This is one of a series of blogs that will look at what’s coming up in 2018 from ME/CFS research foundations.
Urgency
When Davis didn’t get an NIH funded research center – he built his own.
Those ten NIH research center proposals contained a hidden gift. Of the ten grant applications, seven failed, leaving at least 21 potential individual research grant applications that could be sent to the NIH. That is potentially a major boost to a field that averages about 15 grant applications a year.
Apparently Ron Davis didn’t get that message. He’s already put in one grant application to support Mark Davis’s project and plans to get two (R21 for nano-needle + ?) more in by February. At some point, Ron Davis is actually going to get funded by the NIH for his chronic fatigue syndrome (ME/CFS) study.
Patient Community Shows up for Stanford Collaborative Research Center
Ron Davis worried that his inability to garner an NIH research center grant would turn donors away. He was so worried and upset at some of the reviewers’ weird comments on his application that he went so far as to publish some of them.
As it turns out he needn’t have worried about the patient community. They responded to the Open Medicine Foundation’s (OMF’s) “Giving Tuesday” request with a blistering $452,000 in donations. The OMF responded to that a couple of weeks later by providing a $1.2 million dollar grant to Davis et. al. for their Stanford Collaborative Research Center.
Thanks to the patient community’s support, Davis and company will actually have more money to spend next year than each of the NIH’s Collaborative Research Centers, which are hobbled by high reporting requirements.
Davis would surely like to have an NIH-funded research center, and the guaranteed multi-year funding and collaborative opportunities that come with it, but his work will continue.
That’s good news because Davis is engaged in three of the most interesting research projects going.
Activating the T-cell Activation Study
First, the OMF will fund an expansion of Mark Davis’s findings that T-cells are being clonally activated at a high rates in ME/CFS. Davis’s initial T-cell findings suggest that these master immune regulators are being tweaked by something. Here’s what Dr. Koroshetz said about that project:
Mark has really pioneered the way to go — from how the immune system senses either an external or internal antigen — and then actually how that response is generated.”
And it’s very groundbreaking work in that he can go from not knowing what the body is responding to, to actually doing detective work and tracking back to find where the original response was. For example, in a large cohort of chronic fatigue patients, he has now found a number of new antigens that correlate with disease. And he hasn’t published this yet, and he’s not ready to tell us because he needs to be 100 percent certain of what these antigens are, but I think the approach itself is really groundbreaking.
With Mark Davis and Derya Unutmaz working on them, T-cells have become of great interest in ME/CFS.
If Davis can determine what that something is – which is not easy at all – any time Ron Davis calls something “non-trivial”, it means it’s not easy to do – he could conceivably get at the heart of what is causing the immune problems in ME/CFS – and who knows, perhaps even ME/CFS itself. This study will use emerging technologies produced by Mark Davis’s lab, the product of which recently appeared in a publication in Nature – one of the most sought after journals in the world.
This study will also utilize advances in understanding the HLA genes produced by Davis’s Stanford Genome Lab. HLA genes enable immune cells to present pieces of viruses to the immune system so that it can react to them. Mapping these highly variable genetic segments was long thought to be impossible but Davis’s Stanford Genomics Center Lab cracked that nut a couple of years ago. The two Davises and others spun a company called Sirona Genetics out of their findings. That company was acquired by another company, Immucor, in 2016.
The Big Data Study Goes Mainstream
The OMF is extending the same kind of data collection and analysis applied to the severely ill patients to the less severely ill and their families. Importantly, the study will use family members who are not ill as healthy controls. Family members are the best kind of healthy controls because they have similar genetics, environment and diet. Anything that pops up, then, will probably not be due to these factors – making the results more meaningful. This project is taking place in Mike Snyder’s lab.
Threading the Nano-Needle
The nano-needle is an exciting bit of new technology but as Davis reminded us in a new video, it is new technology – and that means issues are going to crop up. Basically, Davis stated, there’s going to be “one problem after another”. The nano-needle is in the “one problem after another phase”.
A perplexing blood preparation issue, for instance, caused them to step back. It turns out that freezing blood, keeping it cool on ice, etc. doesn’t work with the nano-needle. The sample preparation that works for the nano-needle, ironically, is the easiest one: keeping the sample at room temperature.
On the bright side, they’ve got 21 samples tested. So far, every ME/CFS patient and no healthy controls have tested “positive” i.e.; their cells appear to be unable to handle the increased stress produced when salt is added to the mix. This very, very consistent finding has resulted in a rarely seen probability factor (p<.00003) which indicates that the needle, so far, is picking up something quite unique to ME/CFS. Davis noted that although the sample size is small, with their billion data points each, each sample reading is very robust.
The nano-needle is a case of technology outstripping our understanding. It’s showing something dramatically different is occurring in ME/CFS patients’ cells but they’re not sure what it is. They are pretty sure that the cells are not dying but they are clearly changing in some other way.
Next up, they will run other disease samples (multiple sclerosis, diabetes, FM, Lyme disease, autoimmune diseases) to see what kind of signature they produce.
Freeing the Data
There’s been a good amount of talk about freeing the ME/CFS data and going open source. Except for perhaps some CDC data, I’m not aware of open source data on ME/CFS. Given the highly competitive research field and the worries about being scooped, researchers have legitimate concerns about providing their hard-won data to others.
A year or so ago, Davis said he was committed to providing the group’s data to other researchers in hopes that it could help inform others work on ME/CFS. That hasn’t happened yet and I asked him why.
Davis said that, like so many other things in science, providing the data turned out to be much more complicated than he’d thought it would. The problem was Stanford. If you look at Davis’s Stanford Chronic Fatigue Syndrome Research Center website, it’s situated inside the Stanford Genome Technology Center’s website. For maximum credibility that’s right where you want it but Stanford told them there was no way in the world they were going to be able present the data on the Stanford website.
Stanford, it turns out, is very protective of its firewall. It doesn’t think kindly of anyone outside of the University being able to penetrate it. Plus, Stanford only wanted researchers to access it. Eventually – it took a year to work everything out – the Davis team housed the data on a server outside of Stanford and it should be accessible – via application for researchers – soon.
The open source platform took longer than expected but it could be a big win. It’s clear that Davis prizes collaboration. He knows he’s not going to solve this disease by himself – at least not in an appropriate timeframe. That’s why he’s putting so much effort into making his data public. It’s why he put together the Symposium last year. The SMCI, to their credit, produced a similar gathering a couple of months ago. The NIH, to their credit, is requiring that their research centers share data and collaborate as well.
The Severely Ill Big Data Project
The sample size of the Severely Ill Big Data project is not large but the amount of data that’s been gathered on each patient is huge. No other study has examined any cohort of patients with the depth that Davis has. Of course, no one has looked at really severely ill patients with any detail at all before.
The severely ill patient data will help tell us what’s going on the severely ill now – and should reap dividends for years as other deep-dive projects (the NIH’s Intramural study comes to mind) featuring healthier ME/CFS patients get finished up and the two groups can be compared.
Analyzing that much data is taking time but the addition of a bioinformatics researcher is helping. Thus far, the genetics portion of the study is finding a lot of polymorphisms e.g. unusual genetic variations in the severely ill patients, particularly in the “KIR (killer-cell immunoglobulin-like receptor”) locus” which is involved in infection. This is a particularly interesting set of genes as they regulate the killing activity of natural killer cells.
The study is too small in and of itself to validate these findings, but with Davis working on other genetic studies with larger cohorts, and with Dr. Klimas hooked into Patients Like Me and doing her own genetic study (See the Great Chronic Fatigue Syndrome (ME/CFS) Gene Project https://www.healthrising.org/blog/2016/09/16/great-chronic-fatigue-syndrome-mecfs-gene-project/), we have some bigger genetic studies underway.
Surprisingly, no infections have been found – yet. While studies have had difficulty finding pathogens in the broad ME/CFS community, Davis thought he would surely find infections in these very ill patients – but not yet. Davis isn’t through; he’s going to use some new technologies to look again for bugs. He’s confident that if an infection is present in the body, it will show up in the blood at some point.
Thus far, the data also suggests that multiple pathways to becoming severely ill exist: no core abnormality has of yet been found in all of them.
The Weird Blood Project
I asked Davis about the next year – I said he’d be focusing on the big three projects, right when Janet cut in – Ron is always investigating; you never know what might turn up. “The Weird Blood Project” (my name for it) is a perfect example of that.
The idea that red blood cells issues might be causing problems is not new. The red blood cells, after all, deliver oxygen to the mitochondria in our cells. If something has gone wrong with them, then energy production would drop.
Could unusually formed red blood cells be having trouble getting to the tissues?
In 1993, Simpson found alterations in red blood cell shape after exercise which he thought could result in reduced oxygen transfer to the tissues. In 1999, David Berg proposed that low level increases in coagulation were rampant in ME/CFS. (At an LDN conference, Dr. Holtorf stated that he finds heparin to be quite effective at times.) In a small (n=20) 2010 study, though, Brenu found no changes in red blood cell aggregation or deformability or fibrinogen levels between ME/CFS patients and healthy controls.
Recently, Anand Ramasubramanian, Ph.D., a bioengineering specialist from San Jose State University (my alma mater 🙂 ) has with Davis begun taking another look at the red blood cells in ME/CFS. Ramasubramanian, who is a blood flow expert and inventor, learned about Davis’s ME/CFS studies from one of his team members. Both groups were interested in the biomechanics of cells, making their collaboration a natural fit. Dr. Amit Saha is leading the effort at SJSU.
Saha is looking at the rate at which the red blood cells from Ron Davis’s patient population flow from a larger test tube to a smaller one; i.e. from a blood vessel to a capillary. The results are still quite preliminary, but thus far he’s finding significant reductions in how quickly the ME/CFS patients’ red blood cells flow into the smaller tube. Ramasubramanian said the early results “are intriguing to say the least”.
Why ME/CFS patients’ red blood cells are getting bunched up in the capillary tube isn’t clear. They could be too stiff and are having trouble deforming. They could be an odd shape, or something else may be going on. Ramasubramanian said they were starting to do microscopy on the blood vessel to see if they were structurally different in some way. He expected to have answers in a couple of months and to be writing a research grant proposal to study the issue in more depth.
Other News
About that Symposium – I asked Davis if there would be another one next year. He said he hoped so. Whether it is or not is largely dependent on funding. I got the feeling that this is something Davis wants to continue with and if it doesn’t happen next summer, it will happen the next.
Dr. David Kaufman MD, a former HIV specialist who turned his talents to ME/CFS about five or so years ago, has been sitting in on the group’s weekly meetings. Kaufman, who’s gotten some great reviews, left the Open Medicine Institute a couple of months ago and formed his own clinic.
More from Ron
Check out a beside chat with Ron Davis – the first in a series of bedside chats with researchers – begun by Janet Dafoe.
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YES!!! Thank you so much for the update, Cort.
I crave salt should i not eat it if it causes havoc with my blood?
Yes, you should eat it. It is probably helping your blood vessel issues. That’s a very common craving for people with ME/CFS.
This is a test which dumps so much salt into a small amount of cells that they have work hard to get it out – using up ATP in the process. It’s a stress test for cells. It uses far more salt than the cells in our body would ever be exposed to
Ron mentioned doing some pilot clinical trials in his bedside chat with Ben. Do you know anything about those Cort, should we expect some pilot trials in 2018?
I have heard that as well but I don’t know any more about them. If Ron talked about them with Ben then they will hopefully, if everything goes smoothly enough (:)), take place. I’m glad Ron is considering them. I haven’t listened to the bedside chat yet.
Cort, this is very exciting news! I am always amazed at Ron Davis’s creative problem solving processes…
Now, I have one question; you mention the ‘Kerr Locus’ and I went off looking for its genetic location or any other information about it, and came up empty handed. (I realize that this title probably isn’t the ‘scientific’ designation). Since I’m involved with a small group of people trying to identify the genetic underpinnings of Hypermobile Ehlers-Danlos Syndrome, and a huge number of hEDSers have both chronic fatigue, POTS and fibromyalgia-like pain, we are always interested in looking at these genetic ‘hot spots.’ So is there any way that you might enlighten us?
And thank you so much for being the spokesperson between the researchers and the patients! You are an invaluable gift!
Yes, well said! Cort is an invaluable gift to us all. Thank you, Cort.
I went looking too! but came up empty-handed as well. Good luck on your search. I can’t but think it will be rewarded over time.
Cort, I did further looking (and thank you for looking as well!) and here is my best guess;
“Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. The KIR genes are polymorphic and highly homologous and they are found in a cluster on chromosome 19q13.4 within the 1 Mb leukocyte receptor complex (LRC). The gene content of the KIR gene cluster varies among haplotypes, although several “framework” genes are found in all haplotypes (KIR3DL3, KIR3DP1, KIR3DL4, KIR3DL2).”
So, I think they are actually nicknamed ‘Kirs’ not ‘Kerrs’ (unless you saw it in print). This would make sense as the researchers are looking at the NK and T-Cells.
It’s the KIR locus. It’s similar to the HLA locus. They are involved in controlling the immune system.
Hi Nancy,
I am one of those patients that would fit into this category, do you think we could get in contact?
Christoph
Hi Christopher, we always like to add data, but all of us in our group have had our entire exome sequenced via NGS–and all of us have some form of Ehlers-Danlos, mostly Hypermobile, but there are some Classicals and a few of us who are not definitely typed.
Do you have your WES raw data at your disposal?
We aren’t a formal research group, just a small bunch of patients who have some amount of expertise among us and we are looking for answers… and we don’t have any funds to go sequencing others for our efforts… but… if you have some data…
You might be interested in my theory involving this connection if you haven’t seen it. http://www.rccxandillness.com
I saw many compliments to the author of this article. Let me be the devil’s advocate. I’m a CFS patient, with no medical science training. I totally get lost in this long story with some very specialized biomedical terms, e.g. HLA genes … Wonder who are the targeted readers, medical pros or common patients. I must miss something here, because I don’t see any “update”. It seems most, if not all, stuff were said before.
The three main projects remain the same butthere are a couple of updates that I’ve never reported on: Dr. Davis’s new grant applications, the new funding for the 3 projects, the blood work project, the KIR locus finding, the suggestion that there may be no core abnormality in the severely ill, the fact that no infections have been found in the severely ill, the open source project and the HLA company Ron and other spun off.
These blogs are not easy! I’m very interested in the research. I do my best to explain – hopefully accurately most of the time (lol) – them in as easy to understand ways as I can (which helps me understand them actually) but it is difficult stuff that’s for sure.
I need to bring back The Gist section which gives bullet-points.
I’m not sure how the maths works i.e. 7 failed applications for a research centre means 21 applications for one off grants.
Possibly one way to get grants would be the European Union Horizon 2020 program – 80 billion dollars ish.
Maybe we could help by contacting Members of the European Parliament [MEPs] etc to ask for support. With the film Unrest about it might be a good time to try.
Re funding, by EU, for ME/CFS research “To date, no specific projects on ME/CFS have been supported by the EU Framework Programmes for Research and Innovation”. [Google response to question “E-006901/2017”].
Re funding, by EU, for Lyme disease: “Overall—-a total EU contribution of EUR 40 million”.[Google response to question “E-003624-17”].
Applying for grants takes time.
Lots of good stuff here re T-cells and nano needle.
Each research center application was required to produce three projects – each of which could be turned into a grant. 3 winners and 7 losers should mean about 21 potential new individual grant applications.
I had no idea the EU was sitting on all that money….
You previously ran a good article re lack of funding for ME/CFS research [if you have a link then I’d be interested]. Lyme disease seems to be much higher profile than ME/CFS in the European Union. This is reflected in the 40 million euro funding by EU for Lyme research; compared to zero for ME/CFS. This is also reflected in the number of parliamentary questions re Lyme (9) versus ME/CFS (1). We should try to use the interest in the film Unrest to put pressure on the EU to fund biological ME/CFS research. Also, possibly those from outside Europe (e.g. America or Australia – Melbourne etc) could link up with European researchers and submit a bid in that way.
I was first diagnosed in 1984 with immune deficiency {low t-cells} and chronic encephalopathy. This was before there was a name for the condition now called CFS. The doctor who diagnosed me put me on dextran sulfate, a non-anticoagulent heparinoid to stablize mast cells. This drug was being obtained on an orphan drug waiver from Germany. This was very helpful in controlling my multiple chemical sensitivity symptoms. In the beginning, I also had horrible migraines that the doctor would treat with a shot of heparin that made the headache go away very rapidly. This all suggests that the blood cell deformation theory may have merit.
I was first diagnosed in 1984 with immune deficiency {low t-cells} and chronic encephalopathy. This was before there was a name for the condition now called CFS. The doctor who diagnosed me put me on dextran sulfate, a non-anticoagulent heparinoid to stablize mast cells. This drug was being obtained on an orphan drug waiver from Germany. This was very helpful in controlling my multiple chemical sensitivity symptoms. In the beginning, I also had horrible migraines that the doctor would treat with a shot of heparin that made the headache go away very rapidly. This all suggests that the blood cell deformation theory may have merit.
Whoa – heparin and chemical sensitivities! My sensitivities actually get better with B3 – niacin – which opens up the blood vessels…Ha!
I don’t know if this fits in but migraine is one of the most common comorbid disorders with FM and ME/CFS and the blood vessels are involved there.
“Why ME/CFS patients’ red blood cells are getting bunched up in the capillary tube isn’t clear. They could be too stiff and are having trouble deforming. They could be an odd shape, or something else may be going on.”
-> interesting paper titled “Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging” in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937982/
“Red Blood Cells (RBCs) need to deform and squeeze through narrow capillaries. Decreased deformability of RBCs is, therefore, one of the factors that can contribute to the elimination of aged or damaged RBCs from the circulation. This process can also cause impaired oxygen delivery, which contributes to the pathology of a number of diseases. Studies from our laboratory have shown that oxidative stress plays a significant role in damaging the RBC membrane and impairing its deformability.”
and “However, the autoxidation of hemoglobin (Hb) bound to the membrane is relatively inaccessible to the predominantly cytosolic RBC antioxidant system. This inaccessibility becomes more pronounced under hypoxic conditions when Hb is partially oxygenated, resulting in an increased rate of autoxidation and increased affinity for the RBC membrane.”
-> I believe we both have highly increased ROS production and hypoxic conditions in the smallest capillary blood vessels so this kinda adds up. Interesting note: My grandfather, father and myself developed pronounced somewhat reversible rheumatic problems with the legs. My grandfather was ?diagnosed? (at the time lots of diagnoses were more based on experience than measurements, but that often worked fine) to have “debris” in his blood. He got a first temporary improvement by having a blood transfusion. Results waned and could not be reproduced later. If I get it correct RBC plus high amounts of ROS equals massive RBC death and sediment in blood.
“It turns out that freezing blood, keeping it cool on ice, etc. doesn’t work with the nano-needle.”
-> may add up with “damaging the RBC membrane” in the linked paper; freezing damaged cells and reheating them causes two things: thermal stress, likely minor and expansion of water (inside the cells) going to ice putting massive pressure on already damaged cells leading to easy cracking of cell membrame; think freezing food losing taste and structure. Gets worse when freezing it slowly so testing this theory may be done by strongly varying freezing speeds from slow to “flash freezing”.
“Why ME/CFS patients’ red blood cells are getting bunched up in the capillary tube isn’t clear.”
-> Reduced RBC flow speed in capillaries easily leads to hypoxic conditions, creating more ROS and damage to RBC cell walls as mentioned in the paper
As some might know I am a staunch believer in impaired blood flow in ME patients being a likely candidate for many of the things that go wrong in ME and hypothesized that increased viscosity from blood in the smallest hair vessels (capillaries) is probably pretty bad.
My idea was based on the ideas that these capillaries have decreased diameter
due to increased ROS killing NO increasing vasoconstriction; low blood volume in ME patients that turns blood supply in a volumetric flow dominated system rather then a blood pressure dominated system and in such system flow to the capillarities is at a disadvantage compared to in the wider blood vessels; infection and inflammation thickens blood making it flow worse; blood is a liquid that has stronger increase in viscosity in small capillaries than water due to RBC being big
-> if RBC already by themselves have increased viscosity as show in this research then this adds up to a very strong candidate for this being a major problem in ME in my opinion. It also coexists well with the observed depleted gluthathione levels, Naviau’s Dauer hypothesis of masive peroxide production, reduced total blood volume and some research indicating there is plenty of oxygen in wide arteries but the cells (located mainly near capillaries) do not take it up. It also can be linked to a possible mechanism for PEM.
Thanks Cort for the write up and thanks so much Ron Davis and dear colleges for their incredible efforts for finding answers!
Kind regards,
dejurgen
Wow Dejurgen gets to the heart of things again! Very impressive. I have though small blood vessels, hypoxic conditions are probably involved. It makes sense experientially to me. Thanks again for the interesting ideas.
Hi Cort,
“I have though small blood vessels”
I’m curious, how do you sense/observe to have though small blood vessels? I would have no clue.
And thx,
dejurgen
I’ve just always intuited that blood flow may be impaired because of the symptoms that show up after exercise….It just seems like a great solution. It’s juust an intuition…:)
Now I come to think of it, “Red Blood Cells (RBCs) need to deform and squeeze through narrow capillaries. Decreased deformability of RBCs is, therefore, one of the factors that can contribute to the elimination of aged or damaged RBCs from the circulation.” in the linked paper is new to me. *Squeeze* RBC through narrow capillaries and having them burst doing so if they are old or worn out??? That sounds cruel! Is this really settled science???
“Why ME/CFS patients’ red blood cells are getting bunched up in the capillary tube isn’t clear. They could be too stiff and are having trouble deforming.” quoted from your blog seems to suggest healthy RBC need to be able to deform well and are often deformed if just pushing them (in a liquid?) through a capillary already requires it…
If it so that RBC are often deformed and squeezed and damaged ones end by being squeezed till they literally burst, it could have far going consequences to ME.
Imagine pushing a 20 cm diameter balloon through a 15 cm diameter plastic pipe. It can be done by adding pressure and deforming the balloon to sort of an American football. It can be done if applied pressure is moderate and you don’t have bad luck. Now image ME patients having “old worn balloons” or membranes that burst more easily and pushing said 20 cm diameter balloon through a 10 cm diameter plastic pipe. The smaller pipe represents the constricted hair vessels. Only 33% diameter reduction is still fairly little. Do you see the balloon burst near always in your imagination just how many times you try as I do? ME patients RBC and constricted hair vessels?
Now that can’t be allowed to happen on a massive scale. It would result in RBC squeezed juice that compares to ketchup rather then to water with pieces of tomato. So how could the body fix it? Just increase blood vessel diameter a lot, but that likely is either impossible or has pretty strong disadvantages too. With me taking meds that increased blood flow caused massive upflares in imflamation like feeling and destroyed my remaining abillity to walk for many months after stopping the meds.
So what solution, beside having smaller infantile RBC, does the body have? One of them could be applying very little pressure to the RBC/blood. As volumetric flow is proportional to pressure the result is clear: blood flow in hair vessels would be only a fraction of what it is supposed to. Likely result: hypoxia, massive ROS production, malnutrition… …possibly building blocks for ME.
One of the best ways to reduce pressure in those constricted hair vessels (rather than having a larger diameter of the vessels): likely reduce combined blood pressure and blood volume…
Now I still was wondering why something like that would happen in a mechanical tube?? Amount of liquid and pressure are set by the operator; the body can’t adjust that. And then I vaguely remembered me an idea someone launched after Naviaux’s Dauer hypothesis (maybe it was himself; to tired to look trough all information). Cell Defence Reaction produces hydrogenperoxide and that would signal the cells to toughen their cell walls as a defensive mechanism.
Now if your cell membrane is worn and torn, having it stretched and squeezed in an American football shape ain’t good. Mechanically speaking there are two things:
* A perfect round sphere has the smallest ratio of surface area to volume of all possible shapes, that’s proven math. So an American football shape would require quit a lot more surface area in order to hold the same volume of internal RBC content. Let’s say for example +50% depending on exact shape. That requires quite a bit of elasticity.
* An American football shape would not only put a lot more average pressure on the membrane due to bigger stretching but it would also create two points of highly increased surface tension: the outer tips. Let’s say for example roughly twice as much tension compared to average for the shape.
=> combining both factors the two points of worst tension would have easily 2 to 3 times as much tension in an American football shaped RBC compared to a perfectly spheric one. Pop and burst??
=> So in CDR making the shape of RBC round is a very sound “decision” the body could make. Reducing surface by making it spherical also helps against pathogens, toxic stuff and so on as it reduces contact area. If worn RBCs have to make lots of hydrogenperoxide to strengthen themselves in order to survive then that may be exactly what they do.
Problem is, an indirect consequence would be that lots of tissue would be in hypoxic condition because round shaped RBC don’t yield sufficient blood flow. That would trigger those tissues (like muscle cells, brain cells, fascia and other connective tissue…) to go in CDR too and create plenty (a sea) of ROS that the RBCs have to wade through. Further degrading their membranes, creating an even worse situation and clear vicious circle…
dejurgen, so a breathing problem is the core problem in a subgroup of ME patiënts? I have the same problems as you desribe my breathing/heartrate is also abnormal, not due to psychologial problems! Maybe the problem is in the brainstem/pons/medulla?
@Gijs: “dejurgen, so a breathing problem is the core problem in a subgroup of ME patiënts?” I’d wish I knew ;-). It’s mainly guesstimate.
Many people have breathing problems without having ME/FM. I look more at breathing problems as an enabling factor to get this disease and get it stick really bad.
For example the combination poor blood flow with breathing problems seems to be quite strong to me. I look at it from an engineering point of view.
Tissue oxygen delivery for example contains a large “chain” of events that all impact total efficiency. It starts with breathing air in, goes over delivering to and consuming oxygen in tissue and removing waste products afterwards.
A very simplified (far more factors are important) equation for (non normalized, for easiness) overall efficiency could be:
overall_efficiency = other_factors * breathing_ability * blood_flow_in_hair_vessel ^ 2
Why the effect of blood flow in hair vessels squared? As it both modulates the blood flow in the lungs determining oxygen takeup as it modulates blood flow at the tissues determining oxygen delivery.
In this simplified equation improving breathing ability has a clear and direct impact on oxygenation of tissue and thus on hypoxia. One could say that blood oxygen levels are fine in the main blood vessels with many patients, but there is another side of this simple equation: at night both breathing ability and blood flow decreases considerably. During the day many patients tend to hyperventilate according to many classic doctors. However I think many patients don’t/can’t hyperventilate at night or after overexertion to get sufficient sufficient oxygen in the blood to compensate for the poor delivery in the tissues.
So, I believe for many patients with more pronounced breathing problems nights get sometimes literally “terrifying”. Improving breathing conditions going from proper room ventilation at night, reducing dust and toxic chemicals in air, reducing mold in air, optimizing air temperature and humidity, slowly learn to breath better and more efficient by going to a really good Physical Therapist learning it to you… offer a range of options that can support many ME patients and many of those options are within reach of exhausted ME patients.
Another interesting route is the controversial “breathing less” approach many ME patients have success with. It has a lot of patients who swear by it, but the explanation they give is so unlikely that it is disregarded by most patients. The thing at work may be here: don’t try to breath more to match the exercise you want to do but live within a certain breathing envelope (Pacing applied to breathing over pacing applied to exercise). If breathing capacity would be a very exhausted resource it would make sense. Saving on this resource would allow to have some more of it left at night and not get so deep into destructive hypoxia causing patients to be lower on energy at the morning then before going to sleep.
David Systrom, pulmonologist, has said that most ME/CFS/FM/POTS patients hyperventilate during exercise.
I know that I can have a lot of problems with dust/particles in the air. I can’t handle being in Starbucks for much, for instance, because the coffee dust hurts my chest and makes it difficult to take deep breaths.
Wim Hoff has evolved breathing techniques which he says boost autonomic nervous system functioning. A blog on that is coming up.
dejurgen, very interesting. I Always thought the ANS was a major problem in ME/CFS (fight, flight system). I totally agree that bloodflow is a big problem. Finally someone is looking at the right place. Bloodflow problems could be due to the overdrive (ANS), bloodvessels will constrict. This problem has a negative impact on the Bohr effect. So, oxygen builds up in the body. I am 99% procent sure that bloodflow and oxygen delivery is the core problem in cells of ME patiënts.
I believe my personal case is showing many sign of a combined bloodflow / breathing problem. There are signs of weaknesses in it littered throughout my life long before I got ill I believe.
They can reinforce each other to provide good health or drive a strong downwards spiral IMO if they “break”. Many other things can initiate ME/FM to I believe but it looks like new/additional signal seem to often “grow” trough derailing the blood flow (and to a lesser extent breathing) first.
The ANS can cause many problems and problems with the ANS can likely initiate ME/FM but the main link could be this: epinephrene (adrenaline) is a very strong hormone. It has a really strong impact on … … breathing, blood flow, increasing lever functioning (clearing/converting/recycling lactic acid ROS, toxic stuff, pyruvate, glutathione…), inflammation (the number one medicine worldwide to fight acute allergic shock) and some hardly understood impact on the immune system. Unfortunately the body has near no feedback system to keep it in check. Depletion is hardly an acceptable feedback system.
Basically, if it were easier to dose according to varying needs and had not such epic side effects, it could be close to the best known ME/FM medicine in my opinion. Remark that 1 out off 3 approved FM medicins is Cymbalta, SNRI reducing reuptake of norepinephrene. By doing so it provides increased amounts of the basic building block for epinephrine/adrenaline. Another 1 of 3 may have a link towards increasing epinephrene too but I’m not completely sure about it.
I believe our highly increased anxiety is a direct consequence of the body using adrenaline as a tool to get us going and even trying to restore our health. I have quite a lot of clear observations that I can link to this behavior. I also read about many people who seem to have likewise experiences without explicitly pointing towards epinephrene.
Of course, in an environment depleted of good blood flow an oxigen delivery a host of nasty stuff builds up that puts a strong load on the nerves. And poor nerve functioning further deteriorates blood flow and breathing…
Yes.
“I believe our highly increased anxiety is a direct consequence of the body using adrenaline as a tool to get us going and even trying to restore our health. I have quite a lot of clear observations that I can link to this behavior. I also read about many people who seem to have likewise experiences without explicitly pointing towards epinephrene.”
I also remember Dr. Bell’s observation of an ME/CFS patient diagnosed with panic disorder who instead had low blood volume – which has got to mean hypoxia in some places?
https://www.healthrising.org/forums/resources/when-panic-isnt-dr-bell-on-maggies-me-cfs-and-fibromyalgia-story.237/
I agree. Make sence. So high adrenaline is a compensation reflex in your theory?
@Ghijs “I agree. Make sence. So high adrenaline is a compensation reflex in your theory?”
Yes, on average increased and sometimes humongous high. Depends on patience case though; some patients that are considered to have adrenal failure will likely differ as their body potentially fails/refuses to make any.
Also the brain is adaptive to what works IMO. So if a patient has *very* bad side effects to increased adrenaline the brains may make less use of it.
What is the “main” driver of ones particular case of ME/FM is likely to be important too. If one has a genetic predisposition to for example auto-immunity problems the adrenaline push will probably be lower (but still highly elevated) then if predisposition to poor blood flow / breathing is the main driver itself as I believe is the case with me.
For me it’s more then theory. This notion helps me to select better approaches in trying to improve my health. Taking it into account highly increased my hit-to-miss ration in my trial and error path.
It’s also a practice for me. My first firm but short flare up of health did go hand in hand with *very* high adrenaline levels (caused by near pure luck but easily scientifically explained later on). Out of nowhere I got increases in “adrenaline-feeling” a *lot* higher then what I experienced when I got the first time mugged by robber who tried to beat me down with a bat. Just when laying at bed during the night. It happened several times. My hart raced very dangerously out of control. Luckily I had learned to somewhat control anxiety levels pretty well over the last few decades so I could get those levels to safe zone in about 15 minutes several times. It was however a very dangerous situation.
After losing this almost magic healing cycle after a few weeks it took me many months to figure out what did happen and why it likely did come to an abrupt end. Adrenaline increasing “things” were the likely (and at the moment completely absurd) cause and I “carefully”/meticulously (I doubt if increasing adrenaline levels being a severe ME patient ever can be called careful…) tried to recreated these circumstances. Result: near instant improvement and a strong positive circle that lasted for months. I somehow managed to long (or mid) term increase my health by surfing a tidal wave/tsunami of adrenaline. And keeping most of the progress afterwards rather then being far worse of! It required a great deal of somehow acquired control over anxiety and adrenaline production. Many times I felt the desire to jump out of bed and to run up and trough the walls. I did realize that was neither a good idea or possible though… IMPORTANT: WHAT I DID IS NOT SAFE! THIS IS NOT ADVICE! IT IS LIKE GROWING VEGETABLES IN AN ACTIVE AND DENSE MINEFIELD!
Then I did some things wrong again blocking and partially reversing progress. Now I am reasonably successful working towards combining slower improvement with reducing adrenaline levels and dependency. In part that is possible by learning new tricks and things. The road is still long, hard and uncertain though. In the very best case it’ll take me 5 to 10 years before reaching somewhat normal health. But compared to how I was it already is a little piece of heaven even if it more resembles the portal of hell.
There was a man names Les Simpson (think spelling is correct) that studied red blood cells & their (shape). He traveled around taking blood from FM & CFS patients many years ago (they would count the number of discoid shaped cells) Think he has since died.
Yes, indeed.
I wonder if the blood cells can’t handle salt because of the sodium channel issue discovered by the National CFIDS Foundation.
Depleted radionuclides, esp uranium which is leaching into water and soil everywhere usea a specific sodium ion channel. I believe the NCF has found the cause. Too bad that Ron Davis doesn’t collaborate with them!
Last post before I crash tonight… I should stop earlier…
Maybe it’s not down to bio-chemistry. I prefer physics for an explanation whenever possible as physics is far better at following a simpler set of rules.
Maybe it comes down to deform-ability. Deforming and bending both greatly increases surface and reduces membrane thickness. Both impact resistance. Also the water/salt/membrane interface can be a major source of resistance (contact resistance). Also the distances electric current travels trough the cell clearly varies with deformation, changing resistance (sometimes called impedance) once more.
Depending on the ratio of liquid volume to cell volume and ratio of current that passes through the liquid versus through the cells, deformation of cells once again could make quite a difference.
If only a small amount of liquid is used to make contact between the nano probe and the cell then shape is an even bigger component in contact resistance as it determines both area and average depth of the contact resistance.
So where comes sodium into play? Sodium, like many other chemicals, dramatically change the resistance of water. Pure water in itself is a very poor conductor. Adding sodium to it greatly changes conductivity in for example the contact layer. And the contact layer is greatly effected by shape of the cells.
Another possible angle is surface contact forces. At first sight forces between a liquid and a solid are small. But as the scale gets to the microscopic surface tension often becomes a dominant force. Some insects for example can walk on water thanks to surface tension. It only works because they are small. On a smaller scale it becomes even more dramatic: small bells of water vapor (caused by very low pressure) are anything but soft. What is soft on a large scale can completely demolish a high quality steel pump in less then an hour because it is so incredible hard. It’s a bit like the “soft” rain shower with big drops versus the “nearly painful” economic shower head with tiny drops. At microscopic scale it’s as bad or worse then sandblasting.
Depending on the exact setup, contact forces between water/liquid and such a tiny cell should easily be able to deform the cell. What’s the role of sodium here: it is one of many chemicals that can change “hardness” of water and the strength of contact forces between liquid and cells (and thus can cause deformation of cells). Next to desinfecting, soap for example softens water quite a bit. Calcium on the other hand makes water a lot harder…
“Weird Blood”: The Zero Erythrocyte Sedimentation Rate.
Which was the first blood abnormality to show up in the
1985 Lake Tahoe Mystery Disease.
https://www.survivingmold.com/community/erik-johnson
Wonder if stat is a requirement class in med school these days. To generalize a personal experience could be misleading, even samples taken from a group of subjects could put a research on a wrong direction. (e.g. the pre-election polls cost someone losing presidency. No intention to get into politics, just offer a prominent example.) Now, there are quite a few different researches on ME and every institute seems very confident. As a patient, just hope they know they are doing the right things, and practice more cooperation, less competition.
Thanks everyone for interesting comments on red blood cells, oxygenation, etc. Has anyone looked carefully at the rate of RhD neg and RhCE neg ( and other variations?) individuals diagnosed with CFS? These “negative” individuals lack certain red blood cell surface proteins. For a long time no one knew the purpose of Rh D/CE surface proteins, but now they are suspected to be involved in the release of carbon dioxide from the red blood cell. Red blood cells must release the CO2 before it can pick up oxygen. Surface proteins must surely affect shape and deformability. And importantly may affect diffusion of oxygen across the blood brain barrier?
I took an informal poll in my support group – only about 17 people there, but 55. % were Rh D neg. Some did not know. I am RhD neg, as are my son and Mom – all exhibiting symptoms. My husband and daughter are Rh D pos – no symptoms. The highest rate of Rh D neg is with the Basque – about 35%.
My husband and I stayed at Circus Circus 6 years ago. Thought I would feel bad with cigarette smoke, noise etc. Well, I woke up each morning feeling great. What???? Found out they pipe extra oxygen into the hotel. Don’t know exact amounts. Has anyone tried extra oxygen at night?????
Hi Merida,
I never heard about this stuff. Haven’t got sufficient energy to look deeper into this topic as it is complicated and requires focus, but my attention was grabbed by one thing:
“but now they are suspected to be involved in the release of carbon dioxide from the red blood cell.”
That may be related to the *very* often cited overbreathing/hyperventillation/low blood carbon dioxide values observed with ME patients.
The idea would be that the blood carbon dioxide values are not low because it is more difficult to release. What goes in must come out so even if release is delayed it must be passed through the blood eventually.
But the speed of chemical reactions often goes quicker if there is less of the end product available. E.g. the less carbon dioxide there is in the blood, the faster the reaction (transfer CO2 from hemoglobin bound to released to the air in the lungs ?via release in the blood first?) goes. Overbreathing, or breathing way too much, is one of the easiest ways to ready blood CO2 levels and could hence speed up the process that would be too slow in many ME patients according to your information.
It reminds me of how often I woke up breathing like a horse so much that my chest hurted but still lacking sufficient breath.
“but now they are suspected to be involved in the release of carbon dioxide from the red blood cell.”
This may help solve another mystery I failed to get my head around: somehow the oxygen to carbon dioxide ratio kept returning as “seeming important” but it remained unclear why. Now this piece of the puzzle could give the answer to multiple questions.
Glucose, the main carbon fuel in the blood, has chemical formula C6H12O6. When fully metabolized this yields:
C6H12O6 + 6O2 => 6CO2 + 6H2O
or for each molecule of oxygen provided by the RBCs it releases one molecule of C02 back.
Fat on the other hand has significantly less oxygen in its chemical formulla. On one formulla (fat has many variants) for unsaturated fat triglyceride in https://en.wikipedia.org/wiki/Fatty_acid_metabolism is C55H98O6
=> That has as much 02 as glucose but far more C and H components. When fully metabolized this yields:
C55H98O6 + 101O2 => 55C02 + 49H20
or for each molecule of oxygen provided by the RBCs it releases only 0.55 molecule C02 back.
Now that is a whopping difference in how much CO2 is released compaired to how much O2 is breath in! I do however estimate the ratio for an average mix of fat to be closer to requiring one molecule of O2 for 0.75 molecules of CO2 released back to the blood, based on previous work I did. That’s still a more then significant difference. Suppose breathing out CO2 is the main limitation of our breathing capacity and you can slash that by 25% by going to a full fat ?aka paleo diet? diet.
Now it is still ATP produced per amount of O2 consumed and CO2 released but in the provided link “When compared to other macronutrient classes (carbohydrates and protein), fatty acids yield the most ATP on an energy per gram basis, when they are completely oxidized to CO2 and water by beta oxidation and the citric acid cycle.” and based on previous work I did (good data on ATP per molecule is harder to find with fat then glucose) I came at an estimate that it requires about the same amount of oxygen per ATP but about 25% less of CO2 per produced ATP.
=> So this RhD neg and RhCE neg thing could provide both a decent link to our massive “hyperventilating”, “scoring somewhat normal on oxygen in blood tests” and as to why the palleo diet could work. On plus it is a simple explannation an the simplest are often the best. A simple one that could crack several unsolved mysteries at once is a good candidate IMO.
On plus, having lower lactic acid in the blood reduces blood acidity. And higher blood accidity once more reduces transfer speed from hemoglobin CO2 to blood. Both the palleo and vegan diet are at work here once more: the palleo diet reduces lactic acid in a straigthforward way by blocking sugar produced lactic acid. It however does produce acidic ketones that likely in part or wholly compensates for this. The vegan diet on the other hand does it in a more indirect way: the large amounts of fiber in it make the blood sugar level more stable and reduce peeks. Having less high peeks reduces the need to burn the sugars fast in an anaerobic way (in order to avoid dangerously high blood sugar levels). What’s more: the vegan diet is one of the more alcalic diets ever reducing blood acidity and hence increasing CO2 removal speed as well.
If a process is simple and has many advantages to happening this way… then it is quite a good candidate IMO
Question: do you happen to know if Parkinsons and Epilepsy patients have significantly more often this “neg RBCs”? I ask the question because the palleo diet wroks there quite well too.
One last one:
“Found out they pipe extra oxygen into the hotel. Don’t know exact amounts. Has anyone tried extra oxygen at night?????”
Never tried oxygen but I do signifficantly sleep better and am recovering better when I sleep with my window open. Unfortunately cold drafts causing colds only allow it some part of the year. That was another mystery as fresh air hardly contains more oxygen. It does however contain 0.4% C02 compared to about 3% for in house air. Once more: if breathing out CO2 would be the bottleneck here…
That was one thing that puzzeled me long time too: In experiments with healthy people upping the CO2 content to 5% in a room let them have headaches, drowsiness, perform and think poor… Long time it was thought it was due to poorly ventillated rooms containing plenty of other bad chemicals but releasing a few % of pure CO2 in the room (thus not having other polutants) did just the same…
It’s a bit like the very common thing said to students: after a while get out off the house to breath in some more oxygen…
Everybody knows it can make quite a difference, but common 20% of oxygen versus 18 to 19%?? Going to the hills makes a larger difference in oxygen content per liter. And going to the mountains does reduce oxygen per liter even further. If they are not too high, many patients with breathing problems do fare well with going to the mountains. Can’t be based on more oxygen ;-). But it in general does contain less CO2. And so does air blowing in at the beach from over sea.
Also a common medical oddity struck me. On one hand doctors tell that oxygen saturation rates in blood are high enough so that you can’t increase it significantly anymore with breathing any deeper. One the other hand the often advice stressed persons to get out, take a walk and *breath deep* to get more oxygen ;-).
Funny thing is, everybody knows it works while oxygen saturation theory says it shouldn’t…
So if breathing in general population would be affected quite a lot by CO2 content and many of us would have additional problems removing it…
Regarding to the hotel: the extra O2 probably came with high ventillation volumes reducing CO2 in the air as well.
“It does however contain 0.4% C02 compared to about 3% for in house air.”
400 ppm of CO2 or 0.04% compared to 3000 ppm or 0.3% would be better ;-). It’s still much more indoors.
When thinking over what I wrote I came to one thing many doctors would see as an inconsistency in my ideas: if you can breath that much that CO2 content / CO2 partial pressure becomes significantly below that of an average person then there isn’t a problem removing CO2 to begin with. This would invalidate the idea that removing CO2 is a bottleneck in (our) breathing.
This contradiction could lay in the way C02 content is most often measured: as a partial pressure. I am non to sure about the exact setup of this medical measurement procedure but I do know what partial pressure is from a physics point of view. It is a measure that describes how easily a chemical goes from a solid or liquid to the gas state and viceversa. Or better: how equilibrium settles when left sufficient time.
If the tests *would* equal CO2 partial pressure to be a good measure for blood CO2 content (meaning lower partial pressure equals less CO2 in the blood per ml of blood), as it seems it is done, then it does not take into account that some peoples RBC may be much more fond of keeping their CO2 with them then other peoples RBC do. This could be due to this “neg proteins”. In that case people with such “neg” RBCs would push CO2 to remain attached to the RBCs and thus remain more in the blood and be less in the gas state compared to other people.
Depending on measurement setup this could result in significantly different amount of CO2 molecules per ml blood for equal CO2 partial pressure when comparing patient to patient. If this could be trough it could swipe the idea that we are hyperventilating from the table. And with it it could shine light on quite a few unsolved questions and contradictions.
Together with our ability to push trough short durations exercises such as a breathing test (compared to our average exercising ability) it may clarify why so many of us get trough a lung test “OK” while lacking so often sufficient breath.
Dejurgen – Wow. So glad my comment stimulated such interesting detailed thoughts from you. I Must read your comments again carefully, remembering that mature red blood cells have no mitochondria and depend on anaerobic metabolic pathways.
This would be very easy to test. First, just find the rate of RhD and RhCE negative individuals in our group. ( and there may also be some other relative red blood cell surface proteins) Also, the conundrum that peripheral blood oxygen measurements ( with the finger gizmo) may not reflect the diffusion of oxygen and CO2 across the blood brain barrier.
Yes, I have always felt a bit panicky in closed in, tight spaces. I have woken at night with the lack of oxygen feeling. But I suspect it is my neck at the root problem.
One more thing- I have tested low on the enzyme lactate dehydrogenase – consistently 60 to 70 % of normal. They were looking for elevated values, so this low value was ignored. This enzyme is critical in the anaerobic metabolic processes of the red blood cell – since they have no mitochondria. Depressed LDH is considered glycogen storage disorder – was number 11. Wish I knew more.
Hi Merida, thank you for bringing up the topic. We desperately need better and more information to move forward.
“remembering that mature red blood cells have no mitochondria and depend on anaerobic metabolic pathways.”
-> Good for bringing that up. I now vaguely remember having read about it but wasn’t actually aware of it. That means that I can scrap the idea that RBCs produce H202 to toughen up their cell membranes. The most likely path to produce H2O2 would be through the mitochondria that ain’t there… That’s a good thing, reducing the search space :-). They could still be toughening their cell membranes by signaling from H2O2 in the blood.
“One more thing- I have tested low on the enzyme lactate dehydrogenase – consistently 60 to 70 % of normal. They were looking for elevated values, so this low value was ignored. This enzyme is critical in the anaerobic metabolic processes of the red blood cell – since they have no mitochondria.”
-> IMO both low and high lactate dehydrogenase could indicate too much anaerobic metabolism. Many may frown upon it, but I look at it from a push-pull perspective. If aerobic metabolism isn’t sufficient the body may produce much more lactate dehydrogenase to encourage more anaerobic metabolism. That’s the push mechanism that produces more to get more result. On the other hand enzymes, although often lasting many many cycles, don’t last forever and get consumed eventually. So *if*, and that’s an important but quite plausible if, there is another mechanism encouraging anaerobe metabolism then actual anaerobe metabolism may be greatly increased (that’s the pull mechanism) and out consume the increased output of the enzyme. In plain words: the body could be only able to produce 2 times as much enzyme but other factors increase anaerobe energy consumption by 3 times.
Result: the body is short on enzyme even if it produces more. It’s a bit like being a street vendor selling twice as much umbrella’s on a rainy day and still burning trough his stock in minutes. As there are good indications ME patients have increased anaerobic metabolism you may be an example of this combined push-pull mechanism.
“Yes, I have always felt a bit panicky in closed in, tight spaces.”
-> Could people with claustrofobia have also higher chance of this RBC defect?
“But I suspect it is my neck at the root problem.”
-> I believe ME is a disease where the end effect is the sum (or closer, multiplication) of many things that break in the same way. In that view poor RBC and tight neck combine to even poorer oxygen delivery. I consider that a good thing. While very annoying to study in a scientific correct and significant way, chains of events leading to disease give more opportunities to diminish it’s effect. That’s part of what I try to do: find a “weakness” in the chain that can be addressed with doable cost and effort.
“peripheral blood oxygen measurements ( with the finger gizmo) may not reflect the diffusion of oxygen and CO2”
-> Good you added that. Got me thinking.
The finger Gizmo is based on color I think. It’s the oxygen bonding to Hemoglobin that is making a deep red color and is quite likely a good indication of blood oxygen content. That would lead to the contradiction that oxygen isn’t too low; something some researchers reported too. So this needs some answer.
Warning: this is the most far fetched piece about ME I did ever wrote. I still do it because it somehow fits a few odd bits about our disease. So take this with a spoon of salt.
I started my thoughts with: if a layer blocks CO2 going out it *very* likely blocks CO2 going in as well. Very few materials are one directional towards diffusion. But blocking CO2 going in (at decent speeds anyways) has a chance to solve mystery number 1: how could we (or some of us) have sufficiently high oxygen levels but don’t be able to use it?
If CO2 leaves the cells it sees a mixture of blood liquid and RBCs. Science doesn’t seem to be very settled and opinions differ but http://education.seattlepi.com/effects-carbon-dioxide-bloodstream-3546.html says “Most free CO2 is taken up by the red blood cells.” So if RBC would be slow to take up CO2 then many RBC would have given their O2 to the tissue but would have passed the tissue and be in the blood stream “empty” as in not have taken up much CO2.
As https://en.wikipedia.org/wiki/Carbonic_anhydrase states the conversion of CO2 to H2CO3 and back is very fast and not rate limiting *if* there is a sufficient concentration gradient.
Here may lay the problem however: as many RBC have taken up less CO2 they arrive “near empty” at the veins (away from the cappilaries already). Slowly (as the protein barrier slow things down and they are swimming in H2CO3 filled liquid) they absorb the CO2 from the high concentration CO2 blood from the tissue. This keeps on going till there is a new balance where CO2 neither diffuses from nor to the RBC. In doing so the RBC significantly/dramatically lower the concentration of CO2/H2C03 in the blood as it is now divided from one “moderate size bucket (the blood liquid)” into “a moderate size bucket (the blood liquid) plus a large size bucket (the RBC)”.
If one was now to measure the PCO2 at this spot, it would be *bellow* normal. But very close to the exersising tissue it should be *above* normal and in the exercisising cells *significantly above* normal as there needs to be a big gradient to drive this.
Now at the lungs it gets the other way around. As the PCO2 in the blood at the lungs is already relativly low, CO2 removal is slowed. But worse, even if CO2 is removed out of the blood liquid then it is not quickly “refilled” by emptying “CO2 loaden RBC” into the blood. That goes quite slow. So per unit of CO2 expelled by the lungs the PCO2 drops faster then with normal people. This further decrease CO2 removal to the air. One way to overcome this is hyperventilation. Breath like a horse to get CO2 levels as low as possible in the lungs, in order to increase the concentration gradient as greater concentration gradient speeds up things.
All this potentially can happen while PCO2 measurements are low indicating hyperventillation and *hypo*capnia. While reality may be that we have far larger a CO2 concentration gradient then healthy people so we have really low lung CO2 concentration but far too / dangerously high tissue CO2 concentration causing tissue acidosis and maybe even risk of release of CO2 gas in the tissue (would very likely be not good at all).
Also, depending on conditions it could go hand in hand with either normal, reduced or high O2 blood content in the arteries. So theoretically one patients O2 values could differ significantly from another’s, or O2 values could vary much on exact conditions. This could align well with contradicting research outcomes towards O2 measurements. It’s quite possible that all go one way as well, but this mechanism does not exclude high oxygen saturation rates.
What could damaged cells have to do with it? Well, diffusion rate is controlled by concentration gradient, surface area, thickness of membrane and diffusion constant of the membrane. It’s hard to tell if a damaged membrane allows for faster or slower diffusion. While faster would make sense as it is “leaky”, it could also be slower as it is “dusty, wrinckled, polluted”.
So that leaves the easy ones: if RBC are bended “American footballs” then they have larger surface area and smaller thickness as stretched membranes are thinner. That combined factor enhances diffusion thickness a lot. We appear to have more spherical ones, and this shape slows down diffusion quite a lot. Depending on exact shape it could go up to a factor of 2. Both in tissue and lungs…so causing two increased CO2 gradients or reduced speed for the overall removal of CO2.
How could the body solve this? It’s like a big train with only 1 working door. If all people are to get in, the train has to spend a lot more time in the station. Or the RBCs need to go really slow in both tissue and lungs.
This would decrease amount of oxygen that gets in also a lot as if RBC pass slowly through the tissue then they also carry oxygen slowly to the tissue.
This slow blood speed would both drastically reduce exercising capacity by decreasing tissue “productivity” as drastically decreasing lung capacity as if there only pass “droplets” of blood through the lungs then it can carry only that much oxygen from the lungs into the body.
How could blood flow be reduced to a crippling halt? Reducing blood volume and hart output helps. What also helps is constricting the capillaries a lot by…for example producing plenty of H202 killing NO constricting capillaries.
Reducing blood volume could be done with a mechanism that also expels some CO2 out of the blood: not only expel H2C03 out into urine but also NaHCO2. Thats both losing CO2 and Sodium (so also blood volume). Two birds in one stone. Night sweats could help if the salty taste was in part caused by Sodium (bi) carbonate (removing CO2 too to some extent). And the combo blood flow/breathing or lack thereof IMO gets whacked worst at night.
There is also the observation that inflammatory diseases often go hand in hand with decalcification/calcification. If tissue H2CO3 would indeed be to high causing acidity then it could chip away at calcium. And removing it again into the urine or depositing it at tissue locations with lower acidity. Like H2CO3 both carves caves in limestone and deposits limestone pillars (stalagtites/stalagmits).
People with inflammatory diseases often have calcification of for example tendons. Izzy (a valued forum member) had a really large chunk of calcium deposit in her body discovered during surgery. Also notice: decalcification is far more common in women then in men, just as ME/FM are. And there is a clear link between low Vitamine D and lack of calcium. Many of us have low to very low Vitamine D values. When my doctor ordered a Vitamine D test on my blood and saw the results his attitude towards my disease immediately and drastically changed. Maybe he had never seen something low like that.
And now comes the controversial part: if CO2 removal was far more difficult then O2 uptake some scientific reports that we have plenty of oxygen in our RBCs but can’t use it would make sense. If CO2 is dangerous and could not be removed fast enough after all above measures then there is only one thing left to do: further reduce it’s production. Easiest road would be: decrease oxygen in blood. But as the easiest way to do that is reduce breathing and that would make removing CO2 impossible other measures need to be taken.
Possibilities:
1) inhibit O2 use or inhibit mitochondrial functioning by rationing key enzymes. In short largely reduce the speed at which mitochondria work.
2) introduce an “oxygen shunt”. Meaning: make oxygen unavailable to the tissues. By for example turning mitochondria from energy producing factories to oxygen burning factories producing H2O2 in large quantities. -> CDR to protect cells against dangerous lack of ability to remove CO2??????
2) may sound very unlikely, but it answers one more very “odd” thing: why on earth does NO act as a modulator for vascoconstriction? O2, CO2 and lactate I could get. They are indicators of sufficient oxygen or lack of it. But the funny thing is O2 content barely is used to regulate blood flow. It can’t be that difficult for nature to create a sensor for such large quantities of oxygen can’t it be? Compared to detecting a trace element as NO it should be piece of cake. Even measuring sugar or fat to regulate blood flow makes more sense as they can reduce flow by clotting or plaques. But NO???
Now NO has the property that it is a radical reacting very sensitively to H2O2 that destroys it. So it is a very good indicator for “rapid increase in H2O2 production” that is more sensitive then H202 content itself. *If* H202 production would shunt O2 away from the tissues to avoid dangerous CO2 buildup then a good reaction would be to strongly reduce blood flow by constricting the capillaries.
* It would work once by reducing amount of CO2 produced per time reducing buildup speed.
* It would work once more by allowing RBC to take up more CO2 by letting each RBC spend more time near the tissue at work
* It would work once more by increasing the ratio “blood liquid flow to RBC flow”. How? In tight capillaries the big RBC would flow quite a bit slower then the watery liquid surrounding it than can “pass alongside the RBCs” through any small space between RBC and blood vessels. It’s a bit like motorbikes passing all traffic on a jammed highway: the smaller vehicules pass a lot faster. By doing so the ratio between oxygen delivered by almost exclusively RBCs (oxygen solves poor in body temperature blood) to CO2 removed by both RBC and the in proportion increased amount of blood liquid would increase. This would effectively decrease waste removal bottlenecks.
🙂 Sorry for the rant. It’s only online brainstorming so it could turn out to just be completely crazy; in that case just ignore and forget.
dejurgen – Thank you for taking my simple observations to the next level. Wow. Wish someone would look at this structure and function of the red blood cells more carefully. How do viral infections or immune function interface wth these red blood cell ideas? My son’s issues absolutely started with a virus carefully classified as Epstein Barr – 1986, age 5.
Also, when you can, check out the research of Flegr etc al. On Toxoplasma and RhD negative people. They found more neuro problems in Rh D neg people infected with Toxoplasma.
“How do viral infections or immune function interface wth these red blood cell ideas?”
-> I believe ME is at least in part a “pile up” of disease mechanisms that end up in a synergy like in 1 + 1 > 3 way. If someone is predisposed with several weaknesses that have “good potential” to combine and wreak havoc, then only another one in that category is needed to break the delicate balance that there was before. Having for example a RBC deffect as you described plus small lung capacity is not much for something that can resemble good health while it lasts. Add infection which produces blood thickness through cytokines and produces H202 to combat infection and you have two factors than can negatively effect delivery of oxygen to tissue. That’s one of those (many) chains I see as a possibility in this disease. At adult age EBV can wreak havoc for years. If a younger person has decreased immunity against the weakened respiratory chain could wreak havoc long enough to set in motion a chain of negative events and a viscious circle.
“when you can”
-> thanks for the information, but for now I’d have mainly to rely on information that you, other forum members and Cort do provide. I am good at making associations and produce original concepts with them. I am also good at using a search engine. For my information I have to rely on things I knew before my disease and daily refresh current knowledge and make associative links between them to remember it in an active way. Knowledge and concepts that are to new to me are very hard to learn right now. Can barely focus, luckily I learned to think with very low need for focus (only for topics with current associative links).
Red blood cell deformability, metabolism and extracellular vesicles in ME/CFS http://followmeindenmark.blogspot.com/2018/11/red-blood-cell-deformability-metabolism.html
I suggest a pilot study:
ME/CFS vesicles put together with red blood cells from healthy controls. Can microvesicles from ME/CFS patients decrease deformability of RBCs from healthy controls in vitro?
Very nice. Thanks Helle…