Although the personal questions in the comments of the last blog were asked very rudely, I will try to answer them anyway. I have represented myself as an open book, and I truly am, even though it gets me in trouble, as witnessed by the tone of the questions. Most of this has been said before, but things have changed, and perhaps it needs to be said again, from our current vantage point. So, I’ll give it a go.
I am not trying to persuade anyone to take anything. I share my reasoning, with references, within the limits of my writing ability. I intentionally report before I know the outcome so that it won’t be seen as my pushing a particular protocol. I am in the same boat as everyone else. I don’t know what to do to fix it. I don’t believe that anyone else does either. Arv’s are only one of the treatments I have written about here. I am sharing my thoughts and experiences in real time.
This is a blog. Opinion. If you read it carefully, there are inconsistencies. I even reserve the right to change my opinion from time to time. I try to summarize occasionally, but yes, a “casual” reader might come away with something I didn’t intend. I am not sure what to do about that. I cannot recapitulate the entire blog each time I write. It is an ongoing discussion, not “the truth” at a moment in time. Almost everybody gets that, I think.
I am endlessly surprised that my opinions are so controversial and can evoke such ire. Most of it seems common sense to me. It is incredible, and very telling, that there are actually people that want to restrict my freedom of speech! Why does anyone care if others find my musings useful? I am not telling anyone else what to think. I have said repeatedly that I could be wrong about anything. If I were to say nothing until everything is scientifically validated and I was positive, I would never say anything at all. I am learning as I go, as is everyone. For some peculiar reason, I seem to need to write, and some people find it helpful. The blog is the best I can do, with the limited energy and time I have left, and I am grateful for it. When Ali suggested I write a blog, I didn’t know what a blog was:). The patients who comment and write are very sophisticated and opinionated all on their own, not needing me to tell them what to think. They ask for my thoughts so they can put the information into their own equations, not take it as some kind of truth written in stone. The reflex to restrict what I say so that the poor gullible patients won’t hear it is patronizing. And to the conventional physicians who might be reading, why the sudden concern for our well being? There are many useless things that you are willing to prescribe that are much more dangerous than arv’s.
I have never claimed to be anywhere near “well” and I have said all along that there were confounders with respect to our treatment with arv’s. As noted in the comments, gamma retroviruses replicate by clonal expansion, so we need specific drugs, but transcription of viral proteins and the assembly of new viral particles may be involved in pathogenesis, if the hypothesis is correct. I am endlessly reevaluating everything with new information as it becomes available. I am not in fact a “true believer”. I would love to hear any alternative hypothesis that fits close to as well. Anything at all that might suggest a direction to turn for efficacious treatment. I am dismayed that we are back to having an idiopathic immune disorder, albeit repackaged to sound like good news. Redefining it as a syndrome, yet again.
There is no way to know if arv’s are helping us at this time, as I have said several times. I expected viral load measures and other ways to monitor that didn’t pan out. I did monitor several likely parameters which showed trends, but not convincingly enough to be useful. There are specimens sitting at the WPI that might contain valuable information. I certainly hoped it would be less ambiguous than it turned out to be. But there are others that experienced what we did, apparent cause and effect improvement from starting arv’s (often after an initial mild symptom flare). Some of them have written on this blog. I am NOT saying anyone should take arv’s, and never have, only that they shouldn’t be forbidden. The main problem I have recommending it as an option now, is that because it isn’t being studied, anyone starting will likely find themselves where we are, not knowing what to do for the long haul, and no help coming anytime soon. I actually think it is probably mostly a moot point now; the forces against have essentially won, shut it down for all practical purposes. The important thing isn’t really even arv’s, which at best only help incompletely, but our inability to get any help at all due to the attitude displayed in the reaction we have seen to the idea.
There are many drugs that are used because they work, even though the mechanism is unknown. One would think that for a debilitating disease which affects millions of people, for which there is no meaningful treatment, somebody would want to find out if that might be the case here. The usual way that happens is somebody has a good case, publishes it and then it gets studied. I have reported our experience. The burden of proof is not on me. What if it was a serendipitous discovery for the wrong reasons? The reaction of the medical community to trying arv’s is irrational, as the reactions of the medical community often are, especially when it comes to anything to do with this disease. The reaction of the scientific community is a joke, with no basis for an opinion at all; practicing medicine without a license, understanding nothing of the disease about which they are so opinionated.
Take a look at this paper: Zidovudine in primary Sjögren’s syndrome. Steinfeld. Rheumatology (Oxford). 1999 Sep;38(9):814-7. Did everyone get up in arms about this small clinical trial? Were the authors discredited for trying it? It doesn’t look like anyone followed up on it.
I have shared many personal details here, both physical and emotional. I have been very forthcoming, approaching undressing in public at times, so it is strange to be accused of “hiding”. The problem is that my sharing a list of symptoms that are “better” than before isn’t terribly illuminating, since some things are better or gone and some things aren’t. I even have a couple of new things. Like most ME/CFS patients, my condition changes from day to day and tweeting my moment to moment condition would benefit no one. However, I will try to define the big things.
The most tangible thing that happened to me, seemingly from arv’s, was the near resolution of my chronic malaise. I had it much of the time for 15 years. It went away shortly after starting AZT/Isentress and I almost never have it now. So 90% of the time before, 10% or less now. That alone was life changing for me.
My down periods used to last for 5 days to a week at a time, and now, rarely more than part of a day. The worst moments happen less often.
When I started arv’s, I never slept more than two hours without awakening, and I didn’t dream at all. I now often sleep all night with one or two awakenings and I dream normally. My day to day wellness is linked to the quality of my sleep in a chicken or egg fashion, so this improvement is key.
Painless migraines (scintillating scotoma without headache) and hypertensive crises are much reduced in frequency.
Another “big thing” that happened: I experienced a definite decrease in my peripheral neuropathy pain at one point early into arv’s. However, trying to explain one’s pain to anyone else is an exercise in futility. The pain I have now is worse than pain that almost drove me insane at the beginning of my illness, but my coping skills are very different. Still when the reduction happened, it seemed definite. I am not pain free, but my pain is quite tolerable and does not require pain medicine. Others have also reported less pain on arv’s. Again, I am reporting, not selling. For everyone who thinks they were helped, somebody else thinks they weren’t, but the risks of trying it are pretty minimal with proper monitoring.
I acknowledge that it is possible that all these things happened in spite of, and not because of, arv’s.
A big disappointment for me has been that the abnormal response to big time stressors remains, though it may be attenuated. Impossible to tell.
As for my daily functioning? I am able to work long days, most days, electronically (phone, Skype, email). I don’t have brain fog, but do sometimes have more symptoms after mental exertion. I am limited physically, more so in Santa Fe than Hawaii. I can climb a couple of flights of stairs with some dyspnea, more if needed, if I go slowly. I can usually walk several blocks, but might have some mild PEM if I overdo it, though my exercise tolerance is very variable. I don’t need handicap parking. I have no difficulty lifting groceries, etc. Resistance exercise is easier than anything aerobic. Swimming is easier than walking. Standing still is the hardest. The most physically challenging thing I have to do is negotiating airports and I use the airport wheelchair service for that. Gentle yoga is helpful. Pretty much all of the above is better than before I started arv’s, though as a commenter said, and, as I have said all along, other things happened too, before, during and after. Also my illness historically follows my state of mind (knowing full well how unPC it is to say that out loud). I am also much more tolerant of symptoms than I used to be, and not a very compliant patient, more confounders.
I can only work part-time face to face, a couple of hours at a time, but I’m OK for many successive days. I could fake it for longer hours than that, but don’t want to do that. My patients travel a long way to see me, and I want it to be useful and special. I am seeing new patients for 4-5 hours on two different days, which is working out well for all concerned. It is a unique, collaborative endeavor. Sick doctor and sick patient. I am limited, but can function fairly reliably, though there are days when it’s tough; however, there are more days when it isn’t.
When I started arv’s, I was unable to speak on the phone, because of auditory processing disturbance. I also had to lie down most of the day, only sitting or standing for a very short time, and I now sit up most of the day. Standing is more difficult some days than others, but there is never a time when I can’t if I need to; that was not always true.
So huge functional change in the last 20 months on arv’s, but improvement started about 6 months before that, with cessation of Lyme and symptom-based treatment. From housebound to functional, but not at all “well”. I have written about the reasons why I abandoned the use of rating scales to evaluate our experiment and don’t want to rehash it again. It is sad that it’s all we have. I am collecting them on my patients, but don’t expect them to be as useful as patients’ subjective reports. Yes, I do believe what my patients tell me.
My illness certainly isn’t gone, though it has lifted, lessened, but it is a relapsing, remitting illness all on its own, making it extremely difficult to assess cause and effect. I have said this over and over again. I am fully aware that many ineffective or harmful treatments have been perpetuated because of this feature of the illness (see my prior blog entries about Lyme Disease treatment). Whenever anyone gets better, they think it’s because of whatever they were doing at the time. I received an email recently from a patient who was housebound for fourteen years and suddenly improved enough to get a life, having changed nothing. I was of course influenced by the fact that there were two of us sharing the same experience; Ali and I had similar experiences with respect to the timing of improvement, though she had no side effects and I did experience a flare of symptoms initially. And for the record, neither of us has a history of placebo responses.
Ali went uphill during her first 6 months or so on arv’s, but had more therapeutic interventions concurrently than I did. The goal was always to get her better, not demonstrate something scientific to others. Her treatments did not prevent her crash when she tried to engage life again a year ago. She is doing well again now, but it is impossible to say if this level of wellness is the same, above or below her last remission. The “crash” didn’t become as serious as prior crashes have been for her. The important thing to her now, I think, is that she is better at this moment, and seems still to be slowly improving. Will it last? She is savoring it while it does.
My baseline was better prior to the events of early July than it is now, though I am not “crashed”. I have been under a great deal of stress, though I am hoping things will calm down a little now, so I can regain what I have lost. There is no way to know if I tolerated the crisis better than I would have without arv’s. I suffered the kinds of losses and persistent stress that have historically set me back in a major way. I stopped Isentress a while back, and am worse. Cause and effect? Who knows, but I don’t want to stay on monotherapy and am afraid to stop Viread, since a couple of patients who were forced to go off have lost gains. I may go back on Isentress. Also thinking about Lexiva (see Li on the sidebar).
I have received several demands for an apology from me to Dr. Peterson. As I said when I mentioned his name for the first time, I have never met him. Making enemies was never my intention, just the inevitable consequence of stating one’s opinions openly and publicly in such a contentious arena. My frustration feels overwhelming sometimes and it comes out in my writing. I hear from patients that love Dr. Peterson, and that does make a difference to me, but it still seems inconceivable that he abandoned the pursuit of a retroviral etiology when he jettisoned the WPI, knowing what he knows about the science and the disease. His teaming up with Konstance Knox to sink the WPI still seems really sleazy to me and his claim that it was to protect patients disingenuous. He could not have known there were problems with the VIP Dx test, or questions of contamination, at the time that he left, so how could he have been “right”. His agenda appears to go beyond figuring out how to treat the disease and help patients. I am not saying that I know precisely what that agenda is. It would seem that everyone who was involved with the WPI was hurt, likely including Dr. Peterson. I only wish that he hadn’t thrown the baby out with the bath water.
I regret any pain that I have caused, but some truths are painful. For me, it is painful to acknowledge how few friends there are worth having in the medical or scientific communities. My referral list for mainland doctors is a very short list. When I think back over the people I have mentioned by name in an angry or personal way, it is a select few that had it coming. My lack of professional decorum, or whatever you want to call it, comes from outrage, and mostly justified. I challenge anyone who has been sick with this disease for any length of time to write their truth and not say some angry things. My writing is also full of hope for the future. It’s just that it is the hope of learning to live well with the disease, rather than to truly vanquish it any time soon.
I really think many have too much confidence in “science”, especially retrovirology, which seems to have an unusual number of landmines scattered across its landscape. Even if Dr. Lipkin were to say tomorrow that he agrees that there are gamma retroviruses infecting ME/CFS patients, it will be a long time before that translates into specific treatment. Compassionate use of existing drugs should be tried and available, especially for the sickest patients. There are possibilities besides arv’s. Lenolidamide? Pentoxyfyllin? Nexavir? Existing drugs. What others? I recently heard of a big time response to Copaxone. Is anyone looking in a systematic way? Really looking? Why does it feel almost subversive to talk about it? The idea that these patients should, or can, wait is indecent. Again, I am not trying to convince anyone to do anything other than consider my ideas. I continue to write because some find it helpful, and I have made many friends, but I have made enemies too, and that gives me pause. I do grow weary of the personal attacks, on top of everything else that has happened recently. I need to focus on my patients, but want to continue to reach out to readers; there is so little information with respect to how and what to consider for treatment in the here and now. Five or ten more years is too late for many of us.
OK. Now I have some actual work to do:).
Aloha,
Jamie
Today’s song: Can’t Find My Way Home
>Well here is something that is no joke. My father is sick with Parkinson's, his wife has MS, my mother has Breast cancer, another brother Graves disease, My sister and I have ME/fibromyalgia, and I've lost one brother to leukemia. My only healthy brother has been showing symptoms of unexplained illness for the last 5 months. I work in the area of health. Eight of my co-workers have unexplained illness. One of them has MS. They have worked around me for 12 years. There is no previous history of any of the illnesses I listed in my family. I have tested postitve for HGRV. What a coincidence all this is!
>>This is a group of people that needs–no, DEMANDS–that EVERY area of research that can be explored be explored, and no longer ignored as it has been for decades. If there is even a shadow of possibility that any one angle if research may shed light in breaking this thing open, it needs to be pursued.
Unless of course it has anything to do with mold, in which case we throw the information right into the garbage can.
Because we all know that Jamie is correct in asserting that avoiding mold is no different than "strengthening the spirit," and that the only reason that the "mold warriors" have for objecting to her purposeful minimization of their reports is because they're just frustrated with the illness and taking it out on her for no reason.
Right?
After all, there's no way that toxins might CAUSE illness, right?
Because we all know that an MLV is the CAUSE.
(Even though there's now not one shred of evidence that suggests that one has any connection to the illness at all and the hypothesis has been discarded by every scientist in the world — except for a couple of current and former employees of the WPI with a financial stake in it.)
All those people who died after Hiroshima must have been suffering from an MLV retrovirus that hit the population at the same time as the atomic bomb. Because if people look like they're being poisoned, and feel like they're being poisoned, it has to be downstream from an MLV retrovirus.
RIght???
God forbid, we wouldn't want scientists to take a look at why our bodies don't detoxify things like normal people's. We wouldn't want drug companies' help with that. It's antiretroviral drugs or nothing.
Even though activated folate supplements — which are pharmaceuticals that detoxify things — are "hot stuff" for Jamie's daughter.
That's beside the point. We wouldn't want drug companies to develop any more things to help us detoxify. Of course not.
Let's not even explore that route.
Because of course, the toxins couldn't _possibly_ have anything to do with it.
So now, MLV research is going nowhere, except in the fantasies being spun by "our Dr. Judy." No other researcher on the planet is going to touch it. No pharmaceutical company is going to touch it. Patients' obsessing about it is making the whole world think we're a bunch of kooks.
But still — it's far more productive to sit around being angry about the fact that no one is looking at it (even though many millions of dollars have been spent on it already), and distributing petitions designed to keep Dr. Judy's fantasies going, than to encourage researchers to look at another hypothesis that hasn't been discredited.
Right????
>The hypothesis in Lombardi et al. was confirmed by Lo et al. There are no other papers on HGRVs, as the other papers used VP62, which does not exist and is not the viruses found to be associated with ME/CFS. Any paper that used Silverman's primers can also no longer be included as that was VP62 plasmid contamination that was in Silvermans labs and has been shown to have not been contaminating the WPI and NCI samples. The VP62 plasmid has never been in the WPI or NCI/Ruscetti labs.
Paprotka et al. is a separate paper that should be retracted for omitting use of a third assay. Coffin's paper is relevant as XMRV in prostate cancer still holds as a finding. Coffin would like Lombardi et al. to be retracted. Paprotka et al. is being used to push Science into a retraction, when there is no reason for such a step to be taken, when that paper cannot be about HGRVs and when that paper HAS failed to include details of the 3rd assay. Coffin has also known for 2 years that AZA was used by Frank Ruscetti, he has seen all the Lombardi data and had access to the slide. He was also in the audience at the CFSAC in 2009 when the use of AZA in Lombardi et al. was discussed.
>The pathogenesis of HGRVs will be explored in later research. Currently the only two papers on HGRVs have looked at association and confirmed that hypothesis.
>Anonymous@October 11, 2011 1:15 PM said…
"Lombardi et al. discovered HGRVs using multiple methods, including serology, culture and RT-PCR. Lo et al. confirmed the finding using RT-PCR. Lo et al. did no serology. None of these viruses are VP62/XMRV. HGRVs are yet to be fully sequenced"
–OK, but shouldn't the final pronouncement of having found novel HGRVs wait until they are sequenced? Sequencing seems to be the only sure way of establishing uniqueness and novelty. Serology is prone to cross-reactive antibodies; culture means nothing by itself (the moldy bread on my counter is evidence of culture, but not of novel HGRVs, right?) And the PCR in Lombardi et al. was retracted, correct? The only data that still survives are the Western blots, some flow cytometry, and some EMs showing budding virus particles.
"The VP62 plasmid has never been in the WPI or NCI/Ruscetti labs." –I thought samples were sent to Dr. Mikovits when WPI was starting up. See
Cohen and Enserink, "False Positive", Science, 333, 22 Sept. 2011: "Silverman was happy to collaborate and sent WPI a clone of the virus, known as VP62. The institute could use it as a reference to start hunting for the virus in CFS patient blood samples that Peterson had stored." Has Silverman any recollection of this event and has he denied or confirmed this account?
"Paprotka et al. is a separate paper that should be retracted for omitting use of a third assay." According to the Supplemental Online Materials for Paprotka et al., RT was used on only one sample, the 2152 xenograft. The other late-stage xenografts apparently had enough genomic DNA in them to proceed to PCR directly. So it seems that RT-PCR was not really an essential part of the paper. Perhaps Paprotka et al. considered it not germane to the work. If 5-AZA is not germane to Lomardi et al., why not extend the same professional courtesy to Paprotka et al. and exempt the omission of RT-PCR under the "non-germane" clause? I still fail to see how vanquishing Paprotka et al. saves Lombardi et al.
"Coffin has also known for 2 years that AZA was used by Frank Ruscetti, he has seen all the Lombardi data and had access to the slide. He was also in the audience at the CFSAC in 2009 when the use of AZA in Lombardi et al. was discussed." Interesting. Is there any video or slides available from the CFSAC 2009 talk? The use of 5-AZA seems to have surprised everybody.
>"They are there now, Jason. I hate Blogger's spam filter. I have never needed it in 4000 comments. Have thought about moving the blog, but so much trouble…"
wordpress is far superior in my opinion. That's where I started my blog:
http://www.sciencebrewer.com
Jason
>""Paprotka et al. is a separate paper that should be retracted for omitting use of a third assay." According to the Supplemental Online Materials for Paprotka et al., RT was used on only one sample, the 2152 xenograft. The other late-stage xenografts apparently had enough genomic DNA in them to proceed to PCR directly. So it seems that RT-PCR was not really an essential part of the paper."
You explained it better than me!
Jason
>@AnonymousNonRetrovirologist said…
It is a fact that the WPI, NCI and Silverman will confirm that they have never had the VP62 plasmid in their labs.
The data in Lombardi et al. is extensive and backed by the Lo et al. findings. Only Silverman evidence was retracted as he had VP62 plasmid contamination in his lab alone. The WPI and NCI have proven that was not in their samples.
"According to the Supplemental Online Materials for Paprotka et al., RT was used on only one sample, the 2152 xenograft. The other late-stage xenografts apparently had enough genomic DNA in them to proceed to PCR directly. So it seems that RT-PCR was not really an essential part of the paper. Perhaps Paprotka et al. considered it not germane to the work. If 5-AZA is not germane to Lomardi et al., why not extend the same professional courtesy to Paprotka et al. and exempt the omission of RT-PCR under the "non-germane" clause? I still fail to see how vanquishing Paprotka et al. saves Lombardi et al."
The paper hinges on the 2152 cells, as those are the only link to 22Rv1 cells. The RT-PCR assay that was used is not described in the paper, so the paper can never be replicated or understood. What were the cycling conditions, the annealing temperatures, etc. The paper must be retracted.
Coffin knew about the AZA as would have Science. Every bit of evidence anyone would ever need is available and will be used.
Paprotka et al. left out the details of the RT-PCR assay used in the paper. That is an automatic retraction. Who reviewed that paper?
>Vinay Pathak makes it clear that all the later xenografts were only screened with the RT-PCR assay they omitted from the paper.
>@Jason
I welcome your interest and comments. I find them to be well-balanced and believe that you do sympathise with our suffering and am grateful that you are willing to acknowledge the possibility of some sort of viral cause of the illness.
Please continue to contribute and exchange opinions with us. The more you read, the more interested you will become.
My illness started at 34. It took away my teaching career. My children were only 5,3 and 1 at the time and I have raised them whilst being incredibly ill – you have a baby, you know how hard it can be even when you are healthy.
Keep with us Jason, we aren't all scientist haters, far from it.
Jamie, I love your honesty. I love that you say what you really feel but go easy on Jason – he could turn out to be one of the good guys in the end.
>Thank you, Jason, for sharing your blog. Your wife and new daughter are beautiful! Mazeltov! And you look like a very nice person. The beer looks good too:). I will share your site with my husband who is an aficionado.
I think there is an opportunity for healing here. If you met me, I don't think you'd be so angry with me. The context in which I started to write was one of total isolation with a suffering child, suffering myself. Angry and without a voice. Not a leader, but a victim. I don't feel powerless any more. I want to heal it, if it can be healed. Sensitivity training may not have been so far off.
My goal is to get to the truth. I really do want scientists to consider what I've written, in an objective way, not because you disagree with me about arv's. I do have a few scientist friends, though they probably disavow knowing me:), who didn't see any huge holes in my hypothesis. Forget XMRV. Forget the politics and whether you like me or not. Go back and read the stuff I wrote in early March. People who say happily that XMRV is dead tack on begrudgingly, "maybe there is another retrovirus". Well, hello? Millions of sick people are waiting. Husbands and children with subclinical illness. Wondering every time they have a cold. Is this it? Is this the time he won't get up? I have to wonder, if it happened to my son, would I give him arv's? Why have two years past and I still have no help in making these decisions?
Warmly. Really.
>Anonymous@October 11, 2011 1:15 PM said…."Lombardi et al. discovered HGRVs using multiple methods, including serology, culture and RT-PCR." From the Partial Retraction of Lombardi et al. (3 August 2011; accepted 16 September 2011. Published online 22 September
2011;10.1126/science.1212182): "the CFS peripheral blood mononuclear cell (PBMC) DNA preparations are contaminated with XMRV plasmid DNA (2). The following figures and table were based on the contaminated data: Figure1, single-round PCR detection of XMRV sequences in CFS PBMC DNA samples; table S1, XMRV sequences previously attributed to CFS patients; and figure S2, the phylogenetic analysis of those sequences. Therefore, we are retracting those figures and table."
Which means, unfortunately, that there is no PCR data in the Lombardi et al. paper.
"Paprotka et al. left out the details of the RT-PCR assay used in the paper. That is an automatic retraction." An erratum or correction probably would suffice in this instance. Lombardi et al. should consider doing same regarding 5-AZA omission on the Western blots.
The quote from Cohen and Enserink, "False Positive", Science, 333, 22 Sept. 2011 ("Silverman was happy to collaborate and sent WPI a clone of the virus, known as VP62. The institute could use it as a reference to start hunting for the virus in CFS patient blood samples that Peterson had stored.")
should be retracted if not accurate. The prinicpals involved are still alive and kicking; it should be an easy matter to clarify.
>Gerwyn
the oo studies used high stringency PCR conditions which were only capable of detecting VP-62 sequences.The sequences in patients with ME are not related to VP-62.The oo studies are totally discredited.
The reliance on the vp-62 clone was always atrocious science .No family of retroviruses has ever been confined to one genetic sequence.
Singh used an isolation technique which would have sheared off the SU region of the env protein that her antibody was targeting.This is only attached to the envelope by hydrogen bonding.Hence there would have been no antigen for her SU specific antibody to detect even if the viruses had been present
she abandoned a PCR assay which had been successful in detecting a gammaretrovirus in prostate tissue in favour of an unproven assay
her culture technique failed to produce any viruses in clinically positive samples
when challenged re this point by Mindy she said that it was a mistake caused by poor use of words and of course the clinically positive PMBcs had produced gammaretroviruses when cultured
so the result was the exact opposite of that claimed in her paper
retraction anyone?
>@Jason
"You explained it better than me!
Jason"
The 00 studies, Paprotka et al., the blood working group have nothing to do with Lombardi et al. or Lo et al. They were not looking for HGRVs. Paprotka et al. should be retracted for omitting use of a 3rd assay.
>Jamie, I love this one:
"I am seeing new patients for 4-5 hours on two different days, which is working out well for all concerned. It is a unique, collaborative endeavor. Sick doctor and sick patient."
You have to be one, to understand one.
>Jason, has Columbia U. stopped working on murine retrovirus research in humans? I know you have been moved to work on genetics and HIV.
If they have discontinued such research does it worry you that there is evidence that some murine viruses seem to be infecting humans?
How do you account for Mikovits finding antibodies to XMRV in cultures?
Have you read about DeFrietas' finding of a virus in CFS patients back in 1989-91? She worked at the Wistar Inst. in Philadelphia. The CDC didn't bother to even fly up there and check out her methods. They claimed they had not been able to find the virus. It is curious that the same person still working at the CDC has denied Mikovits discovery as well.
I realize that as a post doc you don't have a lot of control over what is happening in your department, but I hope you will take this issue seriously and not assume the research on this is closed.
If you get down to DC and can talk personally with Dr. Lo you might get some interesting leads to follow.
>Really liking the tone that's evolving over the course of this discussion. Kudos.
I don't want to let Jason or any other developing or mature virologist off the hook wrt our burning need for more research into potential infectious causes of this disease. However, I really do want to remind everyone that researchers don't get to just explore any ol' hypothesis that comes to mind.
Research requires funding. And, look at this: the only 2 really interesting funding initiatives in the 12 years my daughter has been sick have come from private sources. Federal attention to this disease in the US would be laughable, if the few research pennies the govt has spent on it had not resulted in so much continuing harm. (I can only sputter about the UK.)
Engaging Jason and/or MattK and/or any other virologists in dialogue about this disease is a really good thing, whether the dialogue begins in anger and mutual attacks, or through some other means (note how clearly surprised Racaniello was to meet patients and carers and discover we aren't all holy terrors). We need to pique their interest and, hopefully, educate them about what this looks like, as Jamie and other commenters are doing.
I personally appreciate it that Judy managed to get all the virologists up in arms, bless her, that V99 and other "wild thing" commenters on Racaniello's blog drove him nuts enough to get involved, and that ERV's "ilk" are over here posting. This uproar is focusing more attention on the disease than all the years of using our pillow-muffled "inside voices" to ask, in a sweet, small whisper, if someone other than psychs might, pretty please (bats eyelashes), look, at least in a teeny weeny way, into possible bio reasons that so many are so fucking sick. Woo hoo on the bad behavior!
But, regardless of bad behavior on anyone's part, I'm quite positive the scientists would be knocking down our doors to try to understand the disease if say, NIH came up with $100 million in grant money to nail it down. Fingers crossed the $10M CFI "seed money" leads to something like that.
Like Jamie, I'm personally "not done" with RVs as a potential cause and am eagerly looking forward to the results from Dr. Snyderman, Lipkin's studies, and whatever Judy does next.
So what if it's not XMRV? This may be the first time in ME history that funding agencies and scientists have paid enough attention to us to actually rule out an hypothesis!
But we can't let up now. Yes, ok, I'll concede VP62 isn't in humans. But, virologists, immunologists, endocrinologists, and especially govt research policymakers — If it's not that, then…WHAT IS IT?
@Jason, y'all may have no frikkin clue, but I KNOW you have some worthwhile ideas… Govt policymakers, WHERE is the $$ Jason needs to explore them?
btw, since you virologists are here, how about explaining, in layman's terms, what deep sequencing is?
>I should go watch TV and stop posting, but I can't help it. I find it curious that someone as young as Jason has Meniere's. Hey, Jason, you realize you could have Lyme disease. Ouch!
http://www.earsurgery.org/site/pages/conditions/menieres-syndrome.php
>"I should go watch TV and stop posting, but I can't help it. I find it curious that someone as young as Jason has Meniere's. Hey, Jason, you realize you could have Lyme disease. Ouch!"
There are many pathologies that can mimic the symptoms of Meniere's and Lyme's disease is one. It's also a common misconception that the disease does not strike early. I know someone who got it when they were ten. Mine struck during grad school unfortunately, almost 11 years ago.
Jason
>"Jason, has Columbia U. stopped working on murine retrovirus research in humans? I know you have been moved to work on genetics and HIV. "
As far as I know me and Ila Singh, and another prostate cancer lab were the only ones in Columbia at the time working on XMRV.
We are now longer working on XMRV since its pretty obvious to have been generated in a lab.
However, our lab study retroviruses in general. This includes xenotropic MLVs whether they are found in mice or human (although the human aspect is pretty rare). Currently, my focus is on HIV.
Jason
>I'm so sorry that these people seem to get off on attacking you as well some very sick people. They have no idea what it is to live in these bodies. If they did there would be no more personal attacks. Give it time as the rate this illness is spreading that's all it is, is a matter of time. My entire family is sick and one has already died. Almost everyone I come in contact with knows at least on person with this illness. And nothing is being done to stop it. What hurts the most is the children that have been affected. You would think they would at least care about them.
>Jason, let's keep it simple. How do you account for antibodies to this retrovirus Mikovits found? Also, what would you say about the research showing a murine retrovirus spreading in a lab to human cultures and the warning that lab workers could be infected? (Please overlook my ignorance if the word "antibodies" is not correct. Hopefully you get my point and are aware of what I am writing about.)
Secondly, I have to add that my son at age 31 came down with severe vertigo and inability to stand, work or even drive. He did not have a fever or signs of a new infection. He got a diagnosis of untreated Lyme disease and recovered fully in about 3-4 months of oral cefdiner – not sure I am spelling that right. He then took GarliCell and Chinese herbs for a couple of years. Currently he is fine, works and travels all over the world. I write this simply to caution you that we are dealing with quite a few infectious diseases today for which there are not good lab tests. I hope you can find a cause and solution for your own issues. In case you think I am a nut case, I have to add that everyone in our family had many tick bites, and three of us got sick years after the last bite. The pathogens carried by ticks are difficult to diagnose and treat.
Might we also have a retrovirus? I don't know. We don't have a good test for that, do we? Please try to communicate with Dr. Lo.
>I'm glad Jason stuck around not only for the improved dialogue that has developed but also for the link to his blog, I'm a (former, before my health deteriorated too much) home brewer too & loved making APAs, my motto was there is no such thing as too much Amarillo :P
>You need evidence that XMRV was created in a lab Jason. No one has any. What are you know presenting?
1) Failure to name the only assay used to screen the later xenografts. Results of which are mixed together in Fig. 2E, but are said in the paper to be a PCR assay. At CROI Pathak admitted that this was an RT-PCR assay on RNA. Instead the only 2 assays named in the paper are PCR and quantitative real-time PCR (qPCR).
2) Failure to determine if the later xenografts came from the human prostrate cancer cell line CWR22Rv1 and if they were contaminated with cells from another cell line. This is despite testing other xenografts and cells to ensure the timeline of CWR22Rv1 was available and not contaminated.
3) Failure to base the results of the study and conclusion on the only assay that had a predetermined sensitivity (1-3 copies per 100 cells). The sensitivity having been determined after this assay DID detect VP62/XMRV in the early xenografts, two strains of lab mice and derived cell lines, 22Rv1 and CWR-R1
4) Failure to realize that other regions of VP62/XMRV require much more sensitive assays than the only assay with a predetermined sensitivity, the quantitative real-time PCR.
5) Failure to predetermine the sensitivity of the PCR assay on which all the results were based. Which then at best detected 2000 copies per 100 cells in the derived cell lines, but not in the early xenografts.
6) Failure to objectively name the 1 mouse virus discovered. Instead they choose a political name and called it PreXMRV-2, despite them not knowing if it could be a descendant of VP62/XMRV or even a cousin.
7) Failure to detect PreXMRV-1 in a single source. Instead it was created from sections of unidentified virus from 3 sources and therefore does not exist.
8) Failure to screen any wild mice for VP62/XMRV or PreXMRV-2.
9) Only screening 15 lab mice for PreXMRV-2.
10) Only screening 89 lab mice for VP62/ XMRV.
11) Stating that one set of primers used for the PCR assay, on which the results and conclusions were based, could also detect PreXMRV-1, despite having never detected this hypothetical virus from a single source. That same PCR with those primers then identified positives in the early xenografts, but was claimed to be PreXMRV-1, even though that assay could detect VP62/XMRV and PreXMRV-1 had still never been shown to exist.
>Trying to explain to Gerwyn why he's wrong is like trying to explain nuclear physics to a 3 y/o. It just won't work. Gerwyn is not only ignorant of virology, but he's so ignorant as to be ignorant of his ignorance. It's not an easy thing to escape.
>@Anon 2:09 AM
You are missing any explanation, facts, references, or sense to support your argument, and have in fact failed to put one forward.
>All studies using VP62 are discredited and should be retracted. VP62/XMRV has been proven to not be the viruses discovered in Lombardi et al. and confirmed by Lo et al.
Only two papers have been published on HGRVs and there association to ME/CFS. Both were positive.
>"All studies using VP62 are discredited and should be retracted. VP62/XMRV has been proven to not be the viruses discovered in Lombardi et al. and confirmed by Lo et al.
Only two papers have been published on HGRVs and there association to ME/CFS. Both were positive."
So you are saying that my paper should be retracted then? Because that's the plasmid and retroviral genome I used to study replication kinetics in prostate cells.
My larger point here is that there are a few posters that are calling for a retraction without actually understanding the science/methodology behind them. For example:
"1) Failure to name the only assay used to screen the later xenografts. Results of which are mixed together in Fig. 2E, but are said in the paper to be a PCR assay. At CROI Pathak admitted that this was an RT-PCR assay on RNA. Instead the only 2 assays named in the paper are PCR and quantitative real-time PCR (qPCR)."
I've said it before and I'll say it again. The data presented in the paper only needed to describe those two assays because that was the only thing published. The conclusions were based on genomic DNA samples, NOT RNA samples. Moreover, the RNA samples were contaminated with genomic DNA and doing RT-PCR assay would have been wrong. It doesn't matter whether he gave a talk and said something else that wasn't published.
Actually, all scientists do this when they give a talk, including me. For example, when I published my paper I gave a talk where I showed some data that I did not include in the paper and did not describe the assay. It was basically additional data that could not fit onto the article format. When I did describe my "phantom assay" in my talk I glossed over the details for my audience and gave the conclusions. This happens all the time and is what Pathak did.
I suppose this is not good enough though. Hopefully my VP62 paper won't be called for retraction… ;)
Jason
>Jason, sorry to hear about your Meniere's disease. I know from seeing my mom cope with it for years and years that it can be a very tough row to hoe. Thank you for your contributions to the discussion here and to virology research in your lab. Since being side-lined with CFS/ME I have a new respect for viruses (definite viral onset for me).
Jamie, your blog is a lifeline for me. Many many thanks.
Constance
>"So you are saying that my paper should be retracted then? Because that's the plasmid and retroviral genome I used to study replication kinetics in prostate cells."
A paper that has optimized to VP62 has optimized to nothing. It doesn't exist in nature as it was created from 3 sources. Those papers have failed to provide any evidence they can detect the viruses discovered in Lombardi et al. or Lo et al.
Regarding Paprotka et al.
"I've said it before and I'll say it again. The data presented in the paper only needed to describe those two assays because that was the only thing published. The conclusions were based on genomic DNA samples, NOT RNA samples. Moreover, the RNA samples were contaminated with genomic DNA and doing RT-PCR assay would have been wrong. It doesn't matter whether he gave a talk and said something else that wasn't published."
The results for the later xenografts (2152, 2524, 2272, 2274) in Fig. 2E were obtained with the RT-PCR assay on RNA that is not named in the paper, but which Pathak stated was used for that gel. Watch the video. The xenografts to the left of it, also Fig. 2E were the PCR assay that is named in the paper. That results in a retraction of the paper. The omitted the RT-PCR on RNA from Paprotka.
>If anyone is interested Paprotka et al. can be found here.
http://www.sciencemag.org/content/early/2011/05/31/science.1205292.full.pdf
Who reviewed it?
>"The results for the later xenografts (2152, 2524, 2272, 2274) in Fig. 2E were obtained with the RT-PCR assay on RNA that is not named in the paper, but which Pathak stated was used for that gel. Watch the video. The xenografts to the left of it, also Fig. 2E were the PCR assay that is named in the paper. That results in a retraction of the paper. The omitted the RT-PCR on RNA from Paprotka."
Incorrect. 2152 = RT-PCR assay. Other three samples, 2524, 2272, 2274 were from a genomic qPCR assay.
I've watched the video. Twice.
Also something for you to ponder. RT-PCR can mean two things. Reverse transcriptase PCR or real time PCR. It may be possible that Pathak was referring to real time PCR. I'm sure you won't believe this. But also be aware that when someone does a reverse transcriptase PCR this often involves real time qPCR. For example, I will reverse transcribe RNA then use the DNA generated from this for a qPCR reaction.
Ultimately, your agenda will preclude you seeing my point on this so I'm just going to give up. I guess that since my paper has been optimized to VP62 (I reconstructed the virus in the lab), it amounts to nothing by your arguments.
Jason
>@Jason
Vinay Pathak states the follow regarding the right hand panel of Fig. 2E.
“In contrast if we do RT-PCR of RNA derived from these late xenografts we can readily detect XMRV.“
Not xenograft, but xenografts. Plural. If it were only 2152 the assay would still be absent from the paper and there would be no link to XMRV/VP62 having been created during passage through mice. RT-PCR on RNA is not real-time Jason.
Paprotka et al. should be retracted for omitting the use of a third assay.
>There is science and then there is belief. Paprotka et al. should be retracted.
>The viruses discovered by Lombardi et al. and Lo et al. have been proven to not be VP62/XMRV.
>This section from Paprotka also proves they have no knowledge of if the later xenografts are from the same patient as the earlier xenografts, or if they are contaminated with other cells.
"We verified that the xenograft samples (736, 777, 9216R, 9218R, 8R and 8L) and the 22Rv1 or CWR-R1 cell lines were all derived from the same person by performing short tandem
repeat (STR) analysis at 7 loci (Fig. 1B and fig. S1). The probabilities that the xenografts and the two cell lines have
the same allele patterns for these loci by chance are 1.6 × 10– 13 and 6.3 × 10–13, respectively."
As you can see they never performed the STR analysis on the later xenografts. (2152, 2524, 2272, 2274)
The paper is full of big holes, beliefs and little science and minus 1 assay that was used. The paper should be retracted.
>Again with the Paprotka et al??? Truly, "The (Anonymous poster) doth protest too much, methinks."
Or, perhaps, equally appropriate, "a tale…, full of sound and fury, signifying nothing."
(Astute students may realize I am trying to be civil here by modifying the originals.)
>The evidence in the paper and the video of the conference are available to all for viewing. It is undeniable. Paprotka et al. 2011 should be retracted.
>Is there something wrong with Paprotka et al?
>Jason,
Because there are many overlapping symptoms and signs between Meniere’s and ME/CFS, you should investigate whether you may be in the early stages of ME/CFS.
From the Mayo Clinic:
http://www.mayoclinic.com/health/menieres-disease/DS00535/DSECTION=causes
Meniere’s Disease
Scientists have proposed a number of potential causes or triggers, including:
•Improper fluid drainage in the ears
•Abnormal immune response
•Allergies
•Viral infection
•Genetic predisposition
•Head trauma
>Thank you, Dr. Jamie. The information you share in your blog is priceless. When I read your words, I feel like I have a friend out there who understands what it is like to have this disease, and also has the training and expertise to interpret what is going on in the research and medical communities.
I understand that a lot of what you share comes from personal experience, and that much of what you say is opinion, not proven fact. You're very clear bout that. It's still helpful, like mulling over a problem with a friend.
I am delighted that you are able to work again, despite your limitations. I hope that someday that will be true for me as well.
Thank you for being here for us. You are a ray of light in a very dark time.
>I just have to repost this excellent comment from Mithriel. It is under the older blog by Dr. D-J. I wanted to be sure everyone saw it.
I have a forty year association with diagnostic microbiology and the entire XMRV/HGRV saga has perplexed me from the start. Much of the research seems aimed at disproving the result rather than looking at whether there exists a previously unknown threat to human health.
Many of the scientists involved seemed to have very little insight into diagnostic lab techniques or history.
PCR has many advantages, but its fatal flaw is it can only find what you are looking for.
Older techniques, like tissue culture could show you had something even if you did not know what it was, PCR does not do that.
A scientist at our local lab is doing research on the flu virus and has discovered that some have a mutation so that the diagnostic PCR is not picking them up. To believe that no reaction to the VP62 clone means no HGRVs in vivo goes against everything we know about how these tests work.
The flu virus is also detected in respiratory secretions, not blood. The first step to a reliable diagnostic test is to find the best tissue to examine. Animal studies showed that XMRV could not be detected in blood even when it was present in lymph tissue so negative blood tests are meaningless.
It took years to get HIV testing to the point it could be done routinely and even now new kits come along that don't work. Some viruses they can't get PCR for at all. Viruses mutate and patients can have slightly different ones. Primers have to be continually updated to detect all the variations.
The BWG group were not looking to see if HGRVs cause disease in humans, they were looking to find a test that could be done to screen blood donations.
I could go on but those are just examples of how the HGRV research does not seem rooted in the real world.
I am not committed to HGRVs being the cause of ME, but MLV type viruses cause disease in many mammals and it seems very unlikely we have not evolved our own version given the long human association with mice.
The whole thing seems like a mess with no one looking at the big picture, like claiming contamination was everywhere to disprove positive results, yet using all the negative studies as proof that no one was infected!
I don't think anyone believes that there is some sort of conspiracy in the entire medical profession but the organisations who should be looking out for patients, from the CAA, AFME to the CDC and NICE have done very little to improve our lives and often act in ways that makes us worse. There are politics at work where everyone is seeking a good outcome for themselves, whether it be grants or maintaining their reputation and status. Patient welfare is nowhere in sight.
Mithriel
>All the patient data in the gel from Lombardi et al. are CFS patients.
The 8th lane is of course the SFFV infected cells.
Normal only means they did not express virus.
>"Fig. 2. Expression of XMRV proteins in PBMCs from CFS patients."
>@Anonymous (V99?) October 12, 2011 4:10 PM
"All the patient data in the gel from Lombardi et al. are CFS patients. The 8th lane is of course the SFFV infected cells. Normal only means they did not express virus."
Oh please! Read beyond the first sentence!
The Figure in question is Figure 2C. If you read beyond the general description of Figure 2, you will see that the description for Figure 2C reads, and I quote LITERALLY from Lombardi et al.:
"(C)* Lysates of activated PBMCs from healthy donors (lanes 1, 2, 4, 5, and 7) or from CFS patients (lanes 3 and 6) were analyzed"
Thus, the HEALTY DONORS are in lane 1, 2, 4, 5 and 7, while the PATIENTS are in lane 3 and 6.
So please admit this silly mistake and delete this silly topic from the forums.
>And YES, the "(C)" that starts the quotation from Lombardi et al. in my post is not added by me but copied from the Lombardi paper, and it indicates that they are specifically addressing Figure 2C within the explanation of Figure 2, which is the "not germane 5-AZA" figure.
>Dear Dr. Jamie and Dr. Snyderman,
This is a bit of a rant, but everytime I read this blog I get a little confounded. You all keep saying this is infectious. I'd love to know what that actually means. Because you are also saying it takes up to 20 years for a partner to show symptoms, and that makes me wonder, how in the hell are you tracing causality. And where are you drawing the line? Fibromyalgia? Subclinical symptoms? What does that even mean? That's so vague as to be practically unintelligible. If it's spread that easily in tha lab, doesn't it stand to reason everyone is infected, or at least exposed, and then individual disease patterns depend on genetics, immune function, any other number of variables? Much like HHV6 or EBV. At one point Dr. Mikovits was talking about atypical MS. Are we now speculating MS or Lupus or Rheumatoid arthritis are also contagious, or due to a retrovirus? I know a bunch of discordant couples. He is healthy, she has CFS. Or she is healthy, he has fybromyalgia, and on and on. These folks are having kids, families, ecc. Some kids are healthy, some are not.
I guess my frustration with all this is that everytime you come back to this being infectious, it raises huge existential questions for those of us who are single. Do we get into relationships? What do we disclose? Do we plan on having kids? Every time the Autism link is mentioned, I also have questions, because it seems to me, there's lots and lots of autistic kids around who don't have parents or grandparents with CFS.
So, I'm not railing at you — I, along with you, would be so pleased if science would start moving to answer all these questions.
Yet, at the same time, I'm troubled by some of the assertions you seem to make, which, in the case of infectiousness, have sounded awfully vague and contradictory at times.
Would love to hear your current take on all of this right now.
>http://www.oslersweb.com/blog.htm
Can U Wait Another Twenty Years?
I know I can't!
>Much earlier Jason complained there was a claim that ME/CFS is an infectious disease.
Two things show ME is:
1. Many epidemics. This is also true for CFS.
2. In 1955 in Australia it was shown to be blood transmissible. This is so long ago I have not been able to get the paper. I don't have the reference handy, but it has been discussed many times and I have repeatedly found it on searches. The study involved using blood from ME patients and giving it to monkeys iirc. The monkeys then developed the same brain and spinal lesions that ME patients have, again iirc (its been a while since I read the abstract).
So we have known for 56 years that ME is a transmissible illness, and hence probably infectious, unless it can be shown the 1955 study was invalid. Since I have only read the commentary on this study (it was occasionally quoted) I don't have the capacity to assess how valid it was. Has anyone read the actual paper? Does anyone have a good reference handy?
In the last several decades it has also been shown that about 5% of CFS patients get sick immediately after a blood transfusion. How is this not due to an infectious agent? Is it some other factor of the blood transfusion, maybe a subtle immune reaction? Nobody knows, but taken with the epidemics and blood transmission, its highly indicative.
Bye
Alex aka alex3619
>You might be thinking of this:
The electromyographic picture would fit in well with changes noted when an agent was transferred to Rhesus monkeys from patients involved in the Adelaide epidemic (1949-51). — Parish (via bullybeef)
Parish JG (July 1970). "Epidemic malaise". Br Med J 3 (5713): 47–8. PMC 1700986. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1700986/?tool=pmcentrez&forumid=331851
Also this:
… The organic basis is clear – from the finding that the putative agent can be transferred to monkeys, the detection of an increased urinary output of creatine, the persistent findings of abnormal lymphocytes in the peripheral blood of some patients, the presence of lymphocytes and increased protein concentration in the cerebrospinal fluid of occasional patients, and the neurological findings” (BMJ 3^ rd June 1978). — Summary of RSM symposium, quoted in http://www.meactionuk.org.uk/The-Media-and-ME.htm