Mitochondrial and Energy Metabolism Dysfunction in ME/CFS — Myhill, Booth and McLaren-Howard Papers

[realturbo]

The Lily Foundation website states mitochondrial disease is caused by the mitochondria in the cells not producing enough energy, sometimes being not very efficient, or by not working at all. "Every person with Mitochondrial Disease is affected differently. Each individual affected will have a different combination of mitochondria that are working and not working within each cell." There is also a very useful Question & Answer section on the website. Not sure if this info is useful, although I found it helpful in getting an insight into the importance of ATP energy production in cells.

 

[Hip]

Q. Does "ADM" & ATM both mean adenosisine monophosphate

Thank you, Hip. I must be worse than I thought. iz

@Izola, it turns out it was me who is worse that you thought! I made a mistake, where I incorrectly wrote "ATM" in the original post in a few places, instead of the correct term "AMP" = adenosine monophosphate. So no wonder you were getting confused! Sorry about that. I have corrected it now.

 

[voner]

@Izola, it turns out it was me who is worse that you thought! I made a mistake, where I incorrectly wrote "ATM" in the original post in a few places, instead of the correct term "AMP" = adenosine monophosphate. So no wonder you were getting confused! Sorry about that. I have corrected it now.

@Hip,

Can you explain again why and how AMP is dumped into the urine?

 

[Hip]

Can you explain again why and how AMP is dumped into the urine?

The process is explained in the first post of this thread, in the "Theory of PEM" section.

The theory that Myhill, Booth and McLaren-Howard propose as a possible cause of delayed fatigue and PEM is the following:


The Myhill, Booth and McLaren-Howard Theory of PEM

Mitochondria supply ATP by a process of recycling ADP back into ATP (this process is called oxidative phosphorylation). The ATP produced by oxidative phosphorylation in the mitochondria is sent out into the cell, where the energy the ATP contains is released by converting this ATP to ADP within the cell. ADP (which is like the spent ATP) is then sent back to the mitochondria, to be recycled back to ATP. And this cycle repeats again and again. In this way, the ATP molecules ferry energy from the mitochondria into the cell.

But because this mitochondrial recycling process is apparently running poorly in ME/CFS patients, during strenuous physical exercise, there is not enough ATP produced by the mitochondria to meet demands, so the cells start trying to make ATP by other means.

One such other means of making ATP is the adenylate kinase reaction, in which two molecules of ADP combine to make one of ATP and one of AMP. So now for your two molecules of ADP, you have got yourself one molecule of ATP, which you can spend as energy; but unfortunately the AMP molecule that was produced cannot easily be recycled back to ADP or to ATP, and instead tends to be dumped out of the body in the urine.

Because that AMP molecule dumped in the urine originally derived from an ADP molecule, you have now completely lost an ADP molecule. As this adenylate kinase reaction process continues, you lose more and more ADP molecules from the body, and eventually you have a shortage of ADP, and that means you also have a shortage of ATP, because as mentioned, much of the ATP is made by recycling ADP.

So now you are in a situation where you don't have enough ATP and ADP molecules, and as ATP/ADP are the main means of distributing energy in the cell, you now cannot supply enough energy for cellular needs. This situation, a shortage of ATP/ADP molecules need to convey energy, is what Myhill, Booth and McLaren-Howard propose may be the cause of delayed fatigue and PEM.

The PEM is caused not so much because the mitochondria are functioning poorly (and they are), but because even the energy the mitochondria is able to produce cannot be efficiently conveyed and distributed into the cell, due to the fact that there are simply not enough ATP/ADP molecules available to ferry this energy into the cell.

I takes 1 to 4 days for the body to create new ATP molecules from scratch, to replace the lost molecules, and you will only be able to start efficiently distributing energy in the cell again when these lost ATP/ADP molecules are re-manufactured.

So this is the theory that may explain why you get delayed fatigue / PEM for a few days after strenuous exercise.


This is what they say about PEM and AMP loss in the urine in Myhill 2012:

The problem is that for every molecule of ATP generated, one molecule of the ADP pool is changed to AMP and then, in skeletal muscle, to IMP (inosine monophosphate, via AMP deaminase, EC 3.5.4.6) which is not recycled but mainly lost in urine. The replacement of the lost adenine nucleotides can take several days. This may explain one clinical feature of ME/CFS, namely delayed fatigue.

The Lactic Acid Build-Up Problem in PEM

PEM is compounded and exacerbated by the problem of lactic acid build-up in the muscles, in ME/CFS patients who rely on anaerobic glycolysis to make up for the shortfall of energy (a shortfall originally resulting from dysfunctional mitochondria). This because anaerobic glycolysis produces lactic acid as a by-product.

This lactic acid build-up then further compounds the energy shortage problem of PEM, because to clear lactic acid by converting it back to glucose, it requires considerably more energy than was originally gained from the conversion of glucose to lactic acid.



For a list of supplements and drugs that ME/CFS patients have found reduce PEM, see:

Supplements and Drugs That Reduce or Prevent PEM (Post-Exertional Malaise)

 

[Undisclosed]

In fact, if you read the full story about the GMC case, Stuart Jones, the scientist who originally reported Dr Myhill to the General Medical Council (GMC) and who made disparaging remarks about Dr Myhill on the "Bad Science" forum, ultimately was disciplined for misconduct in this affair, whereas Dr Myhill was vindicated, with the GMC case against Dr Myhill being dropped.

Dr Myhill said of Stuart Jones:


Certainly from your none-too-well researched but nevertheless disparaging comments about Sarah Myhill on this thread, it seems that aphorism about mud is true. If you are going to criticize someone online, at least get your facts right. It is irresponsible not to.

Actually, just to clear things up. Dr Myhill was issued a warning by the GMC that expires in 2017. From the GMC website:

On Dr Myhill's website she made statements in relation to contraception and breast cancer screening that were factually incorrect; clinically unsubstantiated;and contrary to national guidelines. In so doing she used her position as a registered practitioner to exploit patients' lack of medical knowledge by arousing ill found fears for their health. This conduct does not meet with the standard required of a doctor. It risks bringing the profession into disrepute and must not be repeated. The required standards are set out in Good Medical Practice and associated guidance. In this case, paragraph 57, 62 and 65 are particularly relevant. 'You must make sure that your conduct at all times justifies your patients' trust in you and the public's trust in the profession.' 'You must not put pressure on people to use a service, for example by arousing ill founded fears for their future health' and 'You must do your best to make sure that any documents your write or sign are not false or misleading. This means that you must take reasonable steps to verify the information in the documents, and that you must not deliberately leave out relevant information.' Whilst this failing in itself is not so serious as to require any restriction on Dr Myhill's registration, it is necessary in response to issue this formal warning.

 

[Deepwater]

Actually, just to clear things up. Dr Myhill was issued a warning by the GMC that expires in 2017. From the GMC website:

To be fair to Dr. Myhill, whom I have found to be extremely caring and committed, one needs to factor in the extreme rigidity of the medical set-up in England and Wales, where the NICE guidelines, which are themselves often based on very poor research (as we PwME know), must be adhered to to the absolute letter and doctors who express doubts about them risk being gagged. On the breast cancer issue, Dr. Myhill had merely observed that a couple of her own breast cancer patients who had biopsies by syringe had then developed secondaries along the route of the injection, and therefore suggested that people might like to consider whether this was the way they wanted to go. It does not seem unreasonable to me to point this out given that a doctor's first duty is to do no harm (certainly someone I know developed a secondary cancer along the route where the original, awkwardly-placed cancer had been pulled out). Should this not be something on which the GMC or NICE should be gathering data? But of course it's a cheaper procedure.

I can't remember what Dr Myhill said about contraception. She was, however, for quite some time prevented from giving or recommending B12 injections for ME because they weren't approved.

Something that really riled the establishment, though not mentioned in this quotation, was her query that vaccinations might be triggering ME because she'd come across so many cases - one of which was, incidentally, mine. She had to take all material about vaccines down from her website. This is just not permitted to be discussed. A little while ago on one of the PR forums it was suggested to me that people who thought vaccines had caused their ME might be simply recalling a vaccination several months earlier, but this really is not the case. I took sick the very next day, and have not been well for a single day in the more than 2 decades since. Other cases of which I have heard also started within a few days of vaccination.

During this period the GMC also spent months investigating a complaint against Dr Myhill for delivering babies whilst her licence to practice was suspended. What had happened is that she had placed a spoof Christmas article on her website about how she went out in the snow to assist one Rosemary Hogg who lived on a remote farm and was in labour with a multiple birth. There was a link to a photograph of the Hogg family which, if the complainer had bothered to click, would have brought him to a photograph of a sow with a litter of piglets. Rosemary Hogg is one of Dr. Myhill's pet pigs.

The supplements recommended by Dr Myhill have by no means cured me, but they - or some of them - have lifted things enough for me to be able to think straight for a few hours each day and clear the pain out my system quite a bit faster after any activity. She literally was the last thing left on my 'to try' list before suicide, so she saved my life. Until the GMC case the test results also succeeded in getting a certain family member who thought I was malingering off my back. The accusations against her then provided said person with the perfect excuse to ignore all the abnormal test results, including established ones like cell-free DNA, and go back to treating me as lazy.

I think this needed saying. If the benchmark of good medical practice is the dictates of the GMC or NICE, then we in the UK are all sunk.

 

[Barry53]

I think this needed saying. If the benchmark of good medical practice is the dictates of the GMC or NICE, then we in the UK are all sunk.

Well done for speaking out.

 

[Hip]

On the breast cancer issue, Dr. Myhill had merely observed that a couple of her own breast cancer patients who had biopsies by syringe had then developed secondaries along the route of the injection, and therefore suggested that people might like to consider whether this was the way they wanted to go.

According to the GMC website quote posted above by @Kina, the cancer issue relates to a statement on breast cancer screening; this statement apparent was that thermal imaging (breast thermography) was superior to mammography for cancer detection. Ref: here. I have not looked into this issue, so cannot comment on the ins and outs of it.

Something that really riled the establishment, though not mentioned in this quotation, was her query that vaccinations might be triggering ME because she'd come across so many cases - one of which was, incidentally, mine. She had to take all material about vaccines down from her website. This is just not permitted to be discussed.

Are you sure Dr Myhill was told to take this particular statement down, because a statement about the link to vaccination is found on her website here?

Fluge and Mella recently commented that vaccination appears to be one of the triggers for ME/CFS. @charles shepherd of the UK ME Association has a longstanding interest in the role of vaccinations as possible triggers of ME/CFS. Dr Chia's research suggests that vaccination is the trigger in around 1.5% of ME/CFS cases.

All the cases of vaccination-linked ME/CFS I have come across are like yours: very rapid descent into ME/CFS just days after the vaccination.



@Kina, if this discussion of the Myhill GMC case continues, it may be an idea to split the GMC discussion into another thread. That's not in order to thwart this GMC discussion, but I would like if possible to keep this thread focused on an introduction to and understanding of the mitochondrial dysfunction research of Myhill, Booth and McLaren-Howard, the science of which is quite difficult to grasp, and this side discussion on the GMC case may just end up diluting the original focus.

With Fluge and Mella saying that studies suggest that immune system is producing anti-mitochondrial antibodies that are causing mitochondrial dysfunction (see Cort's tweet here), the Myhill, Booth and McLaren-Howard research mitochondrial dysfunction in ME/CFS may become central to understanding ME/CFS pathophysiology.

 

[Alexi]

To be fair to Dr. Myhill, whom I have found to be extremely caring and committed, one needs to factor in the extreme rigidity of the medical set-up in England and Wales, where the NICE guidelines, which are themselves often based on very poor research (as we PwME know), must be adhered to to the absolute letter and doctors who express doubts about them risk being gagged. On the breast cancer issue, Dr. Myhill had merely observed that a couple of her own breast cancer patients who had biopsies by syringe had then developed secondaries along the route of the injection, and therefore suggested that people might like to consider whether this was the way they wanted to go. It does not seem unreasonable to me to point this out given that a doctor's first duty is to do no harm (certainly someone I know developed a secondary cancer along the route where the original, awkwardly-placed cancer had been pulled out). Should this not be something on which the GMC or NICE should be gathering data? But of course it's a cheaper procedure.

I can't remember what Dr Myhill said about contraception. She was, however, for quite some time prevented from giving or recommending B12 injections for ME because they weren't approved.

Something that really riled the establishment, though not mentioned in this quotation, was her query that vaccinations might be triggering ME because she'd come across so many cases - one of which was, incidentally, mine. She had to take all material about vaccines down from her website. This is just not permitted to be discussed. A little while ago on one of the PR forums it was suggested to me that people who thought vaccines had caused their ME might be simply recalling a vaccination several months earlier, but this really is not the case. I took sick the very next day, and have not been well for a single day in the more than 2 decades since. Other cases of which I have heard also started within a few days of vaccination.

During this period the GMC also spent months investigating a complaint against Dr Myhill for delivering babies whilst her licence to practice was suspended. What had happened is that she had placed a spoof Christmas article on her website about how she went out in the snow to assist one Rosemary Hogg who lived on a remote farm and was in labour with a multiple birth. There was a link to a photograph of the Hogg family which, if the complainer had bothered to click, would have brought him to a photograph of a sow with a litter of piglets. Rosemary Hogg is one of Dr. Myhill's pet pigs.

The supplements recommended by Dr Myhill have by no means cured me, but they - or some of them - have lifted things enough for me to be able to think straight for a few hours each day and clear the pain out my system quite a bit faster after any activity. She literally was the last thing left on my 'to try' list before suicide, so she saved my life. Until the GMC case the test results also succeeded in getting a certain family member who thought I was malingering off my back. The accusations against her then provided said person with the perfect excuse to ignore all the abnormal test results, including established ones like cell-free DNA, and go back to treating me as lazy.

I think this needed saying. If the benchmark of good medical practice is the dictates of the GMC or NICE, then we in the UK are all sunk.

Nicely put, Deepwater

 

[Deepwater]

Are you sure Dr Myhill was told to take this particular statement down, because a statement about the link to vaccination is found on her website here?

Fluge and Mella recently commented that vaccination appears to be one of the triggers for ME/CFS. @charles shepherd of the UK ME Association has a longstanding interest in the role of vaccinations as possible triggers of ME/CFS. Dr Chia's research suggests that vaccination is the trigger in around 1.5% of ME/CFS cases.

Yes, I'm quite sure I wasn't misremembering this. But at the time she had a whole page devoted to it - not a tiny paragraph slipped in - with reference to Andrew Wakefield and the old polio vaccines, which I'm sure would have rung alarm bells with the GMC. Since then of course, there have been many papers published identifying aluminium adjuvants as the trigger for autoimmune disease, and Dr Myhill's current comments would appear to be based on these. Hopefully the total gagging of discussion of vaccine involvement in illness is now no longer possible, and even Charles Shepherd is bringing it up with regard to ME. But it's still not something that GPs in the UK will let you talk about.

By the way, she's very recently had to stop prescribing antivirals a la Dr. Martin Lerner. In the US, from what I hear, any doctor who believes in their use for ME would be free to prescribe them. So where in the UK can one go for treatment?

It's difficult to be sure of all the issues since it was all some years ago and the exact nature of the charges against Dr Myhill weren't made clear till a very late stage.

 

[Deepwater]

Found this - the transcript of the GMC hearing:-
http://www.drmyhill.co.uk/wiki/The_Full_Transcript_of_Dr_Sarah_Myhill's_IOP_Hearing

 

[Barry53]

I think that Myhill and colleagues hope for an indipendent study. In the 2009 paper they wrote: "It would be good to confirm the biochemical test results in a second (perhaps government-supported) laboratory".

So: actively seeking open peer review; not shying away from possibility of being proved wrong or right; seeking the truth for the greater good. The only thing she got wrong here I think was naively hoping for government funding in ME research.

 

[Norman E. Booth]

It is gratifying to see the post by Hip on ”Mitochondrial and Energy Metabolism Dysfunction in ME/CFS — Myhill, Booth and McLaren-Howard Papers”, and his decision to examine more closely the 3 published studies. I should introduce myself - I am Norman E. Booth, one of the co-authors of the 3 papers. I don’t normally comment in blogs although I do read quite a few of them. I am replying to this one because there are some misunderstandings that I should try to correct, and also I may be able to supply further information.


I am a retired academic physicist but not a molecular biologist. I am trying my best to learn about and understand the chemistry and pathophysiology of ME at the molecular level. I first learned about mitochondria when Dr Sarah Myhill gave an invited talk at the 2nd Invest in ME Conference in London in May 2007, and at the “Putting the Patient at the Centre” Colloquium at Southampton General Hospital in February 2008. Because mitochondria are the sources of energy for all bodily processes I could see the unique and systemic importance of these organelles. Moreover, I had witnessed what my son went through when he was struck by ME at age 16, and I am still trying to find solutions for my wife. Fortunately, after about 6 years my son has 99.9% recovered.


In my collaborative efforts with Dr Sarah Myhill and Dr John McLaren-Howard I have not interviewed any patients or carried out any laboratory tests. I have worked, in a completely voluntary way, to audit the anonymised results of tests ordered by Sarah and mainly carried out by John, plotting graphs, making tables, studying other publications and making comparisons where appropriate. Finally, when it comes to publishing there are a number of hurdles to overcome. Where to publish (or at least to which of many journals should we submit)? All 3 of us wanted to publish in an open-access journal so that anyone, including patients could read our papers without having to pay. The problem is that open-access journals charge the authors a publication fee that can be as much as US$3,000 or more. This is normally not a problem for health professionals or academic authors because they have a research grant to cover such expenses. I managed to find the rather new International Journal of Clinical and Experimental Medicine that kindly waived our publication fees because we had no research grant. However, this journal, even though it has a high quality peer-review procedure, does not have a high profile.


But let’s concentrate on the science! Hip says that the ATP Profile measures the efficiency of five metabolic pathways. The Profile does provide at least five numerical figures but these all refer to the textbook pathway of starting with glycolysis of glucose, producing two net molecules of ATP, from two of ADP, plus two molecules of pyruvate and two positively charged hydrogen ions (H+, also called protons). The two ATP’s are available for use in the cytosol, shown at the left part of Fig.1 of our 2009 paper, while the two pyruvates and two protons enter a mitochondrion via a pyruvate carrier, as illustrated in the right part of Fig. 1. The other basic parts of the mitochondrial pathway are also shown, starting with the Krebs or TCA Cycle, the electron transfer chain (ETC) and oxidative phosphorylation performed by ATP synthase where another 30 molecules of ATP are produced from ADP and inorganic phosphate, the latter entering via the phosphate carrier. The TL IN and TL OUT channels (or ANT, the Adenine Nucleotide Translocator, or Transporter) are unfortunately usually left out of such diagrams. Fortunately, evolution discovered recycling; otherwise each one of us would have to carry around at least our own body weight of ATP every day. The available energy contained in the ATP molecules comes from the controlled burning of the pyruvate using oxygen to give the byproducts CO2 and H2O. A similar pathway, starting with fatty acids rather than the pyruvate derived from sugars and carbohydrates, is also shown. We are not describing 5 metabolic pathways, but 5 of the basic steps in this basic mitochondrial pathway. Somewhat like an automobile assembly line, one can consider the efficiency of each step, and it is the product of the efficiencies that gives the overall efficiency. This is the Mitochondrial Energy Score plotted in Fig. 4. It is just a convenient way of comparing mitochondrial function or dysfunction with the Clinical Ability of the patients. The science comes in the measuring of each quantity and in interpreting the measured values.


This is an aside. I of course am looking back at our 2009 paper while writing this. At that time I did not take seriously the fact that in Fig. 2E seven of the 71 patients had higher values of TL IN than any of the controls. Once I had more test results to audit it became clear that this was a major effect, now called HI TL IN or Group A2. Also, it forced us to modify our definition of Mitochondrial Energy Score. This is a good example of the importance of having better statistics and also more careful scrutiny.


Hip gives a fairly accurate description of Sarah Myhill’s postulate about the origin of the post-exertional malaise (PEM), but our 2012 paper gives a more accurate description of what is called the purine nucleotide degeneration pathway where 2 ADPs exchange a phosphate group to produce an ATP plus an AMP, the AMP is changed into IMP (Inosine monophosphate) plus ammonia, and the IMP is further degraded to Inosine, and then to Hypoxanthine, then to Xanthine and finally eliminated as Uric acid. Recently, computer simulations of the chemical reactions involved have been carried out and have predicted the timescales of the PEM experienced by ME/CFS patients [1]. In summary, this pathway is an excellent candidate to explain PEM, but remains not yet proven.


I am very wary of the idea of comparing mitochondria or ATP molecules to batteries. Mitochondria are power plants that transform energy from foods plus oxygen into bundles of energy carried by ATP molecules. The British Association for CFS/ME (BACME) has used the battery analogy to tell patients that doing some exercise will charge up your batteries. This completely neglects the fact that the energy required to do the exercise has come from the same batteries. This is tantamount to ‘perpetual motion’ and violates the first law of thermodynamics that all bodily functions must obey.


“Lactic acidosis” is a widely used but poorly understood label. Entering this label into Wikipedia [2] provides an accurate description, and full details are given in the link to the 2004 article by Robergs [3].


I don’t want to reply individually to all of the many comments, but I will reply to some of them here.


I would like to follow up many aspects that Sarah, John and I have found in the audit work that I have carried out. However, I do not have the capability to make and incorporate measurements of related quantities, and both Sarah and John have their own businesses to run. Occasionally John has carried out some additional tests that I have asked him to do, and sometimes he even does further tests on some of Sarah’s patients without additional charges.


One other point — unfortunately, in our 2013 paper I failed in proofreading to delete the first sentence in the Conflicts of Interest paragraph and I apologize to my co-authors and to all others for this mistake on my part.


A number of scientists have quoted published results of other studies of neutrophils that appear to disagree with John’s measurements. I have worried about this and have had several discussions with John about the disagreements. I am convinced of John’s integrity and talent. He measures neutrophils when they are still alive and are in a sterilized, aerated environment. Here they are going about their task of sensing the presence of foreign bodies and pathogens using their motility and chemotaxis. They are not in the process of honing in on pathogens or carrying out phagocytosis, which heavily rely on glycolysis. In one of the first steps in the ATP Profile, John inhibits mitochondrial function with sodium azide, but for only 3 minutes. This short period is adequate and also short enough to prevent apoptosis of any of the neutrophils. In some other studies neutrophils have been inhibited with the toxin Rotenone for as long as 6 hours [4]. If any of the cells are still alive they will have to have found some other pathway to provide them with ATP. As of 1st February 2016 John has made a change in his procedure, and now measures mixed leukocytes containing monocytes as well as neutrophils. There are only small differences from neutrophils only. John is not happy to use lymphocytes alone because of the varying subtypes present and the responses to infection.


But there is no better course than to have some other group to repeat what John has done or come up with some other method to confirm or disprove his results. Fortunately, the Ramsay Research Fund of the ME Association is now involved in funding four research projects involving mitochondrial function, including a new project led by Dr Karl Morten and Professor Joanna Poulton at the University of Oxford [5].


In the meantime I thank Hip and Phoenix Rising for the interest in the mitochondrial aspects of ME. I also found interest at the Invest in ME Conference in June when Linda Tannenbaum and Ron Davis of the Open Medicine Foundation invited me to dinner to discuss the latest unpublished results from my work with Sarah and John. I also note that that there was a special session on mitochondrial dysfunction at the IACFSME conference in October [6].


I am continuing the audit work and hope to be able to publish more results in the near future, including results on young people (under the age of 18), and more repeat tests of adults comparing Mitochondrial Energy Scores and other measurements with Clinical Ability before and after treatment.


Links

[1] Lengert 2015

http://www.sciencedirect.com/science/article/pii/S0301462215000630

[2] Wikipedia Lactic acidosis

https://en.wikipedia.org/wiki/Lactic_acidosis

[3] Robergs 2004

http://ajpregu.physiology.org/content/287/3/R502.full

[4] Maianski 2004

http://www.nature.com/cdd/journal/v11/n2/full/4401320a.html

[5] MEA supported projects on mitochondria

http://www.meassociation.org.uk/201...e-of-the-mitochondria-in-mecfs-10-march-2016/

[6] IACFSME 2016

http://iacfsme.org/ME-CFS-Primer-Education/News/IACFSME-2016-Program.aspx

 

[Barry53]

It is gratifying to see the post by Hip on ”Mitochondrial and Energy Metabolism Dysfunction in ME/CFS — Myhill, Booth and McLaren-Howard Papers”, and his decision to examine more closely the 3 published studies. I should introduce myself - I am Norman E. Booth, one of the co-authors of the 3 papers. I don’t normally comment in blogs although I do read quite a few of them. I am replying to this one because there are some misunderstandings that I should try to correct, and also I may be able to supply further information.

Sincere thanks for taking the time to write this for us.

The British Association for CFS/ME (BACME) has used the battery analogy to tell patients that doing some exercise will charge up your batteries. This completely neglects the fact that the energy required to do the exercise has come from the same batteries. This is tantamount to ‘perpetual motion’ and violates the first law of thermodynamics that all bodily functions must obey.

Observing my wife (who is the one with ME), I came to the conclusion a long time back that her problem is not lack of fuel as such, but a serious restriction in the supply to where it is needed. e.g. Partly blocked petrol pipe, or abnormally high resistance in an electrical circuit. So putting more petrol in the tank, or topping up the battery, does not help her at all - getting the fuel from the tank to where it is needed, at the rate it is needed, seems to be her problem, irrespective of how much energy she "puts in the tank". Lack of power basically.

 

[barbc56]

The problem I see with the Myhill studies is that they are built on a shakey foundation as the atp test has not been validated.

If the ATP test is not validated then any theories based on that test are at best built on a house of cards.

There's always the possibility that she is right but we just don't know until the accuracy of the test is confirmed. It comes down to the fact that the studies are poorly designed. They should be the other way around. You need to use proven measurements before testing a theory.

I have to agree with several other posters, there are just too many red flags.

This has nothing to do with my opinion of Dr. Myhill. That's a different question. Nor am I making judgements about others who are her patients as it's a personal choice.

My perspectives and concerns about these studies are based on my background in research design.

While I appreciate the time taken by Mr. Booth to write his post, and with no disrespect intended, I think it's prudent to wait for the studies by the MEA.

 

[Barry53]

Something I would like to better understand, if anyone can help me please.

If my naive understanding is right, within a cell an ATP molecule releases one of its 3 phosphate groups, when energy demands require it, a phosphate group being the energy form that cells can immediately utilise.

So the ATP molecule, with once of its phosphate groups removed for useful work, has now become an ADP molecule, which by itself is cannot make available its phosphate groups as useful "energy packets" for the cell's consumption.

Without the Krebs cycle, 2 out of every 3 phosphate groups would go to waste, so with my very limited understanding, it would seem that the energy extracted from a cell's fuel supply would be only 33% efficient.

With the Krebs cycle working properly, and assuming the energy demand is not outstripping the Krebs cycle recycling rate, none of the phosphate groups go to waste, so all 3 phosphate groups eventually get delivered to the cell. (I imagine that in reality, because nothing is perfect, the Krebs cycle itself must consume some energy in some way within a mitochondrion, but I am ignoring that here).

So this is what (amongst many other things! I am struggling with at this moment: Given the above, it seems as if the Krebs cycle avoids energy release from ATP running at only 33% efficiency, which is pretty impressive. But when I read in Dr. Booth's post (and I have seen it said elsewhere also) ...

Fortunately, evolution discovered recycling; otherwise each one of us would have to carry around at least our own body weight of ATP every day.

... it seems to me the Krebs cycle must be hugely more efficient than a factor of 3? I do not know how much of our body weight is made up of ATP normally, but I am guessing it is pretty minute.

So I know my reasoning above must be flawed somewhere, but I do not know where.

Any takers to help me understand this please?

 

[justy]

My deepest thanks to @Norman E. Booth for taking the time to publicly comment here on his work and that of Myhill and McLaren. I am very grateful for all your hard work for M.E patients. I found my tests results to be very poor, and unfortunately the standard treatment didn't do much to help, I also don't have a great understanding of science and find the discussion a little over my head, but I follow it with interest and am especially happy to hear about the collaboration between scientists at conferences etc.

I really do feel that the science is moving ahead at a greater pace these days.

 

[Barry53]

This is analogous to saying there is not so much a shortage of electricity, but rather a shortage of rechargeable batteries for storing and carrying that electricity to where it is need. The ATP/ADP molecules are analogous to a rechargeable battery: ATP is like a fully charged battery, and ADP like an empty battery. ADP can be quickly recharged back to ATP at any time, using energy from the mitochondria.

I am just wondering if this is more like a flywheel energy storage mechanism, which some green vehicles utilise. The flywheel stores a lot of kinetic energy, and so holds energy that is (almost) instantly available when needed. The flywheel slows as the vehicle absorbs useful energy from it, and then the fuel source is used to top up the flywheel's kinetic energy store. Also, when the vehicle "brakes", instead of wasting the vehicle's own stored kinetic energy as heat into the atmosphere, it recycles its energy back into speeding up the flywheel, slowing the vehicle in the process. I appreciate this is not a terribly close analogy, but there is definitely energy recycling going on here, with the notion of an energy store of a form that makes it immediately available at the point where it is needed. For ME sufferers, it seems almost as if the flywheel itself is faulty, unable to store and/or dispense energy as it should.

 

[HowToEscape?]

It is gratifying to see the post by Hip on ”Mitochondrial and Energy Metabolism Dysfunction in ME/CFS — Myhill, Booth and McLaren-Howard Papers”, and his decision to examine more closely the 3 published studies. I should introduce myself - I am Norman E. Booth, one of the co-authors of the 3 papers. I don’t normally comment in blogs although I do read quite a few of them. I am replying to this one because there are some misunderstandings that I should try to correct, and also I may be able to supply further info.
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I cannot thank you enough for your work. I can no longer absorb information, much less synthesize it, so merely managing the existing information is outside my new (minimized) capacity. It is only people such as yourself who will move this rock.

It is notable that the one treatment I have had so far which has had any success was also developed by someone outside the main science/grant community: Rich Van Konynenburg, who was a nuclear physicist.

 

[Hip]

@Norman E. Booth, thank you for taking the time to comment on this thread, and for clarifying some of the intricacies of this research. It is very much appreciated. It always raises the spirits of ME/CFS patients here when researchers graciously spend a moment communicating on the forum.

Thanks for identifying the issues and errors in my original post; I have now edited this post to fix these.

And thanks very much for offering to supply further information; there are in fact some aspects of your published papers which I am unclear about, and so if I may, I have asked a few questions below to try to clear up some things.

Hip says that the ATP Profile measures the efficiency of five metabolic pathways. The Profile does provide at least five numerical figures but these all refer to the textbook pathway of starting with glycolysis of glucose

I have now replaced the incorrect term "energy metabolism pathway" with "energy metabolism process." I hope that is better (if there is more appropriate terminology, please let me know, and I will use it).

Also, it forced us to modify our definition of Mitochondrial Energy Score. This is a good example of the importance of having better statistics and also more careful scrutiny.

I did try to understand the new definition of the Mitochondrial Energy Score (MES) detailed in the 2012 paper, but I was struggling with the newly introduced parameter % ATP inhibited. Perhaps you could kindly explain this a little bit, as I would like to get to grips with it.

I understand the concept of multiplying the 5 efficiency factors together to get an overall efficiency figure for the MES (which is a valid approach as all five were found to be largely independent and uncorrelated factors). So in the original MES definition, we have:

MES = ATP Concentration × ATP Ratio × Oxidative Phosphorylation × TL OUT × TL IN

In the 2012 paper it says:

Ox Phos, a parameter related to the efficiency of the oxidative phosphorylation process which recycles ADP (adenosine diphosphate) back into ATP. In order to measure this, the inhibitor sodium azide is added to a buffer solution containing the neutrophils. After 3 min. an aliquot is taken and the ATP measured. The ratio gives us % ATP inhibited.

we take into account the measurement % ATP inhibited and use it to replace the TL IN factor in the calculation of MES

So then the new definition of MES, which is named MESinh, is given by:

MESinh = ATP Concentration × ATP Ratio × Oxidative Phosphorylation × TL OUT × %ATP Inhibited

What I am unclear about is what % ATP Inhibited actually measures and represents, and how it differs from Oxidative Phosphorylation. The Oxidative Phosphorylation figure represents the efficiency by which mitochondria recycle ADP back to ATP; but what does % ATP Inhibited represent?

Later in the 2012 paper it says:

It is important to note that the value of % ATP inhibited is also the percentage of ATP generated by oxidative phosphorylation in the ETC and this can be as low as about 20% for both cohorts.

We are forced to conclude that, for patients with low values of % ATP inhibited, the ETC is already partially inhibited (or BLOCKED, and hence the introduction of the category label ‘B: 'HI Blk'). This could be due to blockages within the Krebs Cycle or ETC, or of the TL protein.

So this seems to indicate that the value of % ATP Inhibited relates to the efficiency of the electron transport chain (ETC), or to a process closely tied to the ETC like the Krebs cycle; but I am still not very clear on the difference between the % ATP inhibited and Oxidative Phosphorylation figures (and whether these are largely independent of each other, which is necessary for the MESinh multiplication of all the efficiency values to be valid mathematically).

It is certainly interesting, though, that you found that the % ATP Inhibited value can be as low as just 20% in ME/CFS patients.



Another thing I am unclear on in the 2012 paper is the Nfn factor, which is an integer from 0 to 6 representing the number of energy metabolism factors that are running at normal efficiency, out of the six factors: ATP Concentration, ATP Ratio, Oxidative Phosphorylation, TL OUT, TL IN and % ATP Inhibited.

As I understand it (and please correct me if I am wrong), this Nfn number is a simpler, rough and ready alternative to the MESinh calculation.

But what I don't understand is why MESinh is plotted against Nfn (in figure 1 of the 2012 study). I can't see what this graph would represent or indicate.

In the original 2009 paper, in figure 4a you plot MES against the patients' severity of illness, as measured on the Bell scale, and this makes sense to me (and it is astounding how well the MES correlates to the Bell scale severity of illness score).

But I don't really understand the significance of the MESinh against Nfn graph. I would have expected the new MESinh value to be plotted against the Bell scale severity of illness score.



A further question if I may: I understand that glycolysis remains anaerobic (leading to lactic acid build up) if the glycolysis product pyruvate cannot be transported to the mitochondria and burnt with oxygen. But if everything is fine with the mitochondria, then I understand glycolysis works in tandem with the mitochondria (with the pyruvate being burnt in the mitochondrial Krebs cycle), and it becomes aerobic glycolysis where no lactic acid is produced.

What is it in ME/CFS that prevents aerobic glycolysis from taking place? Might there be a problem with the pyruvate transporters (mitochondrial pyruvate carrier, MPC), or is it just that the mitochondria are running very inefficiently, so they cannot effectively burn the pyruvate?

I am very wary of the idea of comparing mitochondria or ATP molecules to batteries.

I changed the analogy to one of ATP/ADP molecules being like petrol/gasoline trucks delivering fuel energy. I think that's a better analogy anyway.




By the way, if you would like to quote any paragraph of text in this post in your reply, you can just highlight the paragraph in question, and click on the pop-up "Reply" button that appears, and that will insert the paragraph into the text editor box.