Readit NewsNot being clear about "amyloid" nomenclature threatens to throw the baby out with the bathwater, which will stall an Alzheimer's cure even more. Most proteins are "globular," think kind of round balls of scrunched up string, arranged in alpha-helices and some beta-sheets. "Amyloids" are spine-like fibrillar protein aggregates, where each vertebrate is a flattened version of a protein folded in beta-strands. The vertebrate is created by these beta-strands stacking into beta-sheets. Google "amyloid fiber" versus "globular protein" to see what I mean by this description.
"Amyloid BETA" is a usually disordered protein which can aggregate into ONE of the amyloid fibrils seen in Alzheimer's and other dementia patients' brains. Tau can form amyloid fibers, so can TDP-43, TMEM, alpha-synuclein, etc. This is a good link -- https://people.mbi.ucla.edu/sawaya/amyloidatlas/ -- if you want to see the cross-sections of all of the amyloid fiber structures the field has solved with useful annotations. One "amyloid hypothesis," for example, is that TAU hyperphosphorylation (the addition of a lot of very negatively charged post-translational modifications, think chemical ornaments you can add to a tree) leads to tau amyloid fibers, which then lead to amyloid-beta amyloid fibers. There is lots of speculation about the mechanism, whether amyloid fibers can also have enzymatic function that lead to metabolic dysregulation, whether certain amyloid fibers are actually functional and exist in everyone but that certain types or a certain amount is associated with disease, the catecholamine hypothesis is something that can’t be discounted, maybe amyloid fibers are just a downstream effect of a true ultimate cause (in which case, amyloid fibers are still an important clue, lots of people are doing experiments now where they see how they can get certain amyloid fibers in vitro using co-factors which may be one step back to the root cause).
Another "amyloid hypothesis" is that amyloid beta OLIGOMERs, some kind of non-fibrillar aggregate that we don't know the structure of but that we know contains proteins that usually also make amyloid fibers , causes Alzheimer's. This is what "amyloid beta *56" is, by the way, an oligomer, and what Lesne’s work argued. We find oligomers to be extremely hard to work with and I could write a paragraph or two about why, but the fact that this is true makes OLIGOMER research, some of which is probably legitimate, an easy target for fraud. When molecules are well-known to be extremely difficult to work with, if you try to replicate someone's experiments and you can't, it could be because the molecules are extremely difficult to work with or because the authors whose experiments you tried to replicate committed fraud. It’s easy to think “well, it must be me,” which is how people get away with it for so long.
So, why are we so far behind? Something important to note is that amyloid fiber structure on an atomic level has only recently been cracked. Consider that we've known the structure of DNA since the 50s, but we didn't know the structure of the MOST common amyloid fiber specific to Alzheimer's patients until 20 freaking 16 -- https://pubmed.ncbi.nlm.nih.gov/28678775/. The reason for this is that the method used to solve the structure of most proteins is x-ray crystallography, but nobody has ever successfully crystallized amyloid fibers except for very small fragments of them -- https://pubmed.ncbi.nlm.nih.gov/15944695/. People think this makes physical sense for reasons related to crystal symmetry. The 2016 structure was solved using cryo-EM, which is a relatively recent development and only won the Nobel in 2017. Prior, it was derided as “blobology” because you would get very coarse structures from cryo-EM -- https://pmc.ncbi.nlm.nih.gov/articles/PMC2726924/. So, the field had to wait for cryo-EM to improve, a big part of which was waiting for better computer vision algorithms (i.e. we use YOLO and various CNN-based algorithms, too, we had to wait for that shit just like Waymo), among other things.
Why is structure so important? Drugs have to physically interact with some kind of protein target. So, you should probably know the atomic model of the target so you can make use of computational modeling techniques that can help you figure out what binds to proteins. Alternatively, if you want to do a ton of biochemical screens, i.e. make a bunch of the target protein, treat it with various compounds, and see what sticks, you have to make sure you are correctly making the target protein. In other words, you don’t know you’ve successfully reproduced the target if you don’t know what the target is. And the exact fiber structure matters, since different structures appear to be correlated with different diseases. Then, you have to figure out a method to make that protein, which people also have done recently for various types. The alternative is waiting for brains from brain banks, which is very slow and doesn’t provide a lot of material. Keep in mind this also means you can’t verify your mouse models have the same structures, too.
I do not think these scandals significantly stalled an Alzheimer's cure. It's a genuinely tough field -- you can't do brain biopsies, amyloids are a tricky protein to work with, we didn’t know the structure until 9 years ago. I think there are a lot of people who feel like they were locked out of funding opportunities because of the focus on amyloid-beta. Maybe this is true, I don’t know. The lab I’m in has worked on tau for decades.
Another point -- neurodegeneration starts far before symptoms show up. A lot of the recent drugs were designed for what is basically metastatic cancer. Learning more about earlier stages of neurodegeneration, which we can do with PET-ligands designed to bind to fibers, the recent p-tau blood test, etc. is necessary to uh... treat stage 1 or 2 cancer equivalent.
Finally, I have to get political here, considering recent events. I’m not a professional communicator. Most scientists aren’t. It is things like this that are the reason we are being threatened with funding cuts. Who will read nine paragraphs that I think are necessary context for all of this? 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.
You said that Lesné was "not that highly cited". But his main fraudulent paper was cited 2,300 times, making it the fifth most highly cited Alzheimer's paper since 2006! [1]
Berislav Zlokovic's likely fraudulent papers were cited 11,500 times! [2]
It's hard to imagine these highly papers didn't redirect at least some scientists to do pointless followup studies. Of course, in the counterfactual world the scientists might still have been doing pointless studies, but we'll never know...
[1] https://www.science.org/content/article/potential-fabricatio... [2] https://www.science.org/content/article/misconduct-concerns-...
I wrote a blog post on how to make this easier, including a new criminal statute specifically tailored for scientific fraud. https://news.ycombinator.com/item?id=41672599
I wrote a blog post on how to make this easier, including a new criminal statute specifically tailored for scientific fraud. https://news.ycombinator.com/item?id=41672599
The nature of science is that there are a lot of papers. Not all are replicated but generally “we pursued this direction for 16 years” type of hypothesis are based on many results, which acts as an error correcting code on mistakes and fraud — and is exactly how the system is supposed to work.
How much time could have been saved towards an effective treatment? It could be as high as a decade, but of course more likely it was zero years. I averaged it out to 1 year.
Now suppose you think that 1 year is orders of magnitude too high, and that in expectation it averages out to a 1 day delay. Even then, I estimate 100,000 QALYs would be lost, making this a tragically high impact case of misconduct.
--- Final point: Nobody doubts that science is error correcting. The point is that the errors are corrected far too slowly and many never get corrected at all. It's incredibly hard to develop good theories when you know that 30-50% of the results in your lit review are false.
From the article:
> One-third of major storms arrive unexpectedly, according to the SWPC’s own 2010 analysis. And that’s not just the small storms. According to a news article in Science, the SWPC might be also be poor at identifying the characteristics of severe storms, since they are so rare.