RESEARCH

Chronic Fatigue Syndrome (ME/CFS) Research 2006: the Year in Review by Cort Johnson

“2006 - THE YEAR OF INNOVATION”

2005 was the ‘Year of the Brain’. 2006 could have easily been called the year of the gene - six of the top ten studies involved gene studies - but what really stood out was how innovative many of the studies were. In 2006 researchers again and again looked ‘outside of the box’ for solutions to ME/CFS.

The CDC with its vast, multi-dimensional studies incorporating clinical, laboratory, gene expression and gene polymorphism data lead the way. Dr. Lloyd’s Australian Dubbo’s studies gave us a first look at what’s occurring in the body as people come down with ME/CFS. The Japanese used an old type of technology in novel way to perhaps come with the first objective diagnostic marker for ME/CFS.

The 2006 studies areas highlighted many different aspects of ME/CFS. While the gene polymorphism studies implicated neuroendocrine abnormalities, the gene expression studies swung our attention back to the immune system, and Dr. Lloyds results pointed straight to the brain. ME/CFS more than ever appears to be a multi-dimensional, multi-systemic disease.

RESEARCH PAPER(S) OF THE YEAR

Dr. Lloyd and the Dubbo Studies

Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, Reeves WC, Lloyd A; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study.BMJ. 2006 Sep 16;333(7568):575. Epub 2006 Sep 1.

Cameron B, Bharadwaj M, Burrows J, Fazou C, Wakefield D, Hickie I, Ffrench R, Khanna R, Lloyd A; Dubbo Infection Outcomes Study. Prolonged illness after infectious mononucleosis is associated with altered immunity but not with increased viral load.J Infect Dis. 2006 Mar 1;193(5):664-71. Epub 2006 Jan 30.

Vernon SD, Whistler T, Cameron B, Hickie IB, Reeves WC, Lloyd A. Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. BMC Infect Dis. 2006 Jan 31;6:15.

Vernon SD, Nicholson A, Rajeevan M, Dimulescu I, Cameron B, Whistler T, Lloyd A.
Correlation of psycho-neuroendocrine-immune (PNI) gene expression with symptoms of acute infectious mononucleosis. Brain Res. 2006 Jan 12;1068(1):1-6. Epub 2005 Dec 22.

The Dubbo Studies, which were funded by the CDC, are the first substantial effort to catch ME/CFS ‘in the act’. Several theories have been proposed regarding the end state in ME/CFS; that ME/CFS patients have cardiovascular or cardiac problems or they have an altered ‘set point’ in their nervous system or they have a complex set of neuroendocrineimmune problems.

These are all interesting ideas but they all deal with the ME/CFS patient after she/he gets sick. None purport to show how a simple infection or some other event that the all of us have easily tossed off for most of our lives suddenly turns into such a profoundly disabling event. What actually causes ME/CFS patients to fall apart? That is what the Dubbo studies are trying to answer.

Thus far these studies have been notable more for what they haven’t found than what they have. They’ve found that people who get sicker early in an infection are more apt to come down with ME/CFS. They know that it doesn’t matter which pathogen triggers ME/CFS; patients with different infectious triggers may have different symptoms at first but as the disease progresses they all look very similar. They know ME/CFS patients immune systems are able to recognize and to fight off the virus and that their symptoms are not caused by a chronic immune activation involving powerful immune agents called cytokines. They know that the pathogen appeared to work a bit faster in the patients that stayed ill and they have some evidence this was due to an imbalance in the immune system. They do not, however, think this imbalance caused ME/CFS. Instead they are turning to the brain for answers.

The Dubbo projects haven’t been perfect. They’ve only included EBV infected patients in their laboratory studies and their sample sizes have been small. Although they’ve looked at a broad range of immune factors they haven’t looked at several shown to be abnormal in ME/CFS. Still they’ve provided evidence that some subtle immune abnormalities may aid the disease process in ME/CFS and that the damage done probably occurs in the brain. Dr. Lloyd, the project leader has exciting plans to explore that area.

Unfortunately it doesn’t appear he’ll be able to. In the face of program cuts of its own their main funder, the CDC, cut off funding to the Dubbo project. Three attempts by Dr. Lloyd, an experienced researcher, to gain funding from the NIH inexplicably failed. Unless more funding is secured soon this innovative project will end. (Click here for more on these studies).

THE TOP TEN RESEARCH PAPERS OF 2006

The Genes Have It: Building a Model of ME/CFS

Broderick, G., Craddock, R., Whistler, T., Taylor, R., Klimas, N. and E. Unger. 2006. Identifying illness parameters using classical projection methods. Pharmacogenomics 7, 407-416.

This was the largest gene expression study yet done. Like many of the other Pharmacogenomics studies it was of a higher order of complexity than we’ve seen before. It didn’t just look at gene expression results – it tied together gene expression results with laboratory and clinical findings. This was a truly enormous project.

In the end this study had bad and good news. First these researchers believed that the ‘vast majority’ of gene expression data generated thus far in ME/CFS (90%!) is background noise that has little to do with the disease. But then they turned around and became the first group to use their results to build a model of ME/CFS pathophysiology. That in itself was a breakthrough. Even better, it made sense with what we know about the disease.

They conjectured that increased free radical production due to immune activation in ME/CFS damages the ion channels on the membranes of the cells. As support for this they noted that the top gene highlighted in this study (SESN1) is produced in response to oxidative stress. Ion channels problems have been postulated for several years but they’ve never made it into the mainstream. Given that it was encouraging to find the conservative CDC trumpeting ion channel dysfunction in ME/CFS. It was nice as well to see their results lead us back to the immune system – a part of the body the CDC has not focused on recently.

That was more than good enough but these researchers went further. They found that altered heart rate variability (HRV), which is another kind of unsung abnormality in ME/CFS, appeared to be related to both the symptoms and laboratory findings in ME/CFS. (A recent CDC study replicated the HRV findings.) (Click here for more on this study).

Supergenes at the Heart of ME/CFS?

Fang, H., Xie, Q., Boneva, R., Fostel, J., Perkins, R. and W. Tong. 2006. Gene Expression profile exploration of a large dataset on chronic fatigue syndrome. Pharmacogenomics 7. 429-440.

Like many of the other Pharmacogenomics studies these researchers took a different approach. They attempted to determine which genes were most responsible for the fatigue and depression seen in ME/CFS.

They found 188 and 164 genes that were associated with fatigue and depression, respectively, and 24 genes that were common to both. (The connection between fatigue and depression may lie in the brain. The neural pathways governing mood lie very close to those that may impact fatigue.) They speculated that these ‘super genes’ could play a key role in ME/CFS. What kinds of activities were these ‘supergenes’ involved in? Many of the same activities highlighted in the last study; the immune response, apoptosis (cell suicide), ion channel functioning and metal ion binding, cellular signaling and aberrant neuronal activity.

But the researchers didn’t stop there. After noting that several of the genes were involved in ‘cross-talk’ between the brain and the immune system they focused on a specific cellular pathway called the ‘focal adhesion’ pathway. Genes in this pathway guide the interactions occurring where the cell interacts with extracellular matrix. These interactions are involved in inflammation, ischemia-reperfusion and, perhaps most importantly, blood flows to the tissues – an extremely interesting topic in ME/CFS. This study, then, not only validated past efforts but opened much new ground for the future.  (Click here for more on this study)

Inherited Neuroendocrine Genes Contribute to ME/CFS?

Goertzel, B., Pennachin, C., Coelho, L., Gurbaxani, B., Maloney, E. and J. Jones. 2006. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics 7, 475-83.

Of all the Pharmacogenomics papers this one made the biggest splash in the press. This study suggested ME/CFS patients have a genetic predisposition to their disease centered in a group of polymorphisms occurring in a set of neuroendocrine genes.

The researchers singled out five genes of special-interest: two involved a neurotransmitter, serotonin, that is particularly active in parts of the brain believed dysfunctional in ME/CFS, and that has been implicated in the pain found in fibromyalgia. One is involved in regulating the levels of the two catecholamines, norepinephrine and epinephrine, that play a key role in the ‘other side’ of the stress response; the sympathetic nervous system (SNS). Besides regulating blood flows (a big issue in ME/CFS) the SNS also regulates immune activity. Two genes involved the kickoff agent (CRH) for the HPA axis part of the stress response and the last gene involved the end point of the stress response, cortisol.

This study appears to provide powerful evidence that ME/CFS patients have inherited gene polymorphisms that impair their responses to stressors such as exercise, infection, etc. The statistical part of this study did not, as the authors put it, ‘look spectacular’ but their results have, thus far, been largely confirmed by studies done since then.

The authors were enthusiastic enough about their results to state that "What is encouraging is that this rather mysterious and elusive illness called ME/CFS appears to be finally yielding to attempts at biomarker discovery."  (Click here for more on this study)

A Key Genetic Anomaly in ME/CFS?

Rajeevan, M Nathan., Smith,A., Dimulescu, I., Unger, E., Vernon, S., Heim, C. and W. Reeves. 2006. Glucocorticoid receptor polymorphisms and haplotypes associated with

Our genes come in subtly different forms called polymorphisms. All the polymorphism studies thus far completed in ME/CFS have examined a variety of genes to see if an increased number of polymorphisms are found in any one of them. This study is the first time somebody has been willing to bet their money that polymorphisms in a specific gene were important in ME/CFS.

This CDC group posited that ME/CFS patients would have an unusual form of the gene for the receptor for the main adrenal stress hormone, cortisol. Because cortisol must interact with it in order to affect the cell this receptor is critically important for the functioning of cortisol. People with a genetic alteration that caused this receptor to have a lower than normal affinity for cortisol, for instance, would need higher than normal levels of cortisol to achieve the same affect.

Concentrating on one gene was another bold move and once again it worked. They found that not only were ME/CFS patients more likely to have an unusual form of this gene but that the more unusual their gene was the sicker they were. Not only that but they were able to highlight a particularly disadvantageous form of this gene – people who had it tended to be very ill. When they looked more closely at the gene they found that one part of it appeared to be studded with alterations – this part of the gene they will study in more detail later.

What does all this mean? It suggests that cortisol is interacting differently with cells in ME/CFS patients than in normal, healthy people. If, for instance, the polymorphism found in ME/CFS patients causes the GR not to bind well with cortisol then the effects of the ‘mildly low’ cortisol levels in ME/CFS may not be so mild after all.
Problems with cortisol could result in poor energy, an inability to handle all sorts of stresses well, chronic immune activation and the symptoms associated with that, etc.

The CDC isn’t done with this gene. In 2007 they developed the first mathematical model of ME/CFS using this receptor.  (Click here for more on this study)

Critical Immune Gene Polymorphisms In ME/CFS Uncovered?

Carlo-Stella, N., Badulli, C., De Silvestri, A, Bazzichi, L., Martinetti, M., Lorusso, L., Bombardieri, S., Salvaneschi, L. and M. Cucci. 2006. A first study of cytokine genomic polymorphisms in ME/CFS: Positive association of TNF-857 and IFNgamma 874 rare alleles. Clin Exp. Rheumatol. 24, 179-182.
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While the CDC was busy examining neuroendocrine gene polymorphisms this Italian team assessed whether or not ME/CFS patients have a genetic predisposition towards pro-or anti-inflammatory cytokine activity. They found that increased rates of the two polymorphisms in ME/CFS suggests they have a tendency to produce more of the pro-inflammatory cytokine called tumor necrosis factor than normal.

TNF-a is a very important cytokine that has been linked, interestingly enough, to fatigue in two other diseases; multiple sclerosis and cholestatic liver disease (click here) and something called ‘vital exhaustion’ (fatigue, insomnia, unrefreshing sleep, irritability) that sometimes occurs following heart surgery. This suggests that increased TNF-a levels could play a major role in the many of the symptoms found in ME/CFS.

It’s may actually be worse than that. A recent study suggested that not only do ME/CFS patients produce more TNF than normal but they may over-react to it when they do produce it. This may, in fact, not be so surprising. One ME/CFS researcher believes that high stress levels over time predispose one to becoming supersensitive to TNF-a.

The confluence of neurodendocrine and immune gene polymorphisms is intriguing to say the least. The immune gene polymorphisms suggest ME/CFS patients may be predisposed to produce more TNF-a than normal and the neuroendocrine gene polymorphisms suggest they have difficulty turning it off. (Click here for more on this study).

“It’s Like Star Trek!” – Dr. Charles Lapp

Sakudo, A., Kuratsune, H., Kobayashi, T, Tajima, S. Watanabe, Y. and K. Ikuta. 2006. Spectroscopic diagnosis of chronic fatigue syndrome by visible and near-infrared spectroscopy in serum samples. Biochemical and Biophysical Research Communications 345: 1513-1516.

This little three page study was the big wild card of last year. If these researchers can replicate its results we could be entering a new era of ME/CFS research. Using a process called NIR Spectroscopy these researchers were able to correctly identify 95% of over 200 blood samples from ME/CFS patients correctly The process is stunningly simple. After attaching a probe to ones thumb it only takes about a second for the machine to analyze the results and spit out the answer! Dr. Lapp was right when he said it was like Star Trek!

What a breakthrough this would be. The question of whether ME/CFS was a real disease would obviously be answered and it would help researchers build coherent sample sets and maybe even find subsets. The unique protein signature they’ve found would also give researchers clues regarding its pathophysiology. It sounds almost too good to be true – and it may be. NIR spectroscopy has been used to document blood flows but has never been used as a diagnostic tool in the medical field because of questions regarding its specificity.

This team was quite encouraged by its results. At the 2007 IACFS/ME conference they talked about using it as a worldwide diagnostic tool and called for international collaboration. They are also looking for and finding unique spectroscopic signatures in other diseases such as lupus. This was another very innovative project in a year full of them.

An Immune Subset in ME/CFS Identified? The Breakup of the CFS Label in Sight?

Siegel. S., Antoni, M., Fletcher, M., Maher, K., Segota, C. and N. Klimas. 2006. Impaired natural immunity, cognitive dysfunction, and physical symptoms in patients with chronic fatigue syndrome; preliminary evidence for a subgroup? Journal of Psychosomatic Research 60, 559-566.

This group is on a roll; in 2005 they identified a perforin deficiency in natural killer (NK) and T-cells in ME/CFS patients that may be due to a persistent infection (click here). Just six months later they appear to have identified the first immune subset in ME/CFS.

This study found that those ME/CFS patients with decreased NK cell activity were less vigorous, and had more cognitive problems and poorer daily functioning than did those with normal NKC activity. These are relatively simple findings but they could have a huge impact on the future of ME/CFS research. Much immune research in ME/CFS has been dogged by inconsistent or non-significant findings. This could change in a hurry if researchers were able to identify and focus on the subset of ME/CFS patients who do have immune problems. Finding an identifiable subset is one of the ‘holy grails’ of ME/CFS research.

It is also a way out of the ‘box’ of ME/CFS, a way to break up the name and, importantly, a way to re-invigorate immune research in ME/CFS. This study still needs to be replicated. Thankfully this is one of the few ME/CFS research group the NIH is willing to fund and more studies are on the way. (Click here for more on this study).

A Biomarker For ME/CFS Found?

Presson, A., Sobel, E., Papp, J., Lusis, A., and S. Horvath. 2006. Integration of genetic and genomic approaches for the analysis of Chronic Fatigue Syndrome. CAMDA.

These researchers from the CAMDA project used the same database the CDC research teams did in the Pharmacogenomics studies. First they identified a key genetic polymorphism involving serotonin (trytophan hydroxylase) that was associated with increased illness in some ME/CFS patients. Then they uncovered eight other key genes whose expression was associated with increased illness, and which appeared to interact with many other genes that played a role in ME/CFS.

They then focused on one gene called the Forkhead Box gene (FOXN1). The FOXN1 gene plays a role in T-cell development and polymorphisms in this gene have been shown to cause dysfunctional T-cells and an impaired immune response. This is an intriguing as we know that reduced levels of the main cytotoxic element in both T-cells and natural killer cells (NK), perforin, are found in ME/CFS (Click here). ME/CFS patients also display increased T-cell activation – perhaps in response to impaired T-cell functioning.

This gene’s association with a polymorphism that alters the rate of serotonin metabolism adds weight to the notion, now becoming fairly well established that a neuro-immune interaction plays a role in ME/CFS. Serotonin is fascinating in its connections to brain induced fatigue, mood disorders and vascular problems, all of which may occur in ME/CFS. One nice aspect of this gene is that because genomic and antibody markers are available for it should be easy to study in ME/CFS. (Click here for more on this study).

Blood Deprived Brains in ME/CFS

Yoshiuchi, K., Farkas, J. and B. Natelson. 2006. Patients with chronic fatigue syndrome have reduced absolute cortical blood flows.

Dr. Natelson has been exploring brain functioning in ME/CFS patients for over 10 years now and he is convinced that at least a portion of ME/CFS patients suffer from an encephalopathy – a brain disease. Now he trained his sights on blood flows in the brains of ME/CFS patients.

Dr. Natelson found that the rates of blood flows in the left and right cerebral arteries s were about 25-30% lower in ME/CFS patients than those of the controls (!) (ME/CFS – 45-60 p/m, controls – 65-85 p/m).
Unfortunately there was no speculation as to the cause or the effects of these reduced blood flows but they do fit in with mounting evidence that both vascular and brain problems occur in ME/CFS. Dr. Baraniuk’s recent proteome study suggested a condition sometimes associated with low blood flows called amyloidosis (protein aggregation) condition may be occurring in ME/CFS patient’s brains and several studies have suggested either low blood volume or microcirculatory problems occur in ME/CFS. (Click here for more on this study).

Brain Shutdown in ME/CFS

Tanaka, M., Sadato, N., Mizuno, K., Sasabe, T., Tanabe, H., Saito, D., Onoe, H., Kuratsune, H. and Y. Watanbe, Y. 2006. Reduced responsiveness is an essential feature of chronic fatigue syndrome: an fMRI study. BMC Neurology. 6: 9 doi:1186/1471-2377-6-9

Most brain imaging studies examine brain activity at rest or during a task. This study captured images of brain activity not just under the stress of doing a task but when the participants were mentally fatigued as well. It suggested ME/CFS patients have a reduced ability to pay attention to more than one stimulus at a time. Importantly it was able to link fatigue with brain activity; the more fatigued the ME/CFS patients were, the less well their brains were able to pay attention to more than one stimulus.

This suggests that as the mental fatigue in ME/CFS gets worse and worse more parts of the brain become, so to speak, ‘uncoupled’ from each other. The authors posited this was due to something called cortical spreading depression (CSD). CSD is believed caused, interestingly enough, by constricted blood vessels in the brain – something that could contribute to the low brain blood flows found in the Natelson study we just reviewed. (Click here for more on this study).

2006: The Year in Research - Conclusions

This was another very good year for ME/CFS research. Some officials in the NIH have charged ME/CFS proposals lack innovation but this year was nothing if not innovative with the CDC’s CFS team employing data mining experts to explore enormous amounts of gene expression and laboratory data, and the Japanese ME/CFS research team using a new technique as a diagnostic tool, and the Dubbo exploring what goes wrong as ME/CFS occurs. It was gratifying as well to see the CDC’s research circle back and validate findings by ME/CFS researchers that have mostly been ignored by the research community.

This really was the CDC’s year. The publication of 14 papers in the Pharmacogenomic’s Journal and the kickoff of the CDC/CAA media campaign combined to give ME/CFS exposure it hasn’t seen in many years. This exposure appears to have worked to increase both the extent and quality of stories in the media on ME/CFS over the past year and there are hints that ME/CFS is gaining a new kind of legitimacy.

The Future – Yet there have been substantial setbacks as well. Dr. Friedberg will publish a paper in 2007 showing that publication rates in ME/CFS research - in contrast to fibromyalgia and fatigue research in general - have been essentially flat over the past five years. Despite the successes of 2006, continuing cutbacks in the NIH’s and CDC’s ME/CFS research program mean a dry spell awaits us in the future.

Both the large-scale Pharmacogenomics type projects and the innovative Dubbo studies appear to be a thing of the past. Budget cuts to the CDC’s program mean the next year or two will probably be spent mining data gathered in the past and poor leadership and ignorance at the NIH appear to have doomed the Dubbo studies. Its remarkable to see two successful and innovative projects fall by the wayside and it reflects on fragile position ME/CFS holds in our research institutions.

There is the feeling that ME/CFS researchers are starting to put some of the pieces together but the opportunities the field presents are not being matched by the work being done in it. Funding levels are abysmally low and while exciting progress is being made our understanding of this disease is still primitive. 2007, which is almost over, will most likely not match the successes of 2005/2006 either in quantity or quality. As the major research institutions turn away from ME/CFS continued success in the research arena may depend as much on successful political action as it does on scientific activity.

To The 2006 Research Group of the Year