Tracking my efforts to beat Myalgic Encephalomyelitis (ME), aka CFIDS, aka CFS

Tracking my efforts to beat Myalgic Encephalomyelitis (ME), aka CFIDS, aka CFS

Sunday, February 14, 2016

What Must Happen Next to Solve ME/CFS

We Need Multiple Breakthroughs Before "the Big Picture" Emerges 

The next big breakthrough in ME/CFS research...will be the first.

As sobering as that is, in 30 or 40 years of ME/CFS research, we can't point to a single discovery that truly qualifies as a "breakthrough."  I'm referring to a breakthrough on the order of the XMRV discovery.... if it had turned out to be correct.  We can't claim anything so important.  Not one.  And yet in order to truly "solve" ME/CFS, we might need dozens of such breakthroughs.

When I read accounts of the latest IACFS conference*, or the daily articles that make the rounds in our blogosphere, I have mixed feelings.  A few dozen dedicated researchers are all working on their pet theories and all seemingly churning out important findings.  It all sounds positive...we are surely making "progress."

But it raises a question: Is one of the researchers correct, and the others wrong?  Almost certainly not. There are too many confirmed physiological derangements found in ME/CFS patients that are, by now, beyond debate.  In the immune system alone, there is a constellation of problems, and that's merely one sector of the disease.  We know with absolute certainty we're dealing with a complex multi-system disorder. And so each of these dedicated ME/CFS researchers is probably focusing on what will turn out to be but a small piece of the puzzle.

When a true breakthrough finally occurs, it will look like one of two things:  Ideally someone will suddenly discover the cause--the one event that sets off the long chain of subsequent derangements.  Then we'd have a true focus for treatment research.

But barring such a "home run" discovery, true breakthroughs will begin to occur when someone with a mind toward the big picture starts making connections between the various derangements.... and proving them.  Someone has to start linking these findings in a causal chain so that we can begin to create a comprehensive model of this incredibly complex disease.

Look at the list of derangements involved with ME/CFS below and realize that nobody has yet to conclusively link even two of them together in a causal relationship.  And yet, in order to truly understand ME/CFS, we might need to figure out how they all connect:

1.  Glutathione deficiencies, methylation defects, detox mechanisms
2.  Mitochondrial dysfunction
3.  Neurological symptoms
4.  POTS/OI/tachychardia
5.  Hormone imbalances
6.  Th1/Th2 imbalance
7.  Natural Killer Cell deficiencies
8.  Pro-inflammatory cytokines
9.  Unhealthy gut biome
10.  High viral titers
11.  Cognitive dysfunction
12.  Sleep disturbances
And many more...

A note on terminology.  The list above includes symptoms, imbalances, deficiencies, dysfunctions, and pathogenic markers.  Collectively I refer to them as "derangements."

In addition to linking all these derangements together, a unified model has to explain how we can have multiple routes into ME/CFS:  gradual onset versus sudden onset; viral infection, major bodily injury, etc.  Perhaps this is the test by which all theories of ME/CFS etiology should be judged.  Does the theory explain why we have multiple routes into the same state of disease?  If it doesn't, at best, the theory only explains part of the puzzle, further downstream from the cause.

This is why I believe the theories of so many of our dedicated ME/CFS researchers will be, even if proven to be true, only part of the puzzle.  Many of the theories probably aren't broad enough to explain both sudden onset and gradual onset.  Moreover, many of the current working theories would explain only part of the disease process further downstream, not the etiological origin.

                                                            Possible Models of ME/CFS

When we are finally able to link all of the states of dysfunction together through causal connections, the model that emerges will probably look like one of the following 3 examples:

Linear chain:  Imagine all 12 of the derangements listed above tied together in a simple cause-and-effect chain, from 1 to 12.  This is the most simplistic model, and probably very unlikely to describe ME/CFS.

Hub and spokes:  This is a wheel analogy.  First, you have an axle (the original cause).  Next, the "hub" connected to the axle is a single, master derangement--one that leads to all the others.  Every other derangement stems directly from the hub but is not linked to any of the others.

A-shape waterfall:  This is a hybrid of the two models above.  The brink (the tipping point of the waterfall) is the etiologic cause of ME/CFS.  Perhaps you have a single stream leading up to the brink, but perhaps you have many tributaries (different causes) all leading up to one brink.  As the water falls over the brink (the person becomes ill), the stream becomes divided, and then further subdivided, and so forth.  A similar analogy would be the branches of a tree dividing and subdividing from the thick trunk all the way to the thinnest branches.  

I believe, almost certainly, the model will end up looking like the waterfall example above.  It is the only model that explains the variations in symptoms from one ME/CFS patient to another.  The farther the water drops from the brink, the more likely it is that rocks on the cliff (small variations in patients' body chemistries, from one person to the next) will send each molecule of water in a different direction from the one next to it.  At the top of the waterfall, the path of each patient's disease development probably looks the same, but it starts looking more and more different as we get away from the brink.

One of the implications of the waterfall model would be that the more common the derangement, the closer it would be to the brink.  If there's a derangement that nearly all patients have, that derangement, logically, would be more directly connected to the etiologic origin of ME/CFS (i.e. closer to the brink).  Less common derangements would be further down the waterfall.  This somewhat logical conclusion might provide a basis by which we might begin to construct a complete model.

The Pessimistic View

Each of the divisions in the waterfall model represents a connection that needs to be hypothesized, tested, peer-reviewed, confirmed, and ultimately accepted by consensus before we truly understand the disease process.  There are dozens of these connections that need to be made in this fashion, and we've yet to do even one.  Arguably, only when we finish this process and have a complete model of ME/CFS can we really hope to focus our search for a cure.  The treatment research should focus on putting a damn at the brink, before the water goes over the waterfall.  But if we don't know what the brink is, how can we expect to damn it.

In 30+ years of ME/CFS research, they haven't made even one conclusive causal connection.  In fact, all we're doing is finding more and more pieces that need to be connected together to explain everything.  The big picture often seems to be getting more complex, less clear.  At this rate, it's hard to image ME/CFS ever being fully understood in any of our lifetimes, let alone an approved curative treatment found.  

Further, it is notoriously difficult for scientists to reach a consensus and accept a theory as fact, even with the simplest of theories.  When we're talking about a multifactorial disease that looks something like the waterfall model, it can seem impossible that the proof would ever be strong enough for biologists and doctors to accept any one model.  Even if a model this complex could be somehow "proven," it's such a complex model, the medical community as a whole might never fully understand it.  Doctors and medical schools are accustomed to learning/teaching simple one or two step disease processes.    

                                                               The Optimistic View

Looking at the history of Epidemiology, many diseases have been solved before they were ever fully understood.  Often a drug is discovered by chance, perhaps from research into an unrelated illness, and suddenly there is a cure when nobody was expecting it.  Then it becomes quite easy for researchers to find the cause of the disease because they can simply study why the drug is effective and work backwards.  But at that point, it's all academic anyway.  Who cares exactly why it works?  By the time they've worked it out, we'd be sipping margaritas on a beach in Belize.  

Momentum can build very quickly when just one breakthrough finding is made.  Again, looking at the history of Epidemiology with respect to other diseases, often when one key connection is made, others follow rapidly afterwards.  Imagine what would have happened had XMRV been confirmed.  With a concrete, headline-making finding, research money would have poured in.  Drug companies would have been racing to beat each other to the marketplace with an XMRV anti-viral.  Our small circle of ME/CFS researchers would have likely expanded greatly as virologist and epidemiologists all over the world would have turned their attention to ME/CFS.  Progress would have accelerated exponentially. 

At any moment, we're just one breakthrough away from a rapid acceleration of progress.  The catch is, the breakthrough (whatever it is) has to be sufficiently high up on the waterfall to explain all or most of the disease process.  

Current Treatment Implications

As I look around at how different patients and doctors approach ME/CFS treatment, I see huge variations. There are those that use zero or one or two treatments, and those that take a shotgun approach with 30+ supplements and medications.  Both are valid.

Some patients find that they simply cannot tolerate most treatments.  Others report that most treatments they've tried had no noticeable affect.  Financial affordability is often a limitation too, as are risks and side effects.   

On the other hand, some patients adopt the philosophy that substantial improvements can be cobbled together with many small, sometimes imperceptible improvements, and that each treatment must be provided time to heal slowly.

I think it's safe to say that there is no single existing treatment that can build a damn at the brink of the waterfall.  If such a treatment existed, someone would have stumbled on it by now.  For that reason, my current treatment philosophy is to try to implement at least one treatment for each derangement -- even if that means sometimes merely treating the symptoms.  Since we have no idea which derangements are downstream from others, it arguably makes sense to address a little of everything.

Having said that, I'm still at a place on my disease timeline where I can tolerate most treatments that I try.  That may change.  My hope is that I can stay tolerant of these treatments long enough for a breakthrough to occur of the kind described in the Optimistic View section above (the accidental breakthrough.)  Because if we have to rely on piecing together a full model of ME/CFS before solving it, I fear the disease will far outlive me.

*I originally wrote this post after the March, 2014 IACFS/ME Conference and, for some reason, never posted it.  I found it this week sitting in my blog as a draft and decided to click "Publish." Some of the references therefore might be slightly outdated.


  1. Really well said, and I especially like the way you outlined the list of "derangements." My thesis is we are sick because of multiple insults (toxicity, heavy metals, anitbiotics, etc.) that lead to a chink in the immune armor (NK cells, gut biome, etc). This allows the historical (esp. herpes family) viral load in the body to come on back and have a party, which infects vagus and other nerves, which cause all of the other waterfall cascade you are proposing. But it's just one theory.