The Precipitate

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. ...

 ساعات بنندم عل القرار و ساعات بنندم عل الندم و ساعات بنضحك عل المرار و كتير بنبكي من الألم و نعيش نجاهد في العمار و كله بيروح للعدم و من بعيد نور الفنار فخ و غميق و المية دم  زي الفراش شده الشرار قرب و جرب و اتصدم طريق و معروف المسار و كله كافح و انهزم و لسة بندور في المدار و درس عمره ما اتفهم بنخاف من الديب ليل نهار و الراعي دباح الغنم 

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...

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...

(الفصل الأول) أحلامنا فرسة جموحة راكباها نفس طموحة رابطانا في ديلها و جارية في جبال الشوك العالية و الشوك بيقطع لحمك و بتروي الارض بدمك و هي ولا حاسة بهمك مش طايقة جبال الشوك نفسها في الأرض المفتوحة أحلامنا..   (الفصل الثاني) لعشرين سنةٍ أو أكثر و الفرسُ الجامحُ في جوفي يطلب شيئا لا يتبدّل يجري فَزِعاً كالمجنونِ يركض بسباقٍ مُتخيَّل يرفض أبداً أن يتوقف يرفض حتى أن يتمهل عجباً حقاً.. من أخبر طفلاً مثلَك؟ من أغراك بهذا؟؟ فجَعلتهُ مقصوداً أوّل عجباً حقاً.. ما أدراك.. إن كان هو الأمل الأمثل؟ لعلّ ما تبحثُ عنهُ طيفٌ زائف يسبحُ في عقلِ أجهل أو حتفٌ يزدان نفاقاً حتى إذ تدركُهُ...تُقْتَل كم خضتَ غِماراً بي قهراً قامرتَ بعمري كي ترحل بحثاً عن هدفٍ مفقودٍ بعتَ الحاضرَ للمستقبل و صُدمنا في ألفِ جدارٍ ظنَنتَ تخطّيهم يَسهُل و تَبِعتَ سراباتٍ شتّى تأبى دوماً أن تتأنى تنسى دوما أن تتأمّل من منا يُمسِكُ بزمامِ الآخر؟ من منا يقرر ما نفعل!!؟ أنهكني سعيُكَ يا فرسي قد حان الوقتُ لأترجّل قد حان الوقتُ لكيّ نصبر كي...