science,2 and a subsequent paper by Harvey Alter in Proceedings of the National Academies of the United States of America that identified a similar murine retrovirus, claimed to have established a causal relation with chronic fatigue syndrome.3 Mikovits subsequently was involved in convoluted charges and countercharges of illegal activity and theft by her employer and was briefly jailed.4 Those charges were later dismissed by the court. Attempts by others to replicate the findings of a link failed to do so, and many came to believe the initial work had been sullied by contamination. But questions remained because the confirmatory studies often used different methods and were underpowered. The National Institutes of Health, the Centers for Disease Prevention and Control and the Food and Drug Administration commissioned a study under the direction of W Ian Lipkin, a professor of neurology and pathology and director of the Center for Infection and Immunity at the Columbia University Mailman School of Public Health, to definitively answer the question. Senior investigators from the original studies were involved in the design of the new study. It was overpowered, involving 147 patients with the syndrome and 146 matched controls, recruited by researchers at six sites across the country. Analysis was blinded. Genetic tests that looked for the virus in the blood of the subjects found no evidence of XMRV or related viruses, said Lipkin. It is a very clean result that is impossible to misinterpret. There was a finding of some antibody responses in both groups of subjects, he said, but no association between the presence of those antibodies and disease.

5 It took extraordinary courage for the original investigators to participate in this study Lipkin said. I cannot think of a single instance where an investigator came back, went through this sort of a process, and then stood up and said I made an error here but am committed to moving forward. An advocate of a link between chronic fatigue syndrome and XMRV expressed disappointment that lymph node biopsies were not part of the study and asked whether the murine virus may have been present in a tissue compartment. It is theoretically possible... but it would be extremely unusual to have a systemic illness not to spill into the blood or leukocyte preparations, said Alter. The National Institutes of Health researcher played a leading role in discovering the hepatitis C virus. One has to resist the temptation to keep the murine retroviral hypothesis alive, he said. This study was really quite definitive. Lipkin believes chronic fatigue syndrome is likely to be a constellation of disorders, not necessarily a single agent, be it viral, bacterial, or otherwise. He called the samples gathered during this process an extraordinary resource for addressing questions related to the causes, the treatment, the management, the pathogenesis, the basic sciences of these disorders. The NIH has established a process by which qualified investigators can access the stored samples and it is funding further examination of them.