Hypothesis piece by Amy Proal, a microbiologist with ME/CFS

Hi Jonathan,

Someone referred me to this comment today. I'd like to clarify: you're suggesting that my writing a blog post about ME/CFS and persistent infection is "phoney science?" and that my work has has eroded science "to the extent of being worthless?" What a ridiculous and sad thing to say. If you want to disagree with the science in my post I totally understand - but to insinuate that I'm a bad person...you're doing a great disservice to other patients on this board who seek to approach the latest research on the human microbiome, persistent infection and chronic inflammation with an open mind. PS: Many ideas in the blog post are now published in this paper in "Advances in ME/CFS Research and Clinical Care." The paper has been very well received and while, of course, other researchers often have questions about the paper, not one of them has ever brought up your "concerns" - for example that ME/CFS is not an inflammatory disease or that there's strong evidence against chronic bacterial infection (there is actually strong evidence for both statements):

https://www.frontiersin.org/articles/10.3389/fped.2018.00373/full

 

Also, my paper does not contend that colonic bacteria are good for us...try reading it again and see if you can interpret it correctly

 

Trish hey! This is an excellent summary of several of the main points in the blog post. Thank you for reading carefully and for taking the time to help others better understand what I'm saying!

 

I have not said you are a bad person, Amy. I just think you have been carried along by the tsunami of phoney science that passes for real science these days.

No there isn't Amy. I trained under Spector and Willoughby in inflammation research in the 1980s at Bart's (the hub of European inflammation research). I was a founder member of the British Inflammation Research Association. I worked all my life on inflammation. There is no evidence of inflammation in ME. The so-called evidence comes from people who never studied pathology. There is no evidence of chronic bacterial infection. I realise you may be wedded to these ideas. However, I did try to make it clear in the post you quote that I was trying to be constructive despite the fact that I didn't think you had any evidence base.

This isn't real science. The terrifying thing is that there are so many people around who think it is and cheer each other on. Lots of people will show interest, but that doesn't mean it means anything.

If we want to crack ME we need to be critical - and that means a level laying field for BPS and leaky guts.

 

There are too many errors in this post for me to know where to start. For example, no one on the Marshall Protocol has to avoid sunlight. We we just tried to be very conscious of the fact that many patients were very sensitive to light (on both their eyes and skin). The treatment does require avoidance of vitamin D supplementation under very specific circumstances. If you want to better understand what we actually did, please read this journal article on the treatment...that has also been generally well received. The paper features case histories of patients on the treatment and explains the true rationale for supporting the immune response in ME/CFS. Also, if anyone wants a free copy of the full PDF I'm happy to send it to you:

https://www.ncbi.nlm.nih.gov/pubmed/23576059

 

Jonathan hi,

Your comments don't even make sense to me anymore (research on inflammation has changed since the 1980s). I'm going to get back to work

 

This is very interesting. Would an adenosine singling disorder create PEM--this nightmare symptoms after any slight exertion? And would this kind of disorder put ME into the category of Alzeheimer, MS, Bipolar,Schizopherenia?

And it seems coffee affects adenosine receptors, but it doesn't seem to help the ME?

Are there any promising medications which could help with such signalling gone wrong?

 

Perrier hi,

There is a growing overlap between ME/CFS and Alzheimer's/Parkinson's/Schizophrenia. A key factor linking the conditions is growing evidence of persistent infection in various body sites, including new discoveries which suggest that pathogens in the brain itself may drive much of the neuroinflammation associated with Alzheimers.

I recently spent time at Harvard with Rudy Tanzi's team looking at evidence for the "Brain Microbiome Project." Here's an article that describes their research looking at how multiple pathogens may act together to drive brain inflammation in Alzheimer's:

https://www.the-scientist.com/news-opinion/herpes-viruses-implicated-in-alzheimer-s-disease-64246

During that same trip to Harvard I spent time with Mike VanElzakker's team who are characterizing neuroinflammation in patients with ME/CFS using fMRI brain scans. While their data isn't published yet, I've spoken with Jarred about his team findings on ME/CFS neuroinflammation, of course, we see strong early evidence that brain inflammation is involved in the condition.

I have a meeting with OMF's Chris Armstrong this Thursday to discuss these and related findings, and to get samples needed for another collaboration I'm trying to set up with David Paez-Espino's team at Cal Berkeley. We're hoping to do a study a looks for novel viruses in patients with ME/CFS using computer tools that have not yet been used to analyze samples from patients with the illness. Here's an interview with David if you are interested in better understanding more about the many new viruses currently being discovered in the human body and how to best identify them:

http://microbeminded.com/2018/06/12/david-post/

Best,
Amy

 

Thank you for your detailed response. From what you write there is infection and inflammation. The latter(neuroinflammation) is virtually impossible to control with the meds we now have. How would all this connect with adenosine signaling problems. As for "novel" viruses. This is really an exploration if these are viruses which are unknown yet.

For the severely ill this is all looking like a frightening movie.

thank you for your response.

 

Perrier hey,

I didn't mean to confuse you about adenosine signaling issues. That is not a topic I'm familiar with and hopefully Jonathan can answer you more there.

But as long as you brought up Alzheimer's etc I thought I'd chime in with some thoughts and research updates. You are very right that "novel" viruses simply refer to viruses capable of persisting in the human body that we didn't have the knowledge and/or technology to detect before!

I'm very sorry you're severely ill and I definitely understand how this research seems daunting. Also how it might make treatment options seem harder in the short-term. In terms of treatment, I spoke with Rudy and team at Harvard about how they are approaching that in Alzheimer's. Their goal is to create some treatments that inhibit the activity of immune cells tied to neuroinflammation (these include mast cells, microglia etc). Such treatments might not target root cause (the infection) but could go a long way in providing symptom relief and allowing for better daily functioning. They already have several of these drugs in trials. I also know that Jared Younger is thinking of creating some similar options for ME/CFS.

Then, there's a second effort: if we can better identify pathogens driving the inflammation, we could create drugs that either kill them or block/contain their activity. For example this team recently identified the bacteria p.gingivalis in the Alzheimer's brain and is developing a treatment to target toxic enzymes created by p. gingivalis:

https://www.ncbi.nlm.nih.gov/pubmed/30746447

Some pathogen-targeting treatments might involve a herxheimer response and it would be up to the patient to decide if that's something they want to take on. However, it may also be possible to develop drugs/supplements that help manage a herxheimer response (removal of toxins from blood etc). In addition, treatments that support the immune system to target pathogens are also in early development. For example this group in Australia is developing an immunotherapy that helps patients with MS target Epstein Barr virus. The results of their first small trial are encouraging. The treatment could be re-purposed for ME/CFS since Epstein Barr is often a "player" in both conditions. Or maybe it could be re-purposed to help the immune system target other related pathogens tied to ME/CFS.

https://msra.org.au/news/anti-ebv-trial-shows-promise-in-progressive-ms/

Those are just a few examples, and I realize that none of them can help you right now and I'm sorry:/ But I do have some hope for the future.

Hang in,

Amy

 

I would refer everyone to the research of Dr. Judith Miklossy. Her efforts may be relevant to this discussion, eg, Alzheimers and other dementias and oral bacteria and spirochetes.

 

Is it possible to have inflammation and a low ESR? I have always been puzzled by this but admit to not really knowing much about it.

I know some ME "specialists" have sometimes observed that low ESR is common in ME and my ESR has always been low (often 1mm/hr). Does this fit with inflammation?

 

A convenient answer.

Well, that must be the 2019 version. So now the sun is good, no one has to avoid it. That's funny...

The fact remains that anyone with half a working brain like myself can find the history of the MP and even some of the original pages of it's original site where it is repeatedly drummed into everyone's head to avoid sunlight because it produces...gasp...the Evil Vitamin D...which will...gasp...suppress one's immune system (which is not true).

Anyone can google 'Marshall Protocol" and "sunlight" and find these pages. They can also google "Marshall Protocol" and "dangerous" or "risky" and find dozens and dozens (if not more) of former patients in the comment section talking about how the MP ruined their health. I could post a dozen in less than five minutes but I believe that links to or quotes from other pages aren't allowed on S4ME.

Sorry Amy, not interested in the least. Your 'science' is all backwards as has been pointed out here and on many sites over the last 15 years, despite your valiant efforts. And if it worked, the MP would be thriving all over the net, especially on Facebook where these things tend to get hyped up and followed by desperate patients. Instead, the opposite has happened. Even Meg Carlson and Co has given up shop.

As I've stated before, I know a half dozen people in our small local support group who tried the MP back in 2005-2006, and NONE of them had any benefit. In fact, one of them almost died of kidney failure because despite the fact that tests showed her kidneys were starting to fail, the MP Cheering Squad insisted that she was just going through a 'herx', and needed to stick with the program.

I for one am glad she didn't.

 

I find the blog post of the topic very interesting, so please continue researching the microbiome and its relation to ME/CFS. There are now several leading researchers in ME/CFS who think that changes in microbiome drive the disease, among those Dr. Armstrong, Dr. Lipkin and Dr. Unutmaz who are all involved in major research collaborations.

I don't think there is evidence that Marshall Protocol in particular would solve these issues, but let's not shoot down someone for being involved with it decades ago. It was only 9 years ago that everyone in the ME/CFS community thought they had XMRV and started pursuing antiretroviral treatments for it. Before that it was EBV and antiherpesvirals, etc. Ultimately all that turned out to be wrong, but being wrong about something in the past is the rule rather than the exception in science, especially in medical science and poorly understood conditions. If we are trying to stop every researcher who has once upon a time has been wrong, we are left with no one to help us.

 

Thank you, I did. It looks like "Dr" Marshall (actually a Phd in electrical engineering and no medical training) has produced a complete pile of quackery. Here are a couple of many descriptions:
http://www.cureality.com/blog/post/2008/03/31/the-marshall-protocol-and-other-fairy-tales.html
https://sciencebasedmedicine.org/the-marshal-protocol/

I don't know where you got that from, links and quotes are fine.

That's easy enough to check too. From the Marshall Protocol website itself:
https://mpkb.org/home/lifestyle/light/photosensitivity

Looks to me like lots of people on the Marshall Protocol are advised to avoid sunlight.

Having skimmed the article in the OP, my first impression (and last, because I'm not reading it again) is that it seems to make some bold claims based on flimsy evidence or references to papers which don't exactly support the claim being made. For example, from the article:

That claim links to this paper about mice:

https://www.ncbi.nlm.nih.gov/pubmed/11855293

Which seems like a bit of a leap to me.

Another example - this paper:

https://www.ncbi.nlm.nih.gov/pubmed/27855721

With this conclusion:

Resulted in this claim in the article:

I would also have been an idea for Amy Proal to disclose that she has published papers and written book chapters with Marshall, for example:

http://www.discoverymedicine.com/Am...robiome-dysbiosis-and-inflammatory-processes/
https://pdfs.semanticscholar.org/25...51.565757622.1542418245-2138440345.1527204293

Sorry, anyone who teams up with such a complete quack can't expect much credibility here.

 

And this:

http://www.discoverymedicine.com/Am...nflammatory-disease-and-the-human-microbiome/

And this:

http://autoimmunityresearch.org/preprints/Proal_2013_CurrentOpinion-Preprint.pdf

And this:

http://autoimmunityresearch.org/preprints/Proal_MHB_Chapter_preprint.pdf

And all of this:

http://microbeminded.com/my-research/

@Amy Proal why don't you invite your friend Prof. T.G.Marshall Phd here - we'd love to have a chat with him.

 

By the way @Amy Proal, can you tell us a little more about the Autoimmunity Research Foundation?

I notice on this paper:

http://www.discoverymedicine.com/Am...nflammatory-disease-and-the-human-microbiome/

Two authors, Marshall and yourself, give their institution as the Autoimmunity Research Foundation.

When I google it, the only hit is this page from the Marshall Protocol website:

https://mpkb.org/home/arf

And when I make it to the Autoimmunity Research Foundation itself, it refers back to the Marshall Protocol website:

http://autoimmunityresearch.org/resources/

(some interesting videos on that page by the way).

The two sites even share the same logo. Is the Autoimmunity Research Foundation an organisation set up solely to promote the views of TG Marshall, and why do you list it as your institution on published papers?

 

Only a handful, relatively speaking 'started pursuing antiretroviral treatments'. And I for one never thought I had that silly contamination. Mikovits was an embarrassment within a month of her 'discovery'. The last few years she's completely jumped the shark, appearing on obscure talk radio and youtube channels promoting her conspiracy theories without an ounce of proof. I feel bad for her...

We're not shooting down Marshall for 'being involved in it decades ago'. We're talking about TODAY, where he and his (sole?) associate, Amy Proal continue to push or promote this dangerous protocol -- creating new websites and their own journal(!) in order to keep the 'talk' out there.

 

Thanks for posting many of the links, websites @TiredSam. I wanted to just point out some of the testimonials, albeit anecdotal, from folks who became a lot worse after the MP, and were ignored or belittled by Marshall and his troops at least up through 2010-2011, when they shut down the original MP site (too many complaints, too many unanswered questions) and started the 'new' one that you've linked to above.

At least they now list many warning and risks regarding the MP, something that was verboten prior to...well, either 2015 or last October, when this page was last updated:

https://mpkb.org/home/starting/safety_warnings


Anyway, here are snippets from testimonials taken from the comment section on this page:

https://articles.mercola.com/sites/...y-i-dont-recommend-the-marshall-protocol.aspx

"I have CFS and was on the MP for almost 2 years. Whilst I initially experienced some benefits from the antiinflammatory nature of Benicar anad Minocycline, my symptoms progressively become worse and worse. I was constantly told that this was just 'herxing' and that it was a good thing. Finally my health wasa so bad (almost got carted off to ER) that I had to stop only to find out that when I went off the medication all those 'herx' symptoms stayed. It wasn't baacterial die back at all it was disease progression. Now I am a vitual cripple. I am bedbound 21 hours a day, experience parathesia, neuropathy, caridac pain, breathing difficulties, tinnitus (I had none of these symptoms preMP) and all my previous symptoms like fatigue, joint pain etc.. are much worse."


"I personally was one of the earliest adopters of the MP for CFIDS and fibromyalgia. MercNoNuts, you can find me on the original Chicago DVDs hosting a presentation with Belinda on how the MP works for patients and I was on a panel on their LAX DVDs. Mercola sat in the audience. I was posted on bacteriality.com a few years back as one of the CFIDS people recovering (I saved a copy) but asked Amy to pull the interview from her site after a severe RELAPSE of which I was told was only "part of the healing process and return to recovery" which was not the case."


"I wholeheartedly agree with Dr Mercola that the MP is harmful and can be dangerous to many people. I know many of them, including myself, that have been much sicker than before we began many years later! Some even died."


"I am one such ex-MP patient, having been on it for almost 2 years in an attempt to recover from CFS. I am now virtually a cripple as a result of the Marshall Protocol. While I had some initial improvements due to the antiinflammatory effects of Benicar and minocycline, I progressively felt worse into Phase 2 and 3. I persisted as I was constantly told that these symptoms were a herx and a 'good thing'. After nearly ending ending up in ER, I went off the MP and to my horror realised that the 'herx' symptoms have persisted. They were not baacterial die back at all, but a progression of the disease. I now have a host of new symptoms and all the old ones are worse as well. I am now bed bound 22 hours a day, experience new symptoms of neuropathy, parathesia, breathing difficulties, cardiac pain, tinnitus as well as a worsening of the old symptoms such as fatigue, muscle joint pain, sleep disturbances etc..."


"I was on the MP for a year, and have to say that the ones who weren't recovering as they were supposed to, were simply dismissed. There is no follow-up by Marshall or any of the moderators when this happens with these participants. On the recovery panel DVD put out by Marshall's Autoimunity Research Foundation, there were 5 people on that recovery panel. Of the 5, one of the members is dead, one had a full-blown relapse and quit the protocol, leaving three. I personally spoke with one of the remaining three, and this particpant was still debilitated at last notification I'd received via phone conversation. Not to mention my own fiasco with this protocol. I was hospitalized, as are many that decide to go this route for treatment of their illness."


"I was a vigilant follower of Marshall Protocol for almost 2 years, having suffered multiple "autoimmune" conditions since childhood. My health became precipitously worse on the MP. My doctors now believe I should never have taken Benicar, especially such high doses, and that I never should have allowed my 25D levels to drop to dramatically sub-optimal levels. Both of these MP strategies wreaked havoc with my immune system. I am aware that many with Sarcoidosis have improved on the MP. I didn't have Sarcoidosis and should have been wiser when my health took a turn for the worse on MP -- unfortunately I was led by moderators to believe my numerous setbacks were just "herx." I know better now, and hope it isn't to late for me to turn things around."


"You can count me as another Marshall Protocol failure. I too followed the MP rules to the letter and ended up much sicker. While I was on the protocol I became totally disabled, unable to leave the house. At one time during this fiasco my vitamin D read <4, which to TM and company is an excellent reading. He says the immune system is optimized when 25-D is less than 12, and doesn't even begin to work until under 20. Of course, there is NO data to back this up, not a shred."

 

Again, they claim that vitamin D must be avoided because it suppresses the immune system. This is simply not true. Among many functions, it modulates and regulates immunity, is antimicrobial, and low levels are associated with many serious health conditions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166406/