Keeping It Simple

Posted on by

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:
Cell
DNA
Protein biosynthesis
Retrovirus
Mitochondria
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.

Did you like this? Share it:

121 thoughts on “Keeping It Simple”

  1. >Thank you, Dr Jamie, for this very important "translational" blogpost. It explains what can go wrong to people like my own doctor, who doesn't get it. in fact, very few who are not sick understand what is going on and understand that indeed we are just as sick as a patient with HIV, if not more.
    I appreciate the time you send to share what you know.
    KD

  2. >Thank goodness my doc finally get's it. After 17 years of her trying everything under the sun only to watch me getting worse and wasting away. She believes I have a neurological disease that is as serious as Parkinsons or MS. How can doctors not see what is going on here? There are too many of us that they see on a daily basis. Doctors just can't deny that there is not a problem going on here. It is in their faces, and they are the ones having to try and figure out how to help the growing numbers of us.

  3. >Thank you, Dr. Deckoff-Jones. You have hit another home run here.

    "In summary, there are converging data to suggest a mechanistic link of betaretrovirus infection with the mitochondrial pheno- type of PBC in co-culture studies and in a mouse model. However, we still lack firm patient data linking virus with disease."

    Patricia Carter

  4. >Thank you for a good summary that makes for good linking material.

    I have a question about #2. Is this a part of the body that is not easily damaged? Is that why these symptoms are not widely recognized?

  5. >Samuel,

    I don't think the brainstem is the only place it is happening, but it is a particularly vulnerable place. If the damage were more severe, it wouldn't be compatible with life. It is a subtle derangement which is why it has been possible for the neurologists, and everyone else, to ignore.

    I've been looking for pictures to post or link to, but haven't found the right ones. The Netter drawings are copyrighted, but that's a good place to look. Take a look at pictures of the brainstem, including cross sections that identify what the various tracts and nuclei are, but it is difficult to visualize for someone who has not considered functional neuroanatomy before.

    Jamie

  8. >Very grateful for this post, Jamie, especially the 'For Dummies' piece. Used to be pretty sharp but no more.

    Thanks again!

  9. >Jamie, what part of the brainstem do you need an image of? I may be able to find one for you.

  10. >Fascinating reading as always. Thank you for sharing your thoughts on a regular basis. I do learn a lot but also many questions surface. OK, I just have to ask this even though I may come off as "Stupid". But please bare in mind I tested low, deficient in five neuro-transmitters. ;) Your point #3 – would that be the same type of methylating so popular with us, PWC, promoted by Rich VanK? If so, are you saying some how there is a potential for cancer by "induced latency in tumor suppressor genes"? With earnest gratitude. ~Dee

  11. >Anon 2:43

    Dorsolateral. Surface and cuts through medulla, pons and midbrain, to show the CN nuclei, the reticular formation, sensory afferent tracts, autonomic efferent nuclei.

    Thank you,
    Jamie

  12. >Dee,

    There are no stupid questions. I don't know the answer to your question. I was thinking more that if I had CFS and cancer also, I might not work on methylating.

    Warmly,
    Jamie

  15. >OOOOO, can I play??

    http://tinyurl.com/437etpr

    http://tinyurl.com/3lln6y2
    ———————————
    I remember calling a gal who was the leader of the Riverside Ca cfs support group back in '88, when we moved to that area. She told me something like 'you know, this is a real, serious disease. Its an infection, probably viral, in your brainstem'.

    Things move slowly in medicine…its a very high status profession, but that also means there is a lot of status quo to contend with…

    Jerry and Carol
    El Paso, Tx
    PS. John, message received, email sent…

  18. >Dear John Anon,

    I don't know who you are or whether you know more about retrovirology than I do which I admit is not a lot. My understanding is that there is enough sequence diversity in the different strains of this MLRV to make the contamination theory of little importance. The contamination theory is concentrating on a sequence that may have never existed because of a sequencing problem.

    The response of my leukemia for 9.4 months can only be explained by the fact that the ARVs I took attacked a retrovirus. Please do not use "selective toxicity" as an explanation because this has never been seen in the 40 years of cancer treatment that I have been a part of. Please do not use the explanation that it was an anti-herpesvirus effect because my testing for active herpesvirus infection was negative. Please do not use the explanation of anti-telemorase activity of the AZT because the effect was too quick and too profound. In addition, our informal survey which we hope to expand does suggest that some partners are infected.

    So what is this need to concentrate on XMRV that may not be representative of the retrovirus that I have or that most CFS patients have? Is it because there is a race to patent the retrovirus that is attacking us? Money and power seems to be a big motivation for some people.

    Michael Snyderman, MD

  19. >Dear Dr. Snyderman,

    I am a patient with no education or experience in retrovirology and have simply been following the XMRV developments from the beginning, including emailing various researchers whenever I had a question. Given that, my understanding of the details appears to be somewhat opposite of yours.

    For starters, based on my understanding, there is actually almost no sequence diversity in XMRV. The complete sequences of XMRV uploaded so far, which include the WPI's uploads as well as the Cleveland Clinic's uploads, are all almost identical, with John Coffin stating that the extremely minute differences between the different uploads would basically be what one would expect due to simple sequencing errors.

    Instead of there being sequence diversity in XMRV, what has instead occured is that any virus of the MLV class is being mistakenly called 'XMRV' by a few, whether the sequence and/or virus in question be a murine endogenous retroviral sequence or a different and distinct recombinant cell line contaminant. Based on my understanding this is not accurate. XMRV is a very specific virus which forms a distinct clade from other MLV's and the other sequences uploaded so far all represent other distinct recombinant cell line contaminant viruses and/or murine ERV sequences, not sequence diversity in XMRV.

    I am not sure what you are referring to when you state that 'the contamination theory is concentrating on a sequence that may have never existed because of a sequencing problem.' There is not just one 'contamination theory' in regards to XMRV/MLV research. Instead there are quite a number of ways that experiments have been shown to have the potential to become contaminated. The fact that no one videotaped the WPI potentially contaminating it's experiments in real time is not a defense, especially since the WPI has apparently contaminated several different subsequent experiments as a result of sloppy technique, such as the Blood Working Group study. There is also no shortage of subsequent studies which lead to the conclusion that the XMRV studies were the result of contamination.

    Based on my understanding, basically the only evidence that still stands which cannot be explained by contamination is the WPI's antibody results, however these may end up being associated with a completely different virus than XMRV.

    I am not a cancer physician or researcher so I cannot say what may or may not have occured to result in your response to ARV's, but congratulations on your treatment.

    As far as I'm aware, the 'need' to focus on XMRV is based on the fact that XMRV is the retrovirus which the WPI reported was associated with a high percentage of CFS patients. From a scientific standpoint, I'm not sure how one could focus on something else which hasn't even been shown to exist.

    Finally, your conspiracy theories about money, power, patents and retroviruses are fairly ill informed, detached from what has transpired over the past couple of years and are basically fairly disgusting and delusional so I'll just leave you to them.

  20. >PS- There's one other thing about the patently delusional conspiracy theories you promote, namely that they are also quite hypocritical since you yourself work for an organization which has taken out just as many patents as anyone else has on the issue, so the idea that everyone except the WPI, the Cleveland Clinic and Frank Ruscetti's lab at the NCI (which have all taken out numerous patents related to XMRV) are somehow part of some giant conspiracy theory is quite ridiculous and ill informed.

  21. >The sequence diversity in the GenBank is around 6% for xenotropic and polytropic MRVs. That is not no diversity. The new WPI sequences in the GenBank are polytropic and modified polytropic, not xenotropic/polytropic hybrid.

    There is no scientific evidence for a contamination hypothesis. Your emotions only wish there were.

    Negative studies have not replicated and not validated their assays.

    The Lo paper did validate Lombardi and the JHK virus, discovered in 1989, also validates the paper.

    You need to stop thinking this is a conspiracy anon.

  22. >Dear John Anon.,

    I welcome your admission that you don't know more than I which really isn't a lot. Only time will tell who is correct. In the meantime the evidence that I have posted supports a retroviral cause of my CFS and cancer. As I am not unusual in any sense, I believe my data is typical of what goes on in other patients. Do I have XMRV or do I have a strain of XMLV? Is it critical what the virus is named?

    Bottom line, I have a retrovirus and it responded to ARVs. If I had listened to Dr.Coffin about not using ARVs I would have cheated myself out of an extra 9.4 months of life!

    As you should know this virus or viruses have a history. Three independent labs in the 1970's found it in cancer but NOT normal tissue. One of the labs was Sol Spiegelman who won a Lasker prize and another was Gallo's prior to the discovery of HIV. These studies predated any tissue culture source of XMRV.

    As to patents, I am surprised that you didn't know that I. Singh has already applied for wide patents for XMRV and related cancer. I agree this is disgusting but not in the way you mean. It seems that you protest too much about this. It is a fact.

    The bottom line is that we patients need research to continue on MLRV etiology of CFS and cancer. As an oncologist for 40 year I have seen many things come and go but the retroviral etiology of the disorders in question makes a lot of sense to me. People like yourself seem to want the research to end and I hope our side wins out.

    Michael Snyderman,MD

  23. >dear dr jamie…thanks for your blog! ive been disabled (housebound/bedbound) with severe M.E. for many years. My husband (after what id call a "body-wide decline" of about 2 yrs)was finally dxd with myalgic encephalomyelitis several months ago after presenting with cerebellar ataxia – after a life-time of wellness! i am on high dose acyclovir/equilibrant and Epivir (3TC/"Lamivudine") – interesting, as apparently Lamivudine is an ARV thats being used in a PBC study currently! (My husband is titrating equilibrant as his first course of action). our adult daughter was tentatively dxd (recently)with Primary Biliary Chirrosis – following routine blood tests that revealed elevated liver enzymes, CMV and high/positive Mitochondrial M2 antibodies. Her liver specialists are reluctant to do a liver biopsy (for a positive dx and staging) as they fear that trauma to her already inflamed liver might be inadvisable at this early stage. They have started her on ursodiol for the time being. The question of whether or not she also has M.E. has come up of course…but first things first, in her case!(BTW, her fist cousin has also had M.E. for 20 yrs.) im dumbstruck by this latest news of a link between PBC and a beta retrovirus. im frantically trying to connect the dots. frantically!

    thanks for keeping us in the loop!

  24. >Dear Anon 4:08,

    Thank you for your completely fascinating comment. Please keep us posted. And please make sure you fill out our Family Survey (link on the side bar).

    I moderate a confidential Yahoo group for patients taking arv's. Email back channel and I will subscribe you: jdeckoffjones@gmail.com. Anyone else who may be taking arv's, please get in touch also.

    Warmly,
    Dr. Jamie

  25. >Dr. Snyderman, I'm glad to say that you are not my doctor.

    Even without any experience in retrovirology I can see the fundamental flaw in your logic: while multiple labs are indeed reporting different sequences (esteemed retrovirologists contend that these sequences reflect the same virus, but I'll generously grant you that premise), each individual lab is not reporting any meaningful sequence diversity within a single study population.

    For instance, the WPI seem to be addicted to uploading fragments of VP62 (or clearly related sequences) to GenBank, while Alter/Lo detected none of that but detected 18 MLV gag sequences that were 100% (!) identical to one another but clearly distinct from the WPI sequences.

    This does not make any sense. WPI find *only* VP62 while Alter/Lo find *only* MLV-like sequences.

    With *true* sequence diversity, WPI would find *some* XMRV and *some* MLV-like sequences and Alter/Lo (and Switzer/Hanson/the Lithuanian scientists) would find *some* XMRV and *some* MLV-like sequences.

    They don't, which is clearly consistent with detecting lab contaminants – each lab just "finds" its own lab artifact.

  26. >I am going to start deleting gratuitously insulting comments. Nobody needs the stress. Dr. Snyderman graciously shares his experience and ideas with us. RRM, you need to go back to kindergarten and learn some manners. I'm sure you can still learn to say things in a polite way, even as an adult. If you want your ideas to be considered, don't undermine them with cheap shots. I expect better of my grandson who is a first grader.

    Jamie

  27. >RRM you should look in the GenBank. There are only a handful of full length sequences in there, but already there is a 6% diversity. It cannot have come from a cell line. The JHK virus takes that to over 16%, and it was found in 1989, before 22Rv1.

    Another human retrovirus, HTLV, has been taken from the generations of the same family and been found to have not altered. None of this information fits your impressions of this science.

    The new sequences in the GenBank are modified polytropic and polytropic, the same as the viruses Lo and Alter found. The WPI did report this data at the Cold springs Harbor conference in March 2010, months before that paper was published.

    You are confused because you have not learn't how to identify those variants of HGRV.

    There is still no scientific data of lab contamination. No contaminated cell line has been in the WPI or NCI labs.

  28. >The data in Lombardi et al. was supported with several other experiments, including the EM of the budding virus and immature virions and the immune response. No one has anything to say about those results.

    The immune response was to an MLV that could not have been a contaminant or an endogenous virus (human or mouse). So it was to a HGRV.

  29. >@JDJ

    As I am a guest at your blog I am subject to your house rules and I do respect them, but I respectfully disagree with the notion that I am 'gratuitously insulting' people.

    I have no problem admitting that I am not the most subtle of posters, but you cannot deny the fact that I am at least backing up my assertions with actual arguments.

    In my view I merely explained the gaping holes in Dr Snyderman's argument. Whether you agree with my points is subject to debate but please don't act if I didn't back up mu initial statement with actual arguments.

    If the WPI/FDA's Blood Working Group Phase 3 results support their findings, I am perfectly able to adapt my views. Will you (or Dr. Snyderman) be willing to do the same if the results do no support the initial findings?

  30. >How can a contaminant hypothesis fit with a vast differences in proportion positive between cases and controls?

    Not rhetorical; I think it would be useful to know your personal hypothesis/es, Anonymous and RRM.

    Also, it would be easier to follow for some of us if every Anonymous used a consistent handle.

  31. >@RRM –

    "Dr. Snyderman, I'm glad to say that you are not my doctor." is absolutely gratuitously insulting.

    Since we all know who Dr Jamie is, and who Dr Snyderman is, I'm curious if you're the same RRM that said Osler's Web is a "shitty conspiracy theory book"?

    Only so we can consider the source, of course.

  32. >"If the WPI/FDA's Blood Working Group Phase 3 results support their findings, I am perfectly able to adapt my views. Will you (or Dr. Snyderman) be willing to do the same if the results do no support the initial findings?"

    You've filed it down to an honour dichotomy already? What happened to the debate?

    SJ

  33. >Dear John/RRM/etc:

    I am not insulted that you don't want me as a doctor. I am rather glad. Still I wonder about the extent of your rage. It is quite out of proportion to this situation.

    You are purposely basing all your argument on sequence data and want us to accept your judgements when we don't know who you are and what sort of background you have. When you ignore supportive evidence such as I have posted here, then there has to be an agenda other than the truth. You don't appear to be a patient. What is your agenda? Do you want research on HGRVs and CFS and cancer to stop? Do you want no further ARV treatment to be administered? If these are your goals, please explain to us your motivation.

    Michael Snyderman, MD

  36. >@Dr Snyderman
    I am a close family member of an ME/CFS patient and I also have a general interest in science, pseudoscience and conspiracy theory. It is not my goal to stop HGRV research and I think that people should be able to take ARV's if they want.

    @MEshel
    It's not "gratuitously" insulting because I explained my position. On the other hand, Dr. Snyderman called the behaviour of Dr. Singh "disgusting" without providing a valid argument. I note that she was also called a 'backstabber' on this blog before, because her independent experiments produced results some people didn't like. So please forgive me for finding your reproach rather selective. And yes, I did call Osler's Web that on Virology Blog.

    @SJ
    My question was not an "honour dichotomy". It is a rather accepted and essential principle in science that one should be able to adapt one's views when presented with evidence in support of an opposing hypothesis. Although people have been accusing me of being 'enraged' or at least not objective, I am perfectly willing to adapt my views in light of Blood Working Group (or Lipkin study) results that support the Lombardi and Lo/Alter studies. I hope that others will be able to do likewise, instead of explaining away unwanted results from these sound and costly studies with very unlikely ad hoc hypothesis (perhaps the virus goes dormant during the summer?) or a vast conspiracy to cover up the truth.

    @Anonymous August 16, 2011 12:38 AM
    I am not Ramon R. Mendoza. RRM stands for Regum Magister (which is really just some 'engrish' I overheard when I was about to post my first comment so no, I am not considering myself to be the master of kings). It really is a great example of the "scientific method" employed by some of the "scientific leaders" on the forums though, which is apparently unchecked by skeptical fellow members.

  37. >@RRM

    Dr Singh has an HGRV patent that includes ME, but claims to not be able to detect virus in those same people. It rather speaks for itself. If she were convinced that her unvalidated, non-replication methods worked, she would have pulled the patents too. Singh should have been forced to apply her unvalidated ME assays on the prostate cancer patients she found positive. It is easy to hypothesis that they would be negative with those tests.

    What you believe to be evidence of a supporting view is not actual scientific evidence but speculation. Such politics have no place in science and should be left to testing in the lab. It is however unfortunate that the world is being falsely lead to believe two studies that are being Government lead should be definitive. When that same Government would not wish to deal with the costs of the disease or the reality of their neglect, which the WPI and NCI/Ruscetti would certainly bring.

    Another group that holds a HGRV patent is Abbott labs. Several of their employees have their names on negative unvalidated assay papers looking at patients with ME. Those same Abbott people also have their names on positive abstracts that use different assays. Again, like Singh, they should be forced to try those same assays on people with ME. One of those positive abstracts also contains the names Simmons and Busch. Two people who are members of the BWG. There are too many conflicts of interest.

    You mentioned the Lithuanian isolate and the Switzer sequences that are in the GenBank. They are all XMRV. Again, the diversity is too large to have come from Coffins magical cell line. You are also ignoring again, the fact that the WPI have polytropic and modified polytropic sequences in the GenBank that they reported finding in patients months before Lo and Alter published.

    If you cared about your relative and not coming up with a ridiculous conspiracy around a few scientists who would never have the power to pull anything like that off, you would realise that dirty tricks by powerful people are at play.

  38. >The BWG and the Lipkin studies are only two studies. The evidence provided already proves association. What you are calling unwanted results are only negative papers that have not provided evidence of clinical validation and have not replicated proven methodology.

  39. >The scientific discussion ran out, and it filed down to an honour dichotomy. One that is designed to give the impression Dr Snyderman could only possess limited choices following the blood working group, one of which being instantly disreputable.

    Adaptive views cannot and should never eschew scrutiny, if objectivity is one's goal.

    The fact that the Lipkin study is going ahead demonstrates a professional acceptance on some level that previous validation/replication studies (and I use the term replication dubiously since it ostensibly has yet to occur) have not closed the book opened by Lombardi et al and that contamination theories prior to its commencement were not compelling enough to destroy the potential link.

    I would have much preferred the debate about sequence diversity to continue, I like to see good debates full of nice things like citations which allow us all to challenge our opinions.

    Instead we got a moral crusade and a pissing contest.

    -SJ

  41. >ERV has no background in MLV, or in HTLV, another human retrovirus with a very low or seemingly absent mutation rate.

    Her ideas do not fit the scientific knowledge on retroviruses.

  42. >@SJ

    Replication (according to your definition) has never occured in the history of (retro)virology, at least not to my knowledge. You could direct me to such an exact replication attempt and I would then actually adapt my views on the matter, but I have been asking this for months and everybody is apparently keeping these examples a secret.

    And I was not suggesting at all that Dr. Snyderman (or anyone else) has only two options to consider following negative results. I was asking if he would be able to adapt his views accordingly. This does not assert or imply any 'dichotomy'. So, rather ironically, in your attempt to point out a false dilemma in my post, you have presented a straw man yourself. And please note that I do not have oly two options following positive results either. For instance, it would make a lot of difference to me if the WPI and Lo could only detect their own positive samples or if they both can detect positives from both labs.

    What I consider to be unscientific, is to cling on to initial results for dear life, explaining all contradicting data away with ad hoc explanations in the process. And because I can't see a much needed skeptical approach to one's own views here and in other comments, I think it is a fair question to ask how that results should be valued now that phase III results are to be released shortly. I guess that the answer is that when the WPI and/or Lo would be unable to reliably point out the samples from patients that they themselves have designated to be positive for a HGRV beforehand, would not say anything at all?

    @Anonymous August 16, 2011 5:57 AM

    Yes, the Lipkin and BWG studies are "just" two studies. Just like the Lombardi and Lo studies were "just" two studies. The association between HGRV's and human disease is not conclusively proven, far from it. However, it is exactly this 'we don't need confirmation because it is already proven' attitude that will lead to explaining away sound and rigorous follow up studies when they do not confirm your beliefs.

    I think that Newton's laws are conclusively proven (at least, under everyday conditions), but that still doesn't mean they aren't open to scrutiny. In fact, that is what makes them to be considered "conclusively proven": the fact that scientists are willing to accept evidence to the contrary by skeptical scientists, but that these skeptical scientists are unable to provide any evidence to the contrary. Saying that it is proven and by saying that no longer be willing to accept evidence to the contrary, flies right in the face of the scientific method.

  43. >@ Anonymous August 16, 2011 4:37 AM

    I didn't see you comment before. Thank you for implying that I do not care for my relative.

    I explained earlier why your assertion regarding sequence variation fails to hold up: WPI reported (almost) identical sequences in their study that no one else has thus far reported in blood. If there was true sequence diversity, you would expect WPI to find some A, B and C, Lo to find some A, B and C and Hanson to find some A, B and C. When lab 1 finds only A and lab 2 finds only B, that is more supportive of the hypothesis that lab 1 is contaminated with A and lab 2 with B.

    As for patents, it is historically very normal to apply for far more patents than you will actually need or are going to use. Just to be sure 'in case it does unexpectedly work out'. It happens all of the time in all branches of R&D type situations. There is nothing sinister about it and therefore it doesn't prove anything.

    It would also be patently stupid (pun intented) of Dr. Singh to do such a thing if your accusation were true. First, you "busted" her without any real investigation but by just checking some publicly available material that she had to know would be checked by some of her competitors. Second, if it were ever to come to a "patent fight" in court, her not finding anything using her own methodology would almost certainly not help her convincing any court. Except of course, when the judge is part of the conspiracy… ;-)

  44. >i am a very long-term patient who did not respond to several high-dose antiherpetic drugs, which i tried for years.

    i did, however, respond to AZT, and, to a lesser extent, Tenofovir and Raltegravir.

    before i began these drugs, i was bedridden and was considering a nursing facility.

  45. >@RRM

    Replication occurred with HIV and HTLV

    Science requires putting a hypothesis to the test. In this case, do patients with CCC ME/CFS have HGRVs when using those testing methods. No one has tried to answer this, so they have avoided the scientific method.

    What you are asking it a different question. Namely, if the results are negative for a replication study (that has no mistakes in it) then will people take a different view.

    The science has not been shown to be incorrect because of the above has not been put to the test, so the association still stands. The JHK virus from Grossberg takes that to 3 positive studies. Science does not work on absolutes, and without putting those findings to the test, they are not altered. HIV may one day be shown to be wrong (though I doubt it), because science is not an absolute. You need to realise that.

  46. >@Anonymous

    Replication DID NOT occur with HIV, at least not in the way people are demanding it with XMRV. You seem to be confusing 'replicating results' with 'replicating methodology'. While the first has of course ocurred with HIV (like any finding that is considered to be 'true'), we are talking about exactly replicating other virologists' methodology.

    Can you please reconsider and point me to a study within the field that exactly replicated the methodology of the original study? As you seem to understand science, I take it that you also know that in science, one substantiates one's claims with proper references.

    It is rather ironic that you point out to me that science is not 'an absolute' because that is exactly what I was aluding to in my earlier posts. Because science is not absolute, one should be willing to adapts one's views when new evidence becomes available. I will be, whether new evidence becomes evailable regarding XMRV or HIV. Will you?

    Finally, you argument about 'the association sill stands' does not reflect how science works. To give you an example that WPI have used themselves: when Barry Marshall didn't convince the scientific community with his initial study, he didn't stop there and just told people how his results were true for the rest of his carreer. No, he actually designed and performed additional experiments that CONVINCED fellow scientists that his earlier claims were true.

    Likewise, now that the scientific community is not convinced (at all) by the available evidence regarding the association of XMRV with human disease, proponents should do the same: perform additions experiments that will produce results that put other scientists (and me) to shame. If the association were true, this shouldn't be hard at all. In contrast, conclusively proving that a claim is false is in reality impossible. Again, I would be perfectly willing and able to concede this if you could propose an independent experiment that could conclusively prove this.

  47. >Yes, they did replicate. But you have no interest in how any of this works or what has happened. For whatever reason you have a closed mind and never provide references, only opinion.

    You believe that changing every variable or cranking annealing temperatures to almost double that used in Lombardi is going to produce the same result. This is not a game where people guess at what conditions will detect a virus. You wouldn't find a galaxy and then expect someone else to do the same without using the same method. Discoveries don't fall from a tree every few seconds.

    Again, you are mistaking opinion with evidence. There is no scientific evidence that has any comment on the original findings because those studies used unvalidated assays and in most cases totally different cohorts.

    The association still stands because there is no other evidence and in fact two more positive papers.

    When you say scientific community you mean a handful of people who in many cases have gone to the press. You won't know what the others are saying and doing. I hope you don't think there is any such thing as consensus science and would rather skip passed pesky scientific data.

    Again, you ignore the data on polytropic and modified polytropic variants and several of the other testing methods, such as serology. You are not willing at all.

  48. >I should correct the point about HIV, because there they actually provided positive samples to Gallo so he could optimise his assays.

  50. >You are desperate for others to think that there is a scientific community that has decided it is over. But there you are a few posts above going on and on about the BWG and Lipkin studies. We know that there are labs in countries around the world (Spain, norway, Russia, German, Japan, etc.) saying they are finding the virus. It is obvious that Stoye is still researching it frantically. Emory are finding it too. You are not interested.

Comments are closed.