Treatment implications of the Naviaux study (PNAS, August 2016)

[TiredSam]

(Have to say I'm in awe.....there are some clever people on PR. Imagine what they'd be like without brain fog!!!)

x2

 

[snowathlete]

Thanks for your comments. I appreciate that he's not 'just saying B vitamins and that's that'; I wasn't trying to imply that. I disagree with the overall approach of replenishing these downregulated metabolic pathways, I'm afraid. If the hypometabolic state is adaptive/protective, as some have argued over the years, then switching off the dauer-like state may bring about an increase in functional capacity at the expense of killing us faster by means of conventional diseases.

If the dauer-like state is on because we have an infection of some kind, then clearly it could be fatal to switch it back off. I personally don't think that will be the case, but we'll have to see. Switching off the dauer-like state could also be fatal if our body cannot switch it back on - the first pathogen to come along might then kill us. If we can reset the switch then will we remain cured, or will the first infection or other stressor cause the switch to malfunction again? Might we then need to keep reseting the switch in order to keep ME at bay.

My feeling is that once we identify the switch, and figure out how to turn it off, or adjust it, we will rapidly get better. The problem is going to be identifying the switch (and then figuring out how to safely control it). I think simple identifying it could be pretty difficult.

It may be CDR, and something like Suramin might work, in which case, great. But the way I would approach it would be to examine patients who haven't had the disease very long. As early as possible. Track their metabolomics over months and watch the disease progress. Although some patients can be severe early on, with lots of symptoms, I suspect many are not, and we will then be able to see the beginnings of the impact on the metabolic system. Be able to compare with later patients and discount the metabolic impacts that occur and worsen as time goes on. As well as there perhaps being less noise from secondary consequences and adaptions to confuse the picture, you may also be able to watch the metabolic dysfunction progress, and thus be able to extrapolate back using data of that worsening trend. I think this could help isolate the central problem.

 

[Forbin]

Hypometabolism stuck 'on' or 'no off switch': a fair number of us patients report here that on the very rare occasions when they get a cold they feel temporarily much better (ie a swift albeit perhaps partial remission). Does this indicate that an interruption in the 'hypometabolism on' signalling is rapidly followed by moving out of hypometabolism?

I wonder if cellular metabolism might just be pushed to increase in response to infection (despite the dauer-state), temporarily lifting the hypometabolic state into the "normal" range (instead of the "above normal" range it might otherwise reach during an infection).

 

[Hip]

@Kimsie had some ideas about NADPH and ME/CFS; her ideas are summarized in this post.

The basic thing she points out is that the energy produced in the mitochondria can either be used to make ATP, the universal energy molecule, or to make the pro-antioxidant NADPH.

NADPH is important to make because it protects certain delicate mitochondrial machinery (the iron-sulfur proteins) from being damaged by hydrogen peroxide.

Kimsie hypothesizes that when ME/CFS patients engage in too much activity, most of the energy produced in the mitochondria is directed towards making ATP, in order to provide the energy needs of the body and brain; but this manufacture of ATP is done at the expense of NADPH manufacturing.

 

[adreno]

It may be CDR, and something like Suramin might work, in which case, great.

The findings was the opposite of CDR. I would think suramin is a bad idea.

 

[Sasha]

I got sick after the flu and was bedbound for years. Then I went into remission. Then I relapsed. So I think that if my dauer state got switched off and whatever bug I'd originally had didn't kill me, that's a good sign.

 

[snowathlete]

The findings was the opposite of CDR. I would think suramin is a bad idea.

They said the metabolic signature is the opposite of acute CDR response, yes. But what we are seeing may be the outcome when CDR is left on chronically.

 

[alicec]

NADPH is important to make because it protects certain delicate mitochondrial machinery (the iron-sulfur proteins) from being damaged by hydrogen peroxide.

It does a lot more than that. As Naviaux et al spell out, (my paraphrase follows)

NADPH seems to act as a global barometer of cellular fuel status. When it is high, cellular pathways are shifted to growth and repair. When it is low, synthetic pathways fall to baseline survival mode.

The authors also point out that while it is not the major source of NADPH in the cell, the folate cycle, via MTHFD, makes a very important contribution.

They appear to think that the hypometabolic state has become maladaptive since they are contemplating ways of unsticking it. This will ultimately mean unsticking various pathways involved in NADPH production.

I suspect that people who do respond favourably to various B vitamins, and I include myself here, benefit from a slight stimulation of one or more of these pathways. The folate/B12 cycle seems to be the most favoured from anecdotal reports.

In my case active folate, B12, B2 and B6 give me a little more energy and improve mood and motivation. There is no cure, but the disease is a little easier to live with.

 

[anciendaze]

We used to discuss this kind of thing before, including even here on PR I think. The usual analogy was in terms of chaos theory, and strange attractors. An attractor is a central point which a system is always tied to, a central tendency about which it revolves, though both those analogies are only half right. If something changes and that attractor is moved, then it shifts to a new stable state. You might push the system a bit, and it will change, but unless the attractor moves to a position that is healthier you have not done anything much...

I was one of the participants in that discussion, and I want to inject a little reminder for those who are not familiar with dynamics. What Alex is describing need not be "chaotic", but it is definitely a problem with dynamics. The dauer state appears to have robust stability, at least in nematodes.

Before we get into a long discussion about changing levels of biochemicals, I want to remind people that levels are the less important part of the metabolic story. Reaction rates are extremely important and different reaction kinetics can lead to the same pathologically-low levels. A low level at one stage may be caused by either inadequate production at an earlier stage, or destruction of the metabolite at that stage, or even consumption at a later stage which increases demand for the biochemical. What is more, every one of the biological pathways revealed by this research involves feedback.

In treatment of depression, where the problem was thought to be low levels of serotonin, simply dumping in precursors to serotonin did not work. This is because metabolic pathways must function with varying diet, and an increase in precursors caused down-regulation of the processes producing serotonin.

What Naviaux has now is a research technique which has grabbed a wide range of metabolites to give us a clue about which pathways are important. This has not told us what we need to know about reaction rates along those pathways, or how these respond to change. I'm not even convinced this is a practical clinical test, due to cost and the difficulty in interpretation. Creating such a test in one go would have been overly ambitious, when so little was known at the start.

Now that we know which pathways are disturbed we can start to fill in the missing information about rates. I expect this to be done, and to yield a whole series of insights. One possibility is to use radioactive tracers, but I think that is still a research method of limited clinical application. This condition is so pervasive that I suspect ordinary harmless chemicals which are easy to detect can be used instead. The rate at which these turn up in blood or urine should give us clues about which reactions are impaired. This has the potential to produce a low-cost clinical test which can tell if a particular pathway is impaired in a particular patient.

As I've said before, about the 2-day cardiopulmonary exercise test, we are not dealing with picograms of material, but with a number of grams of biochemicals which take days to be cleared or replaced.

One more thing, I am less than enthusiastic about provocative tests, following tests in the past which left me wiped out for days, but did not impress doctors. The pervasive nature of this condition lends itself to less drastic means of determining rates without killing patients. As an added benefit, we might just illuminate the problems which lead to adverse responses to particular medications, something all of us have experienced. This has big implications beyond our own group of sufferers. Understanding what is going on in unusual cases might even save lives.

 

[Snowdrop]

@anciendaze

Could you give an example or two of what might be a harmless ordinary chemical that one might look for?
And confirm you mean that they would be used in place of radioactive tracer.
Thanks

 

[IreneF]

I haven't had enough brainpower to read the paper or follow the discussion, but it seems this paper compares CFS in humans to dauer in nematodes--barely visible roundworms. Nematodes aren't very much like humans, or mammals, or even vertebrates. (Wikipedia says, "About 35% of C. elegans genes have human homologs.") So I have a hard time feeling excited about the paper leading.

 

[Sidereal]

I haven't had enough brainpower to read the paper or follow the discussion, but it seems this paper compares CFS in humans to dauer in nematodes--barely visible roundworms. Nematodes aren't very much like humans, or mammals, or even vertebrates. (Wikipedia says, "About 35% of C. elegans genes have human homologs.") So I have a hard time feeling excited about the paper leading.

It is often useful to read the study first before dismissing it as useless. The study did not compare humans to nematodes. It was a human study of CFS patients which found a remarkable range of metabolic abnormalities consistent with a state of hypometabolism which happens to be similar to dauer in nematodes.

 

[AndyPR]

I haven't had enough brainpower to read the paper or follow the discussion, but it seems this paper compares CFS in humans to dauer in nematodes--barely visible roundworms. Nematodes aren't very much like humans, or mammals, or even vertebrates. (Wikipedia says, "About 35% of C. elegans genes have human homologs.") So I have a hard time feeling excited about the paper leading.

A whole thread of media stories about the study which, in general, all report fairly accurately (as far as mainstream media goes), so could be worth starting there.

 

[IreneF]

It is often useful to read the study first before dismissing it as useless. The study did not compare humans to nematodes. It was a human study of CFS patients which found a remarkable range of metabolic abnormalities consistent with a state of hypometabolism which happens to be similar to dauer in nematodes.

I'm not dismissing it as useless. I'm just not excited about it.

 

[IreneF]

A whole thread of media stories about the study which, in general, all report fairly accurately (as far as mainstream media goes), so could be worth starting there.

I'll be able to read it as soon as I pull out of my current crash.

 

[anciendaze]

@anciendaze

Could you give an example or two of what might be a harmless ordinary chemical that one might look for?
And confirm you mean that they would be used in place of radioactive tracer.
Thanks

First of all, I think there will be no need to use radioactive tracers in most clinical tests because we are dealing with substantial amounts of metabolites.

Examples: Our bodies do process a wide variety of chemicals in normal diet which don't cause severe reactions. One common example turns up in the mercaptans (thiols) in asparagus. The result turns up in urine, where we can detect it by smell. I don't know that this has any special metabolic significance, but I do think the potential to explore the reaction kinetics of different metabolic pathways by measuring how rapidly we metabolize molecules that are similar to common metabolic molecules, but detectably different, is there.

Another example turns up when people try high doses of vitamin C. Once you get beyond the level the body needs to function, the vitamin goes right out in urine. You can detect it with test strips that do not require a trip to a doctor's office. Again, I don't know that this has any direct relevance to our metabolic abnormalities, but it is an example of a harmless chemical whose participation in human biochemistry is easy to measure.

Clinical laboratories have lists of chemicals which can invalidate their test results, though patients don't hear about these unless there is a suspect result.

Anecdote: One bachelor friend of mine had blood/urine tested when he was admitted to hospital. Before the hospital took action on the alarming results a nurse questioned him about his diet the morning before admission. It turned out he had found nothing in the pantry to eat except a tin of sardines, and ate them all. He had scored very high albumin levels in urine which would otherwise have indicated serious kidney disease.

Natural biochemical enzymes seldom recognize every atom in a target molecule. Often they only recognize a small part. Most drugs are developed from tweaked versions of molecules not found in nature. Huge numbers of such drugs are "on the shelf" because they did not have any desired effect, even if they never caused any significant problems. Use of such "useless" chemicals to probe metabolic function for diagnosis would not require long-term safety because exposure would be quite limited. A surprising number of molecular variants are already found in common foods, which would present even fewer problems with safety. There are many types of chemical indicators like dyes to conveniently show the presence of particular chemicals in samples. Since these would not be put in patients' bodies, they would not be subject to the same regulatory concerns.

I don't think this kind of diagnostic would have to be developed from scratch. I believe we already have a great deal of information about possible biochemical tests. The problem would simply be putting this together into specific tests and getting these approved for diagnostic purposes.

Is it even necessary to do this, since we now have the tests used in this study? For some time to come treatment will be experimental, and each patient may be different. This means we will need repeated tests of particular metabolic functions, which should be cheap, convenient and easy to interpret.

 

[anciendaze]

It came to me a short while ago that this Labor Day weekend (in the U.S.) offers an analogy and lesson in the difference between simply measuring levels of various biochemicals and understanding metabolic dynamics. We happen to have a hurricane moving up the East Coast, and forecasting this has been a problem. The easterly wave was seen as far away as the coast of Africa, but at that time nobody knew if it would ever grow to be a powerful storm, let alone what land it might threaten.

Forecasting hurricanes based on nothing but barometer readings would be pretty hopeless. When you see pressure differences you know air is going to be moving, but the path a particular parcel of air takes is considerably more difficult to predict. Those barometer readings correspond to levels of chemicals, while the winds you need to add to the picture are rates of change.

I've never worked with weather prediction, but I have been involved in things like predicting tides. I had to tell a collaborator who wanted me to predict ocean currents that these are much harder to deal with, and not something we could do using a single computer on a ship. My personal experience with current prediction includes being on a sailboat crossing the Gulf Stream which hit a current traveling at twice the speed forecast. We were set north at about the same rate that we moved east through the water, and ended up a long way from where we intended.

Predicting weather or ocean currents is notoriously difficult, but it is based on dynamics involving a surprisingly small number of important variables like pressure, temperature, humidity, solar input, and nighttime radiation into space. Metabolic dynamics involves dozens of variables. There are techniques for understanding complex dynamics without having complete information, but these will not work without more information than we have at present.

 

[hixxy]

I'm curious about the Suramin treatment for Autism trial results. Anyone heard when these might be published? I guess given it only completed in April there could be a fairly long wait yet.

 

[eafw]

If the dauer-like state is on because we have an infection of some kind, then clearly it could be fatal to switch it back off. I personally don't think that will be the case, but we'll have to see. Switching off the dauer-like state could also be fatal if our body cannot switch it back on - the first pathogen to come along might then kill us.

No, unless they do something which damages the "on" switch (and I have no idea how they'd do this). We have anecdotal evidence that the switch can still be toggled anyway - a lot of people say that they have a transient "remission" when fighing certain infections and then get ill again after. I'd want to ask the researchers what is going on here and is there a way to leverage this effect in our favour at all ?

Although some patients can be severe early on, with lots of symptoms, I suspect many are not, and we will then be able to see the beginnings of the impact on the metabolic system.

It would be good if they could join up the metabolite research with the cytokine profiles and the different patient groups, ie: children/teens who have a much better prognosis (why does the switch not get stuck for them as readily ?), people in the early stages of the illness (who may have a critical window for intervention to halt disease progression) and those of us in the later/longterm/very stuck stage where we will likely need a quite different approach to treatment.

 

[OverTheHills]

I am assuming this study does not give us any hints about which medical specialism should be 'owning' ME. Assuming this 'cos no-one has discussed it yet. I suppose we still have to know more about the mechanism and treatment avenues to decide between eg rheumatology and endocrinology but given that hypometabolism is not localised can we rule out any previous candidate specialisms?

OTH