Keeping It Simple

It was good to hear from “John” again in the comments this morning. My head has been so completely in the clinical world since I wrote that post, that it’s hard for me to come back to it. I’d rather step back and take a look at the big picture. I’m sorry if it’s too loose for you John. I’m a doctor again. I don’t have the time that I did to read the pure science in exquisite detail trying to divine the truth from little bits and pieces of incomplete information. Not my job. Thanks for the input though, and may you never need my services:). Fortunately, the patient community still has a few friends in the scientific world and we will continue to rely on them to help us. Dr. Mikovits and I continue to “translate” for one another.

What if everybody was trying to figure out what is, instead of what isn’t? It is a public health emergency, though it is truly the proverbial closing the barn door when the horse is long gone. Pandora’s box is open for the duration. A retroviral etiology made sense almost two years ago when the Science paper was published, and it still makes sense. So whether XMRV is XMRV’s or HGRV’s or XMLV’s, and whether VP62 is or isn’t the same as XMRV, and which ones have or haven’t been fully sequenced… Einstein said, “If you can’t explain it simply, you don’t understand it well enough.” I’m not saying I understand more than a little, but what I do understand is pretty simple. So here goes, an hypothesis, without references this time. Most of it is referenced somewhere on this blog (which has a search feature on the sidebar).
People have written asking me to write a For Dummies post. For those of you not inclined towards the biological sciences, the following Wikipedia articles are background reading that help to put the rest of this post in context:
Protein biosynthesis
Mitochondrial DNA

All organisms have a strategy for perpetuating themselves. Viruses are the simplest, carrying out their tasks by hi-jacking cellular machinery from the host. Retroviruses have a very efficient evolutionary strategy, inserting into the host genome. Simple animal retroviruses, in particular murine leukemia viruses, MLV’s or MuLV’s insert in places in the host DNA called CpG islands, start transcription sites, where they activate genes, presumably to create favorable conditions for them. They become endogenous when transmitted vertically. Endogenous means that the viral sequences are present in every cell in the body. Once endogenous, a retrovirus can be fully replicative or not. If not, it may still be able to generate viral proteins if activated, setting up a cycle of persistent immune activation as the body tries to deal with the foreign products. It may be measurable in the form of antibodies and sometimes antibodies are generated in response to self, producing the low level autoimmunity seen so commonly in this patient group.

The axiom we were taught that viruses don’t jump species turns out to be untrue. Simple animal retroviruses are infectious to human cells in tissue culture. Animal cells have been used to grow live attenuated virus since at least the early ’30s. The first paper reporting the use of yellow fever vaccine, attenuated in mice, was published in 1932. Vaccines were tested on nurses and doctors. The first outbreak of a disease similar to ours was at LA County Hospital in 1934. The first cases of autism were described in the early ’40s. Kanner’s earliest paper on “infantile autism” was published in 1946. It has been known for a very long time that there were animal retroviruses present in the cells used to produce vaccines, but the assumption was made that it was an insignificant risk compared to the good done by vaccinating.

In general, nature maintains a balance by killing off the weak organisms. There have probably always been a few ME patients, women with failure to thrive, “the vapors”, so the potential was there, the “jump” had already occurred, but then, we had to improve on Mother Nature. So we gave it an incredible leg up. Mainlined it into almost everybody. And not just one virus, but lots of them, some capable of recombining with each other, so that everybody’s infection is a little different. The result? An unbelievable increase in the incidence of all kinds of chronic diseases. Neuroimmune, autoimmune, genetic illness, cancer. It really hurts that I’m so old as to remember how different it was 35 years ago, when I was in medical school. I can actually remember being taught to do a review of systems when taking a history so as not to miss anything, generally expecting it to be negative. A negative review of systems is a relative rarity now, even in children.

Regardless of what is there precisely, with respect to viruses and pieces of viruses, there are generalizations that can be made about the common pathophysiology seen in animals and humans. In mice, similar viruses can produce neurodegeneration or cancer. The viruses that produce neurodegenerative disease cause inflammation, with vascular permeability in the central nervous system. Other MuLV’s cause lymphoproliferation and malignant transformation.

Take a look at the following table:
NIH publication. Increase in cancer incidence 1950-1989. Ries et al.

So where do the dots connect clinically for ME/CFS? Simply put…

1. Persistent immune activation due to foreign viral product fueling inflammation. This happens in HIV disease. The way their disease is playing out, with proper treatment, they die sooner of the usual things. That’s the way our disease plays out without treatment, since untreated the disease doesn’t kill you like HIV. Rather taking the more colorful symptoms out of it, the expectation is earlier onset of cardiovascular, neurodegenerative disease and cancer. Vascular permeability, as in the mouse models, fits. Leaky endothelial junctions in the brain, gut, elsewhere.

2. Symptoms consistent with inflammation in the brainstem and other structures in the CNS. In particular, most of the “mysterious” symptoms of the illness, that have confounded doctors for so long, can be tied anatomically to a strip of dorsal brainstem, which is housed in a tight bony canal and sensitive to any swelling. Structures in close proximity include the cranial nerve nuclei, carrying all the senses above the neck, the spinothalmic tract, carrying sensory information from below the neck to the brain, including pain and temperature sense, the reticular formation, controlling sleep and arousal, and relay nuclei for the autonomic nervous system, regulating all the involuntary functions of the body, including vascular stability and endocrine control. Nuclei in the brainstem are responsible for the production of neurotransmitters, norepinephrine (the locus coeruleus), serotonin (the raph nuclei), and dopamine (the substantia nigra), so dysfunction affects everything which is experiential. There is also a venous plexus that would be subject to compression, consistent with the recent findings that venous insufficiency, poor drainage, is common. The feeling of “brain swelling” that many report is probably accurate, like all the “crazy” sensations that patients describe. Structures in close anatomic proximity to this strip of tissue are the cerebellar peduncles, the amygdala, hippocampus and pituitary.

3. Gene activation. In addition to making viral proteins or particles, simple animal retroviruses turn on genes, which may be clinically important, depending upon the functional integrity of the gene in question. Certain genetic disorders, such as Marfan’s and Ehlers Danlos, and certain autoimmune disorders, such as Hashimoto’s thyroiditis and Sjogren’s, are certainly over-expressed in the patient group. Methylation is necessary for proviral latency and it is clear that many of us have genetic methylation defects. However, it’s not as simple as methylating, as it isn’t desirable to induce latency in tumor suppressor genes.

4. Lymphocyte abnormalities, proliferation, depletion, dysfunction. Currently a focus of my reading, including clonal expansion. Rather than butcher it, I’m going to hold off on this one for now.

5. Mitochondrial dysfunction. The mitochondria are the energy factories of cells. ATP, the energy currency of the body, is produced from glucose in an oxygen dependent chemical reaction. Aerobic metabolism is much more efficient than anaerobic metabolism, to which the body must convert when not enough oxygen is present. Oxygen gets into mitochondria by diffusion along a pressure gradient, needing to cross the mitochondrial membrane. The internal mitochondrial membrane contains phospholipids called cardiolipins, and anticardiolipins turn up on the list of associated auto-antibodies seen in ME/CFS. MtDNA (mitochondrial DNA) is a circular chromosome which is inherited from the mother, unlike the nuclear chromosomes which come from both parents, so mtDNA is not subject to genetic recombination. Maternal inheritance certainly fits the epidemiological picture. MtDNA maintains genetic integrity, so it would be a safe place for a retrovirus to stow aboard.

Andrew Mason MD, from the University of Alberta, has been publishing on a human beta retrovirus associated with PBC (Primary Biliary Cirrhosis). It is similar to MMTV (mouse mammary tumor virus), which was known as the “milk factor” before anybody knew what a retrovirus was. PBC is associated with an AMA (anti-mitochondrial antibody). In the following papers, he makes his argument for an HBRV (human beta retrovirus) and it all looks pretty congruent with our HGRV hypothesis, including his rationale for the use of antiretrovirals.

An excerpt from the last paper:

HBRV and the mitochondrial phenotype 

Arguably, any causative agent linked to PBC should be associated with the aberrant expression of pyruvate dehydrogenase (PDC)-E2 on the cell surface of biliary epithelium and in lymphoid tis- sue, a highly specific PBC phenotype that is thought to lead to the formation of AMA. In vivo, HBRV is detected in PBC patient’s cells with aberrant PDC-E2 expression. In vitro, homogenized PBC patients’ lymph nodes, the conditioned supernatants containing HBRV and even pure MMTV have all been shown to trigger the mitochondrial phenotype in healthy biliary epithelium, whereas control lymph node homogenates and other viruses do not. Importantly, no in vivo patient data exist to link the mitochondrial phenotype with either bacteria or xenobiotics; indeed the idea of molecular mimicry has been circulating for over 50 years and never proven. 

Of interest, betaretroviral infection has also been linked to the mitochondrial phenotype in several immunodeficient mouse models that spontaneously express AMA. For example, MMTV p27 capsid and gp52 envelope proteins have been detected in lymphoid tissues and biliary epithelium that also express aber- rant PDC-E2. Furthermore, we have found that the development of AMA mirrors anti-MMTV production. Indeed, MMTV has been shown to be central in triggering viral cholangitis in the NOD.c3c4 mouse model of PBC, as highly active antiretroviral therapy and MMTV neutralizing antibodies abrogate cholangitis. Of interest, NOD.c3c4 mice treated with lamivudine and zidovudine (Combivir) develop viral resistance with mutations in the YMDD region of the reverse transcriptase gene, similar to muta- tions found in hepatitis B virus or HIV occurring as a result of antiviral therapy. 

Translational studies 

Using the NOD.c3c4 mouse model with MMTV infection, how- ever, we have found that highly active antiretroviral therapy with Truvada and Kaletra is efficacious without the development of resistance. Recently, the same combination has been reported to normalize hepatic biochemistry in a PBC patient with HIV and HBRV co-infection. Accordingly, a randomized controlled trial with Truvada and Kaletra is planned to treat patients with PBC who are unresponsive to ursodeoxycholicacid (UDCA). Indeed, it is notable that clinical trials ultimately led to the recognition that H. pylori infection caused peptic ulcer disease and the proof that a viral association with PBC may be resolved in a similar fashion. 

In summary, there are converging data to suggest a mechanistic link of betaretrovirus infection with the mitochondrial phenotype of PBC in co-culture studies and in a mouse model. However, we still lack firm patient data linking virus with disease. Accordingly, before we can endorse the argument that the evidence supports a viral aetiology for primary biliary cirrhosis, further studies will be required to definitively demonstrate integrations sites in diseased biliary epithelium and the serological reactivity to HBRV in the majority of patients with PBC.

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121 thoughts on “Keeping It Simple

  1. >What I know for sure, is that non-patients will never understand what it's like to have ME, but a very few that are making themselves helpful to our cause.

    I would just like to mention Judy's words
    "XMRV is in 2011 what HIV was in 1983"

    Living hell…

    Thank you Judy, Dr deckoff-Jones, Dr Snyderman, Dr Klimas and all the other ones that escape my memory right now.

  2. >Judy also said it at state of knowledge. It is not mentioned as an offense to Dr Ruscetti whom I admire. but since both said it, can we please drop it? sigh…

  3. >@RRM I have seen you posting on MANY MANY forums REPEATEDLY. I have to say I have never felt compelled to enter the "debate" personally. But there are some things that need to be said.

    1. Regum Magister doesnt make sense to be RRM…it doesnt even logically by any stretch of the imagination fit to the abbreviation of RRM.

    2. you say you have a relative sick with this illness, then please tell me why you rather obsessively post on multiple forums and blogs ALWAYS arguing the point AGAINST xmrv or mlv, surely if you truly had a relative with this illness you would be more akin to "lets see what happens" or "I really hope they crack this" but instead you seem on a mission to convince people its all a red herring…why bother? what does it do for you? it doesnt help your relative….regardless of if xmrv or mlv "is the key" you posting on forums wont change that. I have seen you argue points for days on end on huge long threads….what pupose does it serve? it doesnt speed up time…when time and science are what will hopefully sort this out if they are allowed to run their true course without interference. WHY?

  4. >No, I meant it was Frank Ruscetti who said it, nothing else. Mikovits did say she was quoting him at the State of Knowledge conference.

  5. >@Jack S

    You do know that the actual abbreviation for "Master of Laws" is "LLM" and that this stand for "Legum Magister"?

    Because legum is (in Latin) the genetive plural of lex, those crazy Romans (and everybody after them) have apparently been abbriviating legum with two L's. Please check

    Likewise, because regum is the possessive plural of rex, it makes perfect sense to abbreviate "Regum Magister" to RRM. In short:

    Lex = law = L
    Legum = of Laws = LL
    Rex = king = R
    Regum = of kings = RR

    But others are right: it does indeed make much better sense for me to be a PhD in Dusty Miller's lab, "obsessively" posting on blogs while acting to have no knowledge of virology, with the sick motive of stiffling HGRV research in order for Miller to make billions on "inventing" the same virus as his own.


    If my relative would have to depend on gravity not being true for her to get better, I would also not "really hope that they should crack this" but try to argue with the people who were trying to advance this viewpoint to the community. And no, I am by that not saying that the argument against XMRV is comparable to the evidence in favor of gravity, I am showing through a rather extreme example how your argument about having to stay "in the middle" really does not fly.

    There are now multiple lines of evidence that cumulatively strongly support the notion that both the original Lombardi paper and the Lo paper are wrong. Coincidentally, since the posting of this blog, yet another paper has been published that supposedly (I haven't read beyond the abstract yet) strongly suggests that the earlier sequences found by Lo were not ancestral to the newly found sequences. Now, outside of some massive worldwide conspiracy (which can always be "upheld" by the way, so when we would be considering that we'll have to stay in the middle forever and ever), what are the odds of finding evidence against the hypothesis again and again, doing independent experiments and by using techniques that are widely accepted in the field? In fact, has there ever been a finding in the history of modern science, that after so many negative publications, did still turn out to be right?

    Yes, I relaize all of this can be set aside by new data, just like anything in science that is regarded as being "true" can be set aside by new data. But ignoring the totallity of the evidence at this point, with some even arguing that the case in favor of HGRV's in ME/CFS patients is actually proven (see an earlier comment) is, in my opinion, giving false hope to many sick people who are following this.

    So yes, I therefore feel that it is worth speaking out against people who are trying to advance these highly improbable ideas in the patient community through (yes, only in my opinion), bad, circular and illogical arguments.

    Sorry for yet another long and rambling post.

  6. >You can't pay lip service to the fallacy of ad populum and then claim it back afterwards.

    You might have the energy to compose walls of text and possess a stunning command of muscular language, but it will never furnish you with the level of divinity sufficient to re-write the very rules of logic.

    Imagine I see a man inside McDonalds and Dusty Miller says to me "Hmm he could of had a Fillet O Fish!", McClure wades with "No no, he might of had the big mac" Coffin strikes with "For shame, canst thou not telleth that he could hath imbibed of the bacon double cheese?" and finally Stoye ripostes "What are you talking about, he could of had the chicken mcnuggets with sweet curry dipping sauce!"

    These are all things the man could of eaten. But it could also be that his wife is up at the counter getting their order while he holds the seat and he simply hasn't eaten at all.

    That's the problem with plausible explanations. They are speculation. Positing speculation as some kind of building consensus is pretty irresponsible from my point of view.

    I really hate that term "strongly support", I understand that it is scientifically admirable to avoid definitives (the emergence of definitives ultimately spells the death of progressive science), however, the use of adverbs is purely subjective and I find it unhelpful and unquantifiable. Unquantifiable muscular adverbs seem to abandon the scientific method and be at odds with the whole process of good research – to provide empirical data. There was a paper the other day that used the term "Strongly Rejects". That instantly sets my bullshit alarm service off since rejection implies some level of personification in the paper. As if it came to life and said "Nay, I strongly declare that I am probably right!".

    If results require poetic devices, I am giving them the Rock's raised eyebrow.

    And that's the bottom line.

    I could sit here and make umpteen references to your own terrible uses of logic and suggest that you loosen the straps of the seat you currently occupy atop the loftiest of equines.

    But I'm going to spare myself that energy. It would just fill you with the fervency to investigate and highlight mine I'm sure.

    RRM You have some great points to make and I'm glad to see some critical opposition, I just think you're a little too intoxicated by your own sense of righteousness.

    I do thank you for sticking around and engaging RRM – it's appreciated. It's always been my interest in XMRV that the association is explored to its natural end and not be dumped because of speculative dilution.

    I was initialled riled by the comments made by Doctors and Researchers in the press in the immediate aftermath of the 2009 paper, whom practically described the science required to disprove XMRV as a burden to satisfy the patients.

    To the most underfunded and ignored patient community there is, that's a red rag to a bull. It sounded very much that they had pre-determined about something they had yet to disprove.

    I do accept the limitations of my lack of expertise and I wouldn't respect myself if I didn't routinely ask myself the question – are my beliefs too convenient? I certainly have no desire to fill myself with a poison panacea of false hope.

    -SJ, adverb hater

  7. >@RRM

    Thank you for being the voice of reason. You are helping your relative far more than these nonsensical pseudo scientific conspiracy theorist.

    I am still ROTFLMAO that people continue accusing you of being Dusty Miller's sidekick. This just shows the level of thinking of these people.


    I respectfully say that you are a case of n=1 which does not prove causality.

    It's done, it's over with. Let's move on. That will increase our chances of getting well.

    Get off this merry go round of circular thinking.

    Singh's study has been the best study so far. A true and dedicated scientist.

    The BWG and Lipkin's study will most likely turn out with the same results as Singh.

    Lest you say that if other's only experienced ME, they would feel the same way, you are incorrect. The majority of patients, including myself disagree.

    Get Real.

    Laurie B.

  8. >@LaurieB

    You don't understand the science behind this virus. You have no knowledge of retroviruses, MLVs or this research.

    Singh's study used unvalidated assays that have never been shown capable of detecting positives. And she did not follow what Ruscetti had told her needed to be done. Surely you can grasp those fundamentals if nothing else.

    You have no scientific argument in your post, but an attitude of a flat earther.

  9. >Dr. Jamie,

    I have to admit that I am following this blog with intensifying interest. I check regularly to see if you have posted any new thoughts. You keep people like me connected to some of the more pressing issues and concerns. I am curious as to the prevailing reaction of patients trying ARVs. In your correspondence with them, has it been a mixed bag or do you hear commend trends emerging? Also, what do patients tell their doctors in order to attempt a trial run of ARVs? In other words, if you were just a patient and not a doctor…how might you approach a conversation related to ARVs as a possible treatment option?

    @Dr. Snyderman,
    I really appreciate your perspective and send many thanks and blessings your way! I would love to hear more about your story. If you get the chance, could you either email me privately or direct me to site/page where I can read more about your own personal narrative?

    @RRM…LOL! Did you really break down and attempt a latin lesson? I didn't care for many of your posts–not because they were unscientific or illogical but because they lacked the same panache as your latin breakdown.

  10. >@Kyle

    How is it not illogical (unscientific) for RRM to say no one needs to replicate?

    Consider that there are over 10 assays now proven to detect HGRVs, Ruscetti has said you must use multiple methods, the natural reservoir is not the blood and no one using VP62 has been able to detect the virus with PCR. Even after Danielson et al. said you cannot detect a known positive when you then use an assay optimised with that clone. A know positive having already found positive with another assay.

  11. >@Anonymous

    It's not illogical because replication, like all of science, is not as absolute as some are suggesting. While I freely admit it is not conclusive proof that your demands are wrong, in this context it is pretty telling that neither Mikovits, Ruscetti, Lo or Alter, have ever published a exact replication attempt in their lives.

    Just think about that for a minute.


    Glad to have made you LOL. For an even funnier lesson in Latin (I hope this gets through the spam filter) I suggest the following:


    Thank you. : )

  12. >@RRM

    Replication is a fundamental of the scientific method. Otherwise you are making a stab in the dark for what you don't understand and have no idea if your results are correct. They start to teach this to children around the age of 6 and scientists use if for their whole careers.

    Prove that Mikovits, Ruscetti, Lo and Alter have never replicated RRM. You really are no scientists. They practice this all the time.

    "This is the second important part of science: replication. Do it again. If we observe something, and we describe what we did and other people can repeat our experiment and observe the same result, then we can conclude we've correctly observed what is true."
    Fundamentals of Science: Observation, Replication and Prediction

    Copycats in science: The role of replication

  13. >@Anonymous

    I certainly don't disagree with that quote. In fact, that is what's fundamentally wrong with many of the arguments I've read on the subject. You need to present evidence/references that support your hypothesis as well as (at least partially) reject the other guy's hypothesis. I am not arguing that experiments should be repeated, I am disagreeing about what constitutes repeating an experiment.

    I am saying that "replication" is not a absolute term that needs literal interpretation. For example, if an astronomer detects an alien on the moon using his telescope, a replication study would really "just" require any telescope of the same (or very similar) properties. The second astronomer would not need to get his telescope to the exact same spot or use a telescope of the exact same length. Furthermore, the second astronomer would not need to show beforehand that his telescope was able of detecting aliens on the moon. Would you agree with the level of "replication" in this example? If not, why not?

    And the proof is in the papers that were written by these scientists. For instance, you can check Mikovits' track record here:

    None of the papers that she published are exactly the same experiments of papers that she followed up on, where she copied everything down to the annealing temperatures, cohort selection and all other variables that are suddenly being regarded as "fundamental" for proper replication.

    If you don't agree, pleae tell me which paper from the above link (or any paper by some of the other authors I mentioned*) do you think represents just a single true replication study?

    *here are the links to the papers from the other authors:

  14. >@Anon 3:22 AM
    If you reread what I wrote…please note the sardonic nature of my words. I actually said that I didn't like RRM's posts. I did not say that I thought his ideas were logical or scientific because quite honestly I know very little about virology. One thing that is quite important to me is that I keep my sense of humor in the midst of this horrific epidemic. As I am a former Oxford man that has been laid flat by this illness, I can at least appreciate the inanity of someone posting a latin lesson aimed at qualifying his handle. The idea is so non-sensical that I figure that though I might disagree with RRM on a great many ideas…I would probably appreciate his wit and humor–both of which are needed right now. Anon, I would ask that if you have the energy to spare on critiques of comments like mine that you try addressing the true inquiry of my post: HOW DO WE GET ARVs IF WE AREN'T HIV+???

  15. >Hi Firestormm,

    I realized that somebody might misinterpret the first question, but there was no trash can icon. You misinterpreted.

    Just a boring question. It wasn't a study or an argument or a litmus test or an ideology or a diagnosis. I was curious about a person with a different point of view from my own. It wasn't worth the inferences you drew and it did not entail them. The second question I asked is more important.

  16. >Exact replication of methodology is a farce.

    Attempting to replicate results is the golden goose and scientists will try and do this from multiple angles.

    If Lombardi et al were able to exactly replicate their methodology and achieve those same results (with or without the amendments to that original paper) THEN we might have a fight on our hands.

    I know for some the word 'replication' in this context has a different meaning. And for every so-called 'negative' study (let alone the 'positive' ones that do not receive the same critique), it is very easy to claim 'You didn't REPLICATE' the exact methodology – or where they did in part replicate – to claim 'You didn't REPLICATE completely!'

    If multiple scientists cannot achieve the same result i.e. detection of 'XMRV' in CFS patient cohorts to the degree that Lombardi did – by whatever means they determine should reinforce this link – they it is a no-brainer.

    Of course if you can't even detect 'XMRV' then it is a no-brainer for the person doing the experiment.

    Of course all this talk of 'XMRV' is a no-brainer too if it cannot be linked to human disease – particularly the cause of our specific (or even diverse) symptoms.

    But then certain people have claimed and strongly hinted that 'XMRV' was the cause of 'CFS'. And yet the 'science' has never been able to demonstrate that either – presumably because of the doubt surrounding 'XMRV' itself.

    I have also started to see some patients associating the Lombardi findings with 'ME' and not 'CFS'. This is of course untrue – though for some I suspect they would rather it was true of 'ME'.

    Oh and before anyone starts in on me – my 'credentials' are as follows:

    Absolutely, unequivocally, NOT a scientist or medical professional. Neither do I or have I ever pretended to be one.

    I am simply a patient of 12 years who appreciates ALL those who try to help me learn more about the science and medicine – and allow for questions to be addressed.

  17. >Amendment to the above – sorry:

    'If Lombardi et al were able to exactly replicate their methodology and achieve those same results (with or without the amendments to that original paper) and publish it – THEN we might have a fight on our hands.'

    Added 'and publish it'

  18. >The WPI, NCI, FDA, and NIH have all replicated the same results.

    The Lombardi findings were to CCC ME/cfs.

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