bartathe (u/bartathe)

bartathe commented on Decades of Research Misconduct Stalled an Alzheimer's Cure sciencefriday.com/article... · Posted by u/sorokod

analog31 · 6 months ago

This is true, but it's one thing to justify your funding to a funding agency, and another to justify your funding directly to an angry public that is being fed anti-science propaganda, and to politicians who are not acting in good faith.

I work in private industry, and I certainly have to justify my funding, but nobody's writing news articles accusing me of fraud -- if they even know that I exist.

Sorry, I'm not attacking you, but your comment triggered a reaction that I've been thinking about for some time.

bartathe · 6 months ago

You hit the nail on the head. I'm already noticing points I improperly conveyed, necessary context for that that I left out or did not explicitly clarify, avenues to the creation of new misunderstandings that might lead to new public pressures and criticisms if any of this information propagates. I finally understand "never explain, never complain." I am never commenting in public again without significant editing, trying to consider the out-of-field perspective very deeply to think about misinterpretations that I unintentionally produce, discussing more with my colleagues what kind of engagement is productive and what kind isn't, etc. But when I made this comment, one of the other main comments was literally calling for executions.

bartathe commented on Penn to reduce graduate admissions, rescind acceptances amid research cuts thedp.com/article/2025/02... · Posted by u/strangeloops85

efavdb · 6 months ago

I mostly had to teach throughout my PhD. Curious if funding of that sort is also at risk or if it comes out of tuition from undergrads.

bartathe · 6 months ago

I am on fellowship, but have already been warned where I am that TAships might be cut. New rules have been put in place for maximum number of years one can teach, whereas it used to be a requirement that we TA a certain amount of time at all because of the high need (not sure if it is, maybe this hasn't been removed, just to emphasize that this is despite a need for TAs).

bartathe commented on Decades of Research Misconduct Stalled an Alzheimer's Cure sciencefriday.com/article... · Posted by u/sorokod

akoboldfrying · 6 months ago

I read the comment you refer to, and it does have a lot of useful context. That said (and here I'm quoting a reply to that comment), the commenter claims that Lesné was "not that highly cited", though his main fraudulent paper was cited 2,300 times, making it the fifth most highly cited Alzheimer's paper since 2006. That seems bogus on its face.

Separately, I think it's legitimate for calls for scientific fraudsters to go to jail to rise to the top. There's no contradiction between wanting this, and wanting a more nuanced understanding of the field.

bartathe · 6 months ago

Yes, it is bogus on its face, I was wrong. I also accidentally miswrote that tau might lead to amyloid beta aggregation, when the "both matter" hypothesis usually argues the opposite relationship. I misspelled Eliezer Masliah's name, I didn't qualify that those are the big three scandals I'm aware of, I'm sure there's more. Thanks for forum peer review, don't take everything I say 100 percent, I will be bothering people senior than me to comment on this more broadly and with editing in more official forums, though, because what this tells me is that we are not keeping the public sufficiently informed on the state of the field, challenges, and current research directions.

bartathe commented on Decades of Research Misconduct Stalled an Alzheimer's Cure sciencefriday.com/article... · Posted by u/sorokod

csaid81 · 6 months ago

I know a lot of legitimate research supports various versions of the amyloid hypothesis, but I don't buy that these likely fraudsters had minimal impact.

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-...

bartathe · 6 months ago

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.

bartathe commented on Decades of Research Misconduct Stalled an Alzheimer's Cure sciencefriday.com/article... · Posted by u/sorokod

pessimizer · 6 months ago

> Who will read nine paragraphs that I think are necessary context for all of this?

They are very interesting, but I'd have to be convinced that they were necessary context. Because the question that I think is important is whether this was true and widespread:

> 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.

And you don't know. I don't know either.

We can't say that anything would be farther along if these frauds had not happened, because that is a counterfactual. We can just guess that if we spend resources in areas that didn't have as much fraud surrounding them, we would be more likely to be farther along. Any argument otherwise is an argument that the direction and funding of research doesn't ever really matter.

I don't think any avenue of research should be abandoned if anybody still sees any possible value in it. But I know that funding decisions heavily influenced by fraudulent research are not going to be better made than decisions not influenced by fraud; and that if we were making decisions based on fraud over a long period of time, it is safe to assume that there was a loss. If we want to be less likely to repeat this loss, we probably need to change how we evaluate where to allocate funding.

bartathe · 6 months ago

Thank you for your comment. I am not saying the field was not stalled because of these frauds, I am saying I do not think it was significantly stalled. I think fraud is an easy scapegoat for broader issues, especially when the case that people keep referring to is whether a single amyloid beta oligomer species is involved. There are some very esteemed researchers who do not believe oligomers are physiologically relevant or discrete enough to be analyzed at all. I am trying to point out the ways that "amyloid hypothesis" actually refers to many distinct things to try to prevent very non-specific reactions like another comment that replied to me had, where we decide to throw out amyloid research entirely for chronic inflammation, etc.

If we want less fraud, we need less incentives for fraud. What do you think the easiest route to take is when funding in a field that already attracts some nutso people is cut every year? That so little fraud happens is a testament to the integrity of most scientists. I grew up part of an ascetic religious sect. The personality types of many scientists in the field are that of the hermits I knew as a child. You probably cannot totally get rid of fraud, some people cannot really seem to produce anything themselves, they exist, they will find some way to survive (often better than those who are not this way). You can keep rates of fraud low, but if you think it is more prevalent than it is, you risk developing a social autoimmune disease. Remember that means-testing has its own costs, too.

bartathe commented on Decades of Research Misconduct Stalled an Alzheimer's Cure sciencefriday.com/article... · Posted by u/sorokod

anonnon · 6 months ago

> 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 · 6 months ago

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.

bartathe commented on Decades of Research Misconduct Stalled an Alzheimer's Cure sciencefriday.com/article... · Posted by u/sorokod

anonnon · 6 months ago

> 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 · 6 months ago

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.

bartathe commented on Decades of Research Misconduct Stalled an Alzheimer's Cure sciencefriday.com/article... · Posted by u/sorokod

bartathe · 6 months ago

This is my field. There have been three major scandals in the "amyloid" field -- Sylvain Lesne, Eliezer Masliah, and lecanemab trials not informing patients they had the APOE4 variant, which is associated with cerebral amyloid angiopathy, a vascular condition that the same scientists who led those trials previously noted was correlated with cerebral hemorrhage side effects. Sylvain Lesne produced shitty research that was not that highly cited, below is my take on the field and my concerns regarding journalists poorly communicating the science in this story. My perspective on why we are behind other fields is in paragraph five. The next three paragraphs are just context as to why I think there is no singular “amyloid hypothesis,” and why this kind of journalism threatens our field despite a desperate need for dealing with fraud, too. I realize this is long, I am not a journalist, I am not a good communicator, I am a scientist. If anyone has advice, please share it with me, likewise with questions.

Not 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.

bartathe commented on Fraud, so much fraud science.org/content/blog-... · Posted by u/nabla9

moralestapia · a year ago

I've been saying this for years and have been punished for that. Even here.

I've done Biology and CS for almost 20 years now, I've worked at four of the top ten research institutions in the world. The ratio of honest to bullshit academics is alarmingly low.

Most of these people should be in jail. Not only do they commit academic fraud, many of them commit other types of crimes as well. When I was a PhD student, my 4 year old daughter was kidnapped by staff at KAUST. Mental and physical abuse is quite common and somewhat "accepted" in these institutions. Sexual harassment and sexual abuse is through the roof.

I am very glad that, slowly, these things are starting to vent out. This is one real swamp that needs to be drained.

Some smartass could come up and say "where is your evidence for this?". This is what allows this abhorrent behavior to thrive. Do you think these people are not smart enough to commit these crimes in covert ways? The reason why they do it is because they know no one will find out and they will get away with it.

What's the solution? I've thought about this a lot, a lot. I think a combination of policies and transparency could go a long way.

Because of what they did to me, I am fully committed to completely destroy and expunge people who do these things from academia. If you, for whatever reason, would like to help me on this mission, shoot me an email, there's a few ideas already taking shape towards that goal.

bartathe · a year ago

"Four of the top ten" research institutions is probably part of the reason for your experiences. I went to an elite private undergrad as a scholarship student and was sexually abused by the son of high powered lawyers, probably awful people themselves, who targeted scholarship students, international students, etc. because we were vulnerable with no recourse. I then went to a highly ranked but not super sexy public school for my PhD and my experience has been significantly better.

Bad actors are attracted to glamor and prestige because they're part of the cloaks and levers they use to escape consequences. Bad actors are far less attracted to, just as an example, living in Wisconsin, Michigan, or Indiana and telling people at conferences that they work at UW rather than Cambridge. UCs are also vastly more welcoming and supportive of working and middle class students than HYPSM even at the graduate level. That doesn't mean that you won't find any assholes at these places, and go too low in the rankings and you'll see ugly competition over scarce resources, but there's a sweet spot where more honorable people who aren't chasing prestige cluster and you'll find more support and recourse. Public schools ranked 5-15 are best for students without significant, significant social savvy and other forms of protection, IMO.