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XMRV and Culturing, HERV's and more

G

Gerwyn

Guest
2. The XMRV study in science was compelling. Outside researchers thought this would be easy to test, as WPI showed so many ways they could find XMRV. Their careful reading of the article convinced them to invest their resources. And I am not just talking about the UK and Dutch studies, but also many others, including in the US. When rumors went around that labs were having trouble finding XMRV I started to study alternative explanations and learned the history of retroviral searches for diseases like MS, Breast Cancer, Lupus, and others. Generally the confounding problem in those studies have been endogenous viral interference (HERVs). And in many diseases HERVs are known to be expressed. Interestingly many of the failed studies failed because they had used MuLV antibody tests, and MuLV has been proven to react to some HERV species. Was this somehow happening with WPI? I don't know but thought it was worth exploring. Here is the most interesting reference, listing over 500 publications from studies, mostly failed attempts to link retroviral infection with diseases and many using MuLV:

http://mmbr.asm.org/cgi/reprint/72/1/157.pdf

Obviously this raised some questions. Mostly, could the MuLV antibody studies used by WPI, and being called XMRV antibodies (when they were not), be actually finding activated HERVs? That would be a cross-reactive false finding, it does not identify the role of HERVs in CFS, they could be harmless. However, if present and if cross-reactive with MuLV they could be creating false positives on antibody studies, and many of tests run by WPI relied on those MuLV antibodies.

you dont base a hypothesis on rumours kurt but observable facts a specific anti body response to xmrv env was OBSERVED The significance of that may not be apparent to a layman but would be immediately apparent to anyone with qualifications in this area

The entities isolated were genotyped that ruled out a herv .XMRV was differentiated from all known hervs by urlisman who originally discovered the virus.The idea of herv involvement is an interesting one.It is not a hypothesis however becuae it is not consistent with any in vivo observations infact the idea conflicts with such observations
 
G

Gerwyn

Guest
I very much appreciate Kurt laying out in detail his ideas about XMRV and HERV's - I learned quite a bit.

In science nothing is ever fully established. vertical transfer has been.The virus has also been found in very high titres in saliva and semen.Sexual transmission is a hypothesis consistent with observable FACTS

The observation of cytokine involvement is consistant with the observable fact of XMRV infection Other hypotheses are not consistent with the sum of the observable facts

epidemiology is a complex area.Very few people judge isssues on the basis of appearance
 
G

Gerwyn

Guest
Thanks Knackered, yes I know that was a joke, and I did give the opportunity... argh. But shall we say, just poor sportsmanship?

Regarding your other comment, challenging a scientific finding like XMRV is not challenging the reality of your illness. XMRV is just the latest in a very long string of proposed explanations for CFS. For the record I am a die-hard believer in an organic cause for CFS. But I also have been around long enough to know that things are not always what they appear to be, and lots of flags went off in my head when I started evaluating XMRV. I was quickly out of my league so enlisted the help of others in understanding things. Gerwyn thinks I had the wrong experts, and I don't know, he was a lab technician of some type in microbiology and knows those processes, has apparently run those types of tests. Is he the real expert here? Again, I don't know, but what I do know is that this is science and there are some requirements for the scientific method, and the scientific consensus process, and unless we go through that process we are just gambling by believing that a given explanation like XMRV is the only valid cause of our illness.

So I am not trying to be vitriolic (but maybe come across as oppositional sometimes? my wife might agree with that). Sorry if you feel that way. Here for the record is a short list of my concerns. I would love to see HONEST assessment by those here of these issues, not just dismissing them with a few inspiring words as usually happens. LOOK into this and if these are not to worry about then fine, I won't bring them up again. Promise.

OK, I'll post my concerns separately. Have at it!

There are indeed requirements for the scientific method constructing hypotheses based on observable facts and not supposition is one of them.

As there are stringent requirements involved in the scientific method it is frankly astonishing that the European researches engaged in such flagrant departues.
 
G

Gerwyn

Guest
3. Looking further at HERV expression I learned that they were already being studied for CFS. Note that this is separate from the possibility that HERVs might be interfering with the antibody studies. There was actually a causal model for HERVs in CFS, including studies at Tufts by Dr Bridgette Huber into HERV K18, which is believed to be triggered by HHV infection.



So that is interesting, particularly if WPI found HERVs and not XMRV by the MuLV antibody study. That could be big news given the high rates of positives.

Also I learned that glutathione depletion might play a role in all this, as glutathione levels apparently interact with HHV infection status. At normal glutathione levels herpes can not replicate, but once herpes is active it actually depletes glutathione. So I reasoned that if something was initially depleting glutathione in CFS, such as high oxidative stress from a chronic enterovirus, and if the person has weak methylation genetics as Rich has proven we have, then might that start a vicious cycle that helps activate HHV? The combination of poor methylation, low glutathione and HHV might be activating the HERV. Adequate methylation in the cells is essential for keeping HERVs from expressing.

I guess this point is not so much a concern as an alternate hypothesis for why there would be HERV expression in CFS, if that was what the MuLV antibodies were finding. Also this suggests there might be a causal model for HERVs in CFS in which case the WPI study might have inadvertently revealed some new and important information about CFS pathogenesis and the high rate of HERV activation in CFS.

I can give more references if anyone like, but they are not hard to find. The most groundbreaking work right now for HERVs in disease is probably in MS research. One recent study found high levels of HERV W in the brains of MS patients (tissue studies, not blood), and no expression at all in controls.



So while some HERVs are probably harmless, some maybe even helpful parts of a DNA 'immune response' as Gerwyn has pointed out, some may also be pathogenic. Therefore their presence in CFS is noteworthy. The fact they can be sometimes found with MuLV and the fact they are active in CFS is also noteworthy in light of the WPI study.

not consistent with any observable in vivo observations kurt thus an invalid hypothesis
 
G

Gerwyn

Guest
Kurt - Like everyone else, I was very hopeful that XMRV would prove to be the cause and that a test and cure would quickly follow. That euphoria and optimism lasted a couple of days, then it was back down to earth, and I am glad that you have helped keep my feet on the ground. You have not - in my opinion - been trying to pour cold water on people's hopes, but simply to issue a warning that if our hopes rise too high, they risk crashing hard, taking countless patients with them. IOW, you have been a wonderful counter-balance and I hope you keep posting your views and that others can see them for what they are - another view, as yet neither proven nor disproven, but just as necessary as the unbridled optimism many of us felt just a few short months again.

not consistent with any in vivo observations of course
 
G

Gerwyn

Guest
4. The epidemiology of CFS is strange. We have both outbreaks and individual cases. And both sudden and gradual onset. Some familes have several cases, some have only one. Most partners of CFS patients are not sick with CFS, although a few are and some have other illnesses. Here is the concern, if CFS was a blood-borne disease, like an exogenous retrovirus, that would have been obvious in the epidemiology right from the start, it would be clear CFS was either an STD or had vertical familial transmission. And MuLV type retroviruses are identified in the literature as requiring blood transfer. So for XMRV to be causal for CFS, all CFS patients would need to have a transmission vector that was harmonious with the type of virus involved. Some have suggested that XMRV might be a breakthrough retrovirus that has other transmission vectors. That would make sense if XMRV were the cause of CFS/ME, but it would be a novel finding for that type of retrovirus.

One other point on epidemiology is that prostate cancer patients generally do not develop CFS.

I have raised the epidemiology point before but the general response has to be dismissive without providing any contrary facts or evidence.

Gamma retroviruses are all inactive in the blood Kurt .That does not mean that they can be transferred that way No it would not be obvious from the epidemiology

you have raised the epidemiology issue before but not supported by any facts or indeed evidence.you cant provide something contrary to something that does not exist in the first place

the "epidemiology issue" you have raised refers to observations easily explained by a virus with a COMBINATION of veritcal and horizontal transfer like any other retrovirus.MuLV included.Mulv does not ONLY

infect via direct blood transfer.i am suprised you did not know that.Mice of course do bite sometimes
 
G

Gerwyn

Guest
I have just realised that there are a lot of terms on this thread that lay people would have difficulty in understanding too say the least One of the areas under discussion referrs to HERVS.

The following is some information to make following the discussion easierEndogenous retroviruses (ERVs) are retroviruses derived from ancient viral infections of germ cells in humans, mammals and other vertebrates.

In case there is still some confusion a HERV is not an antigen

Endogenous retroviruses can persist in the genome of their host for long periods

However, they are generally only infectious for a short time after integration as they acquire 'knockout' mutations during host DNA replication. They can also be PARTIALLY excised from the genome by a process known as recombinational deletion. They play a key role in evolution

Human endogenous retroviruses (HERVs) are suspected of involvement in some autoimmune diseases, in particular with multiple sclerosis. In this disease, there appears to be a specially associated member of the family of human endogenous retrovirus W known as "MS-associated retrovirus" (MSRV).[7] [8]
There are many thousands of endogenous retroviruses within human DNA (HERVs comprise nearly 8% of the human genome, with 98,000 elements and fragments[9]).


All appear to be defective, containing nonsense mutations or major deletions, and cannot produce infectious virus particles.

This is because most are just long-lasting traces of the original virus, having first integrated many millions of years ago

. However, there is one family of viruses that have been active since the divergence of humans and chimpanzees.

This family, termed HERV-K (HML2), makes up less than 1% of HERV elements but is one of the most studied.

There are indications it has even been active in the past few hundred thousand years, as some human individuals carry more copies of the virus family than others.

But the absence of known infectious members of the HERV-K(HML2) family, and the lack of elements with a full coding potential within the published human genome sequence, suggests that the family is less likely to be active at present.[10]
 

ukxmrv

Senior Member
Messages
4,413
Location
London
Do people here want to hear more on this line of thinking, challenging the original XMRV finding? If not, I will stop posting on the subject

==============

Kurt, I am very happy for you to continue. My main problem is that your postings are so long that it takes me a long time (and is a huge investment of my limited energy) to read them. When I do not everything is necessarily relevant (in my opinion).

There is also a mix of fact and your opinion that also takes time to work through.

Would it be possible for you to write a prcis of an idea or a paper in a simple manner and then let people read the originals in their own time (if they wish)? I have been doing this and appreciate the references that you have posted a great deal.

Would it also be possible for you to separate the facts and the opinions into different postings so they are clear i.e. post a prcis to a reference and then in another posting your interpretation of it?

I ask this most respectfully and as a favour. There will be no offense if it is not feasible. Thank you.
 

Adam

Senior Member
Messages
495
Location
Sheffield UK
I posted this under Cort's Muddying the waters article. I decided to post here to as it directly relates to this thread.

Hi Cort

As always you have put together another great piece of journalism. Each article dovetailing nicely with the last. There is a but here. I bet you could sense it coming? It's the following paragraph I found out of kilter with the all the others.

Kurt has brought forward another more disturbing possibility; that the validation study results thus far are correct and that XMRV is not found in CFS…but something else is. In this scenario XMRV shows up in those original uncultured samples and then disappears in later uncultured samples and then appears to reappear in cultured samples because the culture process itself is bringing something else out patient's blood that looks very much like XMRV. This is a kind of ‘ inadvertent but possibly very lucky’ scenario in which WPI researchers do possibly find an important factor in ME/CFS - just not the one they were looking for. It’s all speculation at this point; with a new set of studies reportedly about to be reported on, XMRV is at a fork right now; the path it ends up traveling down is still encouraging wreathed in the fogs of the future
.

I have followed Gerwyn and Kurt (and others in the HERV thread), and, whilst I admit I am more than a little biased in favour of XMRV being the cause of CFS/ME (Judy M speculates, and is clear that she is doing so, that she thinks most people with CFS/ME will have the bug) I did not find anything compelling in the pro-HERV argument. From what I can discern, using my less than scientific take on matters, this is highly speculative. It might be best to be a little more clear about this in the article, when you say, 'Kurt has brought forward another more disturbing possibility...'

I understand you wish to achieve balance, but on that basis any number of speculative theories could have made it into the article. If the pro-HERV theory is indeed gaining any credibilty, then it is incumbent upon you to cite a couple of well regarded sources (no offence to Kurt) to back this up.
 
G

Gerwyn

Guest
I posted this under Cort's Muddying the waters article. I decided to post here to as it directly relates to this thread.

Hi Cort

As always you have put together another great piece of journalism. Each article dovetailing nicely with the last. There is a but here. I bet you could sense it coming? It's the following paragraph I found out of kilter with the all the others.

.

I have followed Gerwyn and Kurt (and others in the HERV thread), and, whilst I admit I am more than a little biased in favour of XMRV being the cause of CFS/ME (Judy M speculates, and is clear that she is doing so, that she thinks most people with CFS/ME will have the bug) I did not find anything compelling in the pro-HERV argument. From what I can discern, using my less than scientific take on matters, this is highly speculative. It might be best to be a little more clear about this in the article, when you say, 'Kurt has brought forward another more disturbing possibility...'

I understand you wish to achieve balance, but on that basis any number of speculative theories could have made it into the article. If the pro-HERV theory is indeed gaining any credibilty, then it is incumbent upon you to cite a couple of well regarded sources (no offence to Kurt) to back this up.

no it was xmrv the genotyping clearly proves it.Anyone is allowed to imagine whatever they like of course.
 

MEKoan

Senior Member
Messages
2,630
Kurt, I am very happy for you to continue. My main problem is that your postings are so long that it takes me a long time (and is a huge investment of my limited energy) to read them. When I do not everything is necessarily relevant (in my opinion).

There is also a mix of fact and your opinion that also takes time to work through.

Would it be possible for you to write a prcis of an idea or a paper in a simple manner and then let people read the originals in their own time (if they wish)? I have been doing this and appreciate the references that you have posted a great deal.

Would it also be possible for you to separate the facts and the opinions into different postings so they are clear i.e. post a prcis to a reference and then in another posting your interpretation of it?

I ask this most respectfully and as a favour. There will be no offense if it is not feasible. Thank you.

I would like to second all points in this request.

Personally, I find it very difficult to distinguish fact from opinion in your posts, Kurt, as there is little indication which is which. This is a style issue, I understand, but because of it I am disinclined to read your posts. Also, as we have discussed, I find the issue of uncredited sources problematic.

That said, nowhere is it written that you must write in a style that everyone can understand. I certainly can't manage it myself!

Peace out,
Koan
 

Cort

Phoenix Rising Founder
I know what you're saying UKXMRV but I question - as you noted - whether its feasible. We all have CFS and I imagine it takes Kurt deal of time and energy to put these posts together. I would note that much of what we post on these forums is opinion. I do recognize that because Kurt is posting some kind of hard hitting stuff that you want to be sure to separate the two - but you may asking too much.

Thanks for getting that stuff on HERV's Gerwyn!

The genotyping was done during the Science study -when they were able to find XMRV without using culture or activating cells - possibly a different situation than we have now. I did note that the WPI is continuing to sequence the XMRV they find; this is a check on their original findings and will tell us whether its a HERV or something else. One would think they must know by now- and again we're not seeing any retractions or any sense that things are falling apart.

Adam I agree that the HERV argument is pure speculation. The important part of that blog for me is not whether HERV's are present or not but why the shift occurred from not needing to activate the cells to find XMRV to needing to activate the cells in order to find XMRV. If I got it right and I assume I did - Gerwyn would have corrected me by now - something rather dramatic changed. Why did the virus get so much harder to find all of a sudden? It puts Dr. Mikovits lambasting the other research groups for not culturing the virus - when there was no evidence I could find - of the WPI doing that - in a rather strange light. Maybe she communicated with them after the paper came out. In fact she told me that she told the Imperial Group how difficult it was to find the virus...so they were warned.

Kurts theory is one to explain that strange situation.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
I think we need to lighten up a little on Kurt.

Much of what has been discussed on these threads is speculation, whether it be on cohorts, assay techniques, researchers motivations, whatever, perhaps informed speculation, perhaps not. I'm not in a position to tell. In fact without speculation, these threads would have ended between the last published XMRV article and the next one to come.

As ably outlined by Cort, the picture on XMRV is pretty mixed at present. Some issues remain unexplained and all we are doing is trying to fill in the gaps in the absence of more solid information. Personally I'm happy that Kurt, or anyone else, is offering up alternative interpretations of the findings. If XMRV doesn't turn out to be the culprit, or what they found wasn't XMRV, then I'd like to think there are alternatives to going back to Wessley/Reevesville.

Kurt has been asked to indicate what is fact (sic) and what is speculation and or opinion, and to provide references. Why single Kurt out?

The dialogue here has largely been between Kurt and Gerwyn. To be perfectly honest most of Gerwyn's contributions are like alphabet soup to me. I don't have the background and, while I might understand the science in time, frankly I don't have the inclination as I don't feel qualified to offer an opinion. Kurt has described his background and its limitations. As far as I'm aware, Gerwyn has self described himself in correspondence as a psychologist and has stated on this thread that he has educated himself on virology. I have to ask if this makes Gerwyn any more qualified to speak on the subject than anyone else, in fact he could be a complete nutter.;) As could we all.

As for references, this was Gerwyn's response to the first post on the Interactions between APOBEC3 proteins, HIV-1, and XMRV at NIH on April 1st thread :

cell cell transfer is another way of doing it

What is one to make of that? Is this speculation, opinion, where's the reference? I'm sure he's right but how can I tell?

PLEASE Gerwyn, this is not a personal attack on you, your expertise or your integrity. But you must appreciate that I take any statement made on this forum, that does not originate from a relevant professional, with a little pinch of salt.

Either require anyone posting here to specify fact, opinion, rumour etc and fully reference any statement claimed to be fact, or don't. Personally I believe it would stifle many interesting discussions.
 
Messages
13,774
I think we need to lighten up a little on Kurt.

Much of what has been discussed on these threads is speculation, whether it be on cohorts, assay techniques, researchers motivations, whatever, perhaps informed speculation, perhaps not. I'm not in a position to tell. In fact without speculation, these threads would have ended between the last published XMRV article and the next one to come.

I've also noticed that people are happy to hear positive sounding rumours, but not the negative ones. We should be really careful not to let ourselves filter information in this way, as it could end up creating a misleading impression of how likely XMRV is to work out.

Intellectually, I think I'm quite sceptical about it, but emotionally I can feel that I'm still pretty attached to XMRV working out. Voices like Kurt's have been vital for keeping my feet on the ground. I want to be prepared for bad news if it comes (especially because I'm less positive about the other avenues of CFS research being explored) as well as the possiblity of good.
 

ukxmrv

Senior Member
Messages
4,413
Location
London
Kurt has been asked to indicate what is fact (sic) and what is speculation and or opinion, and to provide references. Why single Kurt out?

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

Marco, If you go back through the discussion you will see that Kurt very kindly asked us to comment

I am not asking (very respectfully and with thanks) for Kurt to reference everything he says. I think that he does a great job of that already. What I am asking is for Kurt to split up the great quotes and references so I can tell which are that and his own very worthy and useful opinions and comments

He is not being singled out by me and this is entirely a question of my not being able to read the link between the two sometimes in his posts (and only because he asked) and entirely my own fault. There is one other contributor to this forum that I do not understand as well (and I will feed back if they ask me to).

I cannot always follow his reasoning and see how he arrived at a point of view. I am also aware that sometimes we do not agree, that things can get heated, but his concerns are valid and I want to be able to follow them

As I said if it is not feasible that's fine with me and I will understand. I will not be commenting further and I apolgise if I have caused any offense.
 

Adam

Senior Member
Messages
495
Location
Sheffield UK
I've also noticed that people are happy to hear positive sounding rumours, but not the negative ones. We should be really careful not to let ourselves filter information in this way, as it could end up creating a misleading impression of how likely XMRV is to work out.

Intellectually, I think I'm quite sceptical about it, but emotionally I can feel that I'm still pretty attached to XMRV working out. Voices like Kurt's have been vital for keeping my feet on the ground. I want to be prepared for bad news if it comes (especially because I'm less positive about the other avenues of CFS research being explored) as well as the possiblity of good.

Esther. If there are positive rumours about XMRV I would LOVE to hear them. All I have heard is negative rumours on the back of failed studies. I am capable (though not scientifically minded) in an intellectual sense to be able to accept rumour, exactly for what it is. I have also said on many occasions that a dissident voice is essential to the debate. But that is all this is - debate. We can argue this back and forth till doomsday and it won't make one iota of difference to what Mikovits, Silverman, Lombardi et all are doing right now. Which I understand is scientific research.

Adam I agree that the HERV argument is pure speculation. The important part of that blog for me is not whether HERV's are present or not but why the shift occurred from not needing to activate the cells to find XMRV to needing to activate the cells in order to find XMRV. If I got it right and I assume I did - Gerwyn would have corrected me by now - something rather dramatic changed. Why did the virus get so much harder to find all of a sudden? It puts Dr. Mikovits lambasting the other research groups for not culturing the virus - when there was no evidence I could find - of the WPI doing that - in a rather strange light.

Cort. I thought this had been answered by Gerwyn. Wasn't it to do with the move from the research stage to developing a viable commercial test?
 

MEKoan

Senior Member
Messages
2,630
Intellectually, I think I'm quite sceptical about it, but emotionally I can feel that I'm still pretty attached to XMRV working out. Voices like Kurt's have been vital for keeping my feet on the ground. I want to be prepared for bad news if it comes (especially because I'm less positive about the other avenues of CFS research being explored) as well as the possiblity of good.

It's so interesting, but not at all surprising, how we each move through this process differently.

Personally, I'm less skeptical regarding the first XMRV study but I am also less emotionally invested in XMRV being "the answer". Initially I felt that everything hung on that one finding but I don't any more.

XMRV energized this community - patients, activists, physicians, researchers, media... we are on the radar in a way we have not been since Tahoe. It's not all good noise, for sure, but much of it is. We have so much more awareness and, should XMRV fail to live up to its promise (I don't think it will fail, myself), we have the Light studies, and others, which are very interesting.

So, I am feeling very positive about XMRV being the key to what's ailed me for three decades but I won't be shattered if it's not. I know that, unlike the situation with Elaine DeFreitas, there are people working on our behalf now who will not, and cannot, be shut down.

I'm also acutely aware of the subtle changes in language being adopted by all the psychologizers - they are being very, very careful to inch closer to the tree on that limb they've been out on for so long. Why is that?

Everything has changed. Dig in your heels, folks, and just don't let anyone change it back!
 

Cort

Phoenix Rising Founder
Cort. I thought this had been answered by Gerwyn. Wasn't it to do with the move from the research stage to developing a viable commercial test?

I don't think that Gerwyn or Dr. Yes have responded to the my understanding that, based on a reading of the Science document, the WPI didn't activate or culture the cells for the PCR tests for the Science paper. My reading suggests that they were able to find the virus without culturing at that point.

Now, however, they state that culturing is absolutely needed and that any studies that do not culture will not find it.

That brings up two possibilities that I, a laymen! can see - the virus was found in much smaller quantities in the second group they tested (ie Dr. Vernon is on the mark with her concerns about how untypical that first group might be). This would be a nice solution - XMRV is there but its more difficult to find than expected.

I think there are problems with this solution; I just don't think researchers are stupid and I don't think they like to be proved wrong; I think the first studies tried to find the virus and couldn't. They all showed that they could detect XMRV in low levels and yet couldn't find it in their samples. I know there are lots of factors involved; the primary one, though, seemed to be the lack of activation - so when it became clear that the WPI didn't activate their cells either - this made me think this factor is not so important. I know there are more questions about the first two validation studies but it removed some doubts about them for me.

It could still be that XMRV is present in the blood of very ill patients but not in the blood of less patients. This is apparently Dr. Vernon asked the WPI to provide more info on those patients; she feels that the hunt for XMRV is going to stop unless they get some positive results.

or as Kurt pointed out:

The culturing process itself is bringing something out in the CFS blood samples (but not the controls) that looks very much like XMRV but is not actually the bug.

In any case, I have a feeling this will all be moot soon as more studies pour out.
 
Messages
13,774
If there are positive rumours about XMRV I would LOVE to hear them.

There was a thread about AZT with a positive rumour about this - not that I would remotely like to encourage any CFS patient to go on AZT at this time. Timothy Luckett's blog had a very positive sounding rumour that I lot of us were excited by last October. But there's been a lack of recent entries.

@ Koan: I've been really relieved by the way the scientific community has been talking about CFS. At first I thought that if XMRV did not pan out it would mean we would be even worse off than we were before - another sign that it's pointless doing research with CFS. Where as it seems that it has gotten a lot of people to learn a little about CFS, and realise that the way it's been treated up until now is just quackery.