Decades of Research Misconduct Stalled an Alzheimer's Cure
sciencefriday.com
sciencefriday.com
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.
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)
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.
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.
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.
(my phd is in structural biology, I've worked across multiple fields of protein structure and function, have worked with Paul in the past, and work in the field of protein structure now, although mainly on the backend infrastructure. So I have some of the credentials necessary to make the statement above.
The parent was specifically asking if crystallography was obsolete, which in my mind is a label with a very high bar, one incompatible with crystallography's continued status as the gold standard against which AF3 is compared.
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.
...
You completely excluded the last sentence of the quote by the GP. That sentence at least partially addresses your concern:
> The lab I’m in has worked on tau for decades.
The lab the GP is working in has been, for decades, funded and working to study ameloid tau -- one of the very alternative hypotheses that are under study. Most of the entire post was about all the other hypotheses that are active and regularly funded.
No one is omniscient, no one can know exactly the right set of funding to get the optimal scientific outcome with the least amount of money. That omniscience isn't going to happen no matter how awesome AI is.
The best course for medical breakthroughs is to fund multiple hypotheses at once which is exactly what NIH does. The more funding to allow research into various hypotheses the better. Whatever it is doge is doing straight shutting shit down is the incompetent fools course plotted by megalomaniacal and ignorant billionaires.
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.
As for people feeling shut out of funding: people feel a lot of things all the time, but I've never seen a good idea be repeatedly denied funding because it wasn't amyloid-primary. Unfortunately, it's usually a lack of rigor, lack of pertinence, lack of preliminary data demonstrating plausibility and feasibility, or some combination. Not always--there are big money and prestige politics going on all the time, but that has nothing to do with amyloid.
To add another nearly useless data point, my lab and those I collaborate with focus on amyloid as well as tau, alpha-synuclein, TDP-43, microvascular changes, and inflammatory contributions. Metabolomics, proteomics, and transcriptomics are other big systems biological approaches. Not to mention social determinants of health, which are also massive.
All that said, I'll read the book, but the "daring journalist finds a crew of whistleblowers" framing strokes me as either ignorant or disingenuous. Off-putting either way, as we face major cuts to public funding of health science, which has overall been an extremely generative and sustainable model for improving national and world health.
thanks for the long comment
Both to an outsider look like protein aggregates.
There is absolutely no question--none at all--that amyloid plaques are a key feature of Alzheimer disease, that they are neurotoxic, and that they fit within a number of mechanistic pathways contributing to dementia (which is the broad clinical phenotype).
Interestingly enough, the actual results of the lecanemab (Leqembi) trial is that those on drug had overall 17 months longer in the mild cognitive impairment / mild dementia range before declining to the moderate dementia range. It doesn't stop the disease, but it does measurably slow its course, and that makes a huge difference to families. Whether the linked author can accept that progress is mostly incremental and not wholly satisfying is, I don't know...his problem, but it is rapidly becoming our problem as dementia scientists.
But people love a conspiracy.
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-...
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.
Research is always going to require some of your time spent justifying the funding.
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.
I think you conveyed the necessary context well. Thanks for taking the time to do so.
The field needs to get better about catching fraudsters, and start delivering results. Otherwise it will be defunded, no matter how eloquent people are. This may not be "fair" but it is the reality.
I agree that the toothpaste is out of the tube here. But do the mods have to fix the reddit community? If HN gets out of hand, is that dang's fault?
For most of us it's a thankless job full of many uncompensated and thankless tasks, but we do it for any number of reasons. Most academic scientists I meet are capable and (mostly) driven by a desire to uncover knowledge.
I don't think it's certain that anything illegal happened here. It was certainly wrong, but wrong how?
This is not at all how the law works. You can't fool investors on purpose then shrug it off as "I win, they should have done their due diligence and second-guessed every aspect of my work that I intentionally falsified" lol. What you're arguing for is equivalent to a diffusion of responsibility for accounting fraud, as if the victims deserve it because auditors didn't detect it immediately.
I don't know the whole story but deceptive practices (deliberate wrongdoing) need to be punished, if that is what happened here.
We have plenty of cases where people have in fact been allowed to fool investors without repercussions. Most famously was the recent collapse of we work. There is in general quite a bit of leeway in the private markets to get creative about how you market your financial products. The public market is of course totally different, and that's also what I'm hinting at in my distinction.
I don't think it makes sense for a public entity to audit things that the public can't buy. Private financial institutions are (or at least should be) competent to audit their own investments. The general public are not competent to audit their own investments, and even if they were it would be extremely inefficient, so we should probably have some government entity for that.
WeWork is a strange case because it relied on creating a market for office space, or else taking market share away from other modes of using office space. You can't look at it on the surface and say it's a terrible business model. That means, any claim against them would need to be quantitative in nature. Also, this deception is forward-looking: you can only claim it was wrong after some time has passed. If they falsified their tenancy numbers (past observables) then that would be more damning.
>I don't think it makes sense for a public entity to audit things that the public can't buy. Private financial institutions are (or at least should be) competent to audit their own investments.
Private investors should audit their own investments, but auditing is not going to succeed when records and research are deliberately falsified. There is no way to put the blame on investors for having been fooled by deliberate deception.
>The general public are not competent to audit their own investments, and even if they were it would be extremely inefficient, so we should probably have some government entity for that.
The general public generally entrusts its investment funds to people who are supposed to do the due diligence required. This due diligence is undermined by deception. As for the government getting involved, I agree it might need to be involved if the public can directly buy something (although there are some negative outcomes that come with it, such as regulatory capture and suppression of new stuff). The need for oversight applies even more when public money is used to fund research.
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.
It has never felt reasonable to me that a small number of papers (highly cited or not) from 2006 could somehow be responsible for our failure to cure this disease over the past decades. It seems so emotionally tempting to give people a scapegoat that it frankly rings all my "too good to be true" alarm bells. And bluntly, it's just implausible.
Like it or not: if we're going to get a cure for this horrible disease, it's going to come out of the scientific community. My fear is that a bunch of non-experts are going to barge in with a weakly-understood idea about what is happening in the field, demand "reforms" with implications they don't understand, and in the process doom millions of people to agony and suffering.
Thank you.
https://www.bbc.com/storyworks/rewriting-cancer/the-exciting...
Ivermectin may or may not be effective against various cancers .. but it is a very safe molecule.
Look at the research independent of popular and institutional opinion.
If you can be part of a well run trial - of any kind, for any treatment - you give us all something of great value.
I can only hope things go well for you, and thank you for your courage.
This is sensationalist and one-sided.
Alzheimer's is the most common form of dementia, and it is not clearly understood. It is potentially the most common form because it is not understood and there are many, myself among them, who believe that multiple different diseases are being assigned a single title because we don't understand the disease enough.
This isn't to say the Amyloid hypothesis is correct, it may be correct in a number of cases, but the Type 3 Diabetes may also be correct.
The Amyloid Hypothesis has not been disproven. Yes, misrepresented data in a few studies have significantly put into question the reliability, however hundreds of other not "doctored" studies have shown the hypothesis holds significant promise.
The pharmaceutical companies did not make up the format of the disease in order to sell drugs, and the current drugs are not very effective, but that doesn't mean the theory is wrong. Just because amyloid build up is a marker of the disease does not mean that removing this metabolic waste would reverse the disease. That's like saying blowing your nose would cure the common cold.
In the case of AD, the suspicion is that the Amyloid/Tau build up damages the neurons ability to signal within the brain, like a blockage in a pipe that causes the pipe to break. Removing the blockage does not repair the pipe.
So why bother removing it at all?
A researcher we work with has posited a theory (which is fairly new, but I'm not sure she is the first) that amyloid build up reduces the power of delta slow waves, and the related glymphatic flushing of metabolic waste. This is why the drugs might be valuable (I'll say might be, rather than are), increasing the removal of waste slows further progression of the disease.
Having said that, there is a point in time where slowing progression is just lengthening time in poor health, and is not valuable, but prior to that, it can be valuable (I'll leave it up to individuals to decide what is right for them or their family members).
We've been developing slow-wave enhancement technology at Affectable Sleep [1] for the last 5 years, and similar tech has shown early promise in people with AD [2] as well as potential preventative in elderly people [3].
[1] https://affectablesleep.com
[2] https://pubmed.ncbi.nlm.nih.gov/39048400/
[3] https://academic.oup.com/ageing/article/52/12/afad228/750330...
[1] https://hn.algolia.com/?dateRange=all&page=0&prefix=false&qu...
How about SSRIs, for which much of the research does not provide supporting evidence? E.g. there's a 2022 meta-study by Moncrieff et al that shows there's no consistent evidence tying serotonin to depression. An earlier 2008 placebo-controlled study by Kirsch et al shows that SSRIs are barely any better than placebo.
IOW, SSRIs are useless horseshit for the vast majority of people (especially in the absence of e.g. CBT) and the theory behind them is not supported by evidence. Why are they still prescribed?
Some have found flaws with Kirsh's study and there is still an ongoing debate about effectiveness. [1] I am not a fan of prescribing so many people a drug that we don't know how it even works for what is often just a small improvement, but I don't think its accurate to say they are useless.
[1] https://academic.oup.com/ijnp/article/14/3/405/906146#156821...
I think they don't work because Depression, like Alzheimer's, is poorly defined.
From a population genetics perspective we can find clear genetic signals for other psychiatric disorders such as Schizophrenia, ADHD, etc. But Depression is notoriously difficult to identify any genetic signal for. Its my opinion that this is because Depression is more often a symptom of another psychiatric disorder and only rarely is the root cause just Depression itself.
Many folks with ADHD, Bipolar, or other "mild" disorders go undiagnosed and get the Depression label instead and this muddies the waters.
I think I read that amyloid may be a body immune reaction to infection which is why targeting that rather than the infection is ineffective. (not expert on this but the article is interesting).
It's easy to look at studies and say "this shit doesn't work" (despite there being plenty of studies that show they're clearly effective and they're one of the best treatments we have). But when you talk to people taking it, clearly there are way too many that benefit from them to just say we need to stop prescribing them. That's just deciding due to your own biases that countless people need to suffer unnecessarily. Why? Why would you want to do this to people? Or do you not actually care about the suffering or wellbeing of the people affected and you just have this vague idea of "SSRIs bad"?
I spent a lot of time reading studies before going on SSRIs to decide whether it was worth it. The literature unambiguously said that SSRIs are absolutely a valid form of treatment that can help (even though it won't help everybody). Who are you to say they're horseshit?