Sunday, April 17, 2011
Whoever organized this conference has no coherent idea of what’s going on in this illness. Granted, there are many gaps in our knowledge, but there are also some pretty consistent themes that are well-recognized, at least by the patients and by some of the doctors that take care of them. Most people have post-exertional malaise. Most have sleep difficulties. Many, if not most, have one of the several manifestations of orthostatic intolerance or other autonomic nervous system dysfunction. Most have evidence of immunological dysfunction. Most have one or more viral infections. Some have other pathogens. Most have pain. Many have associated conditions such as irritable bowel syndrome, interstitial cystitis, fibromyalgia, multiple chemical sensitivity and pelvic pain syndrome. Most have neurocognitive problems, including memory loss, sensitivity to noise and light, word-finding difficulty, executive functions abnormalities. Many have muscle twitching or cramping. Many have low blood volume. And so on.
The Workshop was designed to confuse not to enlighten. This may have been deliberate, or it may be because the organizers (and who are they? Dennis Mangan? Suzanne Vernon?) simply don’t understand the disease well enough to organize it appropriately. They repeatedly said they were interested in reverse translational research, from the patient bedside to the lab bench, but they organized the conference according to medical specialties and research areas: infectious diseases, neurology, exercise physiology and energy metabolism were the medical specialties; systems biology and biomarkers were the research areas. They also included a treatment section, but no new treatments were discussed that can be put on the CDC website as effective treatments. No randomized controlled trials were reported. No acknowledgment that clinicians are having success treating with antivirals. Instead, supportive management was discussed. This traditional approach is what has impeded progress toward understanding ME/CFS for more than two decades. Everybody thinks their part of the elephant is the elephant.
They could, instead, have organized the conference around the prominent symptoms seen most commonly in people who have the disease. That is, organize it around what patients experience. What is happening in the bed. But they didn’t. Autonomic dysfunction is a prominent and measurable problem, but they didn’t have a session on autonomic dysfunction. There were three presentations on autonomic dysfunction-related topics, but they weren’t in the same session. Dr. Freeman talked about the autonomic nervous system in the Neurology session; Dr. Rowe talked about orthostatic intolerance in the Exercise Physiology and Energy Metabolism session (why?), and Dr. Biaggioni talked about Postural Tachycardia Syndromes in the Treatment session. Why weren’t these three presentations grouped, so that the audience would focus on this important symptom complex? Why was there no speculation about how various viruses might affect the autonomic nervous system and/or cardiovascular system? Dr. Biaggioni suggested that ME/CFS might be on a spectrum of dysautonomias. Why wasn’t this idea pursued? If the three presentations had occurred together this concept would undoubtedly have been discussed further. And, of course, why wasn’t there adequate time given to a discussion and formation of a future research plan, with dedicated funds, that would allow these three researchers to work together or separately to continue to study this important topic?
Here’s another example of this organizational problem: two researchers, Dr. Light and Dr. Snell, presented important data about post-exertional malaise, coming at the problem from very different angles. Dr. Snell’s presentation was in Exercise Physiology and Metabolism (there were, by the way, no other presentations on metabolism in this session, despite an abundance of research on oxidative stress in ME/CFS); Dr. Light’s presentation was in Neurology, for reasons that are unclear--adrenergic gene expression upregulation? Well, yes, but just as importantly inflammatory cytokine gene expression upregulation and acid-sensing ion channels gene expression upregulation. This presentation could as easily have been put in immunology or metabolism. But they both really belonged in a separate session called Biomarkers for Post-Exertional Malaise (or effort-induced exacerbation, a better name). This would help patients. Post-exertional malaise is considered by many to be the hallmark symptom of this disease. These two researchers say it can be reliably measured. That means it may be able to be understood and be treated. Or used to follow the response to treatment of other aspects of the disease. This is huge. Why was this not showcased in a separate session instead of being two separate pieces of information in a confusing mix of information? And if acid-sensing ion channels are up-regulated, as seen by Dr. Light, are they reacting to lactic acid produced as patients shift more quickly to anaerobic metabolism, as seen by Dr. Snell? What happens in the autonomic nervous system that upregulates the adrenergic receptors? Put the data right next to each other and scientists will begin to ask these questions. People who aren’t very familiar with this disease (the vast majority of NIH researchers) aren’t likely to make these connections when they’re not fully aware of which of the array of symptoms are most important. There’s a way to present this as confusing. And there’s a way to present it as an intriguing puzzle whose pieces are beginning to fall into place.
This is so important. If post-exertional malaise is the cardinal symptom of this disease then we need to know much, much more about it. It may be that it’s easier to find XMRV or other MLVs in the blood on the second day of a two-day exercise challenge. It may be that EBV re-activates on the second day. Or HHV-6. Or CMV, chlamydia, mycoplasma, etc. It may be that patients‘ orthostatic intolerance is worse after an exercise challenge. It may be that gut flora changes after an exercise challenge. Markers of oxidative stress may get worse. Symptoms of co-morbid conditions like IBS, IC and FM may be worse. Anecdotal evidence suggests that this is so. As someone suggested, it may be that some or all these things happen whenever the anaerobic threshold is exceeded, so it may not be necessary to subject patients to a maximal exercise challenge with the attendant risk of severe symptom exacerbation. Given the difficulty that patients have with coming into a lab and exercising two days in a row, studies should be designed looking at all of these issues (and others). This requires collaboration. And a research plan.
It also requires that people stop looking backwards. Many of the old studies of people with ME/CFS are flawed, because the research groups were not well defined or well described. Although the importance of this issue was fully explained by Dr. Jason at the beginning of the meeting, speakers such as Dr. Kent-Braun blithely reviewed studies that were ten and twenty years old without any mention of who comprised the data set. There also was no mention of a second exercise challenge in the studies she reviewed. She then came to the conclusion that there is no difference in several measures of exercise tolerance between patients and controls. No one questioned her about what criteria were used to define the patient groups in the many negative studies she cited or about the possibility that a single exercise challenge is not sufficient to distinguish patients from controls. No one commented on her own admission that she has been out of the field for years. Dr. Natelson presented data from more than 10 years ago that purported to show that patients with ME/CFS have no evidence of immune dysfunction. He neglected to mention how much the technology for finding immune markers has changed in the last ten years, as Dr. Klimas emphasized.
The somewhat testy interchange between Dr. Klimas and Dr. Natelson (she suggested he stick to his own specialty, neurology) illustrates another aspect of the questionable planning that went into this Workshop. While controversy and discussion is good, it was not necessary to schedule opposing points of view right after each other repeatedly. Dr. Klimas and Dr. Natelson. Dr. Coffin and Dr. Mikovits. Dr. Kent-Braun and Dr. Snell. Disagreement after disagreement. It gave the impression that there is no verifiable data in this disease. It fosters a sense of hopelessness, futility. Nothing to be found here. Keep on moving. If, instead, you put Dr. Snell and Dr. Light together you see consistency. Different ways of measuring it, but consistent abnormalities indicative of measurable post-exertional changes and the importance of repeat testing with an exercise challenge. If you put all the autonomic dysfunction data together you begin to form a picture. You stop. You look. You listen. You move forward, not away.
The session on biomarkers also gave the impression that there are none. (Of course, this is the stance the CDC takes on its website). Dr. Klimas presented some interesting data on potential immunologic biomarkers, which Dr. Vernon described as “overly optimistic”. Dr. Cook gave an interesting talk on the potential for functional neuroimaging to be a biomarker, but, as yet, this is only available as a research tool. Interestingly, he also found that it’s important to challenge the brain to see the differences between ME/CFS patients and controls. Dr. Dean talked theoretically about the as-yet-unrealized potential of genetic biomarkers. Significantly, he emphasized the importance of an accurate definition so it’s clear who has the disease and who doesn’t. He also emphasized the importance of looking at large numbers of patients, which requires adequate funding. Dr. Mikovits said her work on biomarkers was quite fruitful but she wasn’t given a chance to talk about it. Meanwhile, it looks like Dr. Snell and Dr. Light have found biomarkers that just need to be verified and operationalized. Why weren’t they in the biomarkers session? Why isn’t the NIH jumping on this and funding verification studies? Why isn’t Dr. Snell’s protocol on the CDC website? It may turn out that these particular biomarkers don’t identify all patients with ME/CFS, but they may, at the least, identify a very significant subgroup.
Another way this Workshop avoided rather than fostered clarity can be seen in the topics that weren’t even considered: mitochondrial dysfunction and associated oxidative stress (so much data not even mentioned), the other important associated infections, cardiac abnormalities, and, most importantly, the problems of the very sickest patients who have never been studied in any serious way. There was a wealth of knowledge in that room that was not even tapped. Dr. Lerner was in the audience and wasn’t allowed to speak, despite his success in treating patients with antivirals. Dr. Montoya, Dr. Brewer and many other clinicians with a lot of experience “at the bedside” weren’t there. Dr. Deckoff-Jones, with all of her expertise about retroviruses, also didn’t come. Rich van Konynenburg and Marian Lemle, both of whom have made major contributions to the understanding of possible metabolic abnormalities in ME/CFS, were in the audience and weren’t allowed to speak. The unscheduled patient statements were excellent, but each of them would probably have said something different if they’d had time to prepare. There were probably many other people in the audience who are experts on some aspect of this disease that weren’t allowed to speak. Instead, Kim McCleary was given ten minutes to blather about researchers acknowledging their funders (trolling for plugs for the CAA), “responsibly” bridging between scientific journals and popular media, and “helping” people affected by the research to understand the results and the next steps. Pull-eeze. It’s Kim as kindergarten teacher again, admonishing us to use our inside voices. And helping our little minds to understand what the big researchers are doing on our behalf. Oh, and there was the blatant plug for the CAA’s part in some of the research that was presented at the Workshop. Low on funds, Kim? Need some free advertising? Why was the CAA given such a prominent presence on the agenda? Many patients don’t feel the CAA represents their interests on any level. Isn’t this a conflict of interest on the part of the NIH? Annette Whittemore was there and wasn't invited to speak. What's up with that?
Meanwhile, there were some researchers who are new to the field and presented very interesting and promising data and ideas. But the question is: given all this confusion, the lack of funding, the unsolved definition problem, and the little lectures by McCleary about expressing their gratitude to their funding sources, will they come back?
Several of the newer researchers mentioned the importance of the definition. Despite the prominence given to this issue as the first topic of the Workshop, there was no action. There was no agreement that all taxpayer-funded research (CDC and NIH, both intramural and extramural) should be required to use the Canadian Consensus Criteria to define the patient sample. Or even Fukuda plus post-exertional malaise. Or at the very least repudiate the Reeves definition. Huge disappointment. Instead of re-summarizing the summaries, Suzanne Vernon could have exhibited leadership by insisting that at least this single task got done. Nothing. What’s the point of coming together to talk if you don’t even know what or who you’re talking about?
On to the research study design problems. Dr. Rowe pointed out that the heterogeneity of the patients makes it easy to disprove any given hypothesis or the utility of any given treatment. He showed great insight when he said that his own study had shown fluorinef was not statistically significantly helpful in ME/CFS, yet he uses it, and it’s very helpful in a subset of patients. He suggested that different study designs, including n of one studies where patients serve as their own controls, may be necessary.
And, of course, the funding. Several people made the point that ME/CFS is assigned to a part of the NIH (Office of Research in Women’s Health, or ORWH) that does not have money to fund research grants. As Dr. Baraniuk said, where is our home? Essentially, there is no head of an NIH Institute going to bat for us; no one is accountable to us. No one is making sure the correct definition is being used, that data is being collected to allow subsets and their unique responses to be identified, that the studies are large enough to identify subsets, and that they are FUNDED. The need for reverse translational research (patient bedside to lab bench, rather than vice versa) was discussed, but who is going to make this happen? Patients and their doctors have plenty of questions but who among the researchers are listening? Who is assigned to listen?
This isn’t a disease that is confined to women. Why are we consigned to an Office that has no money to disburse for research? It was announced that even the FDA has now assigned ME/CFS to a specific division, the Division of Pulmonology, Allergy and Rheumatology Products. One could certainly argue about that assignment (why not Infectious Diseases--don’t they have that at the FDA?), but at least you know who to call. And you know that person has some money.
Returning to what wasn’t there at this Workshop: again, they talked about reverse translational research from bedside to bench, but most of the doctors who are at the bedside having some success treating patients weren’t there. Instead, among the participants were the usual researchers espousing their usual tunnel vision theories. Some have had little or no success treating patients. Some haven't even tried.
Part of what was missing wasn't there because it hasn't been done, obvious things like longitudinal studies (even in Tuskegee they studied the patients despite deliberately not treating them, so at least someone else could benefit from a better understanding of the natural history of the disease), family studies, epidemiological studies of all the known outbreaks, a search for other outbreaks, in depth studies of the patients who are too sick to get to a clinic.
Another thing that wasn’t there was time for discussion. There were too many short talks, some of which were superfluous. Let me repeat: why wasn’t adequate time allotted for discussion and the formation of a future research plan, with dedicated funds, that would allow these researchers to work together or separately to continue to study this important, and possibly spreading, disease? It would have been gracious of Dr. Vernon to have ceded her time to foster such a discussion. It would have been prudent of Dr. Pinn to make sure that there was a plan for future research and funding mechanisms in place by the end of the meeting, or at least a plan to make a plan, rather than apologizing repeatedly for the lack of time as she ran out the clock.
What there was, of course, was a lot of talk about budget cuts. How ironic that the day ME/CFS finally gets NIH attention is the day the government is about to be shut down. It wasn’t shut down, of course, and, as far as we know, everybody at the NIH is still being paid. Dr. Collins didn’t look worried about where his next meal is coming from. As Dr. Baraniuk pointed out, millions of dollars are spent on giant studies of thousands of patients to prove that one cardiac drug is marginally better than another. We could learn so much from a few studies that looked at a number of measures before and after exercise. We could learn so much from a few studies of long-term antiviral and/or antiretroviral treatment. We could learn so much from a few longitudinal studies. We could learn so much from a few decent epidemiological studies of regional and family clusters. We could learn so much from a few appropriately designed studies of therapies for orthostatic intolerance. We could learn so much from the sickest patients. We could, unfortunately, learn so much from autopsies. We could learn so much even from a carefully designed Workshop that looked closely and dispassionately at what we do know about this disease. We have a lot of data, but it seems like no data because it’s not organized properly. Controversy is diverting (pun intended), but it doesn’t help the patients. This conference was designed to highlight the controversies. What patients and their caregivers need is clarity.
Wednesday, April 13, 2011
Here is a video of Dr. Jose Montoya of Stanford, talking about diagnosis and treatment of ME/CFS. This man is high on my list of people who are trying to make significant progress against ME/CFS. He is collaborating with Ian Lipkin on various viruses potentially involved in ME/CFS. Dr. Montoya does not have a fixed position on the retroviral role in ME/CFS, although he is keeping an open mind. Among other things, he and his team are developing a cytokine profile to identify patients with ME/CFS. Frankly I would have liked to see Dr. Montoya at the NIH State of Knowledge. Dr. Montoya walks into the room and his presence is felt immediately. If the NIH really wanted to get somewhere they would engage more of these infectious disease clinicians/researchers who are courageous enough to engage this illness right now. It would lend an air of immediacy to the precedings and go a long way towards convincing the patients that somebody is trying to engage ME/CFS right now. If the NIH had enough sense to do this, a different picture would be presented - one that was clearer and stronger than the vague wandering that we just observed. They had the chance and they blew it. Incidentally Dr. Montoya looks like he is willing to cooperate with the WPI or Dr. Lerner or Dr. Enlander. Although he is an extremely busy man, he has the right idea and has his heart is in the right place.
Tuesday, April 12, 2011
This conference was not as bad as I thought it was going to be. While many major figures were not present at this conference, there were others whom I was excited to see and hear. (I think the reason why so many key figures were missing is that they have given up on the NIH.) In general there was a sense that information was being exchanged, especially during the breaks. There was also great evidence of the continuing “frozen” response of the NIH towards this disease – years and years and years now.
The first day had excellent presentations by Dr. John Chia and Dr. Leonard Jason. Presentations of these researchers can be seen on youtube, or through videos from InvestinME. To the seasoned viewer, neither of these men said anything new. However what they presented was very important for NIH “investigators” to hear. Both of these independent researchers are guided in different ways to seek clarification with this illness. Dr. Jason’s background in Psychology serves him well in his successful and continuing efforts to define and clarify the ME/CFS patient population. I first heard Dr. Jason five or more years ago and it was immediately apparent to me that this man is very smart, and has the doggedness to follow his arguments and definitions to the very end, backed up by data. His role in sifting things to their very essence has been immensely important, although I am not sure how many people realize this. (It is interesting to consider the idea of Dr. Jason “and his team” at DePaul University. Dr. Jason’s team is Dr. Jason and his brain, Dr. Jason and his heart, with a few graduate students thrown in. This guy is really a key asset.)
The same positives expressed about Dr. Jason can be extended to Dr. John Chia. Dr. Chia, a clinician and researcher, has doggedly followed his pursuit of enteroviral involvement in ME/CFS. He has single-handedly reignited a decades old, but forgotten, UK association of enteroviral involvement in ME/CFS. Dr. Chia has brought this association back in a very big way. Dr. Chia is one of a very few clinicians who has a firm grip on a subset (or more) of this illness. As with Dr. Jason, it is my feeling that Dr. Chia’s work is underappreciated. Dr. Chia needs to collaborate more with other independent researchers and clinicians. His contributions are invaluable. Dr. Chia and his son Andrew continue to look for treatments for enteroviruses, some of which are on the horizon.
These very important figures were presented amongst lesser figures - giving the general sense of the a lack of direction or of trying to cover too many bases. I very much prefer the format at the InvestinME conferences, a focused day of hard-hitting researcher/clinicians. Richard and Pia Simpson take the time to chose what they feel are the most “coherent” speakers for moving the research and treatment field forward. The big difference is that the Simpsons are not “confused” about this illness. They know what it is, its shape and feel, and are intent on “getting at it”. The NIH is into “wandering” indecisiveness.
The first day of the NIH conference was highlighted by an intense exchange between Dr. Judy Mikovits and Dr. John Coffin. Standing in between was Harvey Alter, who did a “professional” job of straddling the fence. He indicated, at this point and again the next day, that this dispute will be resolved by two ongoing tightly drawn studies. This could take up to two years – or longer.
Dr. Coffin was impressive in his lengthy, twice repeated apology for popping the bubble of XMRV. There are those who will take Dr. Coffin at face value, and accept this as a genuine apology of a “pretty good” virologist. I am certainly willing to do this up to a point, but where I have trouble is when he repeats the exact same apology for a second time. Oscar Wilde or Mark Twain would have appreciated the humor here, and seen right through it. I also think he went a “bridge too far” with his recommendation that we leave XMRV behind. It had a very dramatic ring to it, but Dr. Coffin must know that this is slightly premature and one wonders why he did this? It seemed a bit forced, and immediately after declaring it, he started his habitual back up and covering his bets. One could hear the crunching of gears as he put the car in reverse while it was still moving forward. Dr. Coffin was the only participant, or the only one of a few, who had a “hired gun” aura to him. He came in, delivered his information, did his apology thing, and split. It was like he had a job to do, and this job included closing things down without opening anything up.
I was slightly discouraged at the end of the long first day and entertained pitching it in and just going to the museum. However I stuck it out and found the second day somewhat better. I was particularly interested in two presentations - Dr. Michael Dean, and Dr. Theoharis C. Theoharides. Both of these researchers presented interesting angles of research, each with the capability of being rolled into existing research and treatment avenues. Their work had a “translational” aspect to it.
Nancy Klimas and Mary Ann Fletcher, two researchers who work in tandem, gave important presentations. They both seemed to express exasperation at the largely confusing picture of this illness being presented - as they do not see it as so confusing. It is always surprising to me that Klimas and Fletcher do not share cytokine research information with Mikovits or Montoya. Everyone has to invent their own wheel, is that how it works? Everyone seems to go off on their own tangent, even while they are trying to solve the same problem.
Gordon Broderick, a great discovery of Dr. Klimas, added his important information. This fellow could easily work for a consortium of ME/CFS researchers. Baraniuk gave a little speech saying that the NIH needs to uproot its “culture”. The implication was that the NIH was not approaching this problem in the right way, and that they needed to change their ways. Dr. Ken Friedman outlined the abuse that he has suffered at the hands of his university. I had heard Dr. Friedman speak about this and other abuses before and always found his accounts very shocking. He has a lot of guts to get up in this environment and reel off the injustices and prejudices surrounding his association with this ME/CFS. Having myself suffered through 35 years in an academic college setting, I know of the hypocrisy and venality of which Dr. Friedman speaks. Dr. Martin Lerner, the father of viral treatment of ME/CFS, was in attendance although he was not amongst the speakers.
Underlying many of the presentations was the dynamic struggle between things that might have immediate applicability to this illness versus those that will perhaps shed light on this illness one hundred years or more from now. Since I feel a great sense of urgency about this illness, it does not come as a surprise on which side my interests lie.
I am also convinced that an important part of the struggle is over long-standing attempts to establish ME/CFS as an infectious disease. This is the true elephant in the room.
It has become apparent that the WPI is developing a framework to try a number of protocols or combo/protocols on patients in limited trials. Because of a lack of funding it is possible that they might just bypass trials, and start treating patients and building data. Dr. Judy Mikovits pointed out quite clearly that the WPI was not going to wait another two years to move on to the treatment of these sick patients. The WPI’s position has become very clear in the last few months They feel that there is a very sick patient population of ME/CFS patients that can be clearly identified. They feel that that there are means by which these patients' immune function can be measured and tracked. They feel that there are treatments to try both on the side of pushing back pathogens and on regulating the immune system. Some of these treatments already exist, and some are coming down the line. From the WPI’s perspective everything is in place to begin treating these patients. The WPI are also actively looking for clinicians, researchers, and drug companies to help in this effort.
The gap between the WPI's position and the general level of indifference displayed in the conference room could not be more palpable - and one gets a bizarre feeling seeing these divergent ideas on display, played out in one room in a slice of time.
I sought out Dr. Coffin and Dr. Alter and gave each of them a copy of “Lost Voices”, Natalie Boulton’s book about severe ME/CFS. (This book is published by InvestinME and is available here.) Each received a signed copy (to me) from Natalie Boulton. (I figured they could just erase my name and write in theirs). I am not sure that either of these scientists were overly impressed by my approaching them - nor do I expect them to take more than a cursory view of this fine and frightening book. But I figure that this is a job that I can do. Mary Schweitzer had a similar idea, but on a much larger scale. She brought 40 copies of "Lost Voices" and placed one in each of the participant’s laps. What they will do with this document is anyone’s guess. There is no question that many of these participants do not know much about ME/CFS illness, although they will tell you that they do. All of these folks think they have a perfectly clear idea of everything. Living in an insulated world tends to increase the inability to interact in a convincing fashion with reality. These guys and gals should ride the public bus system in Minneapolis, especially the #21, where all folks are on an even plane - and many carry guns to support their positions.
At some point, for some reason, on the afternoon of the second day, the moderator decided to recognize patient statements. Various patients came to the microphone and spoke of the particulars of their illness. This is a difficult thing to do in a spontaneous fashion, to speak in front of a group of people who have marginalized and abused you. It has a bit of the plaintive character of a boy begging not to be beaten again by his father. Each of the patients’ testimonies were descriptive and deeply personal. Of particular affecting power was the presentation of Bob Miller that can be viewed here. Of a heightened expression was his pounding on their flimsy conference table. This was a very great moment of drama, and many people in the room sensed this.
Some of the participants tried to get beyond the particular disputes and inadequacies of the past. It is obvious that there are a few new friends here, and some of them are very smart people. There seemed to be some emphasis on cooperation in various matters. Dr. Mangan made an effort to bring in people from the outside. I was particularly keen on Dr. Dr. Theoharis C. Theoharides. I wonder if he can be convinced to stay around in the ME/CFS world? Often the smart people take one look at the larger “political situation” of this illness, seeded and fed by the government, and decide to go somewhere else. Often sponsored by the NIH, good researchers, according to the game, are beholden to the NIH and susceptible to pressures of various kinds. These larger political elements were on full display at this conference, including the short appearance of NIH director Collins, who has been presented as the new bureaucratic savior. He played his role well, revealing nothing.
The more that I watch these situations, the more I am convinced that there are two irreconcilable positions relative to “XMRV” - or to the investigation into infectious agents, or into infectious agents relative to immune dysfunction (which incidentally includes the brain).
The first is the party line, adopted by the status quo, and this is the view held by the majority of people. This line of “thinking” suggests that the WPI made a quick and lucky hit on a retroviral association that was sufficiently vague and confusing as to not be able to be knocked down immediately. The WPI's decision to attach themselves (hoodwink) the Rushettis and Bob Silverman in the process allowed the WPI discovery to be published in the hallowed Science magazine. The effect of this Science article allowed XMRV to attain a higher elevation than it deserved. Repeated efforts to replicate this study failed, except for one paper by Lo/Alter that was also actually not able to find XMRV. Instead it did find another retrovirus in the same family, but this did not confirm in any way the Science paper. Since then, various studies, papers and presentations contending that XMRV is a contaminant, have emerged – conclusive, but not entirely proven yet. This is seen as the normal progression of science - and now we are finally at a point where we can be assured that the proper outcome will take place with the Lipkin study. This study will be completed in the next year or two or three. Stay tuned.
The second is the alternative interpretation, adopted by the “crazies”, many ME/CFS patients, and the conspiracy theorists. With this line of thinking, the WPI has made a lucky “strike” in attaching an association of the third known human retrovirus with ME/CFS, catching many in the science community off guard. The WPI had the foresight to join forces with the Ruschettis and Bob Silverman and get their study published in Science magazine. – (without these other labs, this paper would never have seen the light of day). The near-unprecedented publication of this study from three separate labs was in itself a replication study. Various negative studies emerged that quickly blunted the momentum of the October paper, with the pitter-patter of negative presentations continuing over the next year and a half. Another positive study, the Lo/Alter was delayed (in a quite unusual fashion) for reasons unknown. Several months later this paper was released, finding a retrovirus from the same family of retroviruses as ME/CFS, thus confirming the first study. Subsequent negative findings have greatly slowed momentum into XMRV research. The orchestrated slow down has had great consequences for ongoing research into XMRV - no funding has been extended to the WPI, at least one ME/CFS researcher has been squeezed out of his job, another’s application for continuing research funding has been summarily cut off, funding for ongoing research into XMRV has been delayed, and researchers have been “encouraged” to distance themselves from XMRV. Two or more renowned retroviralists have claimed decisively that XMRV is a contaminant. A third virologist has unwittingly been caught in a very tight spot, having no previous experience to guide him in this matter. The NIH has funded a definitive study that will reach a conclusion in the next two years and “settle” the matter. This waiting game, this blocking and holding game, is seen for what it is – an attempt to disrupt serious research into ME/CFS by the status quo, for unknown reasons. This “activity’ continues a 25-year relationship between ME/CFS and the United States government. The conclusion of this scenario is that someone, somewhere does not want this retrovirus to surface in this patient group, and that no infectious disease needs to be associated with this illness.
The first scenario maintains the status quo, and the belief that the world of science has its way, that it is slow, and that the truth always comes out the winner. The second questions this idea at every turn, believes humans are fallible (or deceitful) and that questionable activities are taking place.
Suzanne Vernon, the scientific director of the CAA, made a good summation of the conference. First she stated the obvious - that XMRV has elevated ME/CFS, and that its discovery has created new and unprecedented opportunities. She neglected to name the discoverer of the XMRV association with ME/CFS – a habit of hers and a slight oversight. Later she also spoke at length about cooperation among various groups in a low-funding environment. To me this is an extremely important idea. However, I am not sure that the CAA is the proper group to guide this cooperation. The CAA seems to lack both a focus and a constituency. They are too tied to the forces that have buried this illness and these patients. I would like to see the CAA change their stance to be more genuinely open, to be more inclusive. I do not, however, imagine this will happen.
After this conference, my basic position remained the same. “XMRV” does not need to be left behind. Instead, let’s “leave the NIH behind”. It is time to face the reality that these folks are not going to help with ME/CFS. The NIH is not capable of leading here.
There is only one way to move forward. The smart folks who have knowledge of and experience with this illness have to work together. They have to overcome their differences and try harder to work with each other. (I always liked the idea of the Ratna Ling group.) Cheney, Peterson, Klimas, de Meirleir, Chia, van Konynenberg, Mikovits, Lombardi, Deckoff-Jones, Enlander, Montoya. Jason, Baraniuk, Conant, Singh, Hanson and many, many others have to put their angers and frustrations behind them and work for a common good. These are very smart people with a lot of clinical experience and good ideas. The most obvious focal point, or “clearing house” is the Whittemore Peterson Institute.
For another review of the conference please consult Rich van Konynenburg’s write up here.
Liz Willow also writes about the NIH conference here. Check it out.
Saturday, April 9, 2011
Dr. John Coffin delivered the most dramatic moment of the NIH State of Knowledge conference with his knock out blow of XMRV (video 3:36 onwards). The consequence of his statement lasted about three seconds, tops. At this point and earlier Dr. Coffin presented moments of what only could be labeled as "high comedy" - or absurdity.
Earlier, before and after his presentation, Dr. Coffin was impressive in his lengthy, twice repeated apology for popping the bubble of XMRV. There are those who will take Dr. Coffin at face value, and accept this as a genuine apology of a “pretty good” virologist. I am certainly willing to do this, but where I have trouble is when he repeats the exact same apology for a second time. Oscar Wilde or Mark Twain would have appreciated the humor here, and seen right through it. One apology is fine, two invites skepticism or the feeling of carelessness. What is his problem? Are we supposed to believe that this man is genuinely wounded, that his feelings are hurt? What about us, what about the patients who have been left behind? They are not a dumb retrovirus, they are real people, men, women and children being destroyed. These Coffin "apologies" are a bit thick.
It was instantly obvious to me that Dr. Coffin made a little major mistake and went a “bridge too far” with his recommendation that we leave XMRV behind. Carried away by impulse, he overplayed his part. While it had a very dramatic ring to it, Dr. Coffin must know that this is slightly premature - and one wonders why he did this? Of course it was in response to the leading question advanced by Suzanne Vernon, in the controlled detached voice of the wounded lover: "Where do we go from here John?". With Suzanne Vernon's question I knew something was up. In response, Dr. Coffin's declaration to "leave XMRV behind" had an air of languidity to it, and it seemed a bit forced. Compounding the problem was that immediately after declaring it, he started his habitual "backing up" and covering his bets. One could hear the crunching of gears as he put the car in reverse while it was still moving forward. My son Nicholas and I noticed this same behavior on the part of Dr. Coffin at the FDA conference on December 14th - this habitual shiftiness that invites comic disbelief.
Back to reality: Amy Dockser Marcus has written a blog article for the Wall Street Journal that can be found here. This article presents the XMRV controversy that erupted at the NIH State of Knowledge conference in a very accurate and balanced fashion, without any editorializing.
Friday, April 8, 2011
I attended the two-day NIH conference this week. This conference was available to the public at large through a video cast. I will write a few impressions of the conference another time. For now I want to write about the most extraordinary and significant moment of this conference - the two presentations by Pat Fero and Mary Schweitzer. These two women were selected by Dr Dennis Mangan to represent ME/CFS patients on the NIH organizing committee. They were chosen from a list of suggestions from the ME/CFS community. Dr Mangan could not have made a better choice. Those who suffer from this illness could have had no better representation than these two provided. Both Pat and Mary, in their different ways, made articulate stirringly emotional statements about this illness. There was no mealy mouth here. I cannot wait to watch these presentations again, as these were powerfully gripping moments. (These videos are in several parts on youtube.)
In the presence of these two women I feel humbled and inadequate. These women are the real deal, an embodiment of an individual’s rising up and out of the most difficult situation. I repeat: no one could have done a better job of speaking for those of us affected by this illness.
During the presentations, the emotion in the room ran very high. It was an astonishing moment in time. If anything could break the ice with the NIH, it would be the testimonies of these two women. Anyone listening would have to have a heart of stone to not resonate to these women’s words.
Tuesday, April 5, 2011
“What is originality? To see something that has no name as yet and cannot be mentioned though it stares us all in the face. The way men are, it takes a name to make something visible to them.” Frederich Nietzsche
I read with interest Heidi Bauer’s unearthing of the 1992 conference program on CFS connections with virus and retrovirus. Let me see – 1992 - that was 19 years ago. Perhaps the 2011 IACFS conference, which has extended the deadlines for proposals for their September meeting, can save themselves some time and money and just resuscitate this 1992 conference (or maybe just find the video recording of it). I am sure they can find stand-ins or actors for those who have died.
The media story surrounding ME/CFS has been unfocused and widely distorted since the beginning – since the early 1980’s and earlier. One could ask oneself why? One could write a story or a book about this. As a matter of fact Hillary Johnson has written a book about it, and it is called Osler’s Web. Hillary did such a fine job with this book that this story does not need to be told again. However, the book does need to be read, and its central points need to be repeated. (As Stravinsky said, “Some things are worth repeating.”) But the whole past does not need to be retold in the press. However, all journalists “go there”- in one form or another - and get mixed up in the “shell games” that have been going on for years. It is surprising that semi-intelligent people get caught in this trap.
What we need today, in this day and age, is some truthful journalism. We need someone with both a head and a heart. We need a writer who can follow a storyline that emphasizes clarity, and one that stays away from the shell games and diversions of the past. The story is sitting right there in clear view, and it is waiting to be picked up and told. How long are we going to have to wait?
Time after time the same sorry scattered interpretations are rolled out - and they are all distortions of the truth. Is it possible for the truth to be told? Is it possible that a journalist can shed some clear light on this illness? I am not sure. No one seems to have the will, heart or the brains to do this.
This is a story with only one side. Or put it this way, the other side of the story – the shit side – has been told so often that it has to be left out. Please, spare us; no more phony advertising. Continuing the reporting of “both sides” of this story is to participate in untruths. This deception has been in the air we breathe for 25 years. What we need is a writer who has a good air filter – preferably a Hepa brand. We need someone who can filter out the shit.
It is said that journalist have their own mind and their own ideas. While this is a questionable notion, they do have their own agenda. We still have to ask ourselves, what happens if they fall in a dark and muddy pit? Are we to not notice? Are we to applaud them? Is this journalism?
A journalist needs to have a clear idea of the script. Without this, nothing makes any sense - everything wanders over a vast terrain, unmarked by items of significance. It is like a Beckett play.
Someone intelligent has to thread the scattered beads on a string.
The Story – the disease definition.
There is no strict order or hierarchy in the telling of the story - except that there must be a fixed starting point. First and foremost, a clear definition of the illness must be presented. This definition needs to be given once, and then repeated with every article on the illness. This disease definition cannot be left behind, and it has to be pounded home. The essential core outlines of the disease need to be articulated over and over.
This disease definition needs to lean completely on the 2003 Canadian Consensus Criteria. The success with which the CCC clearly identifies this patient population needs to be pushed. Weight needs to be placed on the neuro-cognitive, neuro-immune aspect of this illness. Fatigue has to be removed as “the central symptom”. While fatigue is significant, many other chronic illnesses have fatigue. Heavy emphasis has to be placed on “hallmark symptoms” of post-exertional malaise (PEM) (which needs to be defined for the reader) - orthostatic intolerance (which also needs to be defined for the reader) – viral symptoms (which readers are familiar with and can relate to) and neurological symptoms. Using the CCC, ME/CFS can be separated from idiopathic fatigue and major depressive disorder.
On this issue of disease definition the knowledgeable person has to defer to the studies and writings of Dr. Leonard Jason. His CAA video can be seen here. There are also several of his lectures available on DVDfrom InvestinME. In his lectures Jason advances a significant line of questioning: if you ask a ME/CFS patient what they want to do when they get well, they will give you a long list of things. If you ask the same question to a person with major depressive disorder, the question will elicit little or no response. Major depressive disorder can and should be carefully separated from ME/CFS, and the tools are available to do this.
Journalists have repeatedly failed to clarify these issues. To them, it is all “up in the air”. They present these important items as a matter of dispute, where it is really a matter of fact. One might ask, why can’t they present this illness as it exists? What or who ties their hands? This narrowly defined neuro-immune illness needs to be presented as a serious disease, one that destroys lives and kills people. It is a virally induced acquired immune deficiency. As Hillary Johnson announced in 1996: CFS is a virus that attacks the brain. It has to be put in a class with ALS, MS, Parkinson’s, Lupus and AIDS. All of these illnesses are difficult and serious diseases, and ME/CFS has to be listed among them.
If the journalist falters at this point, they should set down their pen, and do something else.
Subjects of interest:
A story line on ME/CFS should:
- accurately and truthfully examine the means of defining the patient population. The shell game has to stop so that research and treatment can go forward. This is essential.
- accurately and truthfully describe the patients themselves - and the seriousness of their illness. A story should focus on the severely ill patients, or what selected patients used to be and what they are now, or on the tremendous toll that this disease takes on caregivers.
- accurately and truthfully describe the mounting evidence that ME/CFS is an infectious illness.
- accurately and truthfully describe the evidence that this illness is immunological and neurologically driven.
- accurately and truthfully describe the existing diagnostics for this illness. Why does the CDC mostly list tests that are not indicated in this illness? Why does it recommend not to test for some of the treatable co-infections that are common in patients with this disease?
- accurately and truthfully describe the various aspects of treatment - both existing and the possibility of future treatments. Why isn’t there a treatment protocol from the CDC as there is with AIDS? Patients are not even being offered treatments for the infections that they currently have. Why is orthostatic intolerance, one of the most disabling symptoms of this disease, not being studied and treated aggressively?
- accurately and truthfully describe the research (or lack of such) into this illness.
- accurately and truthfully describe the lack of meaningful data on the illness and the consequence thereof.
Focusing on these elements, the storyline can inform and guide the reader on the real problems and possibilities in ME/CFS. Up to now we have coverage where the reader will reach the end of a long article and can draw no firm conclusion as to what is going on with this disease. We do not need more of these articles that appear to be deceptive. The reading public needs to be given an honest assessment of this illness - forgetting about all the incredible garbage and shell game nonsense that has gone on for 25 years. The disease does not need “human interest” stories that carry the storyline off into the ditch.
Other questions and points of interest
Why don't we even know the natural history of the disease? There are patients who have been sick for more than 30 years. Why has there been no longitudinal study of these patients, many of whom have received no treatment. Even in the infamous Tuskegee study of men infected with syphilis the men were followed so we could learn something from their lack of treatment. Why isn't ME/CFS considered to be a disease?
Where is the advocacy, or who is advocating? What happened to the CAA? If the CAA isn't advocating - and they've said they're a research institution now - who is? What should an advocacy group do?
Why is this disease being ignored above all other diseases - while people are getting sicker, and people are dying?
Is it time to access the Federal bioethics commission? Are the current CDC guidelines unethical - no diagnostic tests, no treatment for proven infections? Is this ethical?
Why isn't the WPI getting funding, and why isn’t their research being published?
What conflicts of interest exist in the NIH review committees and journal review procedures? How come there is so little funding in this illness? How come XMRV research funding has dried up?
Where's Congress? Why isn’t there a ME/CFS caucus?
The current trap and the catastrophe scenario
The current trap that journalists fall into is that this is an “all or nothing” battle over XMRV. Nothing, nothing could do a greater disservice than this approach. This means of reporting is apt to have major long-term consequences for those who suffer with this illness. XMRV, for better or worse, is a stand-in for concerted work towards trying to understand the inside of this illness – especially the link to a viral etiology. If and when it gets knocked out, what is going to be left? It will be a return to another 25 years of nothing. The press coverage is trying to set ME/CFS up for a fall. If it turns out that XMRV is not an important pathogen in ME/CFS, it should not be concluded that there is no cause of this disease or that it isn't infectious. There must be continued support for aggressive pursuit of research into what are the cause(s) of this disease.
Over the last year and a half there has been a furious attack on retroviral involvement with ME/CFS. The bottom line: this is less an attack on XMRV than an attack on the dynamic nature of research into this illness, especially the viral connection. Certainly scientists can be combative– and why not? There is a lot at stake and some of these issues are complex. But why such a continued and heightened hostility aimed at any research that sticks its head up? It is the dynamic nature of the research into this illness that is not tolerated. This is an important part of the story. Is it a personality issue - or is there something else at stake here?
To repeat: the struggle over XMRV is a struggle over a larger issue. XMRV is a screen. The larger issue revolves around the WPI's and others’ attempt to compile data on this illness, to find an etiology, and to search for treatments - elements that have always been "disallowed" in this illness. These facts are so painfully obvious as to not even need to be stated.
This disease has had two interpretations. There are those who do not believe that this disease exists, and there are those who are seriously ill with this illness. Can these two sides be reconciled? Can this story continue to be told as tweedle dee and tweedle dum? No, the storyline has to be changed to reflect reality. The storyline needs to be more about the disease and less about the journalist’s squishy needs at any given time. In other words the journalist has to start telling the truth.
What is the consequence of this “phony” reporting, this telling of a non-story storyline or one that is “two-sided” or “balanced?” (“Let’s be open and honest” - that great 1960’s line.) The consequence is that thousands of patients suffer in silence and disgrace for decades, marginalized, with no hope. The consequence is that very little money goes into research, and much of “the research” is on the wrong patient population. The real casualty is that there is no data - so no way for patients or doctors to make intelligent decisions about treatment.
This idea of promoting a data set that can be shared with others is the central point that draws the Whittemore Peterson Institute into the line of fire. This is a very big no-no. XMRV is only a screen that can be knocked back to keep further and potentially broader research occurring on this illness. Good journalistic reporting of a firm storyline could help clarify this. But will it? The need for obscurity, the need for vagueness, is so very profound, and it has been going on for a long time. Why is this situation being driven this way? What keeps it going?
Avoid the traps, avoid the ruses
Many people say that this illness is too difficult. This is a ruse. All infectious diseases are difficult until they are understood. This disease needs to be approached as being caused by an infectious agent or agents. The evidence is there. If it's not XMRV/MLV, keep looking. It occurs in clusters. Clusters of cases are either due to an infectious agent or agents, a toxic exposure or a combination of the two. Keep looking. Don't assume that it doesn't exist because you haven't found it yet. Keep looking. And don't declare the very sick patients "not really sick", so you don't have to help them or do the work of figuring out what the underlying problem is. Keep looking. Following a clear and honest storyline could help this. But so far it has not occurred.
Personally, I do not want to hear any more about how this disease is complicated and hard to understand. I see these patients sitting in a darkened room, walled up from life for years and years, neglected and abused by medical practice, and I am sick of the excuses. We need someone to cover this illness who has some guts. We need something that is better than the slop that is served up presently.
The press (and others, including virologists) have a field-day presenting the current (and past) interest in this devastating disease as nothing more than an all or nothing pitched battle that pits patients against researchers, researchers against doctors, patients against patients, and researchers against researchers. This has been going on for a long time now and seems endemic to the illness. For this illness to move forward, this particular brand of roiling attached to this illness has got to stop. It is not an accurate picture of this illness world. Instead, it is a fantasy/construct designed to further marginalize this illness. It is fundamentally abusive towards the patients with this illness. Why are so many professionals not interested in this illness? Have they all taken the "poison pill"? Why is there so much hostility directed towards these patients?
“Why live in the past?”
Max: “Who cares? Listen, live in the present, what are you worrying about? I mean, don’t forget that the earth is five thousand million years old at least. Who can afford to live in the past?”
Stick to the present, stick to the issues. Naturally, this story, this investigation will lead to the abuses of the past - but this is not the main story. The past is a cesspool and needs to be avoided in order to emphasize the more significant points of this illness. The storyline does not have to go into areas of abuse and neglect, although it will inevitably lead there, and people might have to go to jail for the crimes. This might not be safe territory for a journalist - as these Stalinist bureaucrats like to “take out” the accusers along with the accused.
Marcus Conant says that “the press is not your friend.” Presumably Dr. Conant believes that there are other ways to get the story out. His suggestion is that the press is not going to win or lose this battle, that they have their own agenda. Perhaps, as a million to one shot, a journalist can help move this illness’ awareness in a positive direction, especially now, when everything in research and treatment hangs in the balance. But it will take the emergence of a “special person”, someone who can see what is sitting right in front of us. Do I expect this to happen? No, I do not expect this to happen. Would it be nice if this did happen? Yes, it would be nice if this did happen.
If I were going to give advice to anyone writing about this illness, it would be this: try to restrain yourself from doing more damage to this damaged group of people. Do not do what you are currently doing. Don’t contribute to the negative “force field”. Further freezing out and isolating these patients, who are desperately ill with an immune-mediated shutdown, is cruel and suspect - all motives are suspect. Keep it simple. Look at the patients. Look at the caregivers. Look at the researchers. Look at the clinicians. Stay away from the other side, stay away from the “dark side” - and those with the black haloes. There is a story here, but it needs the right person to ferret it out.
Monday, April 4, 2011
I have attended at least 15 FDA and NIH and CFSAC meetings and have never run into this problem. I find this entire matter very suspicious. This is the best that the NIH can do in a situation were every action they take is under great scrutiny and great suspicion? What is with these people?
In reading further I discover through Hillary Johnson that the meeting was moved from a larger room into a smaller room, or is in a room smaller than might be otherwise. Why do they move (or hold) a meeting of this importance to a smaller room? Why, as the advocate for a disabled person, my daughter, am I denied access to the conference? Why, as an advocate for other disabled persons, am I denied access to the conference? I understand that supposedly there is going to be an outlying room or two available for “overflow”. Presumably the conference attendees using the “overflow” room will be able to watch the performance on television screens. What is this all about? Why can’t they just have the conference in a larger hall where they can accommodate additional attendees?
I have made great efforts in time and money to attend this conference. I have had to give up a great deal to attend this conference. Many patients, including my daughter, are expecting me to listen for them and to represent them in any way that I can. I do not like being boxed out. I am also not interested in being placed, with my son who is also attending, in an adjoining or separated room watching a television monitor of something that I could watch in my room back in Minnesota and he could watch in Baltimore. What is going on here?
One of my friends, disabled with this illness, made a reservation online. She has requested special arrangements so she can put her feet up (a foot stool would do) and have a place to lie down during breaks, and it is suggested that she can watch in an adjoining room. This woman has attended various conferences and always been assured that her special arrangements can be meet without having to leave the main room, where she wants and needs to be. Otherwise she could watch on her laptop in her bed. This patient, an important advocate for us all, believes that making eye contact with the presenters is critical, especially in regards to asking question, a necessary part of any public hearing of this level of importance. I feel the same as it is impossible to ask penetrating questions without seeing the person whom you are questioning - as nuance of expression and body language is critical in such exchanges.
I also object to having ME/CFS patients watch the proceeding on a television. Many of these patients have sensory deprivation and cannot actually watch a television nor tolerate the frequency of the sound that emanates from a television. Just because those that work at NIH can lounge around watching television and computer monitors all day, they are not excused from knowing the minimum problems that some of these seriously disabled patients might have. The NIH should pay a bit more attention to this - perhaps they could read my blog and learn a thing or two.
I have other serious objections. The NIH, on the conference webpage, defines ME/CFS as a “poorly-defined illness”. Who has defined this illness poorly? The CDC and some of their colleagues in Britain have defined it poorly. The Canadians have defined it well. It is a well-defined illness when correctly defined. The NIH should adopt the Canadian Consensus Criteria that would allow them to define this illness with great clarity and confidence. In reality, this illness is not poorly-defined.
And then there is the question of not publishing the schedule of speakers. The conference is four days away and no speaker schedule has been published. What is this about? Doesn’t the NIH know that people have to make plans? Patients make there travel and accommodation plans based on who might be speaking and when. They do not have the freedom of healthy bureaucrats to come and go as they please. Those ME/CFS patients that can actually come to such a meeting have to be able to pace themselves and make elaborate arrangements so that they can get through these talks - talks which have such great import and consequence for their lives. They do not have secretaries to call and make last minute travel arrangement changes. Their travel is all on their own dime and, as disabled patients, they have little money. But they have great, great interest and, in this schedule mishap, they are being cut out. How incompetent are these NIH people?
I am a bit unsure about this “State of Knowledge thing”. I ask around, “What does this State of Knowledge thing mean?” No one knows. My first instinct is to ask myself, “Whose knowledge – mine or theirs?” Someone told me that this is the first NIH State of Knowledge regarding ME/CFS. Someone told me that there was a State of the Science Conference on Chronic Fatigue Syndrome in 2003. Summaries produced at NIH State of the Science Conferences are considered to be "historical" (basically obsolete) after 5 years. When Dr, Hanna, formerly responsible for the CFS program at the Office of Research in Women's Health, was asked at a CFSAC meeting whether it was time to have another State of the Science meeting about CFS, she replied, "There is no science in CFS." Apparently she was unaware of the hundreds of papers published about CFS since 2003. Many of them (although, as we know, not all) used a well-defined patient population and demonstrated infections, metabolic abnormalities, measurable immune abnormalities, cardiac abnormalities, central nervous symptom abnormalities, etc.
It's difficult to tell from the NIH website what a State of the Knowledge conference is supposed to be. There does not seem to have been any RFP (Request for Proposals=grant money) issued in association with this conference. There doesn't seem to be any requirement that any information be disseminated to clinicians as a result of this conference. So what's the point? Is this the reason they haven't firmed up the schedule YET? Are researchers unwilling to come speak because they know this conference is a useless exercise? Just wondering. It seems that a State of Knowledge meeting is one step down from a State of Science meeting. Is that what we need – a downgrade? This is shaping up to be one sorry show.