Special Message for you from Ron Davis (video)

[greeneagledown]

@HTester -- Thanks for the info. I have a question. Ron has indicated that based on his nanoneedle experiments, ME/CFS patients' cells behave fine when in a healthy person's plasma, while both healthy patients' cells and CFS patients' cells "crap out," so to speak, when put into a CFS patient's plasma. That suggests that the problem is something (or a lack of something) in the plasma and the effect that this something (or lack of something) is having on cells, not necessarily a primary problem in the cells themselves. Is that inconsistent with your theory? It sounds like you're studying cells and not plasma.

Thanks.

 

[Pyrrhus]

The other way that the dsRNA state is stabilized is by use of a viral protein called a viroporin. This viroporin punches holes in the endoplasmic reticulum, releasing Ca2+ ions into the cytoplasm. Eventually, late in infection, there are enough positive charges available to shield the negatively charged dsRNA, which results in a long-lived dsRNA intermediate state.

I just wanted to briefly answer two questions that so often arise concerning the increased intracellular Ca2+ concentration in enterovirally infected neurons:

Q: What are the metabolic consequences of an increased intracellular Ca2+ concentration?
A: We don’t know exactly. Ca2+ ions are second messengers or regulators of so many cellular processes, it may be impossible to predict the exact metabolic sequelae. Perhaps Dr. Phair’s software might one day shed some light here.

Q: What happens to the intracellular Ca2+ concentration when the neuron fires?
A: When the neuron fires, there is a sudden, steep, but temporary drop in the Ca2+ concentration as the Ca2+ ions are rapidly pumped out of the cell. This may provide a window of opportunity for the previously stabilized dsRNA, allowing the dsRNA to separate, and allowing viral replication to continue as long as the neuron is firing.

Hope this helps.

 

[JES]

One question from my side as well to @HTester. Do you think there is any way the tryptophan trap model could not only explain the quick worsening following an infection, but also the temporary remission that some of us get during an infection? I noticed that Ron Davis had observed the same effect in the laboratory, i.e., ME/CFS cells behaving more normally following an infection. I have twice caught a cold during the last few years and both times symptoms have improved dramatically.

 

[boolybooly]

This is a thoughtful thread. Its big picture idea is that ME/CFS is now seen by multiple researchers as a change from a physiological steady state to a pathological steady state that is not a consequence of a chronic infection. The initiating stress is long-gone, but the patient is still sick. This emphasizes the contrast with viral and bacterial illnesses that persist only as long as the infectious agent remains undefeated by the combined efforts of the immune system and pharmacotherapy.

Historically, many researchers have sought a chronic infection as a cause of ME/CFS. I'm sure some still do. To my mind, the available evidence points to a switch or a trap, rather than a chronic infection. But if tomorrow someone reports an infectious micororganism in CFS patients and not controls, I am willing to be convinced by the data.

The only unique things about my IDO metabolic trap hypothesis are 1) its dependence on common genetic mutations can explain the existence of CFS clusters/epidemics like Adelaide, Incline Village, and Lyndonville, 2) it focuses on a specific metabolic pathway (the kynurenine pathway of tryptophan oxidation) and substrate inhibition of a specific enzyme (IDO1), 3) a theoretical nonlinear ordinary differential equation model of this pathway can be provoked to transition from a physiological steady state to a pathological steady state and remains there for years, and 4) if this bi-stability occurs in serotonin-producing cells of the gut and in serotonergic neurons in the midbrain, a very large set of CFS symptoms could be accounted for.

At the time of my talk at the OMF Stanford symposium we even had some preliminary experimental data consistent with the predictions of the IDO metabolic trap. But the succeeding six experiments did not confirm the first six. Peripheral blood mononuclear cells (PBMCs) are a heterogeneous collection of immune cells and our theory says only 1% or less of those cells are expressing the kynurenine pathway. This makes it difficult to measure the consequences of the IDO metabolic trap for intracellular tryptophan because all the cells are using tryptophan to make protein while only 1% or less are using tryptophan to make kynurenine. So increases in intracellular tryptophan are difficult to detect against the background of all the cells not making kynurenine and therefore not accumulating tryptophan, and levels of kynurenine are so low they come close to the lower limit of quantification (LLOQ) in our current mass spec instrument. There is nothing wrong with the mass spec data; we are just pushing the limits of what this instrument can do

We see several possibilities we are currently pursuing. 1) We can isolate the subpopulation of PBMCs that we hypothesize to be in the IDO metabolic trap and thus have a more homogeneous cell population. We did not start with this approach because it's slower and it removes those cells from interactions with their fellow immune cells, which might well be critical. 2) It's possible that the standard culture medium for PBMCs drives all the kynurenine-producing cells into the IDO metabolic trap because that medium contains 4- to 6-fold more tryptophan than human plasma, and blood plasma is the normal environment of PBMCs. 3) The literature argues that the kynurenine pathway in PBMCs is only operating when upregulated by immune stimuli such as IFNg. If this is so, the IDO metabolic trap cannot operate in PBMCs and we will have to find a way to study tryptophan metabolism in serotonergic neurons.

Number 2) is my favorite hypothesis at the moment because it would explain our experimental results in a beautiful way. But this is science; we formulate hypotheses and then we test them by designing the best experiments we can. This is where I am. I'm honored that so many of you are paying such close attention. I worked on heart disease for most of my career, and never once was I asked by a patient to explain what I was doing and why I was doing it. I like explaining things. I won a bunch of teaching awards back when I was a professor. So I'm happy to write about what's happening. Just be aware that the hours we invest in communicating the science are necessarily hours that we take away from doing the science.

I talk with Ron every week. We have a problem to solve. We think we have a shot at solving it. Thanks for all you do to support us and to support other CFS research teams around the world.

Well good luck as I said above, I hope you can find some way to help Witney and many others whose tragedy inspires and deserves our most sincere compassion.

To declare my interest, I have a version of ME CFIDS which undoubtedly produces recurring virus, which I can prove because I have had my recurring virus rediagnosed multiple times by PCR via the NHS over the 32 years I have been afflicted. For the sake of biological clarity this virus is HSV2 and it is important to note that contracting this virus in the middle of my studies for a zoology degree at Oxford triggered the ME condition including profound energy loss, neurological dysfunction and increased allergic responses, in the context of prior EBV mononucleosis three years earlier. It still causes a recurring cycle of approximately 45 days on average and I typically have between 8 and 12 infection and clearance cycles per year each with a similar degree of intensity as the first attack even now, 32 years later.

This is why I consider the pathogen or pathogens remain active in ME CFIDS of this kind and it is not accurate to assume the infection has passed and is not a factor. This does not preclude a bistability hypothesis, since a bistable state might describe such chronic dysfunction of the immune system but it seems plausible that pathogen derived molecules could play a part in causing this state given the timing of infection and ME onset which I experienced.

Certainly in my own case something has gone wrong with my immune system as a result of contracting the viruses I did and the result is that other viruses have a tendency to recur such as rhinoviruses which have a temperature trigger and I also have indications of an echovirus like infection recurring as well as patches of distinctly EBV like symptoms, none of which have been tested but which are nevertheless a reality to me and are why I live in a house kept at 27°C and constantly wear fleece hoodies and hats etc indoors to prevent chilling. The HSV2 however is my canary virus if you like and provides empirical evidence of atypical recurring virus because its symptoms are characteristic and unmistakable in conjunction with PCR testing.

I recognise from discussions online that not all ME patients have this kind of experience, though some do and I would attribute the difference to different subtypes of ME CFS. I do not know what proportion of cases without overt viral symptoms are due to hidden viruses which do not have such obvious symptoms and what proportion are due to some other type of condition which could be considered a different subtype of ME CFS and might be explained by a bistable state and metabolic trap model on its own without reference to pathogenic interference.

This kind of trap hypothesis is very interesting because this kind of explanation has the power to explain swift systemic changes to metabolism of an enduring nature which ME apparently causes in many cases so I think research is very worthwhile and may be the key to one or more subtypes and contribute to understanding other subtypes. I do think ongoing pathogenic activity is a reality for some subtypes but this does not mean a metabolic trap is not involved, it just means it does not need to explain a condition without pathogenic causation even though at an abstract theoretical level it has the potential to provide that kind of explanation. I am afraid the reality for many of us is not as clear cut as the abstraction.

IMHO characterising and distinguishing subtypes of ME is very necessary and is the greatest hurdle facing ME research today but I think there is much value in studies which help provide a foundation for doing this.

 

[Inara]

I just wanted to briefly answer two questions that so often arise concerning the increased intracellular Ca2+ concentration in enterovirally infected neurons:

Interesting! Do you maybe habe the name of the paper at hand?
EBV, I think HIV too, and another one of the herpes family (I forgot) release proteins that activate IP3 receptors which release Calcium from the endoplasmic reticulum (there are also ryanodine receptors, but I don't know if and how they're influenced) so that cytoplasmic calcium rises in order to stimulate autophagy. (Note: This is based on animal cell or in vitro experiments if I remember correctly.) Maybe these viruses also activate these receptors in order to use the Calcium pathway via the plasma membrane into the cell. Because if endoplasmic reticulum Ca stores are emptied, extracellular Calcium will be transported into the cell via other Ca channels that then open.

 

[Pyrrhus]

Interesting! Do you maybe habe the name of the paper at hand?
EBV, I think HIV too, and another one of the herpes family (I forgot) release proteins that activate IP3 receptors which release Calcium from the endoplasmic reticulum (there are also ryanodine receptors, but I don't know if and how they're influenced) so that cytoplasmic calcium rises in order to stimulate autophagy.

Hi @Inara, thank you for asking.
Here are some references you may be interested in:

Enterovirus protein 2B po(u)res out the calcium: a viral strategy to survive?
https://www.ncbi.nlm.nih.gov/pubmed/15680759

Coxsackievirus protein 2B modifies endoplasmic reticulum membrane and plasma membrane permeability and facilitates virus release.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1169977/

Potential subversion of autophagosomal pathway by picornaviruses.
https://www.ncbi.nlm.nih.gov/pubmed/18094610

My apologies if the above references are a bit out-of-date.
I haven’t updated my reference list in this area for a number of years.

Best regards.

 

[Inara]

Thank you so much @Pyrrhus! That's really interesting. I also found a paper about Chlamydia using these pathways.

 

[gbells]

Don't know about others but I feel really saddened and flattened by Ron and his words here. He is an absolutely amazing man and I am so grateful to him for his efforts, but the vagueness and not knowing what is going on, with the metabolic trap and others, is killing me! I would rather know everything, good or bad, than wait for months on end with vague comments now and again and yearly talks that offer so much promise but which never come to any further discussion... I feel so sad; so hopeless. What is actually going on? I mean actually - not vague snippets...

I wrote to him with a reseach proposal and he didn't even respond.

 

[Belbyr]

I wrote to him with a reseach proposal and he didn't even respond.

He might not reply, he probably gets emails from lots of patients.

Hopefully we hear something from him soon. I had my hopes up last year when he alluded to he might have something 'in 3 months' for his son, nothing came of that either unless I missed it. It's an aggravating illness.

 

[Neunistiva]

Dr. Ron Davis is a 77 year-old man who works on research every day, then goes home to take care of his severely ill son all the while attending conferences, holding lectures, and spreading word about ME, trying to get funds from NIH, deciding what to fund from donations, bringing in researchers, consulting with and advising other researchers and is currently in the hospital recovering from heart ablation he got for atrial fibrillation

https://twitter.com/i/web/status/1083601227928064000

 

[Timaca]

Prayers for Ron and Janet during this time. I hope the ablation was successful!!!

 

[S-VV]

Quite true. To support this, I can share my (N=1) experience.

I first fell ill while traveling in Southeast Asia during the summer of 1997.

I was diagnosed with an unknown tropical infection. From my background in Infectious Disease, I already knew that very few infections were detectable with modern diagnostic technology, so from the start I gave up trying to diagnose the exact infection via diagnostic tests.

Instead, I decided to narrow down the universe of pathogens by listing the known categories of human infections, and trying broad-spectrum agents aimed at each category. I started with a year of broad-spectrum antibiotics, in various combinations. No effect on my symptoms. Then antifungals, again with no effect. The symptoms persisted, despite pharmacotherapy. Then I tried various anti-parasitic agents, again with no effect.

This left viruses. Since herpes viruses are often claimed to be reactivated in ME, I tried various anti-herpetic antivirals, again for a whole year, in various combinations. Although my laboratory reports strongly suggested that there were reactivated infections that had been suppressed, there was no change to any of my ME symptoms. Again, the ME symptoms persisted despite the combined effects of the immune system and pharmacotherapy.

Then I turned to RNA viruses. The only broad-spectrum anti-RNA-virus pharmacotherapy currently approved is Ribavirin. Within days of starting Ribavirin, I broke out in prominent hand-foot-mouth blisters and herpangina at the back of the throat. A literature search for these symptoms only revealed enteroviruses as a possibility. Although these symptoms may suggest an enterovirus is present, they did not mean the virus is related to my ME symptoms.

So I increased the dosage, carefully, steadily, until there was a sudden disappearance of all my ME symptoms at a certain dosage. I shared this surprising finding with a few colleagues. One wisely pointed out that Ribavirin is an anti-inflammatory at the dose I was using, and ME symptoms are known to be alleviated with anti-inflammatories, so my improvement may be a side-effect of the Ribavirin rather than due to suppression of a virus. Since continued use of the Ribavirin resulted in bone marrow suppression, I stopped the Ribavirin and my ME symptoms returned.

(FOR THE RECORD: Do NOT try Ribavirin. At the doses needed to see an effect, you will likely suffer serious, and potentially life-threatening, toxicity. Please, do NOT try Ribavirin.)

So I wondered if there might be another broad-spectrum anti-RNA-virus drug that does not have anti-inflammatory properties. I found Favipiravir, a drug with the same antiviral mechanism of action as Ribavirin, but without any anti-inflammatory or immunosuppressive effects. Again, I increased the Favipiravir dosage, carefully, steadily, until there was a sudden disappearance of all my ME symptoms at a certain dosage. This time, when I consulted with colleagues, there was a consensus that my ME symptoms had to be caused by some persistent RNA virus. Unfortunately, since continued use of the Favipiravir lead to signs of liver toxicity, I stopped the Favipiravir and my ME symptoms returned.

(FOR THE RECORD: Do NOT try Favipiravir. At the doses needed to see an effect, you may suffer serious, and potentially life-threatening, toxicity. Please, do NOT try Favipiravir.)

Later, I searched the literature to see if there was a known outbreak in Southeast Asia in the summer of 1997, when and where I fell ill. The only outbreak I found was an outbreak of Enterovirus 71. If you’re interested in learning about Enterovirus 71, I’m attaching the slides from a small talk on the subject I gave at Berkeley a few years ago. My apologies that the slides are a bit out-of-date; there have been some fascinating developments in the last couple of years. (For privacy reasons, I have removed my name from the slides.)

Thank you again for all your time and effort.

This is amazing. Have you found any treatment that (to some extent) replicates the effects of Ribavirin and Favipiravir?

 

[Pyrrhus]

This is amazing. Have you found any treatment that (to some extent) replicates the effects of Ribavirin and Favipiravir?

Not yet. But I’m still looking.

I’m sure we’ll have a safe & effective direct antiviral drug for RNA viruses some day. Just not in the near future.

 

[HTester]

@HTester -- Thanks for the info. I have a question. Ron has indicated that based on his nanoneedle experiments, ME/CFS patients' cells behave fine when in a healthy person's plasma, while both healthy patients' cells and CFS patients' cells "crap out," so to speak, when put into a CFS patient's plasma. That suggests that the problem is something (or a lack of something) in the plasma and the effect that this something (or lack of something) is having on cells, not necessarily a primary problem in the cells themselves. Is that inconsistent with your theory? It sounds like you're studying cells and not plasma.

Thanks.

@greeneagledown Your point is well taken. The IDO metabolic trap theory is definitely concerned with intracellular processes, and the nanoneedle plasma-swap experiment surely points to an abnormality in plasma composition. An important principle here is to recognize that blood plasma composition reflects the net result of all the inputs and outputs of molecules. Some of those inputs and outputs reflect exchange with the outside world: dietary uptake, exhalation of CO2, urinary excretion, etc. But inputs and outputs associated with body cells are also important: cell uptake of some molecules and release of other molecules. So the behavior of cells is a strong determinant of plasma concentration just as plasma concentrations can be a strong determinant of cell behavior. The nanoneedle says there is something different about CFS plasma. This could point to a great diagnostic. But to get to a cure we have to trace that change in plasma back to its cellular origin. This search is further complicated by the fact that any change we measure in CFS cells could be secondary to a change in some other cell type. It could even be tertiary or worse. So, no, the plasma swap result is not inconsistent with the trap theory. The change in plasma, whatever it is, could be downstream (even far downstream) of a failure to make kynurenines in a particular cell type. We have to attack this problem both bottom up and top down. I'm a top-down guy.

 

[Wayne]

I’m sure we’ll have a safe & effective direct antiviral drug for RNA viruses some day. Just not in the near future.

Hi @Pyrrhus -- Quite a remarkable story (history) you told. Just wondering, have you considered non-drug therapies, such as some kind of oxygenation therapy, or perhaps an herbal remedy? Or perhaps a course of immune-modulating herbs/supplements? Or IV Vitamin C? I've always been impressed by a 1940's rural doctor (Dr. Frederick Klenner) who used IV Vit. C to cure polio. Not sure why it's not been tried on any number of other viral diseases, including measles. All these therapies are relatively inexpensive, and it would seem far more benign than just about any drug approach. -- Just a thought.

 

[HTester]

One question from my side as well to @HTester. Do you think there is any way the tryptophan trap model could not only explain the quick worsening following an infection, but also the temporary remission that some of us get during an infection? I noticed that Ron Davis had observed the same effect in the laboratory, i.e., ME/CFS cells behaving more normally following an infection. I have twice caught a cold during the last few years and both times symptoms have improved dramatically.

@JES Your observation has indeed been reported by many patients. So any workable theory should propose a way to explain symptom improvement when you get a cold. Our best idea at present is that IFNg up-regulates IDO transcription (this is well known). So whatever kynurenine you're making will be amplified by having more molecules of IDO doing the catalytic work. Is there a delay before the improvement starts? Would you say the improvement lasts only as long as the cold?

 

[S-VV]

Not yet. But I’m still looking.

I’m sure we’ll have a safe & effective direct antiviral drug for RNA viruses some day. Just not in the near future.

Thanks!

I just found out about Arbidol, a Russian antiviral with activity against CVB. Seems to have a tolerable safety profile.

 

[Pyrrhus]

I just found out about Arbidol, a Russian antiviral with activity against CVB. Seems to have a tolerable safety profile.

The problem with Arbidol is that it is unfortunately only effective in the acute phase of the infection, not in the persistent phase of the infection. And most of the publications on Arbidol are in Russian.

 

[JES]

@JES Your observation has indeed been reported by many patients. So any workable theory should propose a way to explain symptom improvement when you get a cold. Our best idea at present is that IFNg up-regulates IDO transcription (this is well known). So whatever kynurenine you're making will be amplified by having more molecules of IDO doing the catalytic work. Is there a delay before the improvement starts? Would you say the improvement lasts only as long as the cold?

Unfortunately I rarely get colds, I should have written down exactly the symptoms and delay, since the last one was in 2016 and the one before that in 2014. I would say that resolution of ME/CFS symptoms follow within 24 hours of getting the first feelings of a cold and since my colds are usually short-lived and resolve quickly, the ME/CFS symptoms begin to settle back within about 24 hours after my cold symptoms started reducing. This is a very rough estimate and I wish I had more chances to feel this recovery, but no luck with catching colds in the last few years.

 

[Rufous McKinney]

Hi @Pyrrhus

Immunologist just canceled an appointment I made seeking help. I don't even understand what type of doctor: would give me the time of day.