Naviaux's metabolism paper is about as big as you think

Robert Naviaux, at researcher at University of California, San Diego, published a landmark paper yesterday on the metabolites of patients with ME/CFS. It made news around the world. Below, an in-depth analysis of the paper’s findings and its implications.
Note: some of the information below is speculative, linking Naviaux’s findings to other research.  Findings not explicitly indicated by the study are summarized at the end of the article.

Introduction

For those who are wondering at the results and their implications, Naviaux’s study in a nutshell states that the cells of ME patients are in a sort of protective hibernation, limiting their consumption of resources and engaging in a hypometabolic state as a response to infection or other stressors.  By examining patients’ metabolites in detail, it was found that this degree of protective hibernation correlates directly to clinical severity.

Naviaux also posits that cells in ME/CFS are cells under enormous stress, for which they create a series of defenses, metaphorically installing a superior lock and alarm system and hiding all the valuables.  However, some pathogens know the code to get in,  and when the resources are hidden, the host can’t use them, either.  Both of these aspects of this mode of cellular defense have profound implications for symptomology.

Naviaux’s study featured differences between male and female patients that have not been described in other studies before:

  • Women, but not men, generally had disturbed fatty acid and endocannabinoid metabolism
  • Men, but not women, generally showed increased serine and threonine concentrations

However, the majority of the findings showed abnormalities in both of the sexes, including decreased cholesterol synthesis in one pathway, and decreased spingolipids and glycosphingolipids.

Glycospingolipids, spingolipids, and cholesterol synthesis low – and that’s a huge deal

Sphingolipid depletion would go a long way to explaining some of the abnormalities seen in CFS patients.  Ceramides, a product of spingolipids, are responsible for the creation of ‘lipid rafts’, which mobilize and aggregate during infection.  Lipid rafts also require cholesterol and other fatty molecules to function properly.

At one time, it was believed that membrane proteins and fats were always scattered haphazardly throughout the lipid bilayer that makes up the cell membrane.

lipid bilayer
What you’ve seen in every Biology textbook ever

However, now there is a theory that there are lipid-rich areas of the membrane, full of glycosphingolipids (sugar-amino alcohol-fatty bits), cholesterol, gangliosides, and proteins.  These exist as little ‘pockets’, though they may be linear as well; and they tend to cluster in this manner when the cell is stressed.  Stress here signifies anything that has the potential to cause cell damage, rather than to intimate that these cells are frightened or upset.  (Last we checked, cells didn’t get very emotional.)

The way they function together in these situations is complex, and might require a bunch of proteins and fats all acting in a little network, pulled along by actin.  If any of these proteins or fats are disrupted, the membrane rafts lose functionality.  And what they do is very important: they help maintain the structural integrity of the cell, while also playing an immune role.  Calveolins and cavins, chemicals that are part of lipid rafts, may promote or inhibit immune activation, and are also involved in neuronal signalling; and the calveolin to cavin relationship often governs inflammatory signalling pathways.

In order to defend the cell, lipid rafts aggregate, making it more challenging for a pathogen to enter.  However, some bacterial and viral pathogens have evolved to not only get around this defense technique, but exploit it.  By ‘sneaking in’ the cellular back-door, these pathogens also escape being sent to the lysosome for disposal, and may therefore survive longer than their traditionally-infectious counterparts.

 

Pathogens that have evolved to enter the cell via lipid rafts

Bacteria Viruses
Pseudomonas aeruginosa [55] and [66] HIV-1
Escherichia. coli [38] and [46] Species C human adenovirus (HadV)
Camylobacter jejuni [71] and [72] Rhinovirus
Chlamydia species [67] and [69] Enterovirus
Mycobacteria species [83], [84] and [85] Echovirus
Brucella species [75], [77] and [81] Simian virus
Listeria monocytogenes[88] Influenza
Shigella flexneri[16] Epstein-Barr Virus
Ehrlichia chaffeensis [89] and [90] Ebola
Anaplasma phagocytophilum [89] and [90] HSV-1
Group A Streptococci[91]
(Zaas et al, 2005) (Suzuki, 2006)

 

It appears as though certain fungi utilize this mechanism as well, although fungal pathogens are the least studied of the three pathogen-types in terms of their lipid raft interactions.

Downregulating sphingolipid synthesis in general, and ceramide synthesis in particular, could well be part of a host-defense response in the presence of these pathogens to prevent their entry, to decrease the risk of cellular apoptosis in response to infection.  It’s also possible that the cells upregulate the creation of lipid rafts as a continued protective measure, resulting in the presence of fewer free lipids involved in this process.

The lipid raft-Rituximab connection

Fluge and Mella recently released a study stating that B-cell survival factors APRIL and BAFF were likely not the cause of the success of Rituximab in abating symptoms in ME patients.  If Naviaux et al.’s research turns out to be replicable, his findings may both explain why the incidence of cancer is higher in ME patients and why Rituximab works for some.  From George and Wu (2012),

Rituxan/Rituximab, an anti-CD20 antibody used clinically to initiate CD20-mediated apoptosis, was used for the study of the activation mechanism of CD20. Upon activation, CD20 translocated to the lipid rafts domains of the cell where they were activated to initiate apoptosis.

In other words, Rituximab may work in ME by creating the necessary disruption in lipid rafts to prevent pathogens from using this ‘back door’ to creep into the cell, in the case of an active infection; or it may force the destruction of only cells that exist in this defensive state, causing a cascade of metabolic events that eventually results in the majority of cells no longer in metabolic hibernation.  This may in part explain the lag in efficacy in Rituximab, if the process involves slowly but steadily replacing cells stuck in hibernation with healthier ones, and those cells replicating.  This would be a gradual process rather than an instant one.

This lipid-disrupting property is also what makes Rituximab effective against cancer, an illness which, in and of itself may itself be profoundly affected by lipid raft dysregulation, which may in turn help explain the increased incidence of cancer in ME.

The most ‘diagnostic’ metabolites:

Out of all the metabolic pathways that Naviaux’s team measured, the following were most often irregular in male and female subjects:

Lipids Naviaux
The most commonly dysregulated metabolic subsets in women and men with ME/CFS
 

Generally, these patterns were the opposite of the patterns seen in acute inflammation and infection: rather than a knock-down, drag-out fight, cells appear to be hunkering down, trying to make as little metabolic ‘noise’ as possible.  Naviaux’s team noted that the pattern in ME patients was almost the exact opposite of that found in systemic inflammatory conditions such as metabolic syndrome and heart disease.

Moreover, Naviaux’s team found that analysis of several of these metabolites could be diagnostic, such that even one metabolite could be predictive of illness; however, Naviaux’s team notes that their small sample size and localized population makes a one-metabolite test too unrealistic, and recommends the study of 8 metabolites for men and 13 in women to make an accurate diagnosis.

Finally, Naviaux’s team found that the metabolic abnormalities observed were directly related to redox or to the availability of NADPH, a high-energy molecule necessary to fuel the reactions of cellular respiration, which was found to be depleted in patients.

Implications:

Provided Naviaux’s work is replicable, and his interpretations are correct, the findings would have enormous implications.

  1. We have a reasonable set of biomarkers that would produce a viable diagnostic test.
  2. We may understand better why ME is associated with illnesses such as cancer and autoimmunity
  3. We may understand better why a chemotherapeutic agent such as Rituximab should improve symptoms in ME.
  4. We may have an explanation for the ‘sick but never sick’ state experienced by many patients: in cells overutilizing lipid rafts to prevent infection, only a select few pathogens ‘know’ how to still enter the cell, and hypometabolic changes create less ‘food’ (metabolites tasty to pathogens) as a result, further preventing the growth of pathogens who do not favor lipid raft-assisted infection.
  5. The sequestering of resources and hypometabolism would explain why patients are so profoundly fatigued, and provide a rationale for PEM: the resources simply aren’t there.
  6. Finally, errors in the makeup or metabolism of lipid rafts would have a profound effect on the biology of every system, since lipid rafts are directly involved in cell recognition (errors would cause autoimmunity), other kinds of cell signalling including neuronal signalling, and general immune function as well as the physical integrity of the cell.

What we do not yet understand is how this will affect potential treatment avenues.  If this ‘hibernation state’ – that Naviaux calls ‘dauer’ – is a protective response, ‘turning it off’ may not be in our best interest, especially if the initial insult lingers.  We remain faced with one of the biggest and most persistent questions in ME research: is the initial-insult pathogen / stressor still there, or not?

Patients experiencing fewer symptoms from taking an antifungal, antibiotic, or antiviral in this case would not necessarily indicate the presence of an active infection.  Some antimicrobial agents disrupt lipid rafts, and aren’t as picky about targeting pathogens as we’d like to think.  Therefore, the effectiveness of antimicrobial therapies in an ME patient would not necessarily indicate the presence of a currently-active infection.

Unfortunately, it may not be a simple yes-or-no answer.  The presence or absence of a systemic pathogen may in fact be a source of patient subsets, with a group of patients still experiencing active or latent infection, and another stuck in an autoimmune-type symptom picture in which the initial-insult pathogen is no longer active, but the system is unable to come unstuck from protective-hibernation mode.

There are still many questions to answer, and replication studies ahead; however, this is likely the most promising research into ME since Lipkin and Hornig‘s landmark cytokine study, with real, positive implications for the ME community.


Access Naviaux et al’s paper here.

Access the supplementary materials here.

Access the Q & A Session on the paper here.



 
Note: The paper created by Dr Naviaux’s research team is more circumspect about implications of the study.  Therefore, I would like to make a clear-cut distinction between my own suppositions and that of Naviaux’s paper:
It is my hypothesis that lipid raft metabolism has implications for the mechanism via which Rituximab improves symptoms in ME patients.
It is my hypothesis that lipid raft disruption is why certain antimicrobial agents may be effective treatments for ME even in the absence of a pathogen.
While it is not my hypothesis that lipid raft aggregation would create an advantage for some pathogens over others, it is my hypothesis that this is what makes certain infections more common in ME patients.
It is my hypothesis that lipid raft dysregulation might create an advantage for some pathogens while inhibiting others, creating the ‘sick but never sick’ patient symptom-picture.
It is my hypothesis that lipid raft dysregulation is what ME and cancer have in common, which may have implications for their increased co-incidence.
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79 thoughts on “Naviaux's metabolism paper is about as big as you think”

  1. Hi Jamie,
    Please contact me at [email protected] or call my cell (XXX-XXX-XXXX) sometime next week after the buzz dies down a little. I would like to talk.
    You did a nice job explaining the implications of the sphingolipids for CFS biology. I had to cut 80% of our sphingolipids results and discussion to meet PNAS page limits. Some of this got relegated to the supplemental online material.
    Kudos to you for a very nice job.
    Sincerely,
    Bob

    1. Thank you so much, Bob! That’s very kind of you. I removed your cell number from the above post, just in case you didn’t really want it shared that publicly. I’ll get it touch with you soon.

  2. This is amazing Jaime,
    Actually i read this in details, back and foward, remember when we were talking about my believe that the pathogen behind Our illness could be also behind other illness, just different trigger(s) and expousures will define the type of illness and severity, also in thesame discution, me and a couple other people were talking about, it was more than clear that our goverments were blocking findings and limiting resourses in our illness becouse the underlaying cause of our illness it had to do with alot more than just ME/CFS….(SOMETHING BIG) much BIGGER & i said after doing so much extensive research, putting all of them together including the answers and actitud to each study from NIH,CDC, & all this NATO partners countries, US, UK,CAN,AUST..Always finding a way to :discredit , dissmise, block, doubt, obscure, savotage every positive finding that give light to this illness they turn it off again, my theorie was that the pathogen underlaying ME/CFS, was probably the underlaying cause of many other diseases, this is the underlaying cause of some type of cancers, that’s why in AIDS you see such a high rates of cáncers also, many others ( I think We ME/CFS , crossed ourself in the way of something that was not intended for us, perhalf something was man created, many years ago for depopulation or another purpose, with out the triggering factors it would of stayed that way till a cancer develope, but with trigger factors, or coinfections it comes the development of all this cronic illness, auto immune and neuroimmune.
    We are collateral damage, it was not intended for us, whatever pathogen, virus o retrovirus causing this wasn’t intended for us, but with acquiring other viruses especially herpes family and toxins etc that develope in ME/CFS.. And since our illness is the one that mimic the most AIDS, do to the level of desability and immune disfuntion it’s the one not so easy to Mask like they do with the others.. Thats why the All been agains the real findings at any Cost… There is no other explanation of to why all this goverments have ingnored and block this illness, Researchers, doctors and tons of studies that have demostrated with science and hard evidences this is a real cronic disease, full of immune, neurological and metabolic disfuntions, with a possible ethiology from a transmisible infectious pathogen.

    1. I wanted to provide direct links to Dr. Naviaux and the researchers involved in this study. Funds are currently being raised for a replication study, which you can learn more about at some of the links. You can also sign up at the GMRC website or the GMA blog to receive updates on the study over time.
      Naviaux Labs – http://naviauxlab.ucsd.edu/
      Gordon Medical Research Center – https://www.gordonmedicalresearch.com/
      DONATE to the Research – https://www.gordonmedicalresearch.com/?page_id=17
      More on the Metabolomics Study – http://www.gordonmedical.com/unravelling-complex-chronic-illness/more-on-the-metabolomics-study/
      Gordon Medical Research Center Now Funding Replication Study on CFIDS/ME Findings – http://www.gordonmedical.com/unravelling-complex-chronic-illness/gordon-medical-research-center-now-funding-replication-study-on-cfidsme-findings/
      Metabolomics Research at Gordon Medical Research Center – https://www.gordonmedicalresearch.com/?page_id=142
      Thanks!
      Susan Friedl
      Gordon Medical Associates
      [email protected]
      http://www.gordonmedical.com
      https://www.gordonmedicalresearch.com

  3. Jaime,
    You wrote a long message to me and I want to get back to you but I can’t remember where the message is! FB? PR? MEAction? CFSRC? I can’t find it. Can you send it again to my email: [email protected]
    btw, Bob Naviaux told me how impressed he is with your analysis, and it’s the best one he’s seen in all the press! Good job!
    Janet

  4. This is a really good breakdown for those of us who don’t have a scientific background (and who also might be suffering from a touch of brain fog ?). Thank you so much for an excellent analysis, what a truly fascinating study. And how lovely for Bob Naviaux to get in touch and compliment your work too!
    Well done to all concerned, and grateful thanks to Bob Naviaux and his team for both believing that there was something to be found and then looking for it. Thanks go out as well to all the very sick patients who volunteered to be part of the research. You all might well have made history.

    1. Thank you, Bluesky, and you’re absolutely right. Every day I’m reminded that when we move forward it’s because of tiny actions at a low level by hundreds of people. I know I’m drinking the advocacy Kool-Aid, but it’s tasting pretty sweet right now. 😉

  5. Fantastic Jamie. When I read the paper I thought , holy hell – now reading your interpretations I’m going holy hell. . Great review and integration . Thanks so so much

    1. Thanks so much, Jill! It’s very exciting. Of course any of my ‘interpretations’ (listed at the bottom) could turn out to be very incorrect. 🙂

  6. Jaime, I was going to tell you how well you had explained things (so that even an arts grad could follow it!) but I see you have a rather more impressive endorsement 😉
    Well done, and thank you. Great job.

  7. Thank you Jaime for such an intelligent, accessible and interesting explanation of this groundbreaking study and its implications. It’s great that the author thinks so too – praise indeed and well-deserved!

  8. From the mother of a 15 year old girl suffering from CFS for over a year and a half (at least we think it is CFS – have ruled out everything else) I can’t thank you enough. This study that I’ve been reading about for the last few days and specifically your article bring tears to my eyes thinking that there could be answers someday and that no one will have to go through what she has had to go through to get a diagnosis and potentially a cure!
    Thank you!

    1. Thank you so much for your comment, Sherri. I feel incredibly lucky to be here to see all the working being done lately. Let me know if your daughter has any questions about the research, though at this point I’m sure she just wishes she were better. 🙂

  9. Jaime s wrote:
    “Rituximab may work in ME by creating the necessary disruption in lipid rafts to prevent pathogens from using this ‘back door’ to creep into the cell, in the case of an active infection; or it may force the destruction of only cells that exist in this defensive state, causing a cascade of metabolic events that eventually results in the majority of cells no longer in metabolic hibernation.”
    I seem to be missing something important here, perhaps because my understanding of biology is extremely limited, and plenty of what I think I know is likely wrong.
    My understanding is that Rituximab works on autoimmune disease because it kills B cells before they transform to the plasma cells that manufacture destructive auto-antibodies, i.e., it only kills B cells, not other cells in the body. Rituximab is used for lymphomas and leukemias, not other kinds of cancer. [1]
    So I don’t understand how killing B cells could potentially turn off the Dauer effect in the rest of the body.
    I do think it is likely there are subsets of patients with infections of some kind, and another subset who are producing harmful auto-antibodies. I’m confident I’m in the latter group, and I have more than one ANA test report to prove it.
    However I have found it impossible to convince any doctor to take the ANA test results and other inflammatory markers seriously. Instead they insist on trying to prescribe anti-depressants or send me to psychotherapists, psychiatrists, and rehab specialists, as well as writing harmful reports such as “Exaggerates symptoms”, “Seeking attention”, “Lacks insight”, etc.
    So in spite of Dr Naviaux’s impressive new study, and this excellent article, I am unable to feel jubilant or excited, or even mildly hopeful. Physicians still refuse to acknowledge the seriousness of my illness, and I am still condemned to live in poverty and isolation by a society that has kicked me to the curb.
    It will take a Zika-like media campaign, led by a CDC and NIH press conference, that makes perfectly clear that doctors can no longer treat patients like garbage and expect to remain on the register. I don’t expect that to happen before I, like so many others before me, can no longer tolerate the isolation and the struggle to get through yet another endless day of endless illness.
    No one should be forced to choose between daily suffering alone in silence, and death.
    I apologize for being Debbie Downer, and I really do appreciate the huge efforts by Dr Naviaux, Dr Davis, and colleagues. I know they are rushing to find real solutions as fast as they can. I know it is very distressing to them that it will not be fast enough to save all of us. But it will be fast enough to help to many people, and that’s all anybody can ask for.
    Silence = Death
    Complacency = Consent
    [1] https://en.wikipedia.org/wiki/Rituximab

    1. ““Rituximab may work in ME by creating the necessary disruption in lipid rafts to prevent pathogens from using this ‘back door’ to creep into the cell, in the case of an active infection; or it may force the destruction of only cells that exist in this defensive state, causing a cascade of metabolic events that eventually results in the majority of cells no longer in metabolic hibernation.”
      I seem to be missing something important here, perhaps because my understanding of biology is extremely limited, and plenty of what I think I know is likely wrong. ”
      I could certainly be incorrect as well, jimells. However, the *mechanism* via which Rituximab destroys B-cells is by disrupting their lipid rafts. It probably does the same thing in other cell subsets, as few chemotherapeutic agents target one cell line entirely exclusively. Let me know if that clears things up, or if I’ve muddied the waters!
      And, as always, getting excited about research doesn’t mean we don’t have far to go, or deny the seriousness of the issue.
      Personally I’ve always had positive ANA results, but they’re always low-positive. In that particular case, I agree with my physicians that it doesn’t mean a lot.

      1. Hi jaime s. You wrote:
        ” However, the *mechanism* via which Rituximab destroys B-cells is by disrupting their lipid rafts. It probably does the same thing in other cell subsets, as few chemotherapeutic agents target one cell line entirely exclusively.”
        My understanding is that Rituximab is not, strictly speaking, a chemotherapeutic agent (like cyclophosphamide, for example) that has widespread (and potentially devastating!!) effects throughout the body. Rather, it is an antibody that targets the CD20 protein found mostly on B cells. [1] Once the B cells are tagged with the antibody, other immune cells come along and destroy the B cells. So I don’t understand what lipid rafts have to do with B cell destruction.
        The Wikepedia article on CD20 [2] does have an interesting discussion on B cells, CD20, and diabetes mellitus involving fat cells, and suggests that obesity may be an autoimmune disorder, but I don’t think that has anything to do with lipid rafts.
        I’ll read your article again tomorrow to see what I am missing. It’s an interesting challenge for me to understand this stuff, since my knowledge of cell biology looks a lot more like Swiss cheese than it does cheddar.
        At any rate, thank you for your response – it has prodded me into reviewing what I think I know and to learn something new, which is always a good outcome.
        [1] https://en.wikipedia.org/wiki/Rituximab
        [2] https://en.wikipedia.org/wiki/CD20

        1. Whew. I re-read your article, and this time I am understanding it better. I actually looked at the George and Wu paper that you cited. And it occurred to me to ask Pubmed what other cells express the CD20 protein:
          “Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3(+)CD20(+) T cells has been described that is also targeted by the anti-CD20 mAb rituximab.”
          “In this study, we confirm that 3-5% of circulating human T cells display CD20 on their surface and transcribe both CD3 and CD20. We report that these CD3(+)CD20(+) T cells pervade thymus, bone marrow, and secondary lymphatic organs. They are found in the cerebrospinal fluid even in the absence of inflammation; ”
          “Functionally, they show a higher frequency of IL-4-, IL-17-, IFN-γ-, and TNF-α-producing cells compared with T cells lacking CD20” [1]
          I don’t know if any of the above has much to do with our illness, but it underscores just how devilishly complex all this stuff is. My hat’s off to anyone who can put together a coherent story from the mass of disparate and sometimes contradictory facts that make up the research literature.
          [1] http://www.ncbi.nlm.nih.gov/pubmed/27412413

  10. Great research! I almost understand it. I completely agree with the answer to the first question in the linked Q & A document and would love for it to be shared with government officials who think ME is psychosomatic.
    Since Dr. Naviaux is subscribed to these comments, I’d like to tell this to him and his team: Thanks a million for taking an interest in ME and conducting quality research that has shed light both on the disease mechanisms and on where additional research could lead to the creation of effective treatments. Please continue working on patients’ behalf and inspiring other researchers to study ME.

  11. Thank you so much for this excellent synopsis Jaime! I tried to read the study last night and even though I could not wrap my head around it, I knew it was groundbreaking. Now I understand why! Thank you for taking the time to write this!

    1. Thank you so much, Larissa! I’m really glad that the article was helpful. It’s hard to know how to strike a good balance in science writing, so I really appreciate the feedback.

  12. I have awful brain fog but the first two paragraphs spoke volumes to me.
    Wish I could read more and see charts and understand them. I am not good at that anymore.
    Thanks so much.

  13. Hi Jaime
    Thank you, brilliantly written. I’ve read everything since yesterday morning but this makes the most sense. I was
    already feeling liberated and more so now. I’m wheelchair bound so pray every day that help will come. Thank you to all the dr’s and their teams amazing work!

    1. The researchers on Naviaux’s team really have done amazing work. Now, *crosses fingers*… replication!

  14. Michael Van Huffel

    Hi. Here’s what I’m wondering. So, this implies that the wide-net spectrum of chronic illness that this seems to (lyme and other vector infections, mold exposure, mycoplasma, a number of viruses) possibly cover (initial injury almost secondary to chronically ill response), right? Explains maddening every-symptom imaginable between them (you have mold llness, lyme/tick, virus—all with same endless crossover list of commonalities). And I think most of us have been on a nearly endless merry go round of trying treatment for one after the other.
    It also seems to imply, not just Rituximab, but other drugs…are having actions quite different than initially thought if they help people get well. This is always THE thing for me. Some people do recover and get well. Some very sick people do. And I think many of us see those stories, more than a few, and want to run in that direction. Drugs, supplement protocols and I honestly think some have benefitted hugely from mind-body. But so many of us get nothing from any of those things, except losing all we have as well as hope.
    I’m wondering, with the benefit of hindsight, if treating-practitioners can take a look at this new research and use it as a lens to view treatment successes they’ve had. Right now, that seems like a mystery to them, really. Or that those who fail in their protocol are outliers, or whatever. What I mean to say is, some people get well. Various modalities seem to lead to it. Could it be, like Rituximab, there are things that help enough in unexpected ways (I’ve read many times, speculation about Valcyte, for example not helping b/c of antiviral, but other actions)—various tx modalities—and treating physicians could try to connect these dots?

    1. “this implies that the wide-net spectrum of chronic illness that this seems to (lyme and other vector infections, mold exposure, mycoplasma, a number of viruses) possibly cover (initial injury almost secondary to chronically ill response), right? ”
      We can’t quite say it explains all of these things fully, but it does lay out a sensible rationale for how patients who start out with such a wide variety of illnesses — and though it’s not as often discussed in the community, surgeries or serious injury — and still end up with the end-picture of ME.
      “It also seems to imply, not just Rituximab, but other drugs…are having actions quite different than initially thought if they help people get well.”
      Many would be surprised to hear how often we really have no clue how a particular drug does its thing — not just in less widely researched illnesses such as ME, but in general.
      “Drugs, supplement protocols and I honestly think some have benefitted hugely from mind-body. But so many of us get nothing from any of those things, except losing all we have as well as hope. ”
      The variation is incredible. I know people who have been dramatically helped by a protocol and swear by it, but it has no effect on me or has a deleterious effect.
      “I’m wondering, with the benefit of hindsight, if treating-practitioners can take a look at this new research and use it as a lens to view treatment successes they’ve had. Right now, that seems like a mystery to them, really. Or that those who fail in their protocol are outliers, or whatever.”
      One of the things that I wish for our illness is that people would be willing to gracefully let go of pet theories. We want so desperately to be right. As a species. A good clinician adjusts his or her protocol both to the new research and to the individual patient, without hanging on to ego.
      In a perfect world… 😉

  15. I’ve been sick with ME/CFS since 1981 and have survived by living a very enclosed life. During these now 35 years I’ve kept as much an eye on research developments as my damaged brain would allow. Nothing I’ve read in all those years has given me the hope I feel today reading the Navieux report and now your so very helpful interpretation of it.
    I’ve always felt that science had to catch up to a certain level for it to be possible to understand what is going on at a cellular level for anyone to truly be able to comprehend this illness.
    I told my husband to mark it on the calendar that the breakthrough we’ve long prayed for has happened. It is not possible to express my thankfulness to those who brought it about.

    1. Thank you, Kathy. It’s a good day for ME research! Now we have to consider replication, and implications for treatment strategies: the translation of research in the lab into the realm of real patients’ lives. It can’t come fast enough for those who’ve had ME for decades.

  16. Humm, the WHO WORLD HEALTH ORG. has said mold/fungi is involved in 50 % of all disease, it also just happens to be very under studied in ME/CFS. just saying, maybe we could get some more attn. here ?

    1. JEANIE,
      Mold Its just a trigger factor, Im not saying mold is not toxic and can cause harm, but Our bodys are built to clean most of toxins , heavy metals, viruses etc.. Normal person with healthy immune systems, with healthy metabolism, normal mathyliation, normal cellular funtion only have minor issues with mold, like allergies, like headaches etc.. But people with impared, weak, disfuntional inmmune And celular funtion acumulate toxins, fungi, viruses and they grow uncheck couse the mechanism of the immune system thats in Charger to do that doesnt do it….
      The Big problem we have is that Our believes are base on what doctors and heart association and institud tell us, like You just said now THE WORLD HEALTH ORGANIZATION.. Unfortunable Its been more than proven that most of the time this Big institud and organizations dont always work and respond to the Best of Our interest. They are control by Big Pharmaceutical conpanies and by the Big Powerfull empires, How ever the want to guide the information, missleading it, to the Best of their interest, and thats what doctors are told and thats what doctors tell us, unfortunable we are living in a society were doctors go to medical school just to have a career and a good life, there is some real passionate scientific and doctors that love their profession, their patients and really dedicate their life to find real causes and treatments for illness, like Robert Naviaux,Dr Davis , Dr Montoya , Dr Nancy Klimas , Dr mitkovits, Frank ruscetti … And many others.. But as we have seen thru out the years, it doesn’t matter their findings, the hard evidences, they always manage to obscure them, block them, control them, what ever from the goverments itself its unrefusable, even the bizarre absurd that Me/CFS is a phsycological illness, but other wise is not thesame, the big bad wolf always manage to keep the Red riding hood in the closet not to be eat.

  17. yeast (candida Al. comes to mind, but so does penicillium, took a quick look and gram negative bacteria witch is known to be found in high moisture water damaged building came up, so a few things could also be involved in the lipid raft. this would also affect receptor function too wouldn’t it, hum, pretty interesting , so is Rituximab, exspecially its affect on B cells , very interesting, Thanks!

  18. Read the paper in more detail and while it is great, there were some silly parts. It’s ridiculous and harmful that he says in the conclusion that depression and PTSD are related conditions that need to be compared to ME! What evidence is there for this?
    He calls it “CFS” throughout (never ME) except where he calls it “Chronic Fatigue.” And they use Reeves criteria prevalence numbers. Also sick of the “finally we have evidence “CFS” is organic” meme. It was nice they used CCC, but why use the IoM definition (and Fukuda) but not ICC and Ramsey? Broke patients funded this study in toto as far as I understand, so why compromise by putting in NIH-friendly lies?
    Smart ppl can be really dumb sometimes…

    1. Justin, I’m always happy to hear constructive criticism, but when we’re upset because patients meet CCC and Fukuda and IOM criteria, I feel we’re barking up the wrong tree. The idea seems to have been to be sure that this data could be used to apply to a variety of patient subsets. I think it’s safe to say that if you meet CCC you also meet ICC in any case.
      I am pretty sick of the “we finally have evidence” meme myself.

      1. Thank you so much for writing this, Jaime.
        I have to point out that I totally agree with Justin’s important constructive criticism about the stated lists of criteria used. The authors did not state why they used three different definitions. If it is true that all subjects were diagnosed with the CCC then why not just state that? Why did they add two inappropriate criteria?
        The IOM criteria were created exclusively for diagnostic purposes so the author’s use of a diagnostic criteria is inappropriate in a research setting (Dr. Davis should know that because he served on the IOM panel).
        The Fukuda criteria are inaccurate for many reasons, one being that they do not demand PEM which is a hallmark feature of ME.
        In addition, if they all fit the CCC then how would they be divided into subsets – as you proposed to Justin?
        The exact cohorts used for a study is critical to the validity of its results. It is critical that patients suffering from the actual disease be the ones who are being tested – bringing in patients who do not suffer from the disease but from another disease will only confuse the results.

        1. You’re very welcome, Gabby!
          Basically, no one can say “this research isn’t applicable to our research because we only study Fukuda” or “this research isn’t applicable because we only use the CCC”. It makes the research more broadly acceptable and applicable. Even if you only recognize one criteria as the ‘real’ one, the researchers have merely done extra work that you may find useless. If the CCC is your preferred criteria, and all subjects meet CCC, then no one is a patient with another disease.
          I will leave the rest of that to Naviaux to answer if he so chooses, since I’m only extrapolating why his team would have done this.

    2. When I read a paper from a well-respected researcher and there is something I don’t understand, I find it helpful to start with the assumption that the misunderstanding is on my end, not the researcher’s.

  19. This study is a big step in understanding what’s really going on in our body’s, why we are so disfuntional , we all have to thanks to Robert Naviaux, that’s an amazing work, thanks also to Jaime s.
    Now the other part is what the NIH, is going to do about it, how they are going to interpretate, they always find a way to discredit everything and looking at the very little they have done so far after they promise to put all fire power, i wont be surprise if they came up with some absurd bizarre answere… After seen what Canadá just did.. I wont be surprise.. Lets hope All the other Countries are living All the credits and leading findings to NIH.

    1. In general, folks, let’s discuss IDEAS (hopefully backed by FACTS or stated overtly to be OPINION) rather than PEOPLE. Comments that don’t will be removed by an unsympathetic editor.

  20. Jaime S – thank you for this analysis and explanation. I have no biology/ medical knowledge at all (yes I probably should learn but I find new things very difficult and I don’t get to do things I want to do, so I am resistant to doing things I don’t really want to do), and whilst I read the Naviaux paper and supplementary, the technical language bamboozled me. Your article makes it more ‘novice friendly’.
    As you seem to know about such stuff and understand it – I remember getting very very excited about the XMRV finding about 5 or 6 years ago. Then it turned out to be contamination in the lab (I think).
    Can I ask
    (a) what are the chances that such an (innocent) ‘mistake’ could have happened with these findings too? Are the actual mechanics of getting from the blood to the answers similar to that of the XMRV team ie what sort of contaminents might there be? if any. What risks are there? Did Navioux’s team have checks and balances in place to minimise such mistakes/human errors? (I realise you might not know the answer, but may know people who can explain).
    (b) how does the replication process work, with people trying to do the same thing elsewhere using different blood from different people in different labs? do we know if there are others who are planning to do replications? or even started them? I think I’ve read, maybe on Phoenix Rising (which is where I found out about this article) that Naviaux et al are already onto a second project following up from this one?
    I should add, this is is NO WAY a criticism of the Naviaux team and paper (and I am not blaming the XMRV people either, they didn’t do it on purpose), it’s just there’s been so much excitement (for me personally) over potential ‘new’ findings, and then enormous disappointments when it turns out not to be, that I don’t know whether to be a little bit cautiously excited, or that there’s a chance I’ll be doomed to disappointment. Again. This is about me not understanding how science (good or bad or with natural human errors) and asking someone who does understand about science. I suppose I’m looking for reassurance if there’s any to be had….
    Thanks Lois

    1. Very good questions, Lois.
      “(a) what are the chances that such an (innocent) ‘mistake’ could have happened with these findings too?”
      Unlikely: controls’ blood was examined for unusual ranges of metabolites, too. Unsurprisingly, when measuring so many different things (hundreds!) even healthy controls had quite a few metabolites in the lower or upper 5% of the population: in the teens. However, patients had metabolites in the top or bottom 5% in the 40s. This is a significant difference from controls.
      One of the weaknesses of the study are its small sample size — I know we’re geared to think that 25 is a goodly number in ME research and 80-something is fantastic, but this will definitely need to be replicated to be validated. Second — and the paper faithfully notes this — patients were all from a very narrow geographic region. While this doesn’t rule out a pattern, it does imply that PERHAPS these patients are exposed to similar environmental triggers, and PERHAPS people in other locations might show something a little different. Finally, there WILL be researchers who claim that all of this is the result of inactivity; therefore, a better group to analyze would have been sedentary age- and gender-matched controls.
      “Are the actual mechanics of getting from the blood to the answers similar to that of the XMRV team ie what sort of contaminents might there be?”
      Highly unlikely. XMRV is one virus — Naviaux’s study showed a wide variety of chemicals that were not where they are supposed to be in a healthy person.
      “Did Navioux’s team have checks and balances in place to minimise such mistakes/human errors? (I realise you might not know the answer, but may know people who can explain).”
      I can’t verify this!
      “(b) how does the replication process work, with people trying to do the same thing elsewhere using different blood from different people in different labs?”
      REALLY good question. The answer is: it depends. Ideally, you’d get a multi-centre trial running next. (Er, sorry folks, if this isn’t what you have planned, ignore the citizen-scientist!) You’d get Klimas to send in patient samples from Florida, you’d get more California samples (just in case), you’d get from one of the clinics in Norway, you’d get Belgian samples, basically ensure you had at least three centres and ensure that they were not all US-based. You would spend some time ENSURING that everyone knows all samples have to be from patients tested re: CCC, Fukuda, and IOM and *pass all three*. You’d have to ensure you had good training in collection protocols: to ensure replication, everyone has to be doing the same thing in the same way… at the same time, because part of Naviaux’s theory (and that of others) is that seasonal variations really count.
      Then you’d run them through using the same metabolomic analysis process to ensure your answers were the same. There are very few companies that do this as of now. I spoke to someone just this summer — the people Ron’s folk are using — and they let me know that what they’re doing is quite rare. Not bragging, just saying that there are few who are equipped to do this sort of work right now.
      “do we know if there are others who are planning to do replications? or even started them?”
      If past is prologue, this same team will now use this data to get better funding and try on a bigger group. It should be replicated by other teams as well, because that’s what keeps science honest.
      “I think I’ve read, maybe on Phoenix Rising (which is where I found out about this article) that Naviaux et al are already onto a second project following up from this one?”
      As did I!
      All your questions are insightful and sensible, Lois. I am sure that this sort of scrutiny is not something that any scientist finds overly critical or insulting. Thank you for clarifying anyway, though. In this weird and wild world, it’s important we all show respect for each other! 🙂

  21. Complex trauma often results in a dis-associative (protective and insulative) state. It would be interesting to see if and where mitochondria reflect a similar effect to that observed by Naviaux et al.
    Thank you Jaime for this write up.

    1. You’re very welcome!
      I would be cautious about linking this metaphorically / symbolically to the behavior of an entire organism, though. 🙂

  22. Thanks Jamie, I’ve not yet been able to read the full article as got no where near enough brain power to tackle it. The Q&A alone caused me to need a nap. So really glad you’ve produced a run down of the key points that I can understand with some of your own thinking behind it.
    So pleased to see Bob get in touch with you to discuss everything that couldn’t go into the paper itself, hopefully there will be a follow up once you guys have had a chat?
    I think reading some of the comments on here made me cry more than the initial statement on the findings of the study!
    Can’t wait to see what comes out of the end CFS/ME project next and the replicated study

    1. Thank you, H!
      I can’t promise a new article on the chat until I hear what Dr Naviaux has to say, but it will be great to learn more. 😀

  23. Michael Van Huffel

    I didn’t see if anyone mentioned this…. but it seems like low body temperature is one of the more shared symptoms of this type of illness. In my case, I had a fever on and off for nearly a year, then it went low (96.5-97.1) and stayed there.
    I wonder if that’s a feature of this hibernation-like state.

    1. Ditto, Michael! My temperature now runs low, though before onset it was dead-center normal.
      I’ve had my immune system ‘switch on again’ suddenly, in which my temperature dropped a moment, then climbed incredibly fast. But that was all ‘early days’; now it mostly stays dauer, or whatever we’re calling it now, with rare, low fevers. 😉

      1. Same here, since initial onset mega viral attack I’ve always run a low temp and also have contracted very few infections in the last couple decades of ‘dauer’. Of course, I also don’t go out very often which probably helps.

        1. I know that people have hypothesized that it’s because we encounter people less, and certainly I do less often than I did in my old job. However, I was very careful to get out into the world whenever possible, and now I am out amongst the living every day. I still don’t get sick. I think the hypothesis that we just don’t encounter others and that’s why falls flat… several friends and family are public school teachers, and I encounter their germs all the time!

    1. Even editors take a weekend sometimes, Mark. 😉
      The comments I approve or don’t rely on their readability (giant blocks of text smished together versus paragraphs); whether or not they constitute spam (same ideas repeated mostly verbatim, or adverts); whether they contain libel (accusations in absence of proof); in absence of the facts, where or not opinion is clearly stated as opinion or framed as fact.

    2. Mark, your second comment contained all the same issues of the first. And I am not an ‘agent of the government’ because I moderate comments. That is my job.

  24. Thank you, Jaime, for grappling with this research and its implications! One question I have is what proof is there that cancer rates are higher in ME? Is this just certain types of cancer such as lymphoma, and not others? I also recall reading that breast cancer rates are lower in ME. Let me know what the latest evidence is.
    My own guess is that most cancer types and rates will turn out to be lower in ME, due to our hypo state and increase in cell defenses. I think our patient community would expect our cancer rates to be higher because we are so endlessly sub par if not entirely disabled. But we are not sick in all the usual ways: high blood pressure, high cholesteral, temperature, inflammation, etc. Our systems turn out to run as “cool” as these run “hot”. Given the many ways our systems run contrary to expectations, I would not jump ahead of the evidence in expecting anything, such as more cancer, more Alzheimer’s or any other of the worst common troubles.
    Anyway, let me know what the latest evidence is about cancer rates for PWME.
    I am glad that Dr. Paul Cheney is advising on some of these studies as he was well ahead of the crowd on this understanding. His work on heart function and his hypothesis about how our bodies in their lower energy state and functioning are actually protecting themselves from something worse struck me as very important.
    I am thrilled we have such terrific researchers in Dr. Naviaux, Dr. Davis, Dr. Hanson and others but hope they will keep the lines of communication open with our expert clinicians too, so that they can traverse the shortest distance between where the scientific understanding is and where we need it to be.

    1. So, since NK cell function is often low in ME, and NK cells help kill cancers, it makes biological sense that cancer incidence would be higher in ME. Check here: http://me-pedia.org/wiki/Causes_of_death and look at the 2012 study for epidemiological evidence of increased incidence of cancer in ME in an elderly population. I know there are other studies as well. Specifically, lung and bowel cancers show the most increased incidence.
      -J

  25. Jaime, I wonder if you would be able to comment on the relationship between this study and another metabolomic study published in 2015:
    ‘Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients’
    Christopher W. Armstrong1 • Neil R. McGregor2 • Donald P. Lewis3 • Henry L. Butt4 • Paul R. Gooley1
    https://meaustralia.files.wordpress.com/2016/07/metabolic-profiling-reveals-anomalous-energy-metabolism-and-oxidative-stress-pathways-in-chronic-fatigue-syndrome-patients.pdf
    I’m not a scientist so I may well be misinterpreting the findings, but it seems that the earlier study has identified a different set of metabolites as being increased or decreased in ME patients. I suppose what concerns me is whether or not this undermines the Naviaux study in any way.

    1. Definitely not, Pamela. I actually did a write-up of Armstrong et al’s work on Phoenix Rising. That was a year or so ago, and I’d probably walk back some of my assumptions now if I were to do it again, but I think you can still get the gist of the paper and its findings by reading there.
      So Naviaux et al’s team stated that generally metabolism is downgraded, and stated it in multiple locations. That’s their hypothesis, so they lean on that narrative. Dr Naviaux has also said to us in the comments that there’s a lot of other information he couldn’t include because of page limitations; and he later let me know that even the supplementary materials couldn’t include everything he wanted to say on the matter.
      Both Armstrong’s and Naviaux’s paper would agree that metabolism is in general, down-regulated.
      They would also agree that there are some metabolic measures that are upregulated in response to these down-regulated metabolic processes.
      Armstrong’s paper noted that glucose was higher than average in ME folk, implying that glycolysis, often depicted as the first major process in the cellular respiration reactions, is down-regulated. He also showed that there are numerous, less efficient cellular processes that are UPregulated in response: processes that might net us one additional ATP molecule or NADH molecule (molecules with high-energy bonds that, when broken, release that energy for the cell to do work). Naviaux’s paper showed that cholesterol production is down-regulated in people, more dramatically in men than women it appears. But blood cholesterol is actually normal, at least on average. That implies that other metabolic mechanism that produces cholesterol MUST be upregulated in response.
      In both cases, what we’re seeing is — get ready for some real science, here — the immune system saying to the metabolism: “…hush, hush. Hunker down and stay quiet.” And then the metabolism settles and quiets and slows; but, like a seesaw, when the immune system pushes down on one end, the other end goes up.
      I know, we probably all needed PhDs in immunology to understand that bit. 😉
      While this metaphor is (ridiculously!) simplistic — the see-saw may go up more or stay the same, depending on the ability of the metabolism to self-regulate, how many back-up mechanisms there are, the raw materials required for that metabolic button to be pushed to max power, and what other factors affect the process.
      -J

  26. You should look at this Jaime s,
    Is a free webinar, about retroviruses, maybe that help you understand a little more what I ment by most of this cronic illness share thesame underlaying cause, or strains from thesame Retrovirus, that depending on how do you adquired , when do you adquired and how many co-infection you are exposed to is the kind of illness and severity of it.
    This will also explain your conversation with sing, I said before what it looks to me that the desregulation of the immune system in Nk cells, methylation etc.. It’s the disfuntion that cause cancers… and depending on exposure it can turn in to an auto or neuroimmune disease… ( I THINK THIS IS VERY STRONG MOTIVE TO NOT WANT TO DIGG IN AND RESEARCH IN OUR ILLNESS… THERE IS NO OTHER..
    I have seen people including you that when they refer them self to a specific topic o publication they copy and paste the link , I’m going to assume there is nothing wrong with that.
    Take a look at this.
    https://app.webinarjam.net/register/21953/1ba276d7e3

  27. Great job Jaime, I would love to hear what Montoya and Klimas has to say about it, I’m sure they will be talking abut it now in this coming up October ME/CFS conference in Florida, let’s cross our fingers, and hope the study could be replicated.
    Every promising studies in the past end up in the garbage, NIH and associates always find a way to discredit and pinpoint another way.
    ” Mark” I have read a couple of your your comments, that have been one of our biggest problems thru out the years
    , we have never avocated the right way, it’s not a lie have been powerless, ereased from earth, blocked, by those with power and control over the medical industry, science and media.
    But now that we finaly have the chance, one in a million , the chance we been waiting for decades is slowly fading away again, we are letting it go.
    The root cause of this illness it’s totally completely immunologica, immune suppression( the word immune desregulation was purposely used by the same individuals that put the wrong name to our illness from the early days of outbreaks around the world, to make it seem as a physiological illness and not as an epidemic infectious disease.
    The worth part is that with have become our worth enemies, we have become our self part of the lie, we believe in the picture that they have painted to us, with the exception of the physiological part.
    All studies from the very beginning suggested a transmissible pathogen, possibly a retrovitus , everything pinpoint to that, from the outbreaks presentation in different city’s to the immune disfuntion, that it’s only see on AIDS, late stages is when Nk cells go totally down, neurological problems, cancers etc.
    Look:ME/CFS is definitely due to immunodeficiency. Here is a webpage of mine highlighting the studies revealing immune suppression in ME/CFS https://www.researchfraud.com/cfs-immune-suppression/
    This is just one in many of them, in the middle you will find some studies and authors that back up the analyzes.
    Even new studies including Naviaux demonstrated , that our cells are in constant protective stage, hibernation agains a pathogen .
    The world doesn’t lisent to us, becouse they are not concern , they are not scare, they are not aware of the danger.
    Zika??
    Can we compare zika to ME/CFS??
    Why Zika is every were Now ?? people scare , concern ??
    Goverment imvesting money and resourses at all Levels??
    Becouse its something minor and They keep people entertained while They do nothing for us… Time keeps passing by.
    Why people are scared, concern abut HIV/AIDS??
    Becouse They see it as epodemic, for what the illness its.. Now is HIV WORTH THAN ME?? nooooo.. Most people with hiv have a very normal life.. is AIDS worth than ME??? noooo at all, healthier case of AIDS can be compare to mild cases of ME, severe cases late stages of AIDS could be compare with severe ME cases.
    Mark’ i wish that many other people would of think like us, like you and me, from the very bigging, things would of been alot different , Now are seatting here, many believing we are people that were born with genétics predisposition and disfuntional system, in stead of seen many husband and wife that don’t share any gens with ME/CFS .. That’s the most real evidence of what this disease is .

    1. I agree that ME and CFS are probably due in part to immunosuppression. I think people use immune dysregulation because some immune factors are high in ME, such as IgE or IgM.

  28. Rituximab is a B-cell depleter, so if you wipe out all the non-functioning cells, you need time to regrow healthy cells. That’s why sometimes we are seeing Ritux followed by stem cells–like a jump start for the new immune cells–and even antivirals. It makes sense, considering that 95% of adults harbor latent EBV infection, among other herpesviruses, which become reactivated when the immune system is suppressed (permanently so in Lyme/MEcfs/fibro et al). The B-cells are there…they just can’t grow up and differentiate into useful fighters because of the EBV and damaged germinal centers. They are stuck in limbo, which I think is a good analogy for these diseases. https://badlymeattitude.com/2015/10/29/occams-razor-all-we-have-are-dull-blades/

  29. Fascinating and understandable analysis (even for us liberal arts types). My question is this: Do the Naviuax findings and your explanation of how rituximab relates to those findings interplay in any way with the MTHFR gene mutation and methylation pathway theories? If so how”
    Thanks

  30. Laura Good Devereaux

    Jamie,
    Thank you for your analysis. Have you seen the thinking being done over at rccxillness.com?
    I’d love to hear your thoughts!
    You did an amazing job.
    Laura

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