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A New Approach To Chronic Fatigue Syndrome

If we ask Nature a question and ask it well, Nature answers. Most of the time the answer refutes our hypothesis. This time, Nature didn’t refute the hypothesis. Robert Phair

Ron Davis mentioned one of chronic fatigue syndrome’s aces in the hole several times – the chance to make a huge difference in a major disease. You could work for decades on cancer and make a difference there – an important difference but probably a small one, or you can take on something like ME/CFS and potentially make a huge difference. One of the reasons we have so many creative researchers in this small field may be because the ME/CFS challenge draws inquisitive minds.

Robert Phair

Phair got involved in Ron Davis’s ME/CFS work after reading about it in the Stanford Alumni magazine.

Phair certainly has a inquisitive mind.  He was one of the most active participants in the three-day Working Group session put together by Ron Davis and the Chronic Fatigue Syndrome Research Center at Stanford University. On the fourth day, the Working Group was featured in the Community Symposium on the Molecular Basis of ME/CFS at Stanford University.  Both were sponsored by the Open Medicine Foundation with a special thank you to OMF Board Member Dr. Deborah Rose.

Phair’s a rare breed – a biological systems engineer. When he started out he caught grief from both sides; his father couldn’t understand why he would top off a good degree (electrical engineering) with a PhD in a bad one (physiology), and the biologists in academia didn’t get him either. He ended up forming his own company, Integrative Bioinformatics, Inc., which produces “models for biomedical discovery”.

That dual focus, however, fits right into Ron Davis’s mold. Davis, geneticist and inventor, after all, is his own unusual blend. He doesn’t run the Stanford Genome Center, he runs the Stanford Genome Technology Center – a blend that adds a pragmatic bent to his efforts. Davis is not an ivory tower theorist: his forte is creating tools that impact human health. Robert Phair – engineer and physiologist – must have seemed like a kindred spirit. Davis said he’d been looking for a systems engineer for a while.

(It bears reminding that the originator of the Metabolic Trap Hypothesis – Robert Phair – came to ME/CFS via an article in a Stanford magazine about Whitney Dafoe and ME/CFS. Sharing makes a difference. The more stories we get out, the more people who know about the disease, and the better chance we have of finding someone who will solve it.)

Beginner’s Mind

He started off saluting what he called the best book on ME/CFS – The Doctor’s Guide To Chronic Fatigue Syndrome: Understanding, Treating, And Living With CFIDS, published by Dr. David Bell in 1994!

That reference to the 1994 book says something about Phair’s approach. He’s apparently read everything he can on ME/CFS and he’s done so with a “beginner’s mind”.  Take the approximately 70 outbreaks that AAMES lists have happened between 1934 and 1990. Outbreaks were what ME/CFS was known for, for decades, but the last one listed happened over 25 years ago, and they are rarely discussed anymore.

With his beginner’s mind, though, those 70 or so outbreaks caught Phair’s eye.  How many diseases, after all, have such a list of virulent outbreaks?

The fact that so many people became so ill so quickly stood out.  A pathogen sweeping through a community was obviously one component, but the wide swath of people suddenly becoming ill suggested that the pathogen had taken advantage of a widespread vulnerability.

Phair’s Factors

Most researchers have looked for rare genetic tweaks but nothing rare could account for the masses of people that typically became ill.  Phair reasoned that the susceptibility to the disease had to be common: if a genetic tweak (missense mutation) set the stage for chronic fatigue syndrome, it had to be one that was common – that many people shared.

Phair's checklist metabolic trap for ME/CFS

Phair had a checklist of factors the metabolic trap hypothesis required to be present for it to be possibly valid.

He wasn’t looking for just any common polymorphism, he was looking for genes tied to systems that featured “bi-stability” – the system could be stable in two different states: a healthy state and an illness state. (The kind of thing only an engineer would look for…)

Plus, once one got into the illness state, the system had to feature a kind of “stuckness” which made it difficult to return to health.

Plus, the system had to be vulnerable to a sudden stressor and it had to feature the ability to suddenly “flip”.

Plus, the gene mutation had to have the ability to affect multiple systems – to generate the kind of widespread illness that ME/CFS is.

A common genetic tweak affecting a bi-stable system which exhibits remarkable “stuckness”, and affects multiple systems, and is vulnerable to a stressor and can suddenly “flip”: that’s a rather daunting set of preconditions to fulfill…

The Hunt

Common Gene Mutations

Nevertheless, the hunt was on. Phair had the complete genome data of 20 severely ill patients (and some more genome data from people who volunteered their data after the last blog on the metabolic trap). The first test of the hypothesis was to find a mutation which was ubiquitous in the severely ill group but which was commonly but not ubiquitously found in the general population.

Up popped a mutation that breaks or damages the ability of the ID02 gene to metabolize tryptophan. A single mutation (or another mutation in that gene, sometimes as many as 3) was found in all his ME/CFS samples but is only found in about 40% of the general population. (55% of ME/CFS patients had the most common mutation and everyone had one or more other mutations. Out of two possible broken copies of IDO2 (two chromosomes for each gene) the severely ill patients averaged 1.7 broken copies.)  The first hurdle was passed.

Bi-Stable System

Next the gene had to be part of a bi-stable system in which the polymorphism could, under certain circumstances, conceivably cause the tryptophan-metabolizing system to take a strange turn.

IDO enzyme

Every ME/CFS patient tested thus far has one or more mutations in the gene producing the IDO1 enzyme.

It turned out that the IDO2 enzyme was part of a system of tryptophan-metabolizing enzymes that also included an enzyme called IDO1.

IDO1 and IDO2 are two of three enzymes that catalyze the oxidation of L-tryptophan to N-formylkynurenine. (The last is tryptophan 2,3-dioxygenase (TDO). IDO1 is the first enzyme out of the gate. It breaks down tryptophan correctly most of the time, but two circumstances can make it fail: if it lacks the substrate it needs to do its job, or if tryptophan levels are very high.

The second circumstance leading to failure is probably the key one. Tryptophan is both required for an optimal immune response and is used by some pathogens to grow.  Some pathogens can inhibit the IDO enzyme (in order to make more tryptophan available to them). Because IDO enzymes also regulate T-cell and NK cell functioning during infections and play a role in immune tolerance or preventing autoimmunity, inhibiting them can hurt immune functioning.

Thankfully, the other IDO enzyme – IDO2 – thrives in high tryptophan environments. But what if a mutation has blunted IDO2’s effectiveness? Then tryptophan levels rise, inhibiting IDO1 even more, resulting in less tryptophan oxidation, causing tryptophan levels to rise even more, and so on. You have a vicious circle resulting in higher and higher cellular tryptophan levels.

You’re stuck in what Phair calls the “IDO metabolic trap”.

Exhibiting “Stuckness”

Phair next had to demonstrate that the system can get stuck and be difficult to reverse. His mathematical models were devastating. Even if you completely stopped all inputs of tryptophan into the cell, ten days of stressor-induced, mutation-enhanced tryptophan concentrations would take 30 weeks to recover. If that situation dragged on for just 8 weeks, the system would essentially never recover – even if all tryptophan inputs were halted. This is a system which demonstrates remarkable “stuckness.”

Affects Multiple Systems

The serotonin system is in the midbrain. Phair pointed out six nuclei or neurons in the midbrain which control serotonergic pathways in the brain. Dysfunction in these nuclei could produce a long list of symptoms found in ME/CFS including impaired cognitive function, movement, and smell, dysautonomia, motor neuron problems, air hunger, dopamine production, POTS, and pain.

Plus kynurenine, which the model predicts will be low, affects hundreds of reactions in the body (including the production of ATP and regulation of immunity).

Testing the Hypothesis

“We can propose theories based on anything – from previous data to pure imagination, but the key (the thing that makes it science) is to use those hypotheses to make predictions and design a well-controlled experiment to test those predictions.” Robert Phair

Ron Davis got up and warned against cherry-picking data to fit one’s hypothesis.  The real way to test a hypothesis is to use it as a prediction tool: if the hypothesis is correct, then when tested, “X” should show up. If it doesn’t, the hypothesis is wrong. Phair’s hypothesis is in the prediction phase – it predicted correctly that certain findings regarding tryptophan would be found in ME/CFS patients’ cells. Calling science a “constant disappointment”, Davis said most of the time hypotheses are wrong.

Passing the Cellular Test

But so far, not this one. Phair’s and Davis’s enthusiasm has grown as the hurdles from genetics to mathematical and other tests of the trap have been passed. The biggest hurdles, though, were the cellular tests. The group wasn’t sure if the trap even existed in the immune cells they were testing. It might have been only present in other cells.

The tests involved determining if altered tryptophan and kynurenine concentrations (high tryptophan, reduced kynurenine levels, increased tryptophan/kynurenine ratios) were actually found in ME/CFS patients’ immune cells. The Open Medicine Foundation stepped in to provide the funding.

Kynurenine tryptophan cell samples

The sample size is small but every ME/CFS sample tested thus far has displayed unusual levels of tryptophan and/or kynurenine.

The first six samples from ME/CFS patients fit the predicted profile while the healthy controls’ cells were absolutely normal.  At that point, the trap appeared to have jumped from being a theoretical possibility to something potentially very real, and the level of excitement jumped substantially. Davis called the cellular test results “very strong support” for the hypothesis.

He grasped onto the cellular results like a mountain climber offered a rope. It was only after positive cellular test results that Phair and Davis felt comfortable explaining the trap in detail. The results are limited – just six severely ill patients – but they provide some scintillating new data to chew on. Whether Phair’s metabolic trap hypothesis is correct or not, Davis now has some new, very unusual, real world data about ME/CFS to think about.

Davis has talked about getting to the core of the disease but he’s never talked about possibly being at the core of the disease. He clearly feels the trap and the data gathered so far offer that possibility. Much testing remains to be done, more hurdles remain to be passed, but the trap hypothesis is clearly on much more solid ground now.

Davis once again noted that hypotheses often turn out to be are wrong.  It’s possible that the trap could become another in a long stream of, as Robert Phair said, paraphrasing the great British biologist Thomas Huxley, “beautiful theories destroyed by ugly facts.” The only way to determine if the metabolic trap is causing ME/CFS is to forge ahead.

High Serotonin Levels / Low Kynurenine

Tryptophan metabolism can go one of two ways – to make serotonin or to go down the kynurenine pathway.  It bears noting that a little serotonin goes a long way. The vast majority of the time (@95%), tryptophan is metabolized to kynurenine; just five percent of the time is it metabolized to serotonin. The implications of the trap – that high serotonin and low kynurenine levels are present – is highly significant.

kynurenine production ME/CFS

Thus far, tests indicate ME/CFS patient’s cells are metabolizing much less tryptophan to kynurenine compared to controls.

Phair’s slide of the serotonergic system in the midbrain – the same one that Cortene used to explain its hypothesis of an over-activated serotonin system – showed the serotonergic system’s immense spread.

Gerard Peirara of Cortene has asserted that the many more receptors for serotonin (14) relative to other neurotransmitters (dopamine (5), norepinephrine (5)) reflects how uniquely pervasive and influential that system is.

Davis focused more, however, on the low kynurenine levels found.  Calling kynurenine a “very important molecule”, he noted it’s used to produce a substance called NAD, which plays a role in about 400 reactions in the body, including the production of ATP. Plus, because kynurenine is an immune system regulator, low kynurenine levels could also increase the risk for autoimmunity.

Phair, on the other hand, thinks that there is plenty of nicotinate (niacin) in the diet, so he’s not convinced that reduced kynurenine production will significantly reduce NAD. But, Phair emphasized, the biological activities of kynurenine pathway metabolites is a burgeoning field and has been for a decade or so.

Don’t Do This at Home

“This is a dangerous pathway to experiment on…by self-experimenting with these critical pathways, you could make yourself much, much worse.” Ron Davis

Self-experimentation is almost second nature to people with ME/CFS, but Davis strongly warned against it. Davis and Phair didn’t release the details of the trap until now, precisely because of the pathway’s dangers.

You can actually induce autoimmunity – an autoimmunity you cannot recover from – by taking tryptophan. Note that if the trap is correct, the brains of people with ME/CFS have probably become adapted to very high serotonin levels. What happens when a brain that’s been wired to high serotonin levels suddenly gets deprived of it? Nobody knows, but everyone can guess what might happen if the process is not done correctly.  The results could be awful – and possibly permanent.

If increased tryptophan levels are the culprit in ME/CFS, the treatment has to be worked out using computer and animal models first. Davis requested that the ME/CFS community give them some time to figure out what’s going on.

Convergence on One Part of the Brain

serotonin midbrain ME/CFS

Phair and Cortene used the same slide to portray the reach of the serotonin system in the brain. (Modified from Phair’s slide presentation.)

Serotonin has hardly been mentioned in ME/CFS but 2018 has brought us two hypotheses from two entirely separate groups which are both converging on the serotonin pathways in the brain.

Cortene believes that stressor-induced dysregulation of the CRH receptors in the hypothalamus results in a serotonin explosion in the brain.

Phair believes that given the right circumstance, the mutations could produce what is essentially an evolutionary mistake at the cellular level (allowing serotonin to build and build), resulting in the same thing in the brain and elsewhere. Phair also noted, though, that depending on the cell type, serotonin levels could be high or low.

The fact that Cortene successfully exposed their brain model to hypothetical testing – which suggested serotonin dysregulation could account for sudden onset, gender differences, movement issues, metabolic problems, etc. – only buttresses Phair’s conclusions.

Cortene – A New Drug for Chronic Fatigue Syndrome (ME/CFS) Pt III: The Clinical Trial

Working Group That Works

When they work, Working Groups provide new insights and new opportunities for collaboration. That certainly happened at the second meeting of Ron Davis’s ME/CFS Working Group hosted by the Stanford Genome Technology Center.  A year of further data gathering – particularly from Davis’s group at Stanford – and an expansion of the group brought more energized discussions and more opportunities for collaboration. The fires that smoldered during the meeting of the first Working Group a year ago burst into flames in this one.

The Trap certainly highlighted how effective Working Groups can be.  Different members offered to produce models of the trap.  Among other things, those models will be able to provide ways to demonstrate that the trap is present in brain serotonergic neurons and to test potential therapies.

Next Steps

 I wake up every morning thinking about what might be wrong with this theory and about experiments to test that worry. We’re working hard. We won’t give up. Robert Phair

A lot of work at Stanford has gone into gathering more and more data and that work is continuing, but with regards to the metabolic trap hypothesis, Davis and Phair are in a new realm. Now that they have a testable hypothesis, they’re going to continue to test the heck out of it.

The next steps include:

  1. First, more tests on ME/CFS and healthy control cells to provide convincing evidence that ME/CFS patients’ immune cells are handling tryptophan VERY differently from healthy controls’ immune cells.
  2. The trap needs to be shown to be present in immune cells in cell culture and it needs to be determined if they can get the cells out of the trap in cell culture.
  3. Concurrently, consultations with experts in metabolism and nutrition will commence, and computer simulations and experiments will be done to figure out how to get out of the trap.
  4. If all this works out, they will do a pilot clinical trial on a few patients, moving on to a larger clinical trial if that is successful.

Funding Request

Davis made an unusually explicit request for funding, stating that if there’s a big donor out there, now is the time to give.  The rate-limiting steps in all of this are funding and resources. Everyone is spread thin. Julie, their lab ace, is working on seven different projects. Their mass spectrometer guy can devote only 1/7th of his time to this project. They simply need to be able to hire more people to quickly figure out if the metabolic trap hypothesis is right or wrong.

 

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