XMRV: Necessary but not sufficient?

[anne]

Tina, that was gorgeously said.

Also, this XMRV stuff isn't "hype." It's a study, one done by very credible people, and backed-up by even more credible ones, and published in about the most credible journal there is. It's a documented study, not a media-created hullaballoo.

 

[Eric Johnson from I&I]

Hi Eric, I'm surprised at you saying this coming as you do (like me) from a Chlamydia pneumoniae background. NAC can and does damage a significant number of chlamydial elemetary bodies, as witnessed by the intense reactions people get to it. In my case an increase in dosage feels like someone has poured gasoline down my oesophagus. There is also the distinct endotoxin reaction one gets - a sudden drop in body temperature that is quite unnatural. These brisk reactions are repeated with other disulphide-bond reducers such as DMPS.

I have high respect for Dr Stratton, but how likely is it that every single one of his beliefs is accurate? I do not have a strong opinion one way or the other on the NAC / EB thing. I notice that Dr Wheldon used a qualifier -- he said, approximately, "EBs are likely destroyed by NAC."

Why do you speak of an esophageal reaction? Could this just be caused by NAC irritating you via reflux of the stomach fluids? I have reflux frequently some months/years.

Corroboration from other reducing agents is highly interesting, but how many people have noted strong reactions from those less-used agents? Even with NAC, has anyone used blinding to make sure the responses do not involve a "nocebo" effect?

Part of the deficiency in my certainty here is my own -- I dont know how the extracellular redox regulation, if any, works. Maybe Rich could give us a clue. This seems like an important thing to know before you can interpret the reported effects of reducing agents on EBs in serum (or was it blood) ex vivo. That is, my question is whether the same thing would happen in vivo -- or would redox regulation by the body prevent it. Even if so, it is one thing for this to be done by Dr Stratton and another for it to be replicated widely.

Its easy, I think, to imagine there being some other mechanism for these responses to NAC etc.

However, regarding Cpn in general, I may well be consistent with the XMRV coinfections model, and I hope Cpn investigations in CFS will get a boost (even if the XMRV model is not true).

 

[Eric Johnson from I&I]

Serg,

PCR is just one assay and was positive in only 67% of CFS cases. The 40% PCR positivity found in a tiny autism sample is not different from 67% in a statistically significant way, because of the small sample size. That is to say, the difference between 40% and 60% could be due to randomness.

Flip a fair coin 10 times and you may very easily get 30% tails, or 80% tails. Flip it 300 times and you will get very, very close to 50% tails, and have only a one in a trillion chance or less of getting 80% tails.

The serologic positivity found in austism, 57%, also was not statsitically different from what was found in CFS.

The same applies to the fibromyalgia PCRs. In short there is no evidence yet that autism or fibromyalgia differ at all from CFS with respect to XMRV in any way.

 

[Eric Johnson from I&I]

"I can only imagine that the same is true for XMRV."

Why?

Why dont reducing conditions inactivate your cells if they kill XMRV and Cpn EBs? For EBs, it is more plausible because they depend on an entire network of many, many disulfide bonds remaining sufficiently intact.

In contrast, XMRV's outer surface is just a lipid bilayer membrane stolen from the surface of my own cell, studded with XMRV proteins. Those proteins have probably had more chance to adapt to mammalian serum and mammailian interstitial fluid than MY proteins have. Theyve tried out FAR more mutations, and have probably done 1000 times more generations inside mammals than mammals have done generations on earth. It is true that they may not be highly adapted to man in particular.

 

[kurt]

Hey, Kurt. By all means, be skeptical. That's your prerogative. Indeed, as you say, if the Science thesis collapses, there will be a lot of hurt.

I, however, have not heard a convincing argument undermining it. ...Not a one.

Here are some quick arguments that I think could be convincing, just as an example. I am no expert here, so might not be using the proper terms, but I have spoken with a retroviral researcher and these are credible challenges that will have to be addressed at some point.

a) There are over 20 different methods of PCR testing (see wikipedia). WPI used an early generation technology for their PCR. The state of the art is quantitative real-time PCR technology (third generation), and there are fourth generation adaptive computational PCR approaches available now although not many labs are capable of that yet. The problem with the old approach to PCR is that it often produces false positives. The use of older technology is a serious risk as false positives are more likely.

b) Antibody studies for new bugs are inherently risky, because cross-reactive species have usually not been identified yet and can not be ruled out. Again this creates a risk of false positives.

c) Culture studies do not help if the PCR is giving false positives because all the culturing process does is amplify the sample, which is then analyzed via the same PCR (or antibody) tests.

d) WPI is now claiming 95% or even 99% positives. That is almost unheard of and suggests a broken test could be responsible. Particularly for CFS where we know there are many subsets. If 99% have XMRV it is probably either totally ubiquitous, or a broken test.

e) Men with prostate cancer and XMRV are not getting CFS, so even if we all have XMRV what does that really mean? The only way the virus could get to the prostate would be through the blood stream, which means they have had XMRV in the blood, just like the PWC that WPI tested. And still they do not have CFS.

f) There are rumors going around that other labs are NOT getting the same results as WPI. Until we get the reports, there is no way to know for certain, but things are not looking good right now.

g) Sample size of N=100 is good if the sample is a fair distribution within the population. However, if the sample comes only from a handful of geographic regions, or is derived from hand-picked cases, then the statistical validity of the study is questionable. WPI might have found a subset of XMRV infections in CFS. This must be addressed in a broader study before anyone can make definitive claims about XMRV and CFS.

I believe there are some good reasons to be a bit skeptical, I just found seven arguments, and I am no expert in this. Experts who are working this problem over will find many more issues than I can.

And while I encourage you to be skeptical, I have an obligation to my neighbors on these fora to correct misstatements.

To address what you state in the quote above:
1. We do have one study showing a link between XMRV and CFS, but it is relatively large by the standards of the field.
2. Judy Mikovits is one of the most experienced retrovirologists in the country.
3. The WPI was joined by the NCI and Cleveland Clinic in their testing. That Cleveland Clinic department is, beyond any possible doubt, the most experienced in the world when it comes to XMRV.

All that is required to break the study is for someone to find a flaw in the testing. Then it does not matter how many people WPI have tested, what Mikovits' credentials are, or whether NCI or Cleveland Clinic were involved. And the only way we will know if the study is valid is for external researchers to get the same results as WPI while using many different testing approaches, many types of PCR for example. That has not happened yet, at least not that has been reported.

Scientific research is published to the scientific community partly for the purpose of review. Dr Coffin understands this, which is why he commented that this was good for a first study on a topic. People here pounced on the 'good' part, but I am looking at the 'first study' part of that comment. He knows the score, he knows that the first study is only raising a question, many more studies are required to really confirm and build a factual understanding of the subject.

If this were an election and not science, then Mikovits would win. But this is empirical research, and one study is far from conclusive, no matter who conducts it. And an N=100 is not the issue, the issue is whether the test can be confirmed. Many more studies will be needed, to address issues like I mentioned above, as well as others that will emerge. This is just the very beginning of the inquiry.

 

[shiso]

Good point, and you are right. What I am saying is that my rational brain says to be infected by a rational hope, hope that this is a turning point for CFS funding, research, and maybe eventually treatment. And not a high-risk hope that XMRV is the cause and toxic ART will be the primary solution. Thomas Edison may have gotten excited working on the light bulb the first time a filament lasted a few hours. But how many more did he have to try before he found a combination that really was workable... We may have a retrovirus, Mikovitz has connected our symptoms to classic retroviral problems in a new and more profound way, but the actual culpret may or may not be XMRV. There is a LOT of work left, many more 'filaments to try-out.'

The science is not very strong yet for XMRV in CFS. People with prostate cancer and XMRV do not get CFS. Think about that. My father has prostate cancer, a serious heart condition, two artificial knees, and is in his late 70s, and he can run circles around me. He still goes golfing and walks the course, in fact he recently had a heart attack while golfing, and his pacemaker/defibrillator implant stopped the attack instantly. My father did not even fall down, he borrowed a golf cart and went home, down-loaded the data to his doctor, and is fine. That is nothing like CFS, I can hardly walk to the mailbox three houses away some days.

What worries me is if there is a collective loss of hope from the CFS community if XMRV turns out to not be involved in CFS. And what I read here is so much excitement and expectation, placing too much load on WPI and Mikovitz to solve our problems. Too much anticipation and not enough caution. That is all I am trying to say.

Well said, Kurt, and thanks for aptly articulating what has been on my mind the past few weeks.

I am not particularly scientifically-oriented and am not equipped to address the scientific likelihood of whether the WPI research will be replicated, further developed, and most importantly, lead to effective treatment - we simply do not know that yet.

The rational part of me who steps out of my shoes of a desperate and suddenly disabled CFS patient is observing though that much of the CFS patient community (at least as reflected on online forums and blogs like Hillary Johnson's), is accepting the findings suggested by WPI's pilot XMRV study (or 3, however you want to count them) as holding THE key to the answer to CFS before science has produced evidence of a causal relationship between the retrovirus and CFS. I happen to share Kurt's concern for too much expectation and not enough caution, however promising the reasons for the high expectations may be.

My other concern relates to the discussions on these forums (for which I am deeply grateful for the intelligent, and respectful community it provides), where it seems that almost any time an individual or scientist expresses less than 100% support for the hypothesis that XMRV holds the key to solving CFS, they are often criticized en masse, either backhandedly or more bluntly or pointedly, for expressing their caution (caution, not disparagement) regarding the study. The criticism mostly seems to come not from personal scientific expertise, but for non-scientific reasons like "Science is the most prestigious journal" and "the researchers who did this study are smart" or reiterating a suggested conclusion from the study itself.

As others have said, I think we should each be entitled to take the XMRV news with as much hope or caution as we wish. But I also think people should be able to voice reasoned caution in places like this forum without feeling like they are going to be instantly criticized or silenced.

I think hope and caution can and should co-exist, especially because we're only in the earliest stages of these particular findings. I don't think truly open discussion is in any way incompatible with supporting WPI's research by way of donations (as many of us have done) and doing everything else in our power to help move the science forward (the faster, with as much funding and talent as possible, the better).

 

[Eric Johnson from I&I]

WPI is now claiming 95% or even 99% positives. That is almost unheard of and suggests a broken test could be responsible. Particularly for CFS where we know there are many subsets. If 99% have XMRV it is probably either totally ubiquitous, or a broken test.

You should be more the bear: "wheres the evidence, my dear dreamers!" There has never been any for the etiologic subsets. Nil. It could easily be true. Its a perfectly plausible idea, which doesnt mean much.

 

[Eric Johnson from I&I]

I dont know anything about you. You exist, which is enough to conclude that youre probably tougher and braver under pressure than I am. But you sure talk too fast about this subject. All six of your objections are false, not counting the rumor. I'll probably be back to my usual talkativeness once I get my hands on a pizza, meanwhile you can cross "c)" off the list by looking at either the paper or the supplement. Its not unsporting or anything to recheck the paper if you dont remember what it said:

After coculture with activated PBMCs
from CFS patients, LNCaP cells expressed XMRV
Env and multiple XMRV Gag proteins when
analyzed by Western blot (Fig. 3A) and IFC (fig.
S5A). Transmission electron microscopy (EM) of
the infected LNCaP cells (Fig. 3B), as well as virus
preparations from these cells (Fig. 3C), revealed
90- to 100-nm-diameter budding particles consistent
with a gamma (type C) retrovirus (13).

 

[jenbooks]

I don't find Kurt's objections significant, particularly the bizarre idea of a completely inadequate i.e. broken test, nor will I personally worry about rumor mongering (other labs, I assume we're assuming qualified, are unable to replicate), as far as I know he's not an insider in this world.

I do find the science compelling. Apparently so do other virologists. Do I think it will turn out to be the single ever present cause for all "CFS" and that it will be easily treated? No. Certainly for instance borrelia alone can cause extreme fatigue in some. Or maybe it's borrelia plus babesia. Etc. So can a simple flu.

But if you can't get over your infection and become disabled by it a retrovirus makes sense. Do I think genetics play a role in how you react? Sure and this has always been true of all pathogens. Why, even in AIDS, 1% of Caucasians are resistant because they lack the receptor the virus uses to first dock onto and penetrate a cell. They have other redundant receptors that their body can use for the same purpose, meanwhile the virus has no entry.

My speculations:
1) The prostate cancer strain has a polymorphism *and* the prostate cancer patients have a genetic vulnerability
2) The CFIDS patients also have a genetic vulnerability
3) A few specific other infections, might switch on virulence
4) This virus will be implicated in other cancers.

One of the most compelling pieces of evidence, for me, is that Peterson took banked blood from a 1984 CFIDS patient who has since died of cancer, and was able to grow out XMRV and infect naive cells.

Well, frankly, almost all the evidence has been compelling. I also think what we learn about XMRV will teach us more about morbidity, cancer in general.

What it means for me personally--well I'm not too excited about that now. I don't really want to be on a strong antiviral. These drugs are not necessarily good for one. And even though the mutation rate of this virus seems unusually low, I'm afraid of a monotherapy. I've heard enough about relapses after people do well on antivirals. I therefore would be in a watch and wait mode, or use herbs, or try to combat the downstream effects (as in Rich's methylation protocol, or stem cell therapy).

I see one lab in England will be seeking to replicate and among their goals is to seek "human polymorphism in the xenotropic receptor." This is very key, I believe. Perhaps some of us carry receptors that allow us to be easily infected by the virus *and* have another genetic vulnerability (such as an r-nase defect). I think the next months and years will be very interesting.

 

[dannybex]

I think the hypothesis is a one two punch first you get the virus, then another event sets it off or gets it going to a point where the body can't deal with it. Maybe it's a a one two punch with a spit in the face from genetics. Sounds plausible to me, but you're right, if they exist, they'll need to prove these kinds of connections.

Cort reported on another thread that Dr. Peterson "still thinks the immune problems (or autonomic nervous system) problems all came first - they opened the door for XMRV."

Just one docs theory of course, but he was one of the authors of the study.

http://forums.aboutmecfs.org/showthread.php?t=950

But I totally agree that we need bigger studies, in different areas of the world...The key will be sorting out the good science from the bad.

I agree as well...

 

[anne]

The criticism mostly seems to come not from personal scientific expertise, but for non-scientific reasons like "Science is the most prestigious journal" and "the researchers who did this study are smart" or reiterating a suggested conclusion from the study itself.

Since I am one of the people saying this, and did several posts up, let me say that I respond that way for two reasons. First, in some of these posts there seems to be a tone of criticism, as if the people believing in this are credulous--and so what I am saying is there is good reason to credit these results. In fact, it is the logical conclusion given the facts of the study I believe that it is so credible that those who dismiss it out of hand (doctors and scientists, I mean, not random people on the internet) do so at the risk to their own integrity.

I also say it in response to those who imply that the study was somehow flawed, that the sample was rigged or there is something dubious about the motives or practices of the people involved. It's simply not possible for it to be shoddy.

I'm not objecting to caution by any means. I am objecting to misinformation, as well as the patronizing attitude occasionally shown toward the people who credit these results. And I object to those who proudly parade their skepticism when their conclusions are based on ignorance.

In other words, I'm not objecting to reasoned caution--Cort, for one, has expressed this beautifully. But I'm objecting to ignorance, misinformation, I object to the idea that this is "hype," and I object strongly to the implication that I am somehow naive for thinking there is something to these results.

We don't need to rehash the arguments about the CAA here--reasonable people can and do disagree. I am not criticizing them for expression of caution, what I say is the manner in which they expressed caution showed, to me, a tin ear for politics and advocacy.

 

[kurt]

you need more than this

I dont know anything about you. You exist, which is enough to conclude that youre probably tougher and braver under pressure than I am. But you sure talk too fast about this subject. All six of your objections are false, not counting the rumor. I'll probably be back to my usual talkativeness once I get my hands on a pizza, meanwhile you can cross "c)" off the list by looking at either the paper or the supplement. Its not unsporting or anything to recheck the paper if you dont remember what it said:

Eric, you need to do more than just dismiss these items. What is your basis for dismissing them?

You mention item c) on my list, which was a culture study. You are correct, I must have missed how they confirmed the cultures, I assumed they used the PCR technique again because that is common. They used Western Blot, which is an antibody study from an isolated protein. However, this does not remove the potential for false positive. If the antibodies used in the study are cross-reactive, then the culture study could fail, just as it would if a problematic PCR were used.

Also, since you brought that up, that quote also said they used electron microscopy and measured a pathogen in the size range of a gamma retrovirus. That is interesting. If there were false positives for XMRV, maybe some other gamma retrovirus would be found in the samples, they just might not have found the right one yet. I am speaking hypothetically of course, my point being that until this is thoroughly evaluated we have to accept that many of the findings could be a case of finding what you look for by defining everything so things go your way.

My point here is not to prove anything, or to disprove the WPI study. My point is that we are at the beginning of the scientific process here. These types of issues will require further study, along with many more issues the experts will identify, before the case is closed. I see a lot of jumping to conclusions and building up of expectations, and that can derail objective thinking.

 

[Advocate]

I just watched the terrific Joe DeRisi video clip that Eric mentioned. That fellow sure talks fast! It was made in 2006, I think, and he talked about XMRV toward the end.

So I started googling DeRisi, and I found an identical quote about XMRV (by DeRisi) on three different websites. I'm trying to track the original source. Can anyone help?
========================

The first place it turned up for me was on October 10, 2009, two days after the article appeared in Science. It was on a website called Silicon Investor: Stocks, Commodities, Indices, Foreign Exchange & Discussion Boards. The DeRisi quote was posted by Biomavin, a Harvard law graduate, who is a biotech investor.

http://siliconinvestor.advfn.com/readmsg.aspx?msgid=26010079
========================
On October 21, the exact same paragraph was posted by an anonymous person on LymeBlog: Users Journal, under the heading "XMRV virus causes CFS.ME.Fibromyalgia - Hope"

http://lymeblog.com/modules.php?name=Journal&file=display&jid=2380
========================
On Oct. 22, 2009, the same paragraph was posted by LymeLifer, at
http://www.first-do-no-harm.com/
========================
Does anyone have the original source? Or was Biomavin the original source? Could he have been posting something he thought would influence the buying and selling of stock in a way that would benefit him? Here's the paragraph:
........................
Joseph DeRisi, a molecular biologist at the University of California, San Francisco, who co-discovered XMRV, was not satisfied with details in the paper: He wanted to know more about the viral load in CFS patients and how the demographics of the control group matched that of CFS patients. And the Mikovits team didn't do enough to rule out contamination, he says. "One has to be very careful about making claims about such a sensitive and emotionally charged issue as CFS, where many claims have been made in the past." At the least, a double-blind study where a third-party lab searches for XMRV in CFS patients and in controls is vital, he says.
=====================

 

[jenbooks]

Hmmm, Advocate, I have used Silicon Investor for years and yeah, people post all kinds of stuff to influence buying and selling of stocks. I just went on and posted to Biomaven asking for the original source of the quote. I'll keep you posted .

 

[Marylib]

Let's hope good will come out of all this

One of the saddest things about the gestalt of the disease for me was watching and absorbing the casualty of truth in the public eye and mainstream media about this strange disease. I have kept my suffering to myself as much as possible, and bluffed my way though challenges and situations as best I could to survive. One of the blessings of CFS, which is also a curse, is that on the surface, most patients can seem very intact for a limited time when it is truly called for. Usually they pay later for it at significant cost, but many of us have that option. Many other seriously ill folks with different diseases do not.

I believe that what is happening is not best described as hope, which has been stolen before to the extent that ME/CFS patients are actually a hard audience now for new developments. Its more like a lust for truth, and it seems like the genie is out of the bottle now. If XMRV research goes down in flames, it would be a blow. But, in the future, things will never be the same for psycho-social adherents trying to heap medical abuse on patients with an organic illness.

Well said, Levi. I found your post very touching.

 

[George]

The agony of waiting

Does anyone know who is doing follow up studies, how long they will take, and when we can expect to hear?

All I truly want for Christmas is one collaborating study, just one, please God.

 

[Alice Band]

Advocate,

As a guess (and sorry if I am barking up the wrong tree)

I think that it may have come from this article in Science originally.

Unfortunately I don't have access to read it

------------------------------------------------------------

Chronic Fatigue and Prostate Cancer: A Retroviral Connection?
Sam Kean

Science 9 October 2009 326: 215 [DOI: 10.1126/science.326_215a] (in News of the Week)

http://www.sciencemag.org/cgi/conte...rv&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

 

[_Kim_]

I think that it may have come from this article in Science originally. Unfortunately I don't have access to read it

I have full text access through my University.

Virology:
Chronic Fatigue and Prostate Cancer: A Retroviral Connection?
Sam Kean

As if chronic fatigue syndrome (CFS) hasn't caused enough brawls, a new study published online by Science (www.sciencemag.org/cgi/content/abstract/1179052) links the disease to a possibly contagious rodent retrovirus, XMRV, which has also been implicated in an aggressive form of prostate cancer. Related work by the authors also suggests that CFS might best be treated with AIDS drugs. Even the lead author, Judy Mikovits of the Whittemore Peterson Institute for Neuro-Immune Disease in Reno, Nevada, says she understands why linking CFS to a retrovirus and to prostate cancer has already drawn skepticism.

In 2006, an unrelated paper found an association between XMRV, which originated in mice, and a deadly prostate cancer exacerbated by a deficient enzyme. Mikovits and colleagues had seen the same deficiency in CFS cases. When they investigated further, the team discovered XMRV in the white blood cells of two-thirds of CFS patients but only 4% of control subjects. Intriguingly, Mikovits says XMRV does major damage in natural killer (NK) blood cells, which attack tumor cells and cells infected by viruses, and other studies suggest people with CFS suffer from high rates of cancer. Unpublished work, Mikovits adds, has found blood serum antibodies for XMRV in 95% of CFS patients.

All previous attempts to nail down a cause for CFSincluding many links to viral infectionshave foundered or been retracted, and many doctors remain doubtful that it's a coherent disease. Mikovits says her work "proves beyond a shadow of a doubt that CFS is a real disease." But some of her peers find the report of a viral link premature.

Joseph DeRisi, a molecular biologist at the University of California, San Francisco, who co-discovered XMRV, was not satisfied with details in the paper: He wanted to know more about the viral load in CFS patients and how the demographics of the control group matched that of CFS patients. And the Mikovits team didn't do enough to rule out contamination, he says. "One has to be very careful about making claims about such a sensitive and emotionally charged issue as CFS, where many claims have been made in the past." At the least, a double-blind study where a third-party lab searches for XMRV in CFS patients and in controls is vital, he says.

Other CFS specialists, including Jonathan Kerr at St. George's University of London, are convinced that the Mikovits team discovered something important. "The fact that the virus was actually grown from the blood cells of CFS patients strongly suggests some sort of role in the pathogenesis of the disease." But exactly what they discovered remains unclear, given that the group is not claiming to have identified a cause.

John Coffin, a molecular biologist at Tufts University in Boston, analyzed the Mikovits paper in a separate "Perspective" also published online by Science (www.sciencemag.org/cgi/content/abstract/1181349). Coffin was highly skeptical of the paper at first, but the team found enough independent lines of evidence for XMRV to convert him. "They will be celebrating in the clinics where these people [with CFS] are being treated," he now says.

Even if the finding of a link to XMRV holds up, treatment suggestions are bound to attract controversy. No one knows how easily XMRV spreads, although Mikovits says transmission can occur via bodily fluids, including saliva. Mikovits also says unpublished preclinical data hints that scientists can treat XMRV with AIDS drugs such as AZT, although AZT itself might prove too toxic. Kerr remained cautious about this: "With present public knowledgewhat is described in this paperfurther work would be necessary before antiretroviral drugs could be recommended."

 

[jenbooks]

Thanks, Kim. I read his statement as someone protecting his turf/discovery.

 

[kurt]

list of follow-up studies

Does anyone know who is doing follow up studies, how long they will take, and when we can expect to hear?

All I truly want for Christmas is one collaborating study, just one, please God.

Here are some that people have posted or that I have heard about back channel (hope it is OK to post these):

Dr. Kerr in the U.K.
Dr. LLoyd in Australia
Prof. Towers at University College London
Dr. Coffin at Tufts University, Boston, MA, USA
Dr. Paul Jolicoeur The University of Montreal, CA
Retroviral research group at the CDC Virology Lab in Atlanta, GA, USA
Jonas Blomberg, Uppsala University, Sweden
Spainish Study (http://www.institutferran.org/fatiga_cronica.htm)

As this is competitive, some of these labs will be trying to get reports out quickly. I know of one additional private study underway that is close to reporting, and suspect there may be quite a few more that are keeping quiet. The CDC has a head start.