| HN Mirror

Thank you for bringing Berislav Zlokovic to my attention. I will bring him up in the office tomorrow. I have personally never heard of him. Neurodegeneration is a really, really large field.

Okay, citation count was a metric I should not have used and also I was just straight-up mistaken about his citation count on that paper. To be honest, citation count is also a lazy argument on my part. I like to think it matters when I think the paper is actually good and that it doesn't matter when I think the paper is bad. A lot of citations get racked up by medical reviews, which are often more highly cited than original work. Keep this in mind when you look at Berislav Zlokovic's "top" papers.

I genuinely do not think Lesne's work is that influential, though. First, if you look up "amyloid beta oligomer" on grantome (https://grantome.com/search?q=amyloid+beta+oligomer), then look up something like "Alzheimer's amyloid" (to make sure you are not getting amyloids that are not associated with Alzheimer's, since I don't know what other diseases amyloid beta oligomers could possibly be associated with), you will see that amyloid beta oligomer research is actually not well-funded at all compared to everything else in the field. Also, how many papers that cite his work actually work on the amyloid beta 56 oligomer in particular (not rhetorical, I haven't checked)? Maybe this would make for an interesting project for a high schooler or undergrad interested in web-scraping and that kind of data analysis. Probably a question for economists or quantiative sociologists. Now is the time to mention a bit more about what trying to replicate his work would have looked like.

Lots of stuff is difficult to replicate not because people are committing fraud, but because people in academia actually "move fast and break things," aka make bad protocols and don't document that well because of pressure to publish quickly. Most people doing the work are also graduate students, who are still students. Wet lab work is very, very, very finicky (this is the reason I have gone into more computational projects, I don't possess the level of finesse or patience required). So, some replication problems are because things are both poorly notated and people don't follow protocol perfectly either. But regardless of the causes, some recent experiences that describe what the process would have been like --

Someone in our lab recently tried to replicate a protocol for generating recombinant (not brain-extracted, but made from purified protein) amyloid fibers that look like disease-associated fibers. She had previously been one of the only people in our lab who managed to replicate another protocol made by the the same lab (she subsequently taught everyone else in our lab). She was not able to replicate this new one. It took her maybe a month while she was also working on other things to decide she was not going to be able to replicate it. There were some other tells that we think they were a little lazy, maybe got lucky a few times, and published it in a easy journal just because other people had published far better work on the same topic, so they wanted to wrap up their work and move on while still publishing to keep their grants. Similarly, someone else in our lab went through a two month long process where someone who claimed to be able to make some kind of oligomer send us stuff that turned out to not be an oligomer. First, they blamed the shipping and tried again. Well, next round, same thing. Next, they blamed us. We tried again, same thing. At that point, someone gave them an earful, and now we are kind of sketched out by them. There was some work expended, but again, we work on multiple stuff at once, since most things don't work. And in this case, collaborators sent samples.

So, to summarize, I highly doubt anyone was trying to replicate their results for years, that just isn't how science works. And I don't think amyloid beta oligomer research got that much public funding compared to other things. You do multiple, different experiments every week just to see what sticks. I'm sure plenty of people lost an experiment slot for a few weeks, though. Extremely annoying and part of the general demoralizing slog, but it's not the reason we have no cure.

Why might the Lesne paper have been highly cited? Because oligomers will be important drug targets if they polymerize to amyloid fibers and can be specifically targeted since they are less stable than amyloid fibers, and lots of people working on on them more broadly than just this species might have grabbed this citation because it was a Nature paper with a lot of marketing. From there, citation propagation kept it going. I try to only cite things that I read now, but part of that is probably because my undergrad advisor had the eyes and memory of a hawk and would really hammer everyone on this. I notice bad examples of citation propagation semi-regularly.

Some more context for what oligomers really are and why they are so difficult to replicate if they exist -- a fiber exists of many, many proteins stacked. Well, how does the fiber begin? Presumably, you don't go 0 to 100 units perfectly stacked, you go in small increments via pre-fibrillar intermediates. Well, that means you're describing a very transient species, so good luck extracting it from brains or making it recombinantly. Oh, and many amyloid-forming proteins are "intrinsically disordered" meaning they have no "native" structures, and might not be that structured if you have only a few of them stuck together either.