A Bold Effort
Collaboration – Dr. Vernon believes increased collaboration will be essential for our research community’s success. She knows the power collaboration can unleash. The Pharmacogenomics projects she lead at the CDC – which ended up thrusting ME/CFS into the research spotlight and helped triggered the National Press Conference – was the result of a single discussion at a conference.
The need to foster collaboration, maximize resources and speed up the pace of research lead Dr. Vernon to produce her boldest project yet; the creation of an International CFS Research Network. I asked her to explain more why a Research Network was needed.
Currently there are CFS investigators throughout the US – many working autonomously or in small collaborative groups. What we have found is that some investigators have promising laboratory techniques and biomarkers for CFS, but no clinical samples to test these on. Further, there are clinical researchers with great medical records and samples but without the time and expertise for laboratory research. This research network brings these types of investigators and resources together and collaborations almost naturally occur.
Have research networks of this type have been formed in other diseases?
There are now numerous examples of the need for and success of research networks and consortiums. These are needed because most of the public health problems we have to solve are incredibly complex, with no one investigator or discipline able to comprehend all there is to know. Examples include autism, cardiovascular disease, diabetes, and infectious disease –there are research networks for each of these.
Once researchers in the network get their data they’ll bank it in a central repository which other researchers can mine for information. They’ll also bank blood and tissue samples. Take a simple thing like sample collection. Small research efforts can often not afford to spend a great deal of time and money advertising for patients, assessing and characterizing patients. I know of several studies that have been held up for considerable amounts of time simply because researchers could not get enough samples. Consider how much quicker progress could move if researchers had a central Sample Bank they could simply request samples from.
Another problem concerns standardization. As crazy as it may sound ME/CFS researchers are using different tests and different techniques to study the same problem. This means it can be difficult to compare tests across studies. When a community is only producing a relatively small number of studies a year that’s a significant problem. Just getting researchers to develop gold standards for testing could help significantly
We are starting by developing best practices and standard operating procedures using a collaborative wiki space. CFS research network investigators will be in working groups and tasked with developing best practices and procedures and investigators will be in working groups according to their area of expertise. For example, we can have working groups for best practices related to imaging brain metabolism, measuring orthostatic intolerance, standardizing actigraphy, etc. Once working groups derive best practices and procedures, these are vetted through a peer review process and then disseminated to the clinical and research community, as well as the patient community when the information is relevant.
It could go further than that. Dr. Cheney, for instance, has a well characterized patient base and presumably enormous amount of data on diastolic functioning on his patients but has never been published it in a major journal. A Research Network could conceivably provide him and others the opportunity to get the assistance they need to publish. Sometimes it’s just a matter of getting people together.
Dr. Vernon is not the first to think a research network would be a great thing. A big problem – not surprisingly – has always been money; how does a poorly funded and scattered group of researchers get the resources to band together? Money will obviously be needed but Dr. Vernon wants to use federal resources as much as possible.
As for data sharing, in collaboration with academic colleagues we are looking at existing research network databases that we can leverage. Some of those we have been looking into were developed either at the NIH or with NIH funds. These are available for use by the research community. Because several of these research network databases are up and running – they have addressed issues such as privacy, data access and sharing, intellectual property; in other words, existing resources are available that have already addressed the sociologic and technologic challenges associated with research networks!
The network is just getting off the ground. When asked how big it is right now Dr. Vernon stated
The only established research network is the one I coordinate for the Associations funded investigators. This includes the 6 PIs along with 20+ co-investigators. Drs. Lenny Jason, Julian Stewart and I are applying for NIH funding to expand this research network to include many of the investigators who were at the Banbury meeting in September. Right now, we have letters of support from 25 of the 35 investigators that participated.
Getting researchers working together and sharing ideas data and samples would benefit all of us. Hopefully Dr. Vernon and the CFIDS Association will find the funding to get this network established.
Dr. Vernon could have won the award simply on the strength of her research. Somehow as all this was going on Dr. Vernon managed to publish six papers on chronic fatigue syndrome (ME/CFS) in 2008. Illustrating a remarkable breath of interest and expertise the papers focused on such subjects as the serotonergic system, inflammation and immune signaling, altered neuro- immune and immune networks, exercise, cytokines and a possible genetic marker.
Dr. Vernon’s Recent Research
- Cytokine polymorphisms have a synergistic effect on severity of the acute sickness response to infection.
- Evidence of inflammatory immune signaling in chronic fatigue syndrome.
- Neuroendocrine and immune network re-modeling in chronic fatigue syndrome
- A systems genetic analysis implicates FOXN1 in chronic fatigue syndrome
Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome.
- Model-based therapeutic correction of hypothalamic-pituitary-adrenal axis dysfunction.
(In 2009 Dr. Vernon outlined an innovative model which suggested the HPA axis of ME/CFS patients might be stuck in a suboptimal loop. The solution? For a very short period of time mop up as much cortisol as possible in order to force the system to reset. No one to my knowledge has tried this yet. )
Since XMRV is on top of everybody’s mind I wanted to get her take on some aspects of XMRV that are germane to the CFIDS Associations and others research efforts
XMRV is a really exciting, really hot finding. A lot of non XMRV research findingsnbsp; have been developed over the years; there’s the low blood volume, the HPA axis abnormalities, the metabolic related exercise problems, the orthostatic intolerance, the gastrointestinal enterovirus findings, etc. There are a lot of research findings that can’t at least at this point be directly linked to XMRV. Lets say XMRV is the ‘Game Changer’ in ME/CFS; will research focused specifically on those areas still be relevant?
Absolutely relevant! I hope that XMRV is replicated as it provides a clear biologic basis for CFS and a context for the ongoing pathophysiology CFS research. Once this is done, we will potentially have a context for low blood volume, the HPA axis abnormalities, XMRV, etc. It is worth noting that even though we can detect HIV and have antiretroviral therapy, people who are managing their HIV infection still have a variety of health issues to deal with including serious endocrine and metabolic problems to name a few.
The CDC research team has done a lot of research on the HPA axis and you developed a model suggesting that ME/CFS patients had become kind of trapped in a dysfunctional HPA axis feedback loop. You also developed a model which suggested that briefly reducing cortisol levels to very low levels could cause ME/CFS patients systems to kind of spring back into normal functioning. XMRV has cortisol receptors. Can you explain how XMRV, cortisol and the HPA axis might interact?
The HPA axis is our body’s “flight or fight” 24/7 system – in other words, it gets activated when the body needs to respond. This can be in response to infection, physical trauma, stress, etc. The HPA axis is also a very dynamic system that must respond when needed and stand down when not needed. Cortisol is one of the major chemicals that mediate the HPA axis response system. When the HPA axis system is alerted, cortisol is produced by the adrenal glands and pumped out into the circulation. There it signals to immune cells to produce cytokines to help fend off the infection or heal the wound.
Immune cells do this because the cortisol enters the cells, binds to the cortisol receptor in the cell and this complex moves into the nucleus where it regulates cell transcription. When it is time for the HPA axis to stand down, cortisol travels to the brain and signals to the hypothalamus to return the HPA axis to standby. There are several viruses that can persist and remain latent in immune cells. It is possible that these viruses alter the function of the cell where they reside.
What is the CFIDS Association doing regarding XMRV?
Since we learned about XMRV through the press release issued by WPI, NCI and Cleveland Clinic and then the Science paper once it was published, we have been busy gathering additional information on the many research and policy implications this important study brings. There are many investigators interested in replicating these findings who need funding to do this work.
At the CFSAC meeting in October, investigators with NIH existing grants were encouraged to apply for supplemental funding, so we contacted funded CFS investigators to encourage and support supplemental requests. This has involved “matching” lab researchers to clinicians who can provide appropriate patient and control samples for testing. We are currently raising funds through our “SolveCFS Campaign” in hopes of issuing another request for proposals (RFP) aimed at early detection, objective diagnosis and treatment of CFS; XMRV proposals would certainly be responsive to such an RFP.
We are also seeking up to date information from the various federal agencies now involved in the XMRV research and response. Interestingly, the detection of XMRV in 3.7% of healthy controls, as reported in the Science paper, raised potential concerns about the safety of the general blood supply. As also discussed at the October CFSAC meeting, the significance of XMRV in the blood supply will be determined by investigators who are expert in dealing with blood supply safety issues and have experience with other infectious agents that could compromise the blood supply.
We are working closely with many different institutions and agencies with each new development so that we understand what types of optimized XMRV assays will be most effective for use in larger studies that will advance collective understanding of the role of XMRV in CFS. Although in many ways the past 2 months have been hectic the CFIDS Association has been doing what we have always done and do best – advocating for and supporting research aimed at the early detection, objective diagnosis and effective treatment of CFS through expanded public, private and commercial investment.
The CFIDS Association is a small organization and much work remains but Dr. Vernon has brought a spirit of innovation and vision to this field that is sorely needed. Given that it was no surprise that the Research Community jumped to their feet and applauded when she was accepted an award at the IACFS/ME Conference. Phoenix Rising is proud to have her as its researcher of the year for 2008/09.