Ron Research Update, March 29, 2021

Research update from Ron Davis March 29, 2021

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Summary by Ben Howell (ME/CFS advocate and patient):
-Intro from Ron. Ron's sole focus is ME/CFS.
-Working on treatments/cure.
-Metabolic Trap idea. This is where critical enzyme gets trapped in it's function.
-Difficult to test in human cells, testing in bakers yeast. Have great technology for this.
-Have taken bakers yeast + put in critical gene that gets trapped (function gets trapped) + that is IDO1 gene.
-IDO1 converts tryptophan (in diet) to kynurenine.
- Kynurenine v. important-regulates immune system, can suppress inflammation etc.
- Placing gene into yeast can control it, but it makes the same protein that is made in humans.
- Many human genes will work in yeast and vice versa.
- Yeast doesn't really have this level of pathway so kynurenine can be used to make NAD.
- NAD is chemical compound that is extensively used in metabolism of organisms, human + yeast.
- In humans NAD used in ~400 chemical reactions, really essential.
- Required for production of energy in mitochondria.
- What they have done is make kynurenine in yeast with this enzyme + require it to make NAD.
- Yeast has multiple ways to make NAD so have removed all genes involved in the production of NAD.
- So ONLY way yeast can make NAD is to have this pathway on.
- If they trigger the metabolic trap, will shut down the enzymatic activity of ido1 then it can't kynurenine, and it can't make NAD. If can't make NAD, won't grow.
-One problem is don't want yeast to consume tryptophan by any other pathway.
-Looked into yeast, all genes have been sequenced + understand their function, found several genes that consume tryptophan for other purposes.
-Have removed these genes.
-This new developed yeast is now suitable for a test.
-Grew on low tryptophan, cells grew fine.
-If raise tryptophan concentration, high level of tryptophan can inhibit enzyme.
-This is very strange.
-Here is an enzyme (IDO1) that converts tryptophan to kynurenine. Would guess that if raised tryptophan would simply make more kynurenine.
-Not true-the high tryptophan inhibits the enzyme and can't make kynurenine.
-If it can't make kynurenine can't grow-so if raise concentration of tryptophan gets to point where it stops growing.
-As long as you leave tryptophan in at a high level, can't grow.
-If you then wash out the high level of tryptophan + put in low level of tryptophan, starts growing again.
-OR if leave high level of tryptophan but give yeast kynurenine (required for NAD) starts growing again even in presence of high tryptophan and absence of activity of enzyme.
-Why are they doing all this? One is to test the Metabolic Trap-something you can do in a test tube-does it work in a cell?
-This experiment shows it CAN work in a cell. It's yeast, but can still work in a cell.
- This is a possibility what is happening in humans.
-There is another reason to do this. Now have system where can shut down the enzyme in metabolic trap + the only way cell can grow is to get rid of tryptophan.
-Human cells not quite the same, it's not growth, it's making kynurenine which is critical factor.
-If this true in human cells, only way to make kynurenine would be to get rid of the tryptophan. The only way to get rid of tryptophan is to convert it to kynurenine.
-That's why it's called a trap, you get into it, you can't get out.
-However if they can find compound-that will 'block the block'-the inhibition that tryptophan has over the enzyme/IDO1 this then will reactivate IDO1, IDO1 will consume the tryptophan and cells will produce kynurenine.
-That's the stage are at at the moment with yeast.
-Fairly simple to do with yeast. Put in high tryptophan + can add drug(s) at different concentrations + look for growth.
- Have a robot that can do all of this, can do 96 at a time + have 3 robots, can do this with different concentrations of drugs.
-Can set up + leave to do experiments. Robot can do lots of experiments! Is being set up now.
-Unfortunately it's an old robot, needs some repairs + is in the process of repair.
-Getting help + are going to get fixed. So is just about ready to start doing drug screens.
-Have all FDA-approved drugs in their freezer. Have already screened all those drugs for their effect on yeast + know concentration that has some effect.
- Ron excited about this, has no idea what the probability is but is optimistic. Lots of things to try at lots of different concentrations.
-Also, if it works out + don't find any FDA-approved drugs, will start screening herbal extracts.
-Wants to have something patients can take + a new compound would take updated approval + take years to do. Doesn't want to do that.
-Optimistic can find something. If metabolic trap is real they have something can treat it with.
-Next thing is move to human cells. In process of doing that.
-Ron says thank you.

[stevengao]

It is a cruel world we live in where a man who is nearly 80 has to work this hard for a cure for a crippling disease, when CFS and many other diseases could be cured if we as a society just gave up funding one generation of an iphone.

[OldNavyWife]

Very exciting stuff. I’m 66 and have had ME/CFS since March 1980. I really only have 1 doctor who cares, and another who at least stays quiet when I discuss it... the rest ignore me. I’ve endured so much medical gaslighting throughout the years... I would not wish this living death on anyone.

[solar]

My daughter has been ill with ME/CFS for 13 years and is getting worse. So yes, time is something we don't have. Thank you.

[emilyp]

Truly superman. Dr. Davis and Team- you have thousands of people rooting you on in your work, including me. Don't get discouraged. You are some of the most brilliant minds on earth and we know you can do this!

[TheLinda]

I was lying here writing a goodbye email to myself and then I received this email OMG I hope and pray that we have have a treatment soon thankyou

[inter_mirifica]

Thank you so much Professor Davis (and Ashley for setting all of this up)! As always, it's fascinating to listen to these updates. And it brings so much hope. Thank you.

[amazinggraceuk]

Thank you so much for taking the time to update us. I'm rooting for you all, what you are doing is amazing.
I have had ME for 4 years, it's severe, my life has changed beyond recognition, and i long for a cure or treatment for all us sufferers.
Much love.

[clairenaylor]

Thank you for your endless commitment to helping us. I love how you explain what you're doing and why it's important. I want to share my admiration for you and your family and say once again, thank you. 🙏

[terrybarone]

Wow! so exciting a possible breakthrough. I know your son suffers from ME/CFS and unfortunately, my daughter is on about the same level as he appears to be. Thank you for the update!

[brittguerriero]

THANK YOU!!! Thank you for seeing us, keeping this going thru a Pandemic, ALL. OF. IT. 🥰 (& thank you on behalf of those of us too sick right now to say it themselves). Keep going team - keep going! 🙌🏼🙌🏼

[namasteinpjs]

Thank you so much for these updates! Every time I hear you talk about continued progress on the metabolic trap theory, it brings tears to my eyes. I got sick in 2018 and I've followed this theory with you the whole way, hoping you wouldn't prove it wrong. Knowing that you haven't, and that the studies are continuing to progress, gives me so much hope!

[suzanecockroft-garnett]

Thank you. I want to cry every time I watch these video updates. I’ve had me/cfs since i was 14. 20 years of swimming upstream and no support. I’m so thankful for you.

[debbiegreenrazey]

Thank you I am from UK and have severe ME

[SonicShamanka]

Big Thanks from the UK. I have been ill for 30 years and can’t wait to get some life back as a consequence of the treatment produced by your research.

[EndersWorlds]

These latest pieces of research being done, this included, are sounding so much more promising than anything has before, like we're actually finding genuinely helpful things out now about this awful condition. I have severe ME and it's been a rough couple of years with it recently. Thank you for everything you have done, for being so dedicated in the search for genuinely useful answers for your son and all of us out here. You are a good man! Good luck with the latest studies. 💚

[datractor]

Not all hero's wear capes, thank you for all that you do, from New Zealand

[kelsey.noelle]

These updates give me hope for a cure for my boyfriend one day! Thank you so much for all you and your team do 💛

[piper]

So happy to hear about Whitney’s improvement, he’s going in the right direction now. Brought a (happy) tear to my eye. Thank you so much for your dedication to this field of studies. You give us all hope and help to validate the seriousness of our disease.

[Mcfads]

Thank you Ron Davies. You gave me hope.

[billt]

Thank you from all of us who are in need of help. You are amazing