[_zagj]

> But it is much easier to read an article like this, where the same point is repeated multiple times, with some “they said this,” “they said that,” etc. than to understand even a small portion of a field. More people will do the former, and then apparently call for executions without any way to judge who will be executed. And I sit down to write code for my experiments, click on one link, and see what I perceive as harmful information, and there goes apparently half an hour. I can either let this kind of stuff lead to my funding being cut, or reply to it and slow down my research

Am I unreasonable to think that funding ought to be re-directed elsewhere, given that we 1) already have effective anti-amyloid monoclonal antibodies, and 2) they don't seem to work that well, and 3) there are alternatives, like the chronic inflammation hypothesis, that have supporting evidence? (e.g., https://www.nature.com/articles/s41591-024-03201-5)

[bartathe]

There are many reasons anti-amyloid mABs might not work that well besides "amyloid hypothesis is bunk." You are giving them to very late-stage patients, they don't actually work that well if you look at the data, and some people also think that if you disaggregate fibers without a molecule that also inhibits new aggregation, you are just creating more "seeds" that can grow into more amyloids. I think the fact that they do SOMETHING despite all these unanswered questions and also their terrible side effects actually suggests we might be on the right track.

[margalabargala]

> 1) already have effective anti-amyloid monoclonal antibodies, and 2) they don't seem to work that well

I fear you may be falling into the exact trap that the person you replied to, is warning against.

There is not just one thing called "amyloid", so not only are the "anti-amyloid monoclonal antibodies" not effective against all amyloid, the amyloid against which they are effective may well not be disease-contributing amyloid.

The state of the field is much more complicated that deciding between pop-sci summaries of "amyloid bad" and "amyloid irrelevant" and directing funding accordingly.

[kurthr]

Yeah, this reminds me of "asbestos" which is not a single thing and has many non-dangerous examples, but has been banned because a few of them (and contamination is a worry) are a significant hazard. If the different structures were just called something different, they might have significant commercial applications, but "asbestos".

Same thing with MRI with the removal of Nuclear from NMR. Sure the 3D imaging is cool, but you know that they had to remove that N from the name for marketing.

Ok, and then there's EUV lithography. Don't call it X-Ray lithography even though it's 13nm, because there were decades of expensive failures with that marketing.

[bartathe]

To step back for a second, why is the question always re-directing funding when science funding overall has been steadily eroded by inflation and cuts since the 60s? A few months ago, I looked up the percentage of the American population that has PhDs and how it has changed over time. We have so, so, so much more advanced work and technical needs now that would benefit from them.

To answer your question more specifically, our lab is actively trying to collaborate with people working on questions related to chronic inflammation (I am not sure what the funding status is, but I know someone from our lab is working there). In particular, microglial activation. Not to get lazy with cancer analogies, but if you look at what causes even a single cancer, it's often hundreds of events lining up perfectly. The question is, which one do we target to make an effective drug? The honest answer I have to this is that it's wishful thinking to think that that decision should be made at the level of basic science. How the funding and research ecosystem is supposed to work, is academia is supposed to explore all kinds of avenues, and then industry is supposed to exploit them and push the most promising avenues after. The problem is that when there's a crunch on science funding, "this is an unexplored avenue" is not enough, and you basically begin to take on the role of industry without any of the money. I think fraud is heavily incentivized by the funding crunch, too, actually. In the case of Eliezer Masalah, my impression is that his fraud was photoshopping images and faking experiments to add to collaborators' points to support other experiments that WERE actually conducted and made the points. I assume he was trying to get a very high impact factor for funding and promotions, but was trying to minimize the chances that he would get caught by making sure his research was part of works he assumed would be reproducible given that he assumed the others' research was legitimate. I haven't kept up with the case since it initially broke, though, and I didn't go through it as closely as I should have (I also do not focus much on alpha-synuclein).

But, if you really want an answer as to why I think there is more funding on amyloids than chronic inflammation, it is that amyloids are Rome. Imagine a funnel. Chronic inflammation is near the entry to it, along with many other things. But shingles is not the only thing that might cause chronic inflammation that might cause Alzheimer's. Herpes has also been linked. So basically everything is at the very top of the funnel. But the reason people study amyloids is that they are at the very bottom of it. Chronic inflammation seems to cause them to misfold, but so do certain mutations, so if we can develop a drug that disaggregates and/or inhibits the growth of amyloids, we are stopping more causes than just looking at chronic inflammation, which is one of many.

[_zagj]

Thanks for your thoughtful replies