I believe this demonstrates a social ‘immune system’ in science which is remarkable for its ability to distinguish ‘self’ from ‘other’. ~ From my email
I feel like we are post-op. The patient got opened, the problem identified and resected, but the smallest movement produces a wince of pain. Still, it is becoming clear, there will in fact be a future. The dilettantes, fair weather friends, have all gone home, closed the shutters, locked their doors, and minds. Nothing more to think about. We have been easy to ignore for a long time. Now, it’s even worse than that. The scientific community is actually making fun of us in their ignorance, as is the CAA, our supposed representatives, who in 20 years have never managed to sound the alarm. If XMRV wasted some money, what about the CAA? If these scientists were truly objective, they wouldn’t all be so happy about the outcome. Mikovits, Ruscetti and Hanson, a very few others, are the only scientists in the world who know anything at all about the disease. And the fact that they care about us, doesn’t make them wrong. The rest of the scientists in this story are completely ignorant of the pathophysiology. Clueless, and not interested. Racaniello, ERV, commenter Jason, et al have not an iota of understanding about why simple retroviral disease is such a good fit. To them, it’s all about a test, not a disease. Money, glory, fame. Most certainly not about patients. They seem shocked to find out there are real people impacted.
The idea that it is better for the patient community if research into gamma retroviruses stops now, so that all the money can be spent on investigating the same old downstream effects and known pathogens, is a cruel joke.
From the limited anecdotal evidence we have, I’m pretty sure the response to antiretrovirals, even without specific drugs and without a PI, is better than placebo. The AIDS community doesn’t want to share their drugs, even though they are available to healthy partners and prostitutes for prophylaxis. Doctors who have already prescribed antiretrovirals are now, on the heels of the BWG results, refusing to refill prescriptions for their own patients who have improved on them! What could this be but politics and money? Why is the scientific community invested in creating a prohibition against these particular, not very dangerous, drugs? Why so much resistance to the idea of a retroviral etiology that they are gloating as the hypothesis takes a hit. Let’s have a party and burn Judy Mikovits at the stake. Glee. At our expense. Like psychopathic children who enjoy pulling the wings off insects. This, while babies are born with it, new cases are occurring every day and huge numbers of patients, already sick for decades, circle the drain.
The question of whether antiretrovirals are helpful or not and for whom, is a question that hasn’t even been asked, let alone answered. It is politics, not medicine, that prevents it from even being considered. The clinical piece still strongly suggests a retrovirus, or retroviruses. It is possible that it isn’t only gamma retroviruses. ALV’s, alpha retroviruses, do pretty much the same things as MLV’s. Although it is likely that ALV’s would be less infectious to human cells than MLV’s, because of phylogenetic distance from mammals, there is evidence in the literature, by none other than John Coffin, that suggests, under some circumstances, it is possible for ALV’s to infect human cells. But he didn’t think we should worry about it: Science Fiction? and Pure Speculation (I can see and hear the virologists, rolling their eyes and snorting, all the way from here). So what’s the motivation for making sure this hypothesis is found wrong? If it is right, it’s responsible for bringing down the health of the species, so some might be a little invested. But it’s so big, that saying it out loud makes you sound crazy. We have a possible source of infection: parenterally administered simple endogenous animal retroviruses. What else causes both neurological disease and cancer? Methylation issues, multiple gene activation in the same patient, persistent immune activation, multi-generational neuro endocrine immune disease. Think top down. What else does that? The fact that not everybody gets sick, that there are various opportunistic infections, that it goes in different directions in different people, that it is of variable onset shouldn’t be so bewildering. There is obviously a greatly increased risk of ME/CFS in the partners, children and parents of patients. Too much autism found in the same families. IT IS AN INFECTIOUS DISEASE. Where are the epidemiologists?
There have been lots of questions, people asking for clarification of the last two blogs I wrote. For the most part, if it was ambiguous, it is ambiguous to me, at least I wouldn’t personally testify to it, especially anything about who did what for the BWG. I don’t think there are any villains in this story. Only people who lost their way, sailing into open ocean in a dense fog without a navigator. People are fallible, and we are where we are because they never had a chance. Much of what ensued was like middle school more than anything else. Nothing sinister. No malice and absolutely no aforethought. It still has a middle school flavor to it, all the way to bullying in order to cover-up.
What I meant by saying that the XMRV testing that was done at VIP Dx is now null and void is that there were likely many false negatives and false positives; therefore it had no clinical utility. It cannot be interpreted. However, everyone knew that it was experimental. At the time, we were grateful to have it. Dr. Mikovits stands by the testing done at the WPI research lab. My understanding of her position is that she was not responsible for quality control or precisely which assays were used at VIP Dx, after the initial release of the test, when Cooperative Diagnostics made their bid for the market. If contamination occurred, it sounds like it wasn’t necessarily with VP62, but with the cultures from hot patients (like us). Apparently, what has been learned through all this is that the labs need to be using precautions required for Mycoplasma. Retroviruses have not been thought to be aerosolized previously, but now it seems, some probably are. There are two papers that show rapid spread through a clean lab in a couple of days, Zhang and Sfanos, linked on the sidebar. The serology is picking up proteins that are, if not actually to HGRV’s, at least very similar to MLV proteins. It has nothing to do with XMRV per se, and cross reactivity has not been ruled out. At least this is how it’s been explained to me, though I know very little about the technicalities of lab testing; more than I used to, but still not much. Therein lies a key problem, little sharing between doctors and scientists.
The slide issue seems like a tempest in a teapot to me, part of the same insanity that requires Judy Mikovits to be a perfect human being or all is lost. There is now an investigation, so in the end, we will find out what the designated judge says. What I would like to know is, how did Dr. Mikovits’s firing go from ‘insolence’ to ‘fraud’ from Thursday to Monday? Dr. Mikovits was fired on September 29 and ERV blogged her over the top accusations on September 30, I’ve been told, though I still have not been to her blog (thousands have visited mine from her site). Who fed it to her? The editors at the Chicago Tribune should be ashamed that Tsouderos was taken in. Nothing more than tabloid journalism. For the record, I waited three days after Dr. Mikovits was fired, before I wrote anything. By then, it was clear to me that it had been decided that Dr. Mikovits’ reputation was the price of the WPI’s survival and my inbox was full of unanswerable letters. I said nothing for a very long time, hoping for a different outcome. Also for the record, I did not send any letters to the press. Trine Tsouderos wrote to me and asked me what I meant by lock-down. I told her “The personnel was locked out of the lab.” (proof of which is on my computer). Nothing else came from me.
Obviously, something went very wrong. Most likely lots of things did. I know Dr. Mikovits would like to have the chance to figure out what. I think the probability that what went wrong was a ‘fraud’ committed by Judy Mikovits is at the very bottom of my list of possibilities. I know her personally and it seems beyond improbable. Inevitably mistakes were made and everyone on the planet has something to hide, so, poor Judy, and poor everyone else involved.
I hope to never be an insider again. Two people have asked me how I could have forgotten what the Whittemore’s did for me. I have not forgotten, but they seem to have forgotten what Dr. Mikovits did for them. I was videotaped for the WPI saying they had saved my life, and it was true. I said nothing, except that I had been fired; I said that because I wanted to distance myself from the decisions being made there. But then Dr. Mikovits was fired. If I hadn’t written anything, Trine and ERV would have had the only say. But I am not going to engage in any further mudslinging going forward. I am now supposed to apologize to this one and that one, who was right because the interloper has fallen; the WPI was wrong and I stood behind them. I was a starry eyed kid then, believing that the cavalry was actually coming over the hill. I am a battle weary soldier now, having taken a few arrows in the heart. I no longer think the cavalry is coming at all, any time soon. Also, I still think that all the people I mentioned at one time or another on this blog in a negative context have behaved very badly, even if everything the WPI ever did is wrong. It’s not black or white. It never was and it never will be. The patients are the ones that get screwed, over and over again. CAA, the most divisive force in our community, HHV-6 Foundation, WPI, it doesn’t matter. Loss and more loss.
So, “Cheshire Puss… Would you tell me, please, which way I ought to go from here?”, said Alice to the Cheshire Cat.
Since I am feeling like my change the world phase is over, as Kita said, what next? My job now is to interpret the events in terms of their clinical significance, one on one. Primum non nocere is my guiding principle, as it was for my first 25 years of practice. When possible, I include the pocket book in that. It is curious what insurance will and won’t pay for, having very little to do with what might produce results with the least risk of harm. In my practice, I am using only LabCorp and Quest for labs. I am no longer interested in results from labs that have a stake in the results.
My attention is on my daughter, as it has been all along. She was “Harvard material”, as my step-father, a Yale/Harvard educated surgeon, said before he died of the late effects of treatment of his Gleason 9 prostate cancer. Ali still might succeed at having a life with the right physical and social support. For a long time I have envisioned a collective with the goal of creating a supportive, assisted living environment for young people with CFS. It is clear to me that I will be dead before there is treatment that approaches a functional cure. Whether you think arv’s are a good or bad idea, we are both doing well on them. Ali is engaging her life again, dating, going out, shmoozing with her illness. Not suffering much at all. Last time she was at this point, she did too much too soon. She is wiser now.
She is very responsive to the right treatments, now that we know what we are treating (not a specific pathogen, but still a context and approach to the illness). Folinic acid is hot stuff for her, Leucovorin 10mg IV weekly for a while, and now she is playing with the oral form, finding some of the same side effects as with Deplin. It appears to build up over a period of time, days to weeks, and cause dose dependent sleep disruption. But some amount helps the overall picture. I am hearing similar things about Deplin from patients. Important initial response, then dose related insomnia, sometimes still with improvement in other things. For Ali, the amount of folic acid derivatives required for positive effect without sleep disruption seems to be decreasing with improved wellness. So she’s tinkering. Next stop, 5-MTHF. I’m starting to order MTHFR mutation testing on my patients (MTHFR Thermolabile Variant DNA Analysis at LapCorp and MTHFR DNA Mutation Analysis at Quest).
She continues to use oxygen with great regularity. We both find it useful for rescue, as well as believing that it supports our recovery, which seems steady and real, but slow. There was a single comment a while back that oxygen had been bad for someone, but without specifics. I want to hear about any problems, since I’ve been advocating its use. I have a lot of experience prescribing oxygen as a hyperbaricist and the risks, without adding pressure, are so minimal as to be almost non-existant. You can always turn it off, after all. Long term, there may be a risk of accelerating aging. That’s all I can think of. I can’t really come up with another reason not to try it, but I certainly want to hear it, if someone has something to add to the discussion. So far, practically speaking, my patients are liking oxygen. It is representative of the insanity in all this that patients can have Fentanyl patches for years and years, but can’t try an oxygen concentrator.
My illness is pretty much refractory to everything, except being positively engaged. For me, helping helps the most. I do best when I don’t mess with it much. I was the sickest when I was taking the most drugs. Antiretrovirals are one of the few things that actually seemed to move me. I sent specimens to the WPI regularly during first year of our experiment. Dr. Mikovits had evidence of our positive response to antiretrovirals, at least initially. I wonder where those specimens are now? I’ve tolerated 5 trips to Reno and 3 to Hawaii in the last 13 months. Pretty good for an ME/CFS patient who had been desperately ill twice in the previous few years. It is becoming clearer and clearer that I do feel better in Hawaii than Santa Fe. I think for me it is the elevation, because Santa Fe is one of the cleanest cities in the country, Los Alamos aside. However I’m hearing from lots of people that say they felt better in Hawaii but who live at sea level (and others who didn’t get better there of course). Some of those people live in really polluted places, like LA and NYC, so that may be the greater factor for them.
I am in complete and total agreement with the mold warriors that environment is critical to success, defining success as the patient’s maximum possible wellness within the context of an incurable, but remittable disease, though my idea of environment is much broader, not just avoidance, but feeding the positive, including strengthening the spirit. Stress makes us sick. My fantasy kibbutz would be organic, as chemical free as possible, MCS friendly, and of course as mold free as achievable. But as important, would be an opportunity to be alone, with necessary help, or to be able to with others who understand and support. To be able to go out, but not fear ruining it for everyone else, if assistance is needed. To not have to apologize for existing. I see the mold warriors insistence that I am the enemy as a microcosm of what anybody with this disease who finds a way out feels. Huge frustration that they aren’t being heard in the face of immense unnecessary suffering. It’s just that from my perspective, hearing from people from the full spectrum of the ME/CFS community, it’s one of many factors, most important for some, but not so much for others.
Almost the most important thing that didn’t happen at the WPI clinic was the use of an electronic EMR by multiple clinicians, so that a large database would be created, which would ultimately be searchable by any parameter chosen. I am using Practice Fusion, free cloud based EMR. It is brilliant. It can only improve patient care for doctors using it. Converting from another method of documentation is difficult, but it’s not insurmountable. It’s possible that physicians might be able to contribute to the creation of a large patient database anyway, even though they are not physically in the same place. I mentioned a particular test above; it is beyond time that clinical research (pardon the oxymoron) was happening in a broader context than one physician’s practice. Thinking about this, and what might be still be possible…
Tonight’s song: Closer To Fine
>@ Anon 7:38, the PACE trial is a horrible example of how to measure disability in this illness. The only objective measure involved steps counted on a six minute treadmill test. It did not do a second day test, therefore it did not take into account post-exertional worsening of symptoms which typically occur hours to days after activity. These are the biggest barrier to functionality in this disease and distinguishable from normal fatigue or fatigue from other health problems.
Early on in Jamie's blog, she spoke more specifically about her improvements month by month (whereas now it has become an outlet for her observations and political views). The information you want is there. She spoke a lot about the PEM and how it has improved for her, and used a functional scale. I suggest you read some of the earlier posts.
>@Jason
"1 – XMRV/gammaretroviruses are causes of human disease including CFS but that conspiracies by the government, big pharma, academic virologists, and now even WPI and CAA are working to deny and suppress this knowledge."
What has your conspiracy got to do with a proven association?
>Jamie,
Just four months ago, on this blog, you engaged in an all-out attack on Dr. Dan Peterson, doing everything that you could to decimate his reputation in this community.
Your stated reason for doing this was because of his participation in the Knox 2011 paper in Science, which found no evidence of XMRV in CFS patients.
http://treatingxmrv.blogspot.com/2011/06/whodunit.html#comments
http://treatingxmrv.blogspot.com/2011/05/sad-day-for-patients.html#comments
Now, the BWG study has been released. None of the labs were able to find any association between CFS and XMRV/MLV’s. As with the Knox study, most of the labs found no evidence of MLV’s in any of the samples (except the purposely contaminated ones). WPI found MLV’s randomly in controls and patients, and was unable to properly identify XMRV when it was present as a result of contamination.
Thus, it seems that Peterson has been vindicated. He participated in a legitimate study that produced results that have allowed the science to move forward.
The goal of science is not to validate a truth that we want to exist. It’s to objectively evaluate the truth that actually does exist.
Thus, it seems that Peterson acted honorably, as a scientific researcher is supposed to act.
In addition, Peterson has worked unceasingly for the benefit of CFS patients since the Incline Village epidemic in 1984, doing his best to fight against the trivialization of the illness by the CDC and helping at least some severely ill CFS patients to experience carefully documented improvements.
You, on the other hand, have thus far done nothing for the CFS community except to write this blog, which seems to mostly exist for the purpose of attacking everyone in sight.
It's time for you to offer Peterson an apology.
>All the problems with the blood working group are in the paper.
In the blood working group study there were several major errors made in the organisation of how it was conducted.
1) All controls were not screened by all labs.
2) Patients were taking drugs that would produce false negatives.
3) No Trizol or equivalent preservative was used on the PBMCs, which would prevent the WPI's assay from working.
4) Length of time allotted for the serology and culture assays was massively reduced, so they were again not using the WPI or NCI/Ruscetti assays.
5) Collection tubes were kept in the same lab as 22Rv1 used to spike the analytical controls.
6) Lo's team used the wrong assay from Lo et al. and instead used the one that could not detect positives.
7) None of the controls had their PBMCs screened prior to blinding, so none could have been ruled as negative.
8) The WPI was not given the opportunity to complete the culture section of the study.
9) The NCI did no PCR and as we know could not use their clinically validated serology and culture assays.
10) All other labs optimised their assays to VP62, never once showed they could detect a clinically positive sample. VP62 does not exist in nature and Lombardi et al. is now known to have discovered HGRVs. Some of those HGRVs will be found to have a xenotropic host range.
>@Robin Durham,
The last time that someone asked Jamie to document her improvements, she wrote the comments below. The other recent comments have all been along the lines of "I improved, so retroviruses cause the disease."
If she's going to continue to use her improvements as evidence, she needs to document them at the same time, so that people who only occasionally (rather than obsessively) read this blog are able to evaluate them.
*
I experienced an exacerbation of symptoms for a couple of weeks, after a period of great stress. As can happen with this disease, my mood was affected, and I thought it might be coloring my judgement.
I went off Isentress as a wash out, planning to start AZT or Lexiva again, probably the latter. I want to get baseline labs before doing anything else, but have to go back to Santa Fe to do that. I'm taking the red eye home tonight.
I think most ME patients know what being all over the place means:).
I believe that we were helped by arv's, but I can't prove it.
>@10:27
Neither Judy Mikovits nor any other researcher working on the BWG paper has issued an objection to its methodology. If we do that, then it can be properly evaluated.
If they don't do that, people reading this blog should not be doing it for them.
>No study has attempted to replicate and every study that used VP62 is now dismissed. As they have now show the viruses discovered are not VP62 and VP62 has never, by anyone, ever been found to exist.
With silvermans retraction the people running the 00 studies have huge problems.
The VP-62 sequence is now known not to correspond to the gammaretroviruses detected by Lombardi et al. It is also known that Silvermans primers are capable of detecting the VP-62 plasmid but NOT capable of detecting the gammaretroviruses which exist in the Lombardi CFS patients. The WPI and NCI tried to use Silvermans primers on the patients who tested positive for their nested PCRs but could detect nothing. A great number of studies used Silvermans primers alone or in combination and thus their negative findings are invalid.
The slide being so viciously attacked demonstrates that the viruses are normally in a latent state, which is maintained by methylation of the provirus.
Remove the methyl groups as shown by the experiment in the slide and the virus becomes active.
So what! everyone says.
Well, the virus or viruses are integrated into G-C rich areas called CpG islands. These are extremely difficult if not impossible to amplify using standard PCR approaches.
Any PCR which has been adjusted to detect the VP-62 clone in a spiked sample would not have a prayer of detecting a human MLV-related gammaretrovirus integrated into such a region even if the virus did have the same sequence as VP-62, which they do not.
Thus, the combination of Silvermans retraction and the discovery that demethylation can activate the virus or viruses in question completely invalidates ALL the negative 00 studies.
The enemy must get Lombardi retracted at all costs before the scientific community as a whole realize that.
permission to repost granted
>From my post at 10:31
>If we do that, then it can be properly evaluated.
Sorry, that included a typo. Rephrase:
"If any of the researchers who worked on the BWG paper issues an objection to its methodology, experts then can evaluate the objection in a systematic manner."
Others (especially anonymous people) have no business doing that at this time.
>Anonymous @ October 10, 2011 12:36 AM said…
"All the problems with the blood working group are in the paper. In the blood working group study there were several major errors made in the organisation of how it was conducted." I am not a virologist. In an attempt to educate myself on the issues, I have some questions regarding the BWG study:
1) "All controls were not screened by all labs." Didn't all labs get the identical panel, a blinded set of pedigreed positives and negatives?
2) "Patients were taking drugs that would produce false negatives." The same drug or class of drugs by all the pedigreed positives? Same dosages?
3) "No Trizol or equivalent preservative was used on the PBMCs, which would prevent the WPI's assay from working." Isn't Trizol a chaotropic
denaturant? Wouldn't it have dissolved any intact PBMCs, thus rendering culture nugatory? I thought Trizol was only used when intact RNA was required.
4) "Length of time allotted for the serology and culture assays was massively reduced, so they were again not using the WPI or NCI/Ruscetti assays."
Doesn't WPI's culture protocol require 60 days? I think this was an understandable logistical constraint. Also, doesn't the report indicate that WPI could not report any culture results because of mycoplasma contamination?
5) "Collection tubes were kept in the same lab as 22Rv1 used to spike the analytical controls." If true, a lapse. But then wouldn't there have been many more false positives reported by more labs?
6) "Lo's team used the wrong assay from Lo et al. and instead used the one that could not detect positives." If true, why did the Lo lab do this? Wouldn't they use the same assay they used in the PNAS paper? Why would they deliberately sabotage themselves and call their earlier results into question?
7) "None of the controls had their PBMCs screened prior to blinding, so none could have been ruled as negative." Regardless of pre-screening, shouldn't all labs have reported identical results for all samples in the panel, false or undiagnosed positives and negatives alike?
8) "The WPI was not given the opportunity to complete the culture section of the study." The report says WPI had mycoplasma contamination, which I understand is quite common everywhere in spite of precautions taken.
9) "The NCI did no PCR and as we know could not use their clinically validated serology and culture assays." Does this mean NCI/Ruscetti? Or NCI/Hewlett? And if a lab didn't do PCR, and couldn't perform serology or culture, then what additional detection assay was used?
10)" All other labs optimised their assays to VP62, never once showed they could detect a clinically positive sample. VP62 does not exist in nature and Lombardi et al. is now known to have discovered HGRVs. Some of those HGRVs will be found to have a xenotropic host range." Weren't the PCR primers designed to amplify conserved regions on gag, pol, env, etc. supposedly similiar across the whole retroviral spectrum? (I have always wondered how anything new can be discovered using exisiting PCR primers or antibodies that require some knowledge of sequence or some idea of the protein being sought. Aren't retrovirologists constrained to looking for similiar organisms because they are limited by the tools at hand that only detect known sequences or structures?)
Thanks for keeping us informed. Those of us untrained in the Dark Arts of retrovirology can find the field daunting.
>1) Didn't all labs get the identical panel, a blinded set of pedigreed positives and negatives?
No. There were no pedigreed negatives in the study.
2)The same drug or class of drugs by all the pedigreed positives? Same dosages?
They were on drugs known to cause false negatives.
3)denaturant? Wouldn't it have dissolved any intact PBMCs, thus rendering culture nugatory? I thought Trizol was only used when intact RNA was required.
Preservative
4) If true, a lapse. But then wouldn't there have been many more false positives reported by more labs?
That is no lapse. So now you are in agreement that Lombardi et al and Lo et al. are not contamination.
5) If true, why did the Lo lab do this? Wouldn't they use the same assay they used in the PNAS paper? Why would they deliberately sabotage themselves and call their earlier results into question?
Lo's team made the mistake.
6) Regardless of pre-screening, shouldn't all labs have reported identical results for all samples in the panel, false or undiagnosed positives and negatives alike?
No, as they were using different assays and none of assays were those diagnostically validated. As controls were not all screened by all labs and none with PBMCs no one has any idea who had what. Then there are all the labs looking for VP62, which does not exist and not the viruses Lombardi et al. discovered. This is also a gammaretrovirus and some will have an immune response, some will not.
8)The report says WPI had mycoplasma contamination, which I understand is quite common everywhere in spite of precautions taken.
They were still not allowed to finish.
9) Does this mean NCI/Ruscetti? Or NCI/Hewlett? And if a lab didn't do PCR, and couldn't perform serology or culture, then what additional detection assay was used?
Ruscetti's is the only lab apart from the WPI and Lo's (which they were stopped from using too) with a diagnostically validated assays. They were not allowed to do their culture or serology either.
10)Weren't the PCR primers designed to amplify conserved regions on gag, pol, env, etc. supposedly similiar across the whole retroviral spectrum? (I have always wondered how anything new can be discovered using exisiting PCR primers or antibodies that require some knowledge of sequence or some idea of the protein being sought. Aren't retrovirologists constrained to looking for similiar organisms because they are limited by the tools at hand that only detect known sequences or structures?)
All assays must be optimized, or they are guessing. VP62 does not exist. Lombardi et al. used the basis of Silverman's discovery and made one of their own.
>HGRVs are integrated into G-C rich areas called CpG islands. These are extremely difficult if not impossible to amplify using standard PCR approaches.
Any PCR which has been adjusted to detect the VP-62 clone in a spiked sample would not have a prayer of detecting a human MLV-related gammaretrovirus integrated into such a region even if the virus did have the same sequence as VP-62, which they do not.
>First off, a gracious (if belated) thank you to our host, Dr. Deckoff-Jones, for allowing all of us (Anonymous cowards included) to discuss pretty much anything pretty much ad naseum and for turning her blog into a "Retrovirology For Dummies" forum. Also, thanks for the Indigo Girls link at top, it's been many years since I listened to them (and now, of course, when I get home, I will have to tear my house apart to try and find my CD collection–thanks!!)
I am glad I'm not a retrovirologist, because I would suck at it. Seems impossible for anybody, on either side of the matter, to deliver any definite scientific conclusion one way or the other, because the entire process is fraught with an infinity of uncontrollable hidden variables, hurdles, pitfalls and complications, some known, most hidden. Look at the debate so far–they can't even agree on what to disagree on! (Contamination? Novel hitherto unknown retroviruses? Laboratory artifact propagated through lab mice? Primers either too specific or not specific enough? Antibodies cross-reactive or non-reactive to novel antigens on a Western blot that may or may not have been treated with 5-AZA? What a mess.)
I still cannot wrap my feeble mind around how any truly novel virus can be discovered using tools that are based on knowing what to look for: PCR primers have to be made against a known sequence in order to spcifically amplifiy it; antibodies have to be made that bind to specific antigens. It's very much like generals fighting the last war–how can anyone claim to have found anything totally new and different if the tools and reagents are specific for what is already known? Lombardi et al. used antibodies for SFFV, which sort of assumes that whatever you find, even if novel, will be similiar, probably to a very high degree, to SFFV, correct? (Or am I missing something fundamental here?) It's a chicken-vs.-egg issue: how can anybody find anything truly novel using reagents and tools that depend on having some pre-knowledge/bias of what to look for? I can understand how these tools would be useful for
finding simliar viruses, but how can anyone claim that these specifically limited tools and reagents can find dis-similiar stuff?
>I just heard a great re-framing of "insane". Try this: In Sane.
The other thing I remember hearing is that to be considered insane in a culture and society as dysfunctional as this one appears to be should be considered a compliment.
What *is* it with the incredible, instant vicious attack from so many "establishment" directions that occurred as soon as the Science paper appeared? It's the elephant in the living room. Why is this happening (again, since I remember so well the 1991 fiasco with Dr. DeFreitas)and who is so freaking scared that they are pulling out all the stops to suppress not only the new research but the patient community as well? Who would prefer us silent or dead to discovering and announcing the truth of causation and treatment in the face of such suffering?
It is true that these are such early days and dead ends and redirection should be expected. That's the creative investigative process.
There have been sporadic attacks on patient populations over the years out of ignorance (MS comes to mind) but this is institutionalized and organized. It hits every note on the scale from gov't institutions to the co-opting of the CAA by the CDC etc. long ago, to almost professional trolls showing up on blog comments spewing vitriol. (The latter are getting more and more obvious and unsophisticated, too.)
This fuels the in-fighting to create so much distraction that our community is halted in its tracks. The community's rightful response of anger to such abuse is then used to further denigrate us, creating a downward spiral. This is a classic tactic, and so obvious. Why?
I think this multifaceted attack is part of the reason that so many of us were hit so hard – it seemed to come right out of the blue. The usual debate and back and forth is reasonable, but this?
This has turned into a war, and a shooting war at that, but what the war is about hasn't been truthfully declared. I'm angry that the people who truly care and are directly involved are casualties of this process. The "collateral damage" (what a disgustingly misleading euphemism) is painfully visible and from my perspective at least, completely unnecessary.
I'm so glad your moderate, compassionate stance is articulated here, Dr. Jamie – it's like a candle in the window when you're walking around in a howling storm. Thanks again.
>"the entire process is fraught with an infinity of uncontrollable hidden variables, hurdles, pitfalls and complications, some known, most hidden."
It's not. People only have to control their variables.
"Western blot that may or may not have been treated with 5-AZA? "
The western blot was treated with AZA. It was not germane to the paper.
"I still cannot wrap my feeble mind around how any truly novel virus can be discovered using tools that are based on knowing what to look for:"
The way HIV and HTLV were found. In this case it was time to see if Silverman's XMRV or a related viruses were associated. They applied what Silverman had shown to work and adapted it based on published research of how gammaretroviruses behave and what is likely to cause the signs and symptoms of ME.
>"Lombardi et al. used antibodies for SFFV, which sort of assumes that whatever you find, even if novel, will be similiar, probably to a very high degree, to SFFV, correct?"
The anitbody to the SFFV will identify polytropic and xenotropic MLV viruses that are causing an immune response, but will not react to endogenous mouse or human viruses
>Thank you once again Jamie for writing your blog. As Wild Daisy said, without your writing we all would be so much more in the dark . In previous ME battles, we, the patients have never known the goings on behind the scenes – we were mushrooms – given the PR spin. Elaine is ill, Mike Holmes became ill. Please don't let Judy become ill. I hear the good news today that Judy retains her grant, cell lines and has already been offered a job in Canada. Lets hope she will be able to work uninterrupted as resolve finally what the role of HGRVs are in our illness and hopefully how to treat them best. Jamie, you and Dr Snyderman help all us patients immensely. It is because of the internet that we are no longer the mushrooms many would like us to be. never give up the good work. Love to you, Jill
>"I hear the good news today that Judy retains her grant, cell lines and has already been offered a job in Canada."
oh Jill! Thank you! Thank you! Thank you! We needed some good news.
>It is so weird for me, as a seven-year veteran of ME, to hear about a "war" being waged on our patient community. (Well, if I lived in the U.K., I think that would make sense to me, because the NHS really does persecute patients and doctors there.) But here in the U.S., I just am not feeling it. I am horribly frustrated by the way the CDC has historically muddied the waters by renaming the illness and redefining it to include all sorts of tired and depressed people. And I am frustrated by not being able to find competent doctors who understand my disease.
But so much of what has happened here seems to me to have arisen from ignorance and from the real difficulty of diagnosing the illness and from the whole culture of medicine. Doctors never do listen to patients very well. Or at least, it is very rare for them to listen well. We ME patients hardly have a lock on this one. Doctors are trained to look at test results rather than to believe their patients. And I'm sure there are plenty of patients who are vague or misleading or confused, which of course makes it hard for doctors to know what to listen to and whom to take seriously. Some patients, including a good number participating on this blog, express a sort of certainty that could make your head spin.
I think this illness is a potentially fascinating one for scientists, because the problem of post-exertional illness should have implications for the study of energy-production in general and therefore should be useful in understanding many other disease processes. I honestly think that as scientists hear more solid information about the illness, it will become a topic of real interest. I am grateful that Mikovits' research, however flawed, has brought the illness to the attention of prominent scientists, because I imagine it will have caught the imagination of at least a few good minds. I only hope the XMRV "fiasco" won't have poisoned the well for scientists seeking research funding.
Personally, I hope that not all the research eggs are put into the basket of retrovirus research, because, although it seems a plausible enough hypothesis, I believe there are also other possible causes. And in any case, there may be valuable avenues to pursue in treating symptoms. For example, if "PEM" could be treated, many of us could probably get back to a pretty normal life. So I am really hoping that, in addition to research into possible infectious causes, there will be research into the malfunctioning of the energy production cycle.
I think the best thing that has happened for the ME patient community in quite some time is the new definition emphasizing PEM (or PENE), because this gives doctors and scientists something definite to focus on and because answering this piece of the puzzle would alleviate a huge amount of suffering.
Meanwhile, I am sick and tired (LOL) of all the talk of "war" and conspiracy. There is plenty wrong with our system of medicine and pharmaceutical research, and some of what is wrong with it leads directly to the kind of bad treatment or lack of treatment that we all face. (And of course, the ludicrous name "chronic fatigue syndrome" has only multiplied our problems.) But if anyone thinks there is a widespread urge among doctors and scientists to keep sick people miserable, then I think you're pretty nuts. (The NHS is another matter, because they have obvious and direct budgetary motivations to minimize most treatments for most illnesses, and very little flexibility built into the system. It's a scary, one-size-fits-all, system.)
>Yeah! Hope she accepts to come here to Canada! Preferably my city!
>Depending on where you are and when you read this: Good morning/day/evening/night to all!
I love what is happening here. I don't always agree with statements made, and sometimes find the random rambling that happens to be irksome. BUT, in all honesty, it is a wonder to behold. Dr. JDJ started a blog about her own personal experiences as a mother and patient-healer. Here we are, though. Guests uninvited. Muddy shoes all over the white carpet. And Anon 7:37…thanks for your incredibly bold sense of entitlement. When I first read your words, I almost chocked on a giant gasp of air. You might ask the doctor for her social security number too–you know…since she's sharing and all. There is some good in what you did, though. It has encouraged me to step up my own game a bit and use boldness as a tool, without becoming a tool.
What I came here to say is simply this: we are like little feverish ants; you can see minds at work and knowledge being exchanged. Too often progress is indiscernible, even more so with this disease. As a community, though, we are growing stronger by the day.
>Silvermans primers, that a few studies used but which had never worked for Frank Ruscetti/NCI and Judy Mikovits/WPI, are no longer relevant. That research no longer applies to the ME/CFS findings. Those studies no longer have any relevance.
VP62 does not exist, it was made from 3 sources.
Detecting a clone that is happily moving about the blood is easy.
Detecting an integrated virus that like CpG islands is very very difficult. Totally different PCR variables must be used. Studies that used VP62 no longer have any relevance.
All studies that found nothing are irrelevant to Lombardi et al and Lo et al. The two positive HGRV papers.
>Joseph said:
"What is the more parsimonious explanation?
1 – XMRV/gammaretroviruses are causes of human disease including CFS but that conspiracies by the government, big pharma, academic virologists, and now even WPI and CAA are working to deny and suppress this knowledge.
2 – Dr. Mikovits' findings were confounded by contamination.
Sometimes, in science and medicine, we have to abandon our convictions in the face of new data.
There was a time, not long ago, when just everybody new that postmenopausal women needed to take replacement hormones to reduce their risk of heart disease. Until the data showed that wasn't the case. Many physcians and researchers were surprised by that finding, but medical practice changed very rapidly in that field in response to the new data…."
As I recall, Wyeth (which was sort of a big pharma) suppressed the bad news about hormone replacement therapy. It was a whole big thing.
>Let this all play out, research go on and study the results. I'm glad that Judy Mikovitz retained her grant and cell lines and has a place to study them.
The outrageous attacks that began as soon as the Science 2009 article came out shocked me. Is this how research is seen that might or might not be right? It is entitlement and the height of arrogance to go on the offensive like that.
However, drugs to treat cancer and treatment protocols are tested: some are good, some not, even about lots of money has been spent on research and development. No media or researcher attacks on those studies or researchers. So I think sexism plays a role, and also the worst arrogance and competitiveness.
How about scientific objectivity? And sharing methods, data, working cooperatively to figure this out.
I have no opinion on the HGRV issue. I'm open and waiting and watching.
We have to keep up the pressure on research and publication of findings, and then see what happens, but we cannot let up.
I do think Mikovits' research, and even the controversy, brought our disease out of the closet and to public view. People learned about CFIDS. Friends of mine who never discussed this with me, sent me the Science article. It validated this disease for several people.
And it opened up the eyes of many researchers and doctors. I don't think Ian Lipkin would be involved if the last two years hadn't happened with controversy.
I do think the CDC does not want this to have a viral cause, due to possible panic about it, as happened with HIV, which they did suppress research and news about in the early days. ACT-UP helped push on this.
Also, I think the government does not want to cough up the funds for the research (much is now being paid for privately by the Hutchins fund), nor pay for medical coverage or disability benefits. I think there is a financial factor, yes, especially now when massive cutbacks are coming on Medicare and Medicaid. (Five states, I think, are putting poor people now on waiting lists for AZT, 9,000 I think, and some are dying. That is criminal!
No one has to believe anything, and can have their own opinions. No one is imposing beliefs on anyone. This is an interesting and informative and compassionate blog. One can choose what to agree or disagree with.
But basic civility is needed.
And because this arguing and tone aggravates my CFIDS symptoms immediately (arm pain, headache, etc.), I'm not going to read any anonymous posts or anything hostile.
Someone is doing a nice thing by creating, maintaining and offering us information and a place for discussion at this blog.
Let's be respectful and kind. Is that so much to ask?
We should be appreciative.
>Um sorry to burst bubbles. Just shouldn't be telling people things before they are in stone. I'll beT you dollars to donuts WPI ends up with the grants. Especially because Dr. Mikovits is in breach of contracts.Oh and she's being investigated.
>Frank Ruscetti and Judy Mikvoits used the slide with the real patient codes. They changed the codes to protect anonymity of patients as per ethical requirements. Frank Ruscetti and Judy Mikvoits have been falsely accused.
Abbie Smith has images on he blog that could never have been produced from the published gel or slide. Frank Ruscetti and Judy Mikvoits can use sunshine laws to access her university computer.
The more parsimonious explanation is 1 as there is no scientific evidence of contamination in Lombardi et al. or Lo et al.
>All 00 paper are now irrelevant.
All studies that optimised to VP62 are irrelevant.
Silverman's primers are now irreverent.
Detecting a clone is not like detecting an integrated provirus that has an affinity for CpG islands. Standard PCR would never be capable of detecting those viruses.
All the negative papers have no relevance to HGRV research that Lombardi discovered and Lo confirmed.
>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
>Another thought, since testing has always been difficult, HGRVs are not easy to find, a good idea would have been to do a trial of ARVs where all the parameters that Anon demanded of Jamie, could have been documented.
Since ARVs are already being used prohylactically to give them to the sickest of patients, especially those closest to suicide, in the same way new drugs are given to very ill cancer patients, does not seem to big a step especially if patient welfare was important.
I found it interesting that those shouting loudest they were saving patients from the dangers of ARVs were those handing out antidepressants proven to be useless in ME and shown to have profound side effects.
Mithriel
>ARV drugs have many modes of action.
They have a profound effect on nf-kappaB and inhibit mitosis.
Thus they would inhibit retroviral replication by clonal expansion as it would inhibit clonal expansion.
Without nf-kappa B immune system switches off and microglia cannot stay activated.
>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.
>some more atrocious science
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?