Hi Guys,
As promised, and huge thanks goes to @Rose49 and Linda Tannenbaum at OMF for orchestrating this. I am just the messenger here!
As you have no doubt seen the metabolomic study with Dr Naviaux, here is Professor Ron Davis, Director of OMF scientific advisory board (and all round hero) response to the studies findings:
Added to this is a Q and A with Dr Naviaux expanding on some key aspects of the study:
Enjoy!
B
[/QUOTE]
Lots to take in guys. Hope you enjoy it-huge thanks to @Rose49 , Ron, Linda and Dr Naviaux, and the whole OMF team. These guys are working so hard for us, it's unbelievable.
Donations to further this incredible research with OMF can be made here:
http://www.openmedicinefoundation.org/donate-to-the-end-mecfs-project/
Thanks so much,
B
As promised, and huge thanks goes to @Rose49 and Linda Tannenbaum at OMF for orchestrating this. I am just the messenger here!
As you have no doubt seen the metabolomic study with Dr Naviaux, here is Professor Ron Davis, Director of OMF scientific advisory board (and all round hero) response to the studies findings:
"The publication, “Metabolic Features of Chronic Fatigue Syndrome” by Naviaux RK, et al. is a landmark in ME/CFS research. It is the most important and groundbreaking study of ME/CFS to date. Extending recent indications of metabolic alterations in ME/CFS, this study provides the first comprehensive, quantitative demonstration of the metabolomic deficiencies that characterize the disease. They define a clear metabolic ‘signature’ that accurately distinguishes patients from healthy individuals. This signature was consistent even among patients with different symptoms or disease-initiating events. These findings are exciting news for both patients and researchers. Not only do they substantiate the biological reality of this stigmatized disease, but they also point to the most promising ME/CFS biomarker candidate the field has seen. An ME/CFS biomarker – long awaited by scientists – would allow the precise and objective diagnostics that have never been possible for this disease. In addition, it would accelerate the search for treatments. Dr. Naviaux’s study suggests that both of these endeavors could be designed in a way that will benefit all patients, regardless of their symptoms and initiating events (which are not always known).
In addition to a common metabolomic response, patients show a variety of individual responses. These individual responses may contribute to the symptomatic differences, and may be caused in part by genetic differences. Similarly, effectively treating ME/CFS might require two components: a common treatment for all patients and a personalized treatment. Interestingly, this might explain the plethora of treatments that have helped individual patients but only rarely work on other patients.
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.
This breakthrough study thus presents several new findings of great importance to the ME/CFS patient, medical, and research communities – and perhaps most importantly, to the search for treatments. For these findings to have an impact on patient care, further investigation and validation via independent studies are crucial. Because of this, the Open Medicine Foundation has funded the next study of a larger patient cohort, in which Dr. Naviaux will validate the ME/CFS metabolomic signature in a larger, geographically diverse sample, and I will explore the role of genetics in the individual responses. These studies are already underway. We appointed Dr. Naviaux to the Scientific Advisory Board of OMF earlier this year, and we are grateful for his expertise in helping to unravel the metabolic mysteries of this debilitating disease. We are finally on the right path to understanding ME/CFS. We and many of our collaborators are working hard to translate this new understanding into general and personalized treatments. The more support our research gets, the faster that will happen. Find out how you can support ME/CFS research here: http://www.openmedicinefoundation.org/donate-to-the-end-mecfs-project/."
Added to this is a Q and A with Dr Naviaux expanding on some key aspects of the study:
Metabolic Features of Chronic Fatigue Syndrome
Naviaux RK, et al. PNAS MS# 2016-07571RR, August 31, 2016
Website: Naviauxlab.ucsd.edu
Q1. Some people still argue that CFS is not a real illness but all in the mind. Does your discovery of a chemical signature help shatter this myth?
Yes. The chemical signature that we discovered is evidence that CFS is an objective metabolic disorder that affects mitochondrial energy metabolism, immune function, GI function, the microbiome, the autonomic nervous system, neuroendocrine, and other brain functions. These 7 systems are all connected in a network that is in constant communication. While it is true that you cannot change one of these 7 systems without producing compensatory changes in the others, it is the language of chemistry and metabolism that interconnects them all.
Q2. How does chronic fatigue syndrome fit in with other kinds of hypometabolic states or syndromes?
All animals have ways of responding to changes in environmental conditions that threaten survival. We discovered that there is a remarkable uniformity to this cellular response, regardless of the many triggers that can produce it. We have used the term, the cell danger response (CDR) to describe the chemical features that underlie this response. Historical changes in the seasonal availability of calories, microbial pathogens, water stress, and other environmental stresses have ensured that we all have inherited hundreds to thousands of genes that our ancestors used to survive all of these conditions.
The body responds differently to the absence of resources (eg, caloric restriction or famine) than to the presence of pathogens and toxins. We can classify two responses: a single-step response to the absence of resources, and a two-step process in response to the presence of a threat. Both responses are completed by a return to normal metabolism and function. When resources are severely curtailed or absent, the full CDR is bypassed, and the flow of nutrients through metabolism is decreased to conserve limited resources in an effort to “outlive” the famine. This is often called a caloric restriction response. On the other hand, when the cell is faced with an active viral, bacterial, or fungal attack, or certain kinds of parasitic infection, severe physical trauma, or even chronic psychological trauma (which produces a similar chemical change in metabolism), this activates the two-step response. The first step is to acutely activate the CDR. Innate immunity and inflammation are regulated by the metabolic features of the CDR. Activation of the CDR sets in motion a powerful sequence of reactions that are tightly choreographed to fight the threat. These are tailored to defend the cell against either intracellular or extracellular pathogens, kill and dismantle the pathogen, circumscribe and repair the damage, remember the encounter by metabolic and immunologic memory, shut down the CDR, and to heal.
In most cases, this strategy is effective and normal metabolism is restored after a few days or weeks of illness, and recovery is complete after a few weeks or months. For example, only a small percent of people who are acutely infected with Epstein-Barr virus (EBV) or human herpes virus 6 (HHV6), or Lyme disease go on to develop chronic symptoms. If the CDR remains chronically active, many kinds of chronic complex disease can occur. In the case of CFS, when the CDR gets stuck, or is unable to
overcome a danger, a second step kicks in that involves a kind of siege metabolism that further diverts resources away from mitochondria and sequesters or jettisons key metabolites and cofactors to make them unavailable to an invading pathogen, or acts to sequester toxins to limit systemic exposure. This has the effect of further consolidating the hypometabolic state. When the hypometabolic response to threat persists for more than 6 months, it can cause CFS and lead to chronic pain and disability. Metabolomics now gives us a way to characterize this response objectively, and a way to follow the chemical response to new treatments in systematic clinical trials.
Q3. You talk about the chemical signature being similar to a state of hibernation. What sort of animals exhibit a similar signature in hibernation?
I wouldn’t use the term hibernation to describe chronic fatigue syndrome. Humans do not hibernate. Hibernation is just one of a handful of hypometabolic states that has been studied in different animals. There are many others that go by names like dauer, diapause, torpor, estivation, caloric restriction, etc. Many environmental stresses will trigger hypometabolism in humans. In our experience, the metabolic signature of dauer is more similar to CFS than some of the other hypometabolic states that have been studied. One of the main points of our metabolomics study of CFS was to give other scientists a new tool to analyze all of these hypometabolic states, developmental stages, and syndromes so that the similarities and differences can be objectively studied, and rational new therapies developed.
Q4. Are men and women really that different in CFS?
Yes. About 40-50% of all the metabolites that we measure in our method have a different normal concentration in males and females. This is not all related to testosterone and estrogen. Literally hundreds of metabolites are tuned to different concentrations in men and women. At the pathway level, we found that men and women shared 9 (45%) of the 20 biochemical pathways that were disturbed in CFS patients. Eleven pathways (55%) were more prominent in males or females. We find that to do metabolomics properly, you need to have an adequate number of age- and sex-matched controls. If healthy males and females are lumped together as controls, the power to see metabolic differences in CFS and many other diseases is much decreased. Likewise, the metabolism of a 25-year old male is different from a 35-year old male, and categorically different from a 25-year old female. In each decade of life there are many metabolic changes that occur as part of normal development and aging. When proper age- and sex-matched controls are used, metabolomics is one of the most powerful new tools available to physicians and scientists to study chronic complex disease.
Q5. How do the metabolic changes you identified in CFS relate to the recent interest in epigenetics and methylation pathways?
All the covalent chemical modifications of DNA and histones that regulate gene expression are the result of metabolic changes controlled by mitochondria. For example, all DNA and histone methylation depends on the availability of S- Adenosylmethionine (SAMe). Phosphorylation reactions depend on the availability of ATP. Acetylation depends on the availability of Acetyl-CoA. Demethylation depends on the availability of oxygen and alpha-ketoglutarate. Other demethylation reactions require the availability of FAD+ and generate peroxide. Deacetylation depends critically on the availability of NAD+. DNA ADP-ribosylation also depends on the availability of NAD+.
The master fuel regulator AMP kinase (AMPK) activity depends on the build-up of AMP or the de novo purine biosynthesis intermediate AICAR (aminoimidazole carboxamide ribotide). mTOR is another key barometer of cellular fuel status. mTOR activity requires the availability of leucine. All of these metabolites that regulate epigenetics and gene expression are controlled primarily by mitochondrial metabolism. This makes sense because all cellular activities must be responsive to local resource availability and remain flexible to respond to potential threats that alter cellular health, and mitochondria are the prime monitors and regulators of cellular metabolism.
With regard to cytoplasmic methylation reactions that involve folate and B12 metabolism, mitochondria also play a key role by regulating the release of formate, the balance of NADPH to NADP+, NADH to NAD+, FADH2 to FAD+, propionyl-CoA to succinyl-CoA, and glycine to serine. Ultimately, all of these mitochondrial reactions influence the tide of substrates available for methionine, cysteine, glutathione, and taurine metabolism. The ebb and flow of these metabolites determines the balance between cell survival and death, controlling epigenetic modifications and gene expression. These reactions are illustrated in supplemental online Figure S6 of our paper.
Q6. How might your results help with treatment of CFS?
This first paper was not focused on treatment. However, metabolomics reveals a new window into the underlying biology of CFS that makes us very hopeful that effective treatments will be developed soon and tested in well-controlled clinical trials. Metabolomics will be an important component of any clinical trial of new treatments for CFS. It will also play an important role in analyzing the similarities and differences of classical laboratory models of hypometabolic states like dauer.
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.
Q8. Since mitochondria have two main jobs in the cell—energy metabolism and cellular defense—is it possible the one function can be overactive at the expense of the other?
Yes. This is a key concept. Our lab classifies all complex chronic disease as being the result of either mitochondrial underfunction or mitochondrial overfunction. Each type has both genetic and environmental causes, but environmental causes outnumber genetic causes in the clinic 10:1. Only expert centers in mitochondrial medicine will typically see the many genetic forms of mitochondrial oxidative phosphorylation and metabolic disorders. Most academic centers will see more of the “ecogenetic” mitochondrial disorders caused principally by environmental factors. These disorders range from autism to asthma, depression and autoimmune diseases, to Parkinson and Alzhemier disease, and many more.
Mitochondria lie at the hub of the wheel of metabolism, coordinating over 500 different chemical reactions as they monitor and regulate the chemical milieu of the cell. It turns out that when mitochondria detect “danger” to the cell, they shift first into a stress mode, then fight mode that takes most of the energy-producing metabolic functions of mitochondria off line. Even normal exercise stresses mitochondria transiently and reminds the cell how to heal. Cells “go glycolytic” under conditions of stress, using oxygen less and sugar more for energy production.
Mitochondria are highly dynamic in the cell. They will fuse with one another and divide, moving about the cell, changing their location according to cellular needs. Sometimes mitochondria will proliferate so a cell has more mitochondria than normal. Other times they will become hypersensitive to minute changes in one or more chemicals in the environment, overreacting to a stimulus that would normally be undetected by cells that have a normal mitochondrial setpoint.
What does all this mean? It means that mitochondria don’t do just one thing. Sometimes, when one function is overactive the other is decreased. This is experienced by athletes in training. Overtraining increases the energy function of mitochondria, but causes a decline in the defense function and they become more susceptible to colds and many other infections. On the other hand, in CFS, many patients report a surprising resistance to the common cold and many other common types of infection. This increase in the antiviral defense function of mitochondria comes at the expense of the energy function.
Energy production and cellular defense are two sides to the same coin—when you are looking at one side, the other side is temporarily hidden. Mitochondrial cannot perform both energy and defense functions at 100% capacity at the same time. Health requires a dynamic balance of both these functions. It is plausible that when a particular patient seems to benefit from long- term use of a drug known to be toxic to mitochondria, that the drug helps rebalance cell defense and cell energy functions by decreasing the over-activity of one function and permitting an increase in an underactive function. My experience is that this is rare in CFS, but exceptions occur and are important to understand if doctors are to get better at treating all patients. Both patients and doctors should carefully evaluate the pros and cons of long-term antimicrobial therapy if the signs of an objective infection have disappeared. Any drug has the potential to be therapeutic or toxic.
Q9. To follow
Q10. To follow
Q11. Many ME/CFS experts have improved the symptoms in some patients by treating with antivirals and Ampligen (polyIC double stranded RNA). I think this proves that ongoing viral infections are causing our symptoms. It is not merely “tired patients” who are stuck in a lowered metabolic state because of a past trigger (which now is gone).
First of all, it is important that people actually read our paper first before drawing conclusions from news reports and blogs and criticizing something that we never said. I have seen a number of generalizations starting to appear in blogs and reports by journalists in even good newspapers and magazines that are starting to drift too far afield from the actual science in our paper. We devoted a section of the paper to this and related questions about infections. The section title was, “A Homogeneous Metabolic Response to Heterogeneous Triggers”. It concluded with the sentence, “Despite the heterogeneity of triggers, the cellular response to these environmental stressors in patients who developed CFS was homogeneous and statistically robust.” As background for this conclusion, I recommend reading our paper on this topic entitled, “Metabolic features of the cell danger response” (PMID 23981537).
Second, many people do not understand that the first response our body mounts against a viral, bacterial, or any kind of infection is metabolic. Yes, our chemistry is our first line of defense. Our chemistry reflects our instantaneous state of health. Innate immunity is coordinated by mitochondria and is an essential first step in developing adaptive immunity to any infectious agent. Without innate immunity there can be no antibodies and no NK cell activation, no mast cell activation, and no T cell mediated immunity.
In addition, all antivirals have metabolic effects that have nothing to do with inhibiting viral DNA or RNA synthesis directly. Many antiviral drugs inhibit the key metabolic enzyme S- Adenosylhomocysteine Hydrolase (SAHH). Inhibition of SAHH causes an increase in intracellular SAH levels. SAH is a potent inhibitor of DNA, RNA methylation. This affects both viral and host cell epigenetics, gene expression, and mRNA translation. The inhibition of methylation reactions in the cell also affects neurotransmitter (dopamine, norepinephrine, and serotonin) and phosphatidylcholine membrane lipid synthesis, and many other reactions. So by giving antivirals, doctors are not just inhibiting viruses, they are also inhibiting many host cell metabolic functions. Sometimes the inhibition of host cell functions can attenuate ME/CFS symptoms for a time, but in other cases, using potent antiviral drugs inhibits mitochondrial and methylation reactions and can delay a full recovery from ME/CFS.
You also asked about Ampligen. Ampligen is nothing more than a form of double stranded RNA called poly(IC) for poly inosinic:cytosinic acid. We have studied the action of polyIC extensively and have published this in our studies of autism and virology. It acts by binding to an innate immune receptor called TLR3, creating a simulated viral infection. If you expose a pregnant animal to a single dose of polyIC at the beginning of the second trimester, she develops a 24- hour flu-like illness then completely recovers. However, her pups have social and cognitive abnormalities similar to autism for life. If you look at their brains, you find that they have
activated microglia and brain inflammation for life. In adults, Ampligen also binds the TLR3 receptor, and activates an incomplete antiviral response characterized by a non-MyD88 dependent activation of interferon and other cytokines. Long-term use of polyIC carries a risk for toxicity because of chronic innate immune stimulation. In certain clinical situations like cancer or Ebola virus infection the toxicity is actually part of the therapeutic effect. Chronic interferon release causes flu-like symptoms, and the inhibition of mitochondrial protein translation. This can lead to secondary mitochondrial dysfunction. As I noted in an earlier Q&A response, sometimes the inhibition of mitochondrial function can make some people with ME/CFS feel better temporarily because some symptoms can come from unbalanced overactivity of some of the hundreds of functions mitochondria perform. However, in the long term, any pharmacologic inhibition of mitochondrial function will delay a full recovery.
Third, latent and reactivated viral and bacterial infections can occur, but in the case of ME/CFS that has lasted for more than 6 months, this may be the exception rather than the rule. Some doctors and scientists have not done a good job at educating patients and other scientists about the difference between serological evidence of infection in the form of antibodies like IgM and IgG, and physical evidence of viral replication like PCR amplification of viral RNA or DNA, or bacterial DNA. We have learned in our autism studies with Dr. Judy Van de Water that supertiters of antibodies do not mean new or reactivated viral replication. Supertiters of IgG antibodies mean that the balancing T-cell and NK cell mediated immune activity is decreased. This is like the famous figure-and-ground illusion that shows the silhouette of two faces that also create the form of a vase. Both things happen. But which is cause and which is effect? Increased IgG antibodies to CMV, EBV, HHV6, Coxsackie, etc. are not good evidence of a reactivated viral infection. This can be proven in most cases by trying to measure viral DNA or RNA by PCR in the blood or swollen lymph nodes. In most cases, supertiters of IgG are PCR- negative. There are exceptions to this generalization. However, chronic PCR surveillance studies in healthy humans are showing that little waves of viral replication happen periodically throughout our lives. We have been, and are regularly infected by hundreds of viruses over a lifetime. Sometimes this is obvious and causes a symptom like blisters or an ulcer around the mouth. However, most of the time these waves of viral replication are silent and produce no symptoms at all because they are handled in the background by the innate and cell-mediated immune system. Even the deadly poliovirus infected 150 to 1800 people producing only mild or unnoticed infections for every one person who developed paralytic disease. In most of the cases of ME/CFS that I have seen where IgG antibody titers have been measured before, during, and after antiviral therapy, the antibody titers remain high after treatment, even though the patient may report symptomatic improvement. I believe the symptomatic improvement after antiviral treatment may have more to do with the metabolic effects of antivirals in ME/CFS than their action on viral replication. The good news is that this hypothesis can be studied scientifically and put to the test easily using the tools of PCR and metabolomics.
Good science needs to remain open, ask the questions without bias, design good experiments, take careful measurements, then have the courage to follow the data wherever they may lead.
Enjoy!
B
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Lots to take in guys. Hope you enjoy it-huge thanks to @Rose49 , Ron, Linda and Dr Naviaux, and the whole OMF team. These guys are working so hard for us, it's unbelievable.
Donations to further this incredible research with OMF can be made here:
http://www.openmedicinefoundation.org/donate-to-the-end-mecfs-project/
Thanks so much,
B
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