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Heresy, Orthodoxy & Time

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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 j...
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Amyloid Toxicity: Myths, Contradictions & Failures

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For over a hundred years, since Alois Alzheimer published his famous plaque and tangle pictures, it has been taken for granted that these plaques and tangles are actively killing the neurons by being toxic. There was no proof needed of why or how they are toxic, the details and mechanisms were to come eventually over time to prove what we already knew all along, these structures are toxic. Observations and experiments were not performed to test the toxic gain -of-function ( GOF) theory of amyloid pathology, but just to verify what we already know, they are toxic. Here, and exactly here, is where the pathology (as a scientific discipline) got its own disease; confirmation bias. No amount of counterevidence was ever enough to challenge GOF. Any counterevidence was either accommodated somehow or simply dismissed, leading to a group of myths and contradictory arguments that are recited almost religiously in papers, reviews, conferences, and media interactions to defend GOF. A smokescreen o...
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Different Colored Eggs in One Basket is Still Risky

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A n interesting paper was recently published by Dr. John Hardy, the father of the amyloid cascade hypothesis, introducing a hypothesis for explaining late-onset neurodegenerative diseases (NDDs) based on the failure of degradation of amyloidogenic proteins. This adds to the list of other interesting hypotheses aiming to explain the etiology and pathophysiology of NDDs, especially the prevalent sporadic forms. The list includes the inflammation hypothesis, the antimicrobial hypothesis, the innate immune hypothesis, and the autoimmune hypothesis. All are interesting and each has its own merits; however, they all have one common problem. They are all gain-of-toxic-function (GOF) hypotheses . They all assume that either amyloids are toxic or that they trigger other toxic cascades that ultimately kill neurons. At the same ti me, they all ignore the very plausible possibility that these peptides and proteins have original functions that are lost due to their ...
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What is biological information?

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Biological information is a well-defined concept. It denotes the specific amino acid  sequence   of a protein that corresponds to a specific base  sequence  in DNA. This concept can be represented simply as: Biological information = amino acid sequence = DNA sequence x the genetic code, where 3 specific bases = 1 specific amino acid. This simple definition of biological information is the core principle at the foundation of modern molecular biology since Francis Crick introduced it in his seminal paper “On Protein Synthesis” published in 1958 1 . In a subsection appropriately titled " The essence of the problem ”, Crick lays out the definition of biological information: “ By information I mean the specification of the amino acid sequence of the protein”.  He called this the  Sequence Hypothesis  which states “ that the specificity of a piece of nucleic acid is expressed solely by the sequence of its bases, and that this sequence is a (simple) code for ...
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The "Protein-Only" Hypothesis: The Emperor Without Clothes

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The protein-only hypothesis has dominated the field of amyloid pathologies for more than two decades now, particularly after the Nobel Prize that was awarded to Dr. Stanley Prusiner in 1997, which acknowledged prions as "a new biological principle of infection". The history of the theory of “protein-only conformational replication” goes something like this:  Brain cells are dying, we went looking for a virus, we couldn't find a virus, instead, we found a protein, only! But, we still assumed it behaves like a virus in two main aspects: 1. It kills the cells →  origin of the gain-of-toxic-function hypothesis (GOF). 2. It self-reproduces without nucleic acid →  origin of the prion/amyloid strain hypothesis. Despite being around for about 40 years (since initial publication in 1982), the theory of protein-only conformational replication still lacks a mechanistic description of its two main viral-like assumptions: 1. Amyloid fibrils are no...
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Why LOF was lost?

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Why LOF was lost? When a protein aggregates, two things happen, one is certain and the other is uncertain. -  The certain consequence is that the protein loses its function, because any protein needs its native conformation and solubility to function  →  loss-of-function (LOF) - The uncertain consequence is that the resulting aggregates become particularly more toxic  →  gain-of-function (GOF) While the two mirror-image possibilities are scientifically valid, the majority of the field studying amyloids, especially within neurodegenerative diseases, chose to focus on the uncertain consequence (GOF) and almost completely ignore the certain one (LOF). A friend of mine asked me why? Why something as obvious as LOF became almost unthinkable and is only mentioned shyly as a heretic belief on the outskirts of the literature? Here, I will try to discuss the historical factors that I think contributed to this huge asymmetry in amyloid science, and how this uni...
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Genetics (only) won’t save us

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In November 2020, a news feature in Nature discussed “ A fringe theory [that] links microbes in the brain with the onset of dementia ” (Figure 1). While it was nice to see that this “fringe” theory is finally being considered worthy of discussion by top journals, the article also highlighted the mainstream view, the one which kept this theory on the fringes for a long time. “ But I don’t think it is going to be provable ” the article quotes Dr. John Hardy, the father of the amyloid cascade hypothesis, “ and I don’t think there is much left that needs to be explained about Alzheimer’s beyond the genetics ”, he added. This statement is not only inaccurate, but it also reflects the core framework that has dominated the field of neurodegeneration for the past four decades. This framework emphasizes that nothing more than genetics is needed to understand these diseases, and if we just keep sequencing more people and conducting more genetic studies, the problem will eventually be solved. ...
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Life & death between the double helix & the cross-β sheet

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The DNA double helix is probably the most famous structure in the world. Since its discovery in 1953; it became an icon for the molecular basis of life, featured in arts and architecture as a symbol of science's triumph and beauty. However, it is less known that another double-stranded structure is involved in devastating diseases such as Alzheimer's, Parkinson's, and mad cow diseases; the cross-β structure . This structure forms the basis of all amyloids and prions.  Both the double helix and the  cross-β  structures are said to have the capacity to replicate and transmit biological information.  But how similar/different are these two double-stranded structures? Why one of them encodes life while the other causes death? The  double-helix/ cross-β  is the relevant comparison when we want to study the question of whether amyloids/prions can self-replicate and what are their functions in biology and disease. We should not be discussing the amyloid supers...
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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 “par...
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Debate Follow-Up: Can Toxic Gain-of-Function (GOF) in Amyloid Pathologies Be Defended?

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We recently had a very interesting  debate  around the mechanisms of toxicity in neurodegenerative diseases (NDDs) and whether it is mainly a gain-of-function (GOF) or loss-of-function (LOF) toxicity due to amyloid aggregation. Before the debate, the inspiring patient advocate Marina Noordegraaf ( @Sparks4PD ) asked me if the GOF and LOF proponents could switch sides during the debate and try to defend the other point of view. I apologized to her saying that it would be very difficult for me to defend GOF since the most common GOF defenses are counterfactual. Here I will list some of the common GOF defenses that we usually get whenever we discuss LOF in papers, reviews, seminars, or on Twitter.   1.   K nock out/down a nimals  of the amyloidogenic proteins show no phenotype, thus not supporting LOF This is just not true . While there is never going to be a perfect animal model that accurately reflects all aspects of the human pathology (and this is true...
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