Professor Ron Davis's response to Naviaux study, including Q and A with Dr Naviaux

[Janet Dafoe]

I appreciate Prof Davis´s efforts on behalf of the ME community (before anyone accuses me of being ungrateful), but I have to disagree with his comments here:

´Another important finding from this study is that the metabolomic response observed in ME/CFS is opposite to the pattern seen in acute infection and metabolic syndrome. This result supports the controversial idea that while infection is often the initiating event for ME/CFS, it does not contribute to the ongoing illness. What is important to note is that in the absence of evidence of an active infection, it is plausible that the long-term antimicrobial treatments often used for ME/CFS patients are doing more harm than good.´

Naviaux et al. were very careful not to rule out ongoing infection, and actually suggested that the abnormalities might be the body´s response to an ongoing infection.

Also, he seems to elide the distinction between ´acute infection´ and ´active infection,´ as well as ´latent infection´ and ´chronic infection.´ The former would not justify the use of antimicrobials, the latter might.

I asked Bob Naviaux to respond to this. Here is his response. I hope it clears things up!
Hi Ron and Janet,
Janet told me about your keen commentary on our paper and told me about what people were calling a “disagreement” between us. I don’t see any disagreement. I’ve added the point to our Q&A. Please let me know if this “agreement” is too controversial for the CFS community at the present time.
Q7. How would you respond to Dr. Ronald Davis’s recent statement: “"What is important to note is that in the absence of evidence of an active infection, it is plausible that the long-term antimicrobial treatments often used for ME/CFS patients are doing more harm than good."

I am in complete agreement.Many antibiotics like tetracyclines, erythromycin, and the fluoroquinolones (eg, Cipro), and antivirals like acyclovir, fialuridine, AZT, and ddC also inhibit mitochondrial functions when used chronically (usually for more than about 3 weeks).Because mitochondria are descendants of free-living bacteria, their machinery for protein synthesis and DNA replication are susceptible to many antibiotics, and for reasons unique to mitochondrial DNA synthesis, they are also sensitive to antivirals.Chronic use of these drugs can do more harm than good if there is no longer good evidence for an active infection.When mitochondrial functions are critically impacted by long-term use of certain antibiotics, a ripple effect in metabolism and gene expression is produced that can further impair energy production by mitochondria, converting an active cell danger response that occurs during active infection to a hypometabolic survival response.

In the field of mitochondrial medicine we are particularly sensitive to these issues of iatrogenic toxicity because some of the drugs that inhibit mitochondrial functions are very commonly used in patients without mitochondrial disease.For example, statins, valproate, and metformin can each produce problems in patients with pre-existing mitochondrial dysfunction.


Bob

Robert K. Naviaux, MD, PhD
Professor of Genetics
Biochemical Genetics and Metabolism
Departments of Medicine, Pediatrics, and Pathology
Co-director, The Mitochondrial and Metabolic Disease Center (MMDC)
UCSD School of Medicine

 

[boohealth]

No issue at all with you having a view and expressing it nicely, but maybe you could get your point across without accusing researchers of having dodgy motives without any evidence to back those accusations up, or without suggesting that some really great research is sloppy just because it doesn't fit your pet theory. It's disrespectful and rude.

I don't have a pet theory. I pointed out that the researcher isn't even aware of the current state of the art in terms of persistent infection in lyme--which was written up in Scientific American, as I linked to, so isn't hard to find. That 20% have persistent symptoms, ie ongoing infection. Johns Hopkins' research on persisters is pretty widely known, too. I have no pet theory, as I said, but if he's going to say that only a small percentage of people who get lyme go on to chronic symptoms, he's wrong. He ought to know better before he makes statements like that. Moreover, as I said, EBV is not equivalent to nor should it be classed with lyme. It's a universal infection that most of us handle--that is, except for later-in-life cancers, such as b-cell related cancers (where EBV resides)

 

[boohealth]

Hi @boohealth

So you are acknowledging a CDR mechanism, but not accepting the findings suggested by the study?

I have read Lyme literature extensively, for various reasons. It is not so far fetched-for myself- to believe that chronic lyme (a concept which I DO believe in, though my interpretation of what that means may be different to you) may be the result of a state very similar to ME/CFS metabolically. Without metabolism working correctly, and if chronic Lyme patients are in a similar dauer-state, how on earth is the immune system going to function optimally, keeping the infection in check?

Yes its a guess, a theory. That's all we can do right now. This was a study on ME/CFS, not on patients with Lyme. The cohort was from centres that are well known for treating Lyme disease, and the patients would have been ruled out-yes I realise Elisa is appalling,and WB not much better-to the best that they could be.

There is a study proposed with OMF that will be looking at other diseased states, Lyme being one of them (last time I checked). The results from this will give us a much better idea.

Follow the money? Can you explain what you mean by this please (I have a feeling I know, but want to check).


B

I brought up lyme because Naviaux did. That's all.

 

[Janet Dafoe]

He needs money to continue doing studies.
I'll leave your other comment--he's dug into his worldview, and within that worldview, he is trying hard to save his son's life. But he won't listen to any suggestions that might help, if they don't fit his framework.

That is a completely inaccurate assessment of Ron Davis. He is the most open minded scientist you could ever meet and he frequently complains about "scientists" who are stuck in their own world view or theory. That is unequivocally NOT how Ron operates. His framework is finding out the truth and following the data. I send him and read to him everything that is sent to us. He reads it all. It's incredible. Your criticism is unfounded and he doesn't deserve it. Here's what you can criticize him for: he doesn't talk very loud, he forgets to tell me when his colleagues get married or have babies, and if someone brings an orchid for him to bring to me he forgets and leaves it at his lab. Go for it!
If you don't believe me, then come meet him. He'd be glad to listen to you.

 

[Gingergrrl]

He needs money to continue doing studies.
I'll leave your other comment--he's dug into his worldview, and within that worldview, he is trying hard to save his son's life. But he won't listen to any suggestions that might help, if they don't fit his framework.

I agree with the reality that of course he needs money to continue doing his studies (and this would be the same for all researchers who do not receive government funding) but I truly believe that he does not have a fixed worldview as to the cause of this illness and in particular, his son's illness. The Metabolomics testing revealed information that was not known and he is trying to do another study which will either replicate it or prove it wrong.

I cannot fathom where you are getting the idea that he will not listen to any suggestions that might help him if they do not fit into his framework. I had the honor to meet him in Oct 2014 at a screening of Forgotten Plague and his goal is to save his son's life. If ME/CFS turns out to be viral, autoimmune, or something we never dreamed of like this "Dauer" state, then he is going to pursue it. His Big Data study has no hypothesis except to study every single aspect that he can and see what he finds! It is the opposite of what you are describing.

 

[boohealth]

I asked Bob Naviaux to respond to this. Here is his response. I hope it clears things up!
Hi Ron and Janet,
Janet told me about your keen commentary on our paper and told me about what people were calling a “disagreement” between us. I don’t see any disagreement. I’ve added the point to our Q&A. Please let me know if this “agreement” is too controversial for the CFS community at the present time.
Q7. How would you respond to Dr. Ronald Davis’s recent statement: “"What is important to note is that in the absence of evidence of an active infection, it is plausible that the long-term antimicrobial treatments often used for ME/CFS patients are doing more harm than good."

I am in complete agreement.Many antibiotics like tetracyclines, erythromycin, and the fluoroquinolones (eg, Cipro), and antivirals like acyclovir, fialuridine, AZT, and ddC also inhibit mitochondrial functions when used chronically (usually for more than about 3 weeks).Because mitochondria are descendants of free-living bacteria, their machinery for protein synthesis and DNA replication are susceptible to many antibiotics, and for reasons unique to mitochondrial DNA synthesis, they are also sensitive to antivirals.Chronic use of these drugs can do more harm than good if there is no longer good evidence for an active infection.When mitochondrial functions are critically impacted by long-term use of certain antibiotics, a ripple effect in metabolism and gene expression is produced that can further impair energy production by mitochondria, converting an active cell danger response that occurs during active infection to a hypometabolic survival response.

In the field of mitochondrial medicine we are particularly sensitive to these issues of iatrogenic toxicity because some of the drugs that inhibit mitochondrial functions are very commonly used in patients without mitochondrial disease.For example, statins, valproate, and metformin can each produce problems in patients with pre-existing mitochondrial dysfunction.


Bob

Robert K. Naviaux, MD, PhD
Professor of Genetics
Biochemical Genetics and Metabolism
Departments of Medicine, Pediatrics, and Pathology
Co-director, The Mitochondrial and Metabolic Disease Center (MMDC)
UCSD School of Medicine

Well-I completely agree with that point of us. I think different mitonuclear pairings, and or an individual's mitochondrial function (I have a double deletion in one of the SOD genes, so I make about 60% of the SOD my mitochondria actually optimally need)--mean that for some individuals, even *with* a chronic infection (which I think is probably almost always there, though maybe occasionally the hit-and-run hypothesis is valid), antibiotic treatment can be harmful longterm. However, antibiotics are fairly dull and bludgeony instruments. There are other ways of inhibiting pathogens that can increase cellular function and repair hypoxic tissue. Such as hyperbaric oxygen.

 

[Gingergrrl]

That is unequivocally NOT how Ron operates. His framework is finding out the truth and following the data. I send him and read to him everything that is sent to us. He reads it all. It's incredible. Your criticism is unfounded and he doesn't deserve it.

I agree @Rose49 and am sorry you are now in the position of having to defend your husband's character while you are preparing to leave for a funeral. I want you to know that we are so incredibly grateful for Dr. Davis's generosity to read the questions that we write on PR. I cannot think of any other scientist who would do such a thing. Please let him know how grateful we are to have direct access to the scientists who are trying to solve this illness and give us our lives back.

 

[boohealth]

That is a completely inaccurate assessment of Ron Davis. He is the most open minded scientist you could ever meet and he frequently complains about "scientists" who are stuck in their own world view or theory. That is unequivocally NOT how Ron operates. His framework is finding out the truth and following the data. I send him and read to him everything that is sent to us. He reads it all. It's incredible. Your criticism is unfounded and he doesn't deserve it. Here's what you can criticize him for: he doesn't talk very loud, he forgets to tell me when his colleagues get married or have babies, and if someone brings an orchid for him to bring to me he forgets and leaves it at his lab. Go for it!
If you don't believe me, then come meet him. He'd be glad to listen to you.

If you mean that, can I skype with him? (I'm all the way across the country). I won't waste his time--I'll prepare what I have to say and seriously ask him to consider it. And it can be anytime in the next few months--I actually work fulltime while dealing with the weirdness of my own complex 'illness' which sort of falls into this bailywick, but which I have done remarkably well with, since I was bedridden at one point; but still am way out of the nice robust middle of the bell curve where most of the population lives.

And warm thanks for responding.

 

[rosie26]

the first time I knew I was in serious trouble was after a swimming session. I felt more exhausted than normal afterwards and when I got home I just collapsed.

The same thing happened to me. A year after my mild ME onset, (which I didn't know I had at the time), a beach holiday I had been looking forward to turned into a week lying in bed at the bach. I had a sore throat the day I arrived on this small island which I had wanted to spend the week swimming and sightseeing. As I usually do when arriving at the beach the first thing I do is dump all the baggage and go down for a swim.

I will never forget how exhausted I was when I tried to surf the waves. It was so bizarre and like nothing I had ever experienced before. I was only in the water a minute or two, I felt sick and utterly exhausted. I did make a point of swallowing some sea water for my sore throat which actually did work a day later.

But that was my first taste of what was to become a whole lot worse.

 

[Zombie_Lurker]

I am in complete agreement.Many antibiotics like tetracyclines, erythromycin, and the fluoroquinolones (eg, Cipro), and antivirals like acyclovir, fialuridine, AZT, and ddC also inhibit mitochondrial functions when used chronically (usually for more than about 3 weeks).Because mitochondria are descendants of free-living bacteria, their machinery for protein synthesis and DNA replication are susceptible to many antibiotics, and for reasons unique to mitochondrial DNA synthesis, they are also sensitive to antivirals.Chronic use of these drugs can do more harm than good if there is no longer good evidence for an active infection.When mitochondrial functions are critically impacted by long-term use of certain antibiotics, a ripple effect in metabolism and gene expression is produced that can further impair energy production by mitochondria, converting an active cell danger response that occurs during active infection to a hypometabolic survival response.

I used tetracycline for a couple years for acne. I wonder about the impact of using tetracycline so long on my developing ME/CFS. Maybe I have been stuck in a hypometabolic survival response since then due to the tetracycline use?

 

[duncan]

Chronic use of these drugs can do more harm than good if there is no longer good evidence for an active infection.

Is it safe to assume he meant "Chronic use of these drugs can do more harm than good if there is no longer an active infection?"

I am in complete agreement.Many antibiotics like tetracyclines, erythromycin, and the fluoroquinolones (eg, Cipro), and antivirals like acyclovir, fialuridine, AZT, and ddC also inhibit mitochondrial functions when used chronically (usually for more than about 3 weeks).Because mitochondria are descendants of free-living bacteria, their machinery for protein synthesis and DNA replication are susceptible to many antibiotics, and for reasons unique to mitochondrial DNA synthesis, they are also sensitive to antivirals.Chronic use of these drugs can do more harm than good if there is no longer good evidence for an active infection.When mitochondrial functions are critically impacted by long-term use of certain antibiotics, a ripple effect in metabolism and gene expression is produced that can further impair energy production by mitochondria, converting an active cell danger response that occurs during active infection to a hypometabolic survival response.

But if there IS a pathogen involved, then risk vs. benefit inserts itself as a variable.

I think the stellar job the study did in generating a metabolic fingerprint for ME/CFS cannot be overstated. What causes those metabolic anomalies is still unclear, at least as far as I can infer.

 

[Neunistiva]

@Rose49 I can't begin to express my gratitude to Dr. Ron Davis for all the work he does and to you for keeping us updated despite both of you taking care of your son. Seeing such high profile researchers like your husband and Dr. Naviaux taking their time to elaborate for us lay people really heals all wounds from being ignored by medical professionals.

I've only heard of OMF and Dr. Davis a year ago and we are already seen unprecedented result from him and his collaborators. I am used to being made to wait half a decade and then being bitterly disappointed and let down.

Being bedbound with ME/CFS means that I don't have much in terms of money but I donate to OMF with a light heart because it's obvious there's no better way to spend money for ME/CFS patients.

 

[alicec]

he's dug into his worldview

But he won't listen to any suggestions that might help, if they don't fit his framework.

Your assumptions are breathtaking. Perhaps they would be better applied to yourself.

That 20% have persistent symptoms, ie ongoing infection.

That's another breathtaking assumption - if you can point to serious studies that show that ongoing infection is the cause of persistent symptoms I would love to read them.

 

[rebecca1995]

@Rose49, thank you so much for taking the time to post here, with all the struggles you have in your own life.

Also, please convey to Dr. Davis and Dr. Naviaux my deepest gratitude for their stellar efforts on behalf of ME patients.

I haven't been this excited about research in many years. I actually have hope that I might be able to walk down the hallway or take a shower again.

Personally, I'm glad when clinicians and researchers sound a note of caution about long term antimicrobials. That's because I became permanently bedbound following two years of aggressive antibiotics for presumptive Bb and other tickborne infections. After brief initial improvement on the treatment, I kept getting weaker and weaker. People said I was "herxing," but I suspect now that I was going deeper into dauer.

I've been in dauer for 2.2 decades. I can't walk to the bathroom or change my nightgown without help; I haven't been able to leave my home in 1.5 years; yet I have lasted, endured, survived. Ich habe gedauert!

I strongly support Dr. Naviaux, Dr. Davis, the OMF, and all their collaborators. Thank you!

 

[Navid]

That is a completely inaccurate assessment of Ron Davis. He is the most open minded scientist you could ever meet and he frequently complains about "scientists" who are stuck in their own world view or theory. That is unequivocally NOT how Ron operates. His framework is finding out the truth and following the data. I send him and read to him everything that is sent to us. He reads it all. It's incredible. Your criticism is unfounded and he doesn't deserve it. Here's what you can criticize him for: he doesn't talk very loud, he forgets to tell me when his colleagues get married or have babies, and if someone brings an orchid for him to bring to me he forgets and leaves it at his lab. Go for it!
If you don't believe me, then come meet him. He'd be glad to listen to you.

Janet:

Wonderful response. What a great partner you are, and Ron doesn't sound too bad himself (despite his minor faults: ))

As you know this community is desperate for help. I'm not sure what drives ppl to make such derisive comments when they disagree with someones views, but I am sorry such negativity is being directed to Ron.

I hope when he reads or hears anything negative he knows that on the scale of life, the positivity and love people feel toward Ron/his team and you outweighs the negative immeasurably.

Thanks to you all for everything you do.

The hard-work and communication with patients is so greatly appreciated. Your words, Ron, Bob and their teams hard work to really figure this thing out bring us hope and light while we are stuck in this very dark world of unexplainable illness.

Hope the next orchid makes it home to you.

Hugs and gratitude from a severely ill, desperate patient.

Lisa(pretend this is an orchid)

 

[alicec]

I am going to try, with Ben's help, to compile a list of things that are questions or misconceptions and Bob is going to add to the Q and A paper for everyone to see

Bottom line: there may be a diagnosis soon, and they are working actively on how to get the process unstuck!

Not only do we have ground-breaking research but also the researchers are actively considering treatments AND are prepared to engage with us and answer our questions.

Setting aside the churlish who will always find something to complain about, this is the best news we have had in a long time.

 

[Research 1st]

I've been thinking...

One main symptom of ME is to feel asleep when awake and the more we use our brains, the more 'stoned' we feel, this can get so extreme, that the effect of thinking/reading/writing/speaking has a metabolic 'feeling' as if we've run a marathon and literally can't sit up or walk - a core sign of deranged brain metabolism and subsequent
brain hypoperfusion. This can get so bad, you can end up unable to speak or move when things flare up to an extreme level. These are 'inside' feelings others can't really see,however we can also get (simply from brain use):

Aggravation in pain and weakness.
Confusion.
Worsening of balance & vertigo.
Worsening of vision (blurred vision, jumping eyes).
Worsening of tinnitus/photophobia/nausea.
Migraines, other headaches.
'Twitching' (muscle fasiculation) etc, from abnormal nerve firing seen in other neurological diseases.
Feeling hot or cold, hot flushes.
Feeling more flu like.
Feeling faint and more light headed.
Raised lymph glands, or further enlargement/sore throat.
And many other symptoms I could list unique to us, so I won't list them all.

Consequently, ME CFS doesn't make you 'tired' from exertion, it traps you. Patients are literally forced to avoid as much as possible using their brain, for intelligent, active minded people, this is a double curse. You live like a hermit, just to survive, and it destroys social contact. (Even typing on this forum makes us ill and can make us unable to communicate if we do too much for days, weeks, months etc). This is what seperates us from other conditions with 'Chronic Fatigue', our extreme reaction, and delayed reaction to using our brains, not just our bodies.
Well the brain uses up a huge percentage of our energy in our body (ATP), so no surprise there.

I'll get to the point:

If you've ever had a QEEG brain wave assessment, you may have seen that despite wide awake, your brain can produce abnormal sleep waves, which should only happen when your asleep or going to sleep. Ergo, we feel drugged, because our brains energy cells, are depleted at a cellular level, proven by a QEEG (an EEG can also show drowsiness).

Perhaps 'drowsy' brainwaves in ME, is another clue to a hypometabolic state.

So?

So my idea is, if anyone has any money left in research, wait to get some people with a positive metabalon CFS blood test, and give them a QEEG and see what's up.

We may get some correlation, we may get total correlation that indeed everyone with well described CFS also has an abnormal QEEG, which if correct may be a useful diagnostic test to add as it demonstrates neurological changes by 'using' your brain, in a cohort of patients with proven metabolic defects.

Personally, I would test folks late in the day, when they're totally exhausted, brain fogged, and thus their brain electrical systems will be more abnormal, rather than first thing in the day, after sleep.

Just an idea.

 

[Groggy Doggy]

But he won't listen to any suggestions that might help, if they don't fit his framework.

Hi @boohealth Could you please give me an example of this (not listening)? What kind of suggestions have you proposed?

 

[PNWMom]

Like others, I have had misgivings about the protracted use of antimicrobials without concrete justifications. Without a clear infectious trigger event in my daughter's case, there has always been the concern of unforeseen comsequences. She has deteriorated over time--and not in the deconditoning way--but in the severity of symptoms way. Whatever process is underway in her body is not over by any stretch of the imagination. But it has to be stopped and I believe that metabolomics and immunogenomics will likely hold the best hope for diagnostics and treatment. For this reason, I am 100% behind Dr Davis and Dr Naviaux.

@Rose49 Bless you and bless the work your husband is doing. I am grateful every day for people who are passionate visionaries willing to challenge the status quo on this disease.

I have only been a full time caregiver for my 20 year old daughter (moderately severe) for almost three years and I can't fathom what you go through. I honor your and Ron's sacrifices on behalf of my family. We have all been transformed by this disease.

Thank you for your time and generosity taking the time to reply and for facilitating answers from Drs Davis and Naviaux.

I am hanging on every word. I actually started looking for online classes in molecular and cellular biology today so I could better understand this research.

Best wishes from Oregon.

 

[Forbin]

If you've ever had a QEEG brain wave assessment, you may have seen that despite wide awake, your brain can produce abnormal sleep waves, which should only happen when your asleep or going to sleep. Ergo, we feel drugged, because our brains energy cells, are depleted at a cellular level, proven by a QEEG (an EEG can also show drowsiness).

It's interesting that you mention this. I once found this old (1973) reference to sleep patterns showing up in the EEG's of wide awake adolescents with signs of "vasomotor instability."

4 c/sec vertex spindles
A.C van Huffelen,O Magnus

Electroencephalography and Clinical Neurophysiology, Volume 34, Issue 5, May 1973, Pages 543-546

Abstract
An EEG phenomenon consisting of rhythmic 3.5–4.5 c/sec triangular waves an average amplitude of 40 μV, strictly localized at the vertex, occurring in spindles with an average duration of 2.5 sec has been observed in 20 patients. This phenomenon was called 4 c/sec spindles. It occurred particularly in awake adolescents with a peak at the age of 14–15 years. The most common diagnosis under which they had been referred was vasomotor instability. The EEGs of 30% of these patients moreover showed a frontal theta rhythm at 6–7 c/sec. In 90% of these patients the EEG was otherwise unremarkable.
http://www.sciencedirect.com/science/article/pii/0013469473900710

Below is just a later reference to the study above.

A rhythmical 4/sec pattern occurring over the vertex solely in the waking state has been described as "4/sec vertex spindles" by Van Huffelen and Magnus (1973), This very rare pattern is likely to represent a mild abnormality. It is found mainly in adolescents with syncopal attacks and other signs of vasomotor instability. The use of the term "spindles" appears to be somewhat out of place when one considers the slow frequency and the occurrence the waking state. Hence, Daoust-Roy (1989) proposed the term "4/sec vertex rhythm."

Electroencephalography: Basic Principles, Clinical Applications, and Related Fields
Chapter 9: The Normal EEG of the Waking Adult - Ernst Niedermeyer (1999) Page 164

Just speculation, but it makes me think that vasomotor dysfunction might be related to poor sleep and the brain subsequently trying to, in some way, "fall asleep" when wide awake.