Special Message for you from Ron Davis (video)

[Tally]

No, where things got confusing for you is I intentionally said 'trap' not 'metabolic trap'.

This is not a discussion about semantics. You can call it a rainbow dragon lollipop for all I care. This is about the fact that their hypothesis are different. To say otherwise is misleading.

Yes, some aspects of their hypothesis are finally converging after decades, and that's exciting, but it's also very good that we don't have all our eggs in one basket. Even Dr. Davis himself is funding as many different promising research as possible with limited funds.

or in other words 'a chronic disease state not caused by a chronic infection

Yeah, I already said that.

I could careless who 'wins' the CFS discovery/cure.

I couldn't care less either (plus, science doesn't work that way, it's not the Olympics. Even if, let's say, Dr. Phair is right, his work rests on countless other researchers and clinicians that measured, published and wrote about ME.)

However, what I do care about is spread of misinformation.

 

[boolybooly]

Thanks for communicating Ron and good luck in 2019.

 

[HTester]

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.

 

[Mary]

Bumping to top of the queue

 

[halcyon]

o 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.

So by your standard, poliomyelitis could not have been caused by poliovirus, or PML could not be caused by JC virus, etc. because you would find those viruses in healthy controls as well. Not every virus has a 1:1 correlation with disease like HIV or HCV.

I would encourage you to read the evidence for enterovirus as the cause of ME. Nobody is saying that every person with a CFS diagnosis has this, but it’s highly likely that this is the problem with people who have what Ramsay and Dowsett described as ME.

 

[Pyrrhus]

Thank you very much for taking the time to join this thread and respond so comprehensively.

I hope you don’t find Phoenix Rising too chaotic or argumentative, as internet conversations tend to be.

To my mind, the available evidence points to a switch or a trap

Could you explain what evidence suggests this possibility to you?

There’s plenty of evidence showing metabolic abnormalities, and even one metabolic abnormality could have complicated downstream effects, just as B12 deficiency leads to the “methyl trap” suggested decades ago. (No relation to the Yasko/VanKonynenburg/Freddd “methylation block” hypothesis.)

However, I don’t know of a single ME clinician who sees bistability in their patients. Clinicians see a range of severities among patients, and severity can also vary drastically in one patient over time. I’m not quite sure why one might suspect bistability to be an important concept here.

Thank you again for your time and effort.

 

[Pyrrhus]

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

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.

 

[HTester]

I would encourage you to read the evidence for enterovirus as the cause of ME. Nobody is saying that every person with a CFS diagnosis has this, but it’s highly likely that this is the problem with people who have what Ramsay and Dowsett described as ME.

halcyon, These are good points. Thanks for making them. Virology is one of my many weak suits. I followed your evidence link and read the tables of paper summaries, and followed some further links. It's fascinating that a non-cytolytic enterovirus can make the full range of its viral proteins in infected cells and still go undetected by MHC antigen presentation. Are there hypotheses for how this is achieved?

Do infected cells accumulate large quantities if viral RNA? How do the few virions produced exit the infected cell?

I also take your points about poliovirus and JC virus. The lack of complete penetrance leads to a question much like my genetic predisposition question: why does only a small fraction of people exposed to poliovirus contract full-blown paralytic polio. Do they have a genetic predisposition?

 

[Pyrrhus]

It's fascinating that a non-cytolytic enterovirus can make the full range of its viral proteins in infected cells and still go undetected by MHC antigen presentation

Neurotropic viruses such as enteroviruses and flaviviruses live in the "immune-privileged" central nervous system, where the only permanent immune cells are the tissue-resident macrophages known as microglia. So MHC antigen presentation is largely irrelevant in the central nervous system, except in cases of a compromised blood-brain barrier.

I hope this helps.

P.S. The other two "immune-privileged" organs in the body are the eyes and testicles. This is why people are declared "Ebola-free" by blood tests, only to find replicating virus in the eyes months after being declared "Ebola-free". Remember that Scottish nurse who was declared "Ebola-free" twice- and then developed Ebola meningitis?

 

[Pyrrhus]

Do infected cells accumulate large quantities if viral RNA? How do the few virions produced exit the infected cell?

In the case of enteroviruses, viral RNA, proteins, and incomplete capsids accumulate within double-membraned proto-autophagic vesicles by the cell body of the neuron.

What happens next is not clear, but recent evidence suggests that the double-membraned vesicles are transported, along with neurotransmitter vesicles, down the neuronal axon and end up accumulating at the pre-synaptic terminal.

Then, when the neuron fires, a single-membraned vesicle is released from the pre-synaptic terminal and fuses with the neighboring neuron. (These vesicles may be the same as the “stealth spheres” recently described by that NIH group.)

Thus, no complete capsids are ever formed and no virus exits the cell. But neuronal stimulation still transmits virus.

There was also fascinating work done by a Finnish group who used microscopy to show an enterovirus move from cell to cell using actin-containing cellular bridges. Thus, there may be multiple ways that enteroviruses move from cell to cell without ever exiting the cell.

I hope this helps.

Edited: added parenthetical re: recent work by NIH group

 

[Pyrrhus]

Then, when the neuron fires, a single-membraned vesicle is released from the pre-synaptic terminal and fuses with the neighboring neuron.

As an historical aside, local health departments in the 1950's posted prominent signs in children's playgrounds warning parents to confine their children to bed at the first sign of polio.

It was well appreciated at the time that physical activity worsened the child's prognosis. This may be because physical activity stimulates motor neurons, enhancing the spread of the enterovirus.

 

[halcyon]

It's fascinating that a non-cytolytic enterovirus can make the full range of its viral proteins in infected cells and still go undetected by MHC antigen presentation. Are there hypotheses for how this is achieved?

Yes, enteroviruses, like most viruses, have evolved countermeasures to evade the immune response. The enterovirus proteases directly interrupt MHC expression (ref) as well as disrupting intracellular viral pattern recognition receptors and the JAK/STAT pathway, preventing the interferon signal from getting to the nucleus.

Also, and I understand this aspect far less, but my limited understanding is that MHC expression in neural tissue works differently in order to protect the CNS from immunopathology, so the infected cells may not express MHC to begin with.

I believe there are additional factors that help maintain persistence, including increased activity of things like IL-10 and TGF beta which are common findings in ME and also critically, the existence of functional T cell exhaustion effected by PD-1 and other checkpoint signalers which cause cytotoxic T cells exposed to chronic infection to lose their effector function and eventually delete themselves. There is also some limited evidence to support this from recent ME research.

@Pyrrhus saved me the typing on how virus may travel from cell to cell without lysis or even assembling virion. There are numerous observed mechanisms in the literature.

I’m not aware of published research that had quantitated viral count in individual cells, however there is some grey literature from Dr. Chia where they did do quantitative PCR on a tissue biopsy of highly inflamed gastrointestinal lymph tissue and saw huge viral copy numbers.

I think the two main host factors here are genetics and immune status. Also, I highly suspect in some cases that small viral mutations are involved. Just look at the recent EV D68 epidemics, a mutated strain turned a relatively harmless respiratory virus into a myelitis causing beast.

 

[halcyon]

As an historical aside, local health departments in the 1950's posted prominent signs in children's playgrounds warning parents to confine their children to bed at the first sign of polio.

Not even just that, they would immobilize limbs or the entire body on Bradford frames to prevent movement.

 

[Pyrrhus]

Do infected cells accumulate large quantities if viral RNA?

To better clarify the fate of viral RNA, I should explain that most positive-stranded RNA viruses go through a replication cycle that includes a dsRNA intermediate state.

Now, double stranded RNA is inherently unstable, unlike dsDNA, and the two RNA strands will separate spontaneously unless something stabilizes the dsRNA. In fact, the two strands *must* separate for viral replication to continue. To facilitate separation, enteroviruses have some secondary RNA structures in the untranslated 5' region.

Early in enteroviral infection, there is nothing to stop the two strands from separating, and the virus replicates quickly. Late in infection, however, there are at least two ways that the dsRNA state is stabilized and the virus replicates very slowly as a result.

One way the dsRNA is stabilized late in infection is by gradual loss of the first ~40 base pairs at the 5' end, which is needed for the destabilizing secondary RNA structure.

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.

Thus, even though enteroviruses may not have a true 'latent' state, it has the next best thing: a very long-lived dsRNA intermediate state.

Again, I hope this is helpful.

 

[Daffodil]

@Hopeful1976 @neweimear both demeirleir and montoya have spoken about the promise of jak inhibitors. montoya wants to use one already on the market whereas kdm wants to wait for one that will launch in the last part of 2019. that is real hope, right? i believe preliminary in vitro studies are promising

 

[HTester]

Thank you very much for taking the time to join this thread and respond so comprehensively.

I hope you don’t find Phoenix Rising too chaotic or argumentative, as internet conversations tend to be.



Could you explain what evidence suggests this possibility to you?

There’s plenty of evidence showing metabolic abnormalities, and even one metabolic abnormality could have complicated downstream effects, just as B12 deficiency leads to the “methyl trap” suggested decades ago. (No relation to the Yasko/VanKonynenburg/Freddd “methylation block” hypothesis.)

However, I don’t know of a single ME clinician who sees bistability in their patients. Clinicians see a range of severities among patients, and severity can also vary drastically in one patient over time. I’m not quite sure why one might suspect bistability to be an important concept here.

Thank you again for your time and effort.

Pyrrhus, When I see chaos and argument in a scientific forum, I see myself as a young man. PR is much like the whole of science; each of us has focused on a subset of what is known. Our individual intellectual histories lead us to choose some data over others as most informative. I love open-minded scientific debate/discussion. I love people who are passionate about their ideas and still eager for someone to prove them wrong. This is how we learn. Patients have taught me at least half of what I know about this disease. One of the reasons I am so fond of mechanistic computer modeling is that models do not forget any of the assumptions the modeler makes. We humans often do. I've also been a daily Buddhist meditator for 7 or 8 years. It's a practice not to be attached particular views. Attachment only causes suffering. On the other hand, it's important not to abandon a new hypothesis too early. Someone must champion new unproven ideas or they will easily be lost in the rush of history.

Bistability is different from simple complexity. Bistability allows a system to remain in an altered state even after the initiating stimulus is removed. This is why the search for bistable systems uncovered by common mutations is so attractive to me as an explanation for the etiology of CFS.

Hence, I would say that every clinician confronted with a CFS patient is potentially viewing a bistability. Just as there is a range of steady states associated with the locus of physiological functioning, there is also a range of steady states associated with pathological functioning. The bistability is in the transition from healthy to sick; it is a feature unique to nonlinear systems. Once sick, the patient does not revisit normalcy unless actively cured. A range of severity is readily compatible with remaining on the locus of pathological steady states. In the particular case of the IDO metabolic trap, a range of severity is even more likely in that many patients are merely heterozygous for damaging IDO2 mutations. In this case there are pathological steady states that still produce some kynurenine (potentially relieving some symptoms), but only at the expense of very high intracellular tryptophan, which has (potentially) its own deleterious consequences.

Bistability fairly jumps out at a mathematician or systems theorist viewing the clinical history of ME/CFS. I am certainly not the first to think so. There is a 2007 PLoS paper from Suzanne Vernon and colleagues at Georgia Tech where the bistability is envisioned in the HPA axis, and there is an appendix written by a mathematician colleague of Sarah Myhill's that also suggests we should consider bistability. I'm sorry I cannot find that appendix right at the moment. The IDO metabolic trap is just one example of a nonlinear bistable system that might precipitate the initial crash of a healthy individual becoming a CFS patient.

 

[halcyon]

In the particular case of the IDO metabolic trap, a range of severity is even more likely in that many patients are merely heterozygous for damaging IDO2 mutations. In this case there are pathological steady states that still produce some kynurenine (potentially relieving some symptoms), but only at the expense of very high intracellular tryptophan, which has (potentially) its own deleterious consequences.

I have been curious if you had reviewed any of the literature on the apparent increase in serotonin sensitivity in ME patients (e.g. ref, ref, and several other replicative studies). Given that this might imply actually a deficiency of serotonin or tryptophan, or an increase in diversion of tryptophan towards the kynuranine pathway, I was wondering how you might address these findings in the context of your hypothetical trap model.

 

[HTester]

I have been curious if you had reviewed any of the literature on the apparent increase in serotonin sensitivity in ME patients (e.g. ref, ref, and several other replicative studies). Given that this might imply actually a deficiency of serotonin or tryptophan, or an increase in diversion of tryptophan towards the kynuranine pathway, I was wondering how you might address these findings in the context of your hypothetical trap model.

At this rate I'll be investing all my CFS research time in writing on PR. Please forgive me if I become less responsive than I have been on my first PR day.

I have, indeed, thought a good deal about serotonin sensitivity. A significant complication is that there are at least two isoforms of the hydroxylase, TPH, the first enzyme on the pathway to serotonin from Trp. The peripheral (presumably mostly gut, but also pineal and mast cells) isoform (TPH1) is reported to be, itself, substrate inhibited while the CNS (TPH2) isoform is not. So I've been thinking that there may be too much serotonin in the CNS and too little in the gut. Do the data you cite suggest increased serotonin sensitivity in BOTH CNS and periphery? If you know of data on this, one way or the other, please send me some links. Thanks.

 

[halcyon]

Do the data you cite suggest increased serotonin sensitivity in BOTH CNS and periphery?

It would seem to imply only in the CNS given their methodology. While prolactin can be secreted peripherally by immune cells, I assume that is controlled by non serotonergic mechanisms, though I don’t know for sure.

I appreciate your time spent interacting with patients, I understand it’s better spent on actual research. We look forward to what you can come up with, and thanks again.

 

[Pyrrhus]

Pyrrhus, When I see chaos and argument in a scientific forum, I see myself as a young man. PR is much like the whole of science; each of us has focused on a subset of what is known. Our individual intellectual histories lead us to choose some data over others as most informative. I love open-minded scientific debate/discussion. I love people who are passionate about their ideas and still eager for someone to prove them wrong. This is how we learn. Patients have taught me at least half of what I know about this disease. One of the reasons I am so fond of mechanistic computer modeling is that models do not forget any of the assumptions the modeler makes. We humans often do. I've also been a daily Buddhist meditator for 7 or 8 years. It's a practice not to be attached particular views. Attachment only causes suffering. On the other hand, it's important not to abandon a new hypothesis too early. Someone must champion new unproven ideas or they will easily be lost in the rush of history.

Thank you for taking the time to share an eloquent and thoughtful explanation.