Report From the OFFER Conference

Posted by Cort Johnson

Dr. Singh

4127 Singh.An Old Murine Leukemia Virus (MLV) Hand

Dr. Singh knows these viruses well and she’s not surprised at the difficulty researchers are having pining them down. She has been studying XMRV for four years and a close relative of it (Moloney Murine Leukemia Virus) for 12 years. ](How lucky we were that a major MLV researcher in the area located just down the street from Dr Bateman). I asked her if she was having more or less trouble with XMRV than she did with the Moloney Virus when she first got started with it and she said it was about the same.

She’s been studying XMRV prostate cancer and was ‘very surprised’ to see XMRV turn up in CFS since the disorders share very little similarity. (Whether or not XMRV causes prostate cancer is still very much up in the air. For one thing it’s not found in most cases of prostate cancer and Dr. Singh said that the tumors themselves contain ‘very tiny’ amounts of the virus. However, even if it caused only a small percentage of prostate cancer tumors it would still be implicated in a large number of deaths).
Citing all the traffic between Europe and the US she can’t believe that geography plays a role in a disparate results. Instead she thinks that sequence variation in different areas is probably the key and could easily throw the PCR’s off and her study is focused on pining that aspect of XMRV down.

An Excellent Study – Kim McCleary believes her study could end up being one of the definitive ones. As Dr. Bateman noted in one of the CAA’s webinars Dr. Singh is building on past studies and filling in the gaps. She is using fresh, not stored blood and is being extremely careful with blood handling and her test protocols. With 200 healthy controls and hundred and five CFS patients she’s got a very large study going and she is using multiple methods to detect XMRV including qPCR for proviral DNA, RT-PCR, two types of antibody tests and culturing.

A Different Kind of PCR – While she stated she could not see any way the WPI’s or Dr. Alter’s results could be due to contamination, the quantitative real-time PCR she is using makes it impossible for one patient sample to contaminate another. Nested PCR – the type of PCR most researchers have used including the WPI and Dr. Alter is more sensitive and specific but because you have to open ‘the tube’ it’s theoretically possible for contamination to occur. You don’t have to ‘open the tube’ in qPCR – it’s a one-shot process. With all her work on these viruses Dr. Singh stated that she’s created an extremely specific qPCR test for XMRV.

Different Sampling Techniques – Dr. Singh noted that the samples in the healthy controls and CFS patient samples in the original Science study were handled in different ways, and that while the patients came from across the US all the healthy controls came from Maryland. (In one of those odd coincidence’s all of Alter’s healthy controls also came from Maryland as well.) is not to knock the original study; all studies have their weak points but to illustrate how her study will fill in some missing pieces. Dr. Singh’s patients and controls will come from the same area and the blood storage methods will be identical for both. This will control for differences in blood preparation and geographical variations in viral persistence and in viral sequences. Importantly, with the help of Dr. Bateman, she is also breaking up the patients into three cohorts depending upon severity. Dr. Mikovits is also having a phlebotomy company take fresh samples from previously identified XMRV positive patients and send them to her for testing.

A Researcher with Culture :) She is also (very carefully – as she put it) culturing the virus. She said that she felt researchers should concentrate on the most ‘sensitive’ methods of detecting the virus that were described in the original paper – and that was clearly culturing – so that’s what she’d doing. To my mind she basically inferred that researchers that were not doing that were not giving the authors of Science paper a fair shot. The problem with culturing is that it takes six to eight weeks and is expensive and labor intensive.

The XMRV Autopsy Study Is Wrapping Up (Has Wrapped Up) – She has been working on her XMRV autopsy study for THREE years. She started it in Columbia and was able to bring it (and her entire team) over to the Univ. of Utah. (Think of that! Her entire team left the intellectual backwater that is Columbia to move to that paragon of medical research- the University of Utah; she obviously inspires alot of loyalty in her team members. Let’s hope they were shipping slides not corpses :)).

She has been taking samples of every organ in the body, putting them on a slide, and then examining them for evidence of XMRV using her Immunohistochemistry protocols – an exhausting procedure. (These cause XMRV infected cells to be highlighted.) We have some idea where XMRV shows up in rhesus monkeys; now we’ll know where it shows up in humans. (I assume that she has cause of death and medical histories so she should be able to determine if XMRV is associated with specific diseases as well). The exciting news is that the study will be done in the next month and should be published sometime around the New Year. I asked her if the fact that the XMRV was a hot topic would speed up publication? She said it was the just the opposite; because every journal is afraid of being wrong on a hot topic everybody on the editorial board would take a look at it and that would slow things down.

That Rare, Rare Virus – XMRV appears to be really rare in the blood (but see the Ruscetti/Mikovits abstract in the XMRV Workshop which suggests it may be present in other immune cells) and so I asked her if such a rare virus could cause such signficant effects as ME/CFS? Did researchers need to find it in higher levels somewhere else for it to really be doing something? She said ‘No’ and referred to another retrovirus, HTLV, that she believes could be a model for XMRV. HTLV clearly causes leukemia in some people but even in those people it’s found in very low levels. Interestingly, only causes leukemia in a subset of the people that it infects. Why it causes leukemia in some people but not others is unclear.

Can XMRV cause disease if it’s not replicating? – she noted that several viruses cause cancer simply by inserting themselves next to oncogenes in a cell’s DNA. But ME/CFS is not leukemia and even if cancer is associated with it’s not be present in many people with ME/CFS. What about the disease itself – the numbing fatigue, etc? I asked if XMRV could disrupt another type of gene simply by settling down next to it? She thought that was a possibility but couldn’t come up with an instance in which that had happened with another virus.

Treatment Trials – Dr. Singh again brought up the possibility of treatment trials and even outlined some parameters (60-80 patients in a placebo controlled multi-drug trial) and named two companies she is in very preliminary discussions with. We know she’s gotten some results back from her study. Her autopsy study is done – she knows where XMRV is found in the general population. She’s mentioned treatment trials twice now – should we conclude anything about her results? We’ll find out in a couple of months!

Name Change – Will we be getting a formal name change? She doesn’t think so; for one thing the original discoverer is in charge of naming a virus and two, she imagined there would need to be much more consensus on the virus before one would occur.

Dr. Vernon’s Talk

A New and Exciting Time in ME/CFS

Dr. Vernon is clearly absorbed in finding ways to maximize the technological revolution going on around us. (Her work on the Pharmocogenomics project at the CDC was one of the first in the medical field to attempt to tie together clinical (patient), laboratory, genetic and gene expression data. That work required bringing in data mining experts from outside the medical field to interpolate the data. One of the CFIDS Association’s research grants involves a similarly cutting-edge approach with its mission to interpolate and make sense of huge masses of data. In fact, three of the grants started off as separate grants and ended up feeding data into each other, in effect creating a kind of super-project.

One of them involves characterizing the genomic content of our guts -something she said has never been done before – and which will cost much more than the CFIDS Association is paying the researchers to do it. She’s not sure how they are finding a way to do it but they are on the cutting edge of science – a place innovative researchers love to be – and they are finding a way.

Biomarkers, Biomarkers, Biomarkers – She started off her talk stating that medicine has NOT taken advantage of the technological revolution to the extent to the extent it could. The question is, how can we take the knowledge we have about ME/CFS to solve it? The way to do this is through using biomarkers. She noted that medicine is moving towards a system that relies on biomarkers and that finding biomarkers can be a long, drawnout, complicated and often expensive process.

In fact, not many diseases have biomarkers but ME/CFS has a fairly long list of potential biomarkers ranging from natural killer cell functioning to R NaseL to metabolic dysfunction, blood flow problems, signaling problems, cortisol abnormalities, EBV/XMRV, genetic differences and on.

Brain – She believes the brain is responsible for many of the symptoms ME/CFS patients experience; the fatigue and pain, cognitive problems and sleep problems and often created in the brain plus the commands from our brain affect all our bodily systems. We will see that she believes that the command and control system system is messed up in ME/CFS.
Autonomic nervous system (ANS) – she noted that 75-80% of people with ME/CFS have significant ANS problems involving blood flow problems that probably caused by chemical signaling screwups. She believes problematic ‘signaling’ processes may play in key role in ME/CFS. This suggests that ME/CFS may be more a problem of communication between systems than it is of a damaged organ.

Think of the brain, for instance telling the blood vessels to constrict when they’re supposed to expand or muscle receptors telling the brain the muscles are hurt (aka Dr. Light’s work) and thus causing the brain to make them painful. In this scenario it’s the interplay between systems, the ‘dance’ that allows the body to work efficiently and gracefully that is damaged. Does she believe the virus could cause this? Absolutely she does; in fact she believes a virus is the most likely cause of such a problem.)

Immune system – The immune system consists of a huge and immensely complicated network of immune cells. (Dr. Vernon and Dr. Klimas have published a paper suggesting that the immune cells in ME/CFS are not ‘networking’ properly; ie ‘x” cells are sending signals to (and affecting) ‘z’ cells instead of ‘y’ cells, which makes mounting an immune response a) more difficult and b) less effective. )These strange networks suggest that low-level of inflammation is present in the body. Again we potentially have a problem with signaling – with communicating between different tissues in the body. Feel like the wires got crossed in your body? That’s exactly the type of response a signaling problem could cause.

Cortisol – we know that the levels of the ‘fight/flight’ hormone are low in ME/CFS and that cortisol is an important immune regulator as well. Some people with ME/CFS have genetic abnormalities in their glucocorticoid receptors which make them less effective at maintaining the correct cortisol balances; ie – a signaling problem may be present there as well.
Infections – including XMRV and EBV are other potential components of a biomarker; they can cause perturbations that, among, other things, interfere with cell to cell signaling.

(Eludicating biomarkers – a biomarker is not necessarily a single thing; in fact, many ‘biomarkers’ are series of factors; they are multiple aberrations that combine to create ‘a’ biomarker. One biomarker in ME/CFS might have to do with cortisol (low cortisol), a cytokine that is not been regulated properly (high IL-8, low IL-10) and an infection (active XMRV) that’s spun out of control because of that (or caused it); low cortisol, high IL-8, low IL-10 and active XMRV that could be one biomarker for one subset of ME/CFS patients. If you get that biomarker nailed down then in your further research you ONLY examine patients that have that biomarker. )

The Path to Solve ME/CFS There are plenty of intriguing leads in ME/CFS yet we still have no validated biomarker; why not? Because ME/CFS IS a mixed batch of different diseases and if you throw a bunch of diseases together in a research study you’ll never be able to replicate and validate biomarkers.

Dr. Vernon believes ME/CFS is a bunch of different conditions that end up with a similar symptom presentation. To demonstrate that she turned to me and another patient and asked us what happened? By the time we were done it was clear we had two very different stories that ended up with a similar (but not identical) symptom picture) and that we probably have two different disorders.

( It’s true that XMRV may be the great unifier (my speculation) but even then you’re still stuck with a bunch of people with very different stories, a wide range of symptoms and a huge number of permutations on an illness. Even if XMRV is found in 85% of patients you’re still going to have to determine which other factors are causing all this variability.)

(The main problem in ME/CFS is NOT that people think it’s a psychological disorder; if the research community was convinced that this disease was psychological we would be drenched in money – psychological disorders get lots of money! The main problem is that most people don’t believe ME/CFS is any one thing and pouring money into a bunch of different diseases masquerading as one disease is like pouring water into a sieve.)

Breaking up the Great Melting Pot – So how do you break up the melting pot? First you gather as much data as you can on every patient – enough data to begin to flesh out the different subsets, – then you make sure every person’s blood sample is collected the same way in the same tubes and everybody is tested the same way. When you look for XMRV you make sure that everyone uses the same validated test to do so. When you do a tilt table test you make sure everyone stays up on that tilt table at the same angle for the same period of time. When you do an exercise test you make sure everyone exercises at the same rate and is measured in the same way.

Then you test the heck out of them.

An Organized Rigorous Process Yields Results – Big Results – By gathering lots of data, collecting samples properly and using standard operating procedures (SOP’s) Dr. Vernon believes she can cut a 20 year process for gathering biomarkers to 3-5 years. Why does she think so? Because that’s what not for profits did in another notoriously heterogeneous disease, multiple sclerosis, not too long ago. Thus far they’ve identified 19 possible biomarkers and are now in the phase of validating them. The CAA’s Research Network/BioBank is modeled on that plan. (Expect to be reading about breakthroughs in understanding MS in a couple of years and new treatments on the way).

(Validated biomarkers are gold; they are like gold pieces of string that lead to the heart of an illness. They give researchers a foothold on a disorder. What biomarkers do is give researchers the confidence that they can work their way down that string to disentangle what’s going on in the disorder. XMRV has been so successful because it’s the biggest string found yet in ME/CFS; it’s given them the biggest chance yet to be successful.)

Alzheimer’s organization’s did the same thing Dr. Vernon is proposing and now their laboratory’s are investigating dozens of potential treatments for biomarkers in a disorder they found utterly perplexing not long ago. That is the future Dr. Vernon proposes we can be living into if we can marshall our forces, work together and tackle ME/CFS in an organized fashion. That is what the BioBank and Research Network are about.

Dr. Wood on Advances in FM

Adding Fibromyalgia to the Conference proved to be fascinating and Dr. Wood was an entertaining speaker. There are so similarities between the two disorders that it’s hard not to believe that they don’t share core elements. FM is characterized by mildly low cortisol levels (check), low human growth hormone (check), increased baseline sympathetic hypersensitivity (check), decreased parasympathetic activity (check), poor response to physical and mental stressors (check!), brain atrophy (check), abnormal brain metabolite (check – but different types in ME/CFS), increased ‘alpha-delta’ sleep, disrupted dopamine neurotransmission (?), reduced mu opioid receptor levels and lastly cervical compression (?).

Fibroymalgia is also a heterogeneous disorder that is probably filled with subsets and considerable debate is centered around, just as in CFS, how to define it. One proposal is to drop the tender point criteria and to produce a more ‘empirical’ criteria that looks, yes, very reminiscent of the Empirical Definition in ME/CFS in its use of questionnaires that elucidate symptom severity and widespread pain. No physical examination is necessary.

Dr. Wood said if there were five or six distinct subsets in fibromyalgia he (jokingly (?)) imagined there were 50 or 60 in ME/CFS. He is engaged in some exciting research that may be able to peel off a distinct subset in FM using an oxidative stress factor that has never been closely looked at before. He asked that it not be published but my guess was that it could be translated to ME/CFS; it will certainly be looked at.

Spinal Cord Compression Subset – The other subset that is emerging is a ‘spinal cord compression’ subset. He gave the impression he thought that spinal cord compression was voodoo for many years but now appears firmly convinced it plays a significant role in some FM patients pain. It occurs when the spinal cord canal narrows putting pressure on the spinal cord and appears to happen mostly in the neck area. He noted that animal studies have shown that light spinal cord compression results in autonomic arousal (CHECK!) and that neck trauma (from car accidents?) is common in fibromyalgia. Procedures to reduce the compression of the spinal cord have been very effective in some people.

(What about CFS? Does the success of the Perrin technique and chiropracty in some patients suggest spinal cord compression could be involved? (One chiropractic video shows a person failing the Rhomber test and then passing it after a manipulation). How about Dr. Lapp’s observation that many people with ME/CFS have tightened, constricted upper body muscles and poor posture? Could that contribute in subtle ways to ME/CFS? Could people with ME/CFS either be more prone to spinal cord compression or more prone to be effected by it?).

Fibroymyalgia is several steps forward in delineating subsets and the next couple of years could be quite exciting.

Dr. Wood took a close look at the three FDA approved drugs for FM (Lyrica, Duloexetine and Milnacipran) and seemed not to be that impressed with any of them.

“Clinical Pearls”


• Consider anti-epileptics like Lyrica if you suffer from insomnia, anxiety, low BMI, traumatic onset (esp. cervical), tingling sensations and/or restless leg syndrome
• Do not take anti-epileptics if you – have strong cognitive dysfunction, obesity, history of angioedema


• Consider Anti-depressants if you have: depressive symptoms, fatigue, cognitive dysfunction and insidious onset under psychological stress
• Do not take anti-depressants if you have: restless legs, grind your teeth, experience sexual dysfunction, hypertension, increased heart rate, or are bi-polar

He is a big fan of pyridostigmine. He noted that sodium oxybate is excellent for sleep but costs $2400 a month (!)

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