Cores & Protective Belts in Amyloid Thinking

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When is it time to give up a scientific theory and embrace a new one??

Three philosophers of science had opinions about this. Karl Popper laid the foundation of the modern view of science that a theory should have testable and falsifiable predictions. For example: if we have a theory claiming that all swans are white, then the observation of one black swan is enough to falsify our white swan theory. This observation should force us to adopt a more general theory that explains the phenomena of swans being black or white.  

Another philosopher of science, Thomas Kuhn, objected. He argued that looking at the history of science; this is not how things always worked. Scientists do not abandon a theory at the first negative test. Instead, science progresses in phases. The phase of “normal science”, where negative results are not rejected, but attempts are made to incorporate them within the old theoretical paradigm. Then comes the phase of “scientific revolution”, where a “paradigm shift” takes place and a new theoretical framework is adopted. This means that in case of observing one or two black swans, the white swan hypothesis can be maintained by claiming that these swans are diseased or exposed to too much sunlight for example. This helps keep the old white swan paradigm alive. But we keep seeing one black swan after another until a whole flock is observed. Then, it is finally recognized that they have an independent existence, and the old theory is abandoned for a new one; a paradigm shift.  


Another philosopher of science, Imre Lakatos, combined those views in his theory of cores and protective belts in scientific thinking. Lakatos postulated that scientific theories comprise a central “hardcore” hypothesis surrounded by a “protective belt” of auxiliary hypotheses which are introduced to explain experimental failures (Figure 1, source and more details here). He further illustrates that a progressive research program is one where the auxiliary hypotheses lead to new falsifiable predictions and new applications, while a degenerative research program is where the auxiliary hypotheses only serve to keep the core alive no matter how much evidence builds against it.

Figure 1. (source and more discussion here)

The story of these three eminent philosophers of science brings us to the story of the amyloid gain-of-function (GOF) hypothesis. The hardcore of this theory is that endogenous proteins turn rouge and form fibrillar aggregates (amyloids) that kill the cells. Since this is the mechanism of neurodegeneration, therapies targeting the aggregates should be the way to go to save the neurons. But black swan negative experiments kept flocking in. However, for every negative result, emerged an auxiliary hypothesis forming a protective belt that kept the core amyloid GOF hypothesis alive.

For example:
  • Amyloids fibrils are not toxic → It’s the oligomers that are toxic
  • CSF soluble Aβ goes down → But Aβ 42/40 ratio go up
  • Some people have amyloids but no disease → They have cognitive reserve
  • Antibody trials failed → We’re interfering too late
  • Worsened cognition and toxicity of BACE and γ-secretase inhibitors → They have other targets
  • What about knock-out and knock-down animals that show pathology without any aggregated protein →….
Examples of the auxiliary hypotheses defending the amyloid GOF paradigm from negative results are summarized in Figure 2. 
Figure 2. The hardcore of the amyloid GOF hypothesis and the protective belt of auxiliary hypotheses protecting it from the attacks by negative results (by Kariem Ezzat).  

A big protective belt with many auxiliary hypotheses and few successful predictions or applications are signs of a degenerative (ironically) research program, according to Lakatos. Maybe it's time for a paradigm shift. Maybe it's time to recognize that amyloids are normal proteins that lost their native conformation, solubility and hence their function, and that loss-of-function can be, at least initially, an important contributor to the pathology. This doesn’t only replace many of the paradoxes of GOF with clear mechanisms; it also opens up new avenues for helping the patients by focusing on replacement therapies for the lost soluble proteins.

More details in our paper here and our review here.    

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