An analogy to explain ME/CFS complexity: Three body problem

Three body problem https://en.wikipedia.org/wiki/Three-body_problem

“The three-body problem is the problem of taking the initial positions and velocities (or momenta) of three point masses and solving for their subsequent motion according to Newton's laws of motion and Newton's law of universal gravitation.”

Analogies of disease are notoriously unhelpful, but there is a conceptual problem that I find difficult to explain without something illustrative. Even then to describe it I’ve had to fall back on some jargon – here the term “dimension of illness” by which I mean any specific process from activity on a scale of within a cell up to disease of an organ, and from gene behaviour to skeleto-muscular response, which encapsulates a distinct pathophysiology.

Historically the most common conception of ME/CFS pathology has been as a schema of: single dimension of illness = symptoms, with the single dimension being enigmatic but still understood to fall within the known clinical contexts of immunology, endocrinology, neurology etc.

Biopsychosocial adherents sought to add fuzzy extra dimensions to ME/CFS pathology, which served only to detract from productive conceptualizations of what disease processes may actually underly ME/CFS.

Clearly adding complexity for the sake of it (or to promote professional interests) is not helpful, but with the accumulated evidence of very substantial heterogeneity in ME/CFS, a single dimension of illness schema might not meet the demands of accurately characterising the pathophysiology of ME/CFS.

We already talk to some extent about ME/CFS pathology having more than one dimension with a tacit acceptance that genetics play a role, however this is characterised as a chronologically dimensional – genetic predisposition is inherent (from birth ?) and only becomes relevant after some external impact such as a ‘hit and run’ infection. What is less often discussed is the possibility that in the ME/CFS patient, two or more separate disease processes (dimensions) are in play but which only in interaction produce evident disease.

The proposition that more than one clinical dimension is a feature of ME/CFS pathology isn’t exactly satisfying from a scientific standpoint where parsimony is preferred. Looking for more than one clinical explanation provides challenges in terms of falsifiability and perhaps plausibility. Planetary astronomy however is built around looking for extra bodies to explain gravitational inconsistencies, and it might help illustrate what lies behind the variability in ME/CFS both in the individual, and across the patient population

The three body problem is an illustration of complexity within an apparently simple system – just three objects; for those not affected by vertigo etc, there’s a cool visualisation here:

https://www.youtube.com/watch?v=cev3g826iIQ

If we hypothesise that in a particular patient, ME/CFS is a disease that is the result of features in three illness dimensions and we represent each dimension as a body in free space that is able to influence two other bodies, the behaviour of the three illness dimensions becomes ever more chaotic as they interact with one another. It would wrong to overstate the relevance of this to ME/CFS but this complexity of interaction between separate physiological entities might be expressed in the confusing symptom exacerbations that most of us experience, for example in the unstable nature of PEM.

If this notion of three or more clinical dimensions operating in complex inter-relationships is reflective of at least part of the reality of ME/CFS pathophysiology, then it could also explain why there is such huge variation both within an individual’s experience of ME/CFS and across the patient population as whole.

What might this mean for research ?

There’s some personal confirmation bias here in that I’ve long thought that we will only really get a handle on ME/CFS by having a far better description of the patient population, the progress of disease in individuals, co-morbidity profiles and first degree relative health status. Consigning everything to ‘heterogenous’ is (IMO) avoiding essential questions, which is why I think that epidemiological research is undervalued in ME/CFS.

When it comes to biochemical research, if multiple dimensions of illness do underly ME/CFS then a stratigraphic approach may be needed because no single biomarker would yield the secrets of ME/CFS nor be of definitive diagnostic value. Instead biochemical researchers would need to consider multiple indicators each layered by interactive processes to build a profile that maybe specific to a single patient though which might in turn yield viable phenotyping of ME/CFS.

Science can break down complexity, but unless the complexity is acknowledged there can be no determined approach to achieving parsimony. ME/CFS may have a simple pathophysiology but looking for the single magic key to the single magic door looks increasingly unrewarding.

 

A big factor is probably how rested patients are and how long ago the last significant exertion was. We already know that exertion causes significant changes (at least for a few days, maybe more) and if we don't ensure that all study participants are similarly rested it could introduce a lot of variation due to patients being at different timepoints in a PEM process that has different molecular fingerprints various stages.

In a high quality study where cost was not an issue one would bring participants to a quiet apartment close to the lab, with measures to ensure similar levels of exertion and run provocation tests after a week.