Heresy, Orthodoxy & Time

Following up on yesterday's discussions about lecanemab, some points to address.

Maybe I am old-fashioned, but I believe that science should be about well-defined entities and mechanisms. I also believe that scientific theories should not be self-contradictory and must make sense within the known laws of physics, chemistry, and biology. From this perspective, I do not think that the two major hypotheses used to describe the amyloid phenomenon (The Amyloid Cascade Hypothesis (ACH) & The Prion Hypothesis (PrH)) fulfill these criteria. I also think that this is the reason behind much of the confusion and the scarcity of clinical success in the field.

The ACH & the PrH were unorthodox hypotheses when they were developed in the 80s & 90s. The ACH boldly stated, in contrast to conventional biological and physicochemical wisdom at the time, that the endogenous proteins that form aggregates, even if evolutionary conserved & highly expressed in their native state, are just toxic. Unlike any other protein, these proteins serve no important biological purpose, their depletion is totally inconsequential, and they have to be destroyed. Not only that, the PrH added that these aggregates can also replicate and propagate their toxicity within and across hosts without the need for nucleic acids. However, several decades later, while these once unorthodox ideas became the orthodoxy, they still fail to provide clear mechanistic descriptions for their claims.

The ACH was supposed to be about the toxicity of the well-defined amyloid plaques. But since plaques did not correlate well with disease progression and could also be found in healthy people with no disease, the ACH became about something else: toxic oligomers. To this day, no one knows for sure what oligomers are exactly. However, the entire theory & its therapeutic approaches are based on this vague, unknown entity with no clear structural or physicochemical understanding. Even more, the plaques that used to define the disease suddenly became protective for the brain from the elusive oligomers (Figure 1.). The hypothesis shifted 180 degrees in a blink of an eye, and still, with no clear toxic entity or mechanism for toxicity.  

 Figure 1.

The PrH took the idea of protein toxicity to a whole new level, asserting that not only these proteins are toxic (somehow), but they can recruit other proteins to become toxic as well via a protein-only replication mechanism without nucleic acids. But again, 40 years after its inception, the mechanisms of how a protein can store and faithfully replicate conformational information as per the PrH remain unknown (Figure 2).

Figure 2.

The American writer Helen Keller once said, “The heresy of one age becomes the orthodoxy of the next.” Apparently, this has worked its way within the scientific community as well, where time magically transformed yesterday’s heresies into the orthodoxies of today. However, time alone could not solve the fundamental scientific shortcomings and contradictions of these theories.

The ACH is still about the toxicity of something that is unknown with a mechanism that is also unknown. It advocated for lowering and destroying the toxic proteins, even in their native form before they aggregate, leading to drugs that worsened the symptoms of the disease. Lowering soluble CSF Aβ was the target of such therapies (secretase inhibitors & solanezumab for example) and how their pharmacological success was assessed.  Now, with the first hints of clinical success, the ACH wants to have its cake and eat it too by ignoring the fact that the drugs that seem to work did the exact opposite of what it has advised and actively pursued for decades. Lecanemab increases, rather than decreases, the exact substrate (soluble Aβ) in the exact compartment (CSF) that has been the target for ACH-based pharmacology for many years. However, apparently, it is not a problem for the ACH to explain such a blatant contradiction, because:

a.  It contradicted itself before, where the plaques were toxic one day and protective the next. So, what’s the problem?

b. With no clear biological entities or physicochemical mechanisms of toxicity, anything can go. There can always be a particularly toxic oligomer species in particularly toxic conformation in a particularly toxic “parenchymal” location.  How can you disprove that?

It gets even more mysterious when you add the assumptions of the PrH to the ACH, where the toxic protein entities can also replicate and propagate their toxicity. Without a proper mechanistic explanation of where the energy comes from for such an exquisite, nucleic-acid-free replication process, the PrH is incompatible with the laws of thermodynamics themselves. More details about this here: https://www.mdpi.com/2079-7737/11/4/535.  

The ACH and the PrH are weak scientific theories. They are vague, mechansimless, and contradictory within themselves and with other laws of nature. There is nothing noble or courageous in sticking by them no matter what, as much as there is nothing mean or hateful in stating their shortcomings and trying to come up with better ones. I think the pre-ACH, pre-PrH simple biological and physicochemical principles can fully explain the amyloid phenomenon without the need for the once-novel assumptions of the ACH and the PrH. These old-fashioned principles include:

1.   Proteins, especially neuropeptides, are not there just to be toxic, and are conserved and expressed for important functions.

2. The genetic evidence links the disease to these proteins, the mechanism can equally be due to the aggregates or the concurrent protein depletion.

3. Protein depletion is never good or inconsequential, and targeting native proteins for complete destruction is not a good idea.

4.  Replacement therapy is one of the most successful approaches in medicine since the discovery of insulin.

5. DNA stores biological information and faithfully replicates it. It takes a lot of energy and an army of machinery to perform this process. Amyloid aggregation is nothing like that.

6.   Proteins, like any other molecules can exist in different phases including liquid (LLPS) or solid (amyloid). Transforming from one phase to the other is phase transition, not replication. Phase transition is governed by the laws of thermodynamics, driven by supersaturation and catalyzed by nucleation. It can take place in the complete absence of a protein seed, indicating that templating is not required, and is dependent on environmental conditions (temperature, pH, shaking) that cannot be structurally encoded nor faithfully replicated.

I think these principles are more than enough to understand the amyloid phenomenon, without the need for postulating oligomers to account for the missing toxicity or prions to explain a simple phase transition. They are free of contradictions and consistent with the rest of what we know about physical chemistry and biology. They are mathematically precise, accurate, and quantifiable.  And they open the door for trying new therapeutic approaches, including replacement therapy, which has not been tried before for neurodegeneration, except perhaps inadvertently as a result of lecanemab treatment.

However, in the age of ACH and PrH orthodoxy, adopting these principles now to understand the amyloid phenomenon is heretical. I hope, one day, these old-fashioned principles will once again become the orthodoxy, not just by the passing of time, but by providing better data, better explanations, and better therapeutics.