Community symposium on molecular basis of ME/CFS at Stanford Discussion Thread
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AshleyHalcyoneH
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Robert Phair
dreampop
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I feel bad for that one CFS patient at the top - looks like his cells were almost going to find a way to deal with the challenge but could never quite get there. Actually it looks an interesting demonstration of how health and sickness is different for everyone.
Murph
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Phair is not stinting on details on the metabolic trap!
He is talking about how one of two enzymes might be broken: IDO2.
It's a backup system we use when tryptophan is high, and it leaves us stuck in the metabolic trap.
He is talking about how one of two enzymes might be broken: IDO2.
It's a backup system we use when tryptophan is high, and it leaves us stuck in the metabolic trap.
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Murph
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Phair appears to be telling us that all the data they have so far supports the metabolic trap hypothesis!!!
I predict a lot of tryptophan threads popping up on this website!
I predict a lot of tryptophan threads popping up on this website!
Murph
:)
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Should we be losing our minds with excitement? because I think I am.
edit: had another cup of coffee and a think about the odds. controlled my enthusiasm.
edit: had another cup of coffee and a think about the odds. controlled my enthusiasm.
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I think 'quiet hope' might be appropriate right now
But you're right, he sure didn't skimp on details
B
AshleyHalcyoneH
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ljimbo423
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I think either Ron or Robert Phair said it could be either increased or decreased, depending on the person.
Sushi
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Didn't he say that it was serotonin that might be either increased or decreased? I thought he said that tryptophan was definitely increased.
It seems to be me that Dr. Phairs theory goes deepest to the root cause and all the other things presented are a result of the negative affects the metabolic trap is having on the brain and the body. He also presented the most detailed and rational explanation for the disease and all the variety of symptoms. I could see it unfolding like this Metabolic trap leads to T-cell clonal expansion leads to inflammation in the brain which then sets off all of the symptoms we have.
His explanation was also the most hopeful and seemed closest to actionable results.
I hope he is correct and they can start testing some treatments. Dr. Youngers theory is compelling too, but like he said in ending still doesn't explain what is causing brain inflammation; just gives us another symptom that causes sickness feelings. Also at least a year b/f there will be any results .....too long and far away; more will die over this year. Need to work fervently on the hypothesis that can bring us results sooner. How can they get a big Silicon Valley entrepreneur to donate!!!!!!!
His explanation was also the most hopeful and seemed closest to actionable results.
I hope he is correct and they can start testing some treatments. Dr. Youngers theory is compelling too, but like he said in ending still doesn't explain what is causing brain inflammation; just gives us another symptom that causes sickness feelings. Also at least a year b/f there will be any results .....too long and far away; more will die over this year. Need to work fervently on the hypothesis that can bring us results sooner. How can they get a big Silicon Valley entrepreneur to donate!!!!!!!
I was unable to make it through the entire program today. However, it was an enormous pleasure and treat to meet some other patients (@Sing, @Learner1, @JaimeS) and I wish I could have stayed for the reception.
I want to stress to this community how much dedication the Davis-Dafoe family has to solving and supporting this illness. This family is fighting for this community. My gratitude for their leadership is immense am humbled by what action I saw today. @Janet Dafoe (Rose49) @AshleyHalcyoneH ...never seen two busier people in service to others.
Many doctors were in the audience (Montoya, Chheda, Bonilla, Peterson, Bateman...may be missing some). I want PwME to know that this disease is being taken seriously.
I also want to give a tremendous shout-out to @JaimeS for putting in long hours and providing constant updates on Twitter. If you don't know, Jaime is also working for MEAction. Her efforts are no small feat for someone also suffering from this illness.
While I did not meet @Cort, he was there and also disseminating information like mad over Twitter. I'm looking forward to his Symposium write-ups. He has been, and remains , hot on the trail.
So much gratitude for all of the people working in the lab...so many were there...and to OMF. Linda is so often behind the scenes, but she's making this research possible...and @Ben H for keeping the communication alive by keeping us all in the loop no matter his current state of affairs.
We are still in beginnings of understanding this illness, but more and more lights are starting to flicker brighter and longer.
In your moments of weakness and pain, keep hope alive. This disease is not a joke and the science of it is going to be blown open by this team Ron has amassed. No one is giving up, each insight is leading them to dig deeper and the desire to connect the dots is a focus of the OMF team.
We are not forgotten...we are not missing...we are alive...and we are seen.
I want to stress to this community how much dedication the Davis-Dafoe family has to solving and supporting this illness. This family is fighting for this community. My gratitude for their leadership is immense am humbled by what action I saw today. @Janet Dafoe (Rose49) @AshleyHalcyoneH ...never seen two busier people in service to others.
Many doctors were in the audience (Montoya, Chheda, Bonilla, Peterson, Bateman...may be missing some). I want PwME to know that this disease is being taken seriously.
I also want to give a tremendous shout-out to @JaimeS for putting in long hours and providing constant updates on Twitter. If you don't know, Jaime is also working for MEAction. Her efforts are no small feat for someone also suffering from this illness.
While I did not meet @Cort, he was there and also disseminating information like mad over Twitter. I'm looking forward to his Symposium write-ups. He has been, and remains , hot on the trail.
So much gratitude for all of the people working in the lab...so many were there...and to OMF. Linda is so often behind the scenes, but she's making this research possible...and @Ben H for keeping the communication alive by keeping us all in the loop no matter his current state of affairs.
We are still in beginnings of understanding this illness, but more and more lights are starting to flicker brighter and longer.
In your moments of weakness and pain, keep hope alive. This disease is not a joke and the science of it is going to be blown open by this team Ron has amassed. No one is giving up, each insight is leading them to dig deeper and the desire to connect the dots is a focus of the OMF team.
We are not forgotten...we are not missing...we are alive...and we are seen.
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Yes, tryp up, kyn down, and serotonin could be either.
It seems like if this trap is true, there are a couple ways to fix the issue. One is to supplement with kynurenine; I believe this is the couple day therapy that Ron has eluded to in the past. This would hopefully balance out the kyn/trp ratio, and keep patients on the healthy steady state equilibrium. If that only helps temporarily then we would need a new drug that could upregulate IDO1 - so maybe patients would need to take it regularly. Which would take a long time to develop and approve.
That’s just my, terrible, understanding of things.
ljimbo423
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Mary
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Another cup of coffee calmed you down?
You are much more of a scientist than I am, and I don't want to derail this thread but wanted to point you to these studies which indicate that BCAAs can play a role in reducing tryptophan and that high tryptophan can cause something called central fatigue. And many members (including myself) have had some benefit from taking BCAAs. So in case you were inclined to start a tryptophan thread, I thought these might be useful (or not!)
http://www.ncf-net.org/forum/Fword.htm
http://www.dynamicchiropractic.com/mpacms/dc/article.php?id=41341
http://jn.nutrition.org/content/136/2/544S.full
http://www.ncbi.nlm.nih.gov/pubmed/11310928
http://www.sportsci.org/jour/9901/rbk.html
Murph
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Quick summary of metabolic trap. Some concepts in this are new to me and I will happily yield the floor to anyone with proper expertise, but here's my take:
TWO WORKER BEES
There is an important job in the body that needs to be done: turning an amino acid called tryptophan into another molecule called kynurenine.
Two enzymes work hard at doing that. One (IDO1) is good when there are low levels of tryptophan but totally gives up when levels get high. The other enzyme (IDO2) is good when we have high levels of tryptophan.
Robert Phair suggests IDO2 is not working.
THE TRAP
The trap here is due to the special feature of IDO1. It doesn't keep trying when Tryptohan is high - it throws up its arms in despair and weeps. So what happens if Trytophan gets really high? If you've got no functioning IDO2 and IDO1 is sitting in the corner drinking whiskey, you have no good way to turn tryptophan into kynurenine. Tryptophan just accumulates and accumulates. Things get worse.
(This process happens inside the cell, but not inside the mitochondria, just in the common and/or general area they call cytosol.)
The theory is that MECFS kicks in if you have a broken IDO2 (predisposition to disease) and then somehow (often during an infection) you get to the level of tryptophan that causes IDO1 to quit and walk off the job. There's no (easy) way back.
GENETICS
So, is IDO2 broken in CFS patients? Phair had a look in the genetic data from the Severely Ill Patients Study and found that on average, they had 1.7 genetic mutations in the gene that makes this enzyme. [However, he says these mutations are actually very common in humans. So it is unclear to me if this finding is especially relevant. Maybe it's not solely genetic? I don't find this part very satisfying.]
The metabolic trap can be demonstrated in various computer models though: If people without a working IDO2 get high tryptophan for long enough, they get stuck with it for basically ever.
EXPERIMENTAL SUPPORT
The rubber really hits the road when he tests patients. (n=6, so very preliminary.) Experiments in me/cfs patients cells comapared to healthy controls show tryptophan is high, kynurenine is low, and the ratio of the two is high, just like the metabolic trap hypothesis would predict.
(This is not the whole story, much has been omitted for simplicity, but it is, I think, the key parts.)
The end.
FINAL WORD:
Ron Davis himself issues a big warning on not trying to manipulate your own cellular tryptophan. You could give yourself brain damage or die. They think there could be an easy cure but they want to test it properly and are very worried about patients hurting themselves.
TWO WORKER BEES
There is an important job in the body that needs to be done: turning an amino acid called tryptophan into another molecule called kynurenine.
Two enzymes work hard at doing that. One (IDO1) is good when there are low levels of tryptophan but totally gives up when levels get high. The other enzyme (IDO2) is good when we have high levels of tryptophan.
Robert Phair suggests IDO2 is not working.
THE TRAP
The trap here is due to the special feature of IDO1. It doesn't keep trying when Tryptohan is high - it throws up its arms in despair and weeps. So what happens if Trytophan gets really high? If you've got no functioning IDO2 and IDO1 is sitting in the corner drinking whiskey, you have no good way to turn tryptophan into kynurenine. Tryptophan just accumulates and accumulates. Things get worse.
(This process happens inside the cell, but not inside the mitochondria, just in the common and/or general area they call cytosol.)
The theory is that MECFS kicks in if you have a broken IDO2 (predisposition to disease) and then somehow (often during an infection) you get to the level of tryptophan that causes IDO1 to quit and walk off the job. There's no (easy) way back.
GENETICS
So, is IDO2 broken in CFS patients? Phair had a look in the genetic data from the Severely Ill Patients Study and found that on average, they had 1.7 genetic mutations in the gene that makes this enzyme. [However, he says these mutations are actually very common in humans. So it is unclear to me if this finding is especially relevant. Maybe it's not solely genetic? I don't find this part very satisfying.]
The metabolic trap can be demonstrated in various computer models though: If people without a working IDO2 get high tryptophan for long enough, they get stuck with it for basically ever.
EXPERIMENTAL SUPPORT
The rubber really hits the road when he tests patients. (n=6, so very preliminary.) Experiments in me/cfs patients cells comapared to healthy controls show tryptophan is high, kynurenine is low, and the ratio of the two is high, just like the metabolic trap hypothesis would predict.
(This is not the whole story, much has been omitted for simplicity, but it is, I think, the key parts.)
The end.
FINAL WORD:
Ron Davis himself issues a big warning on not trying to manipulate your own cellular tryptophan. You could give yourself brain damage or die. They think there could be an easy cure but they want to test it properly and are very worried about patients hurting themselves.
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Murph
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Here's what might be a reason to stay netural on the metabolic trap hypothesis.
If the kynurenine pathway were disturbed, it would flow to NAD. Naviaux's metabolomics data was far from clear on nicotinamide. While patients differed massively from controls, it was in different directions between men and women! It showed strong results due to a few outliers. Wild variance (and I mean wild, check out the graphs below) obscured a distribution that was not really very different.
Axis on graph one goes to 4.5 million but exercise caution:
Axis on graph two goes to 60 million!
If the kynurenine pathway were disturbed, it would flow to NAD. Naviaux's metabolomics data was far from clear on nicotinamide. While patients differed massively from controls, it was in different directions between men and women! It showed strong results due to a few outliers. Wild variance (and I mean wild, check out the graphs below) obscured a distribution that was not really very different.
Axis on graph one goes to 4.5 million but exercise caution:
Axis on graph two goes to 60 million!
Thanks for all the great notes and comments! So if I am understanding this correctly, and tryptophan is high, would lowering the tryptophan levels to the point where ID01 can work again be a possible intervention? Does that make biochemical sense?
If metabolic trap is right, maybe we have a new type of hypertryptophanemia.
If metabolic trap is right, maybe we have a new type of hypertryptophanemia.