13 ms·

Faked Beta-Amyloid Data. What Does It Mean?

250 points by hprotagonist 4y ago

jvanderbot 4y ago
How did we rule out an underlying pathology that triggers toxic buildup of these substances, either as a byproduct or even as a defense mechanism (perhaps to isolate / destroy neurons that are infected). It would seem that if cognitive decline were caused by some neurological disease and the body were fighting that, it might cause all kinds of dangerous looking things to happen to neurons. And, if you do dangerous things to neurons, perhaps you also get cognitive decline.
- lazide 4y ago
  It hasn’t been ruled out, it just hasn’t been able to be identified either. Some research is ongoing related to viral infection from some common viral species for instance. The problem is that we have non-destructive and reliable way to image or sample the brain at the resolutions necessary to see what is going on right now. If you can’t see or sense what’s happening until it’s too late, it’s really hard to figure out what is going on. If doing post-Mortem brain biopsies (most common way) for Alzheimer’s patients and the plaques is the equivalent of picking through the wreckage of a lost war, it’s pretty hard to figure out who was the enemy and who was collateral damage.
  - mitjam 4y ago
    There are some but research into viral origins or other competing ideas seem to be marginalized and underfunded, I don‘t have first hand insights into it but read about it here https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/ https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte... and elsewhere.
  - throwawaymaths 4y ago
    > we have non-destructive I think you meant to say we don't have non-destructive?
    - lazide 4y ago
      Thank you, yes. I can’t edit my comment anymore. :(
- throwawaymaths 4y ago
  We didn't rule it out. I worked in an Alzheimer's lab about 15 years ago. In our outside voice for Grant committees, publications, etc. We acknowledged the amyloid hypothesis but internally almost every other group meeting the postdocs and grad students disclaimed that we still couldn't rule out "common factor X". It was also morbid humor we would say "oh maybe the amyloid hypothesis is wrong" whenever something strange would come up. We only about 10% joking. It's nice to see that skepticism has finally bubbled up across the field. I like to think we were one of the more honest groups in the field -- I have post-publication corrections on my papers, the lab issued an 11-page retraction (with cautions about what not to do experimentally) when it turned out one of our lab's major findings was an artifact [0]. It's worth noting WHY the amyloid hypothesis sticks around, it's because the prion hypothesis is extremely well supported by the data (even though I think pruisner is a shady dude), so it's not a stretch to think that other amyloid diseases work in a similar way [1]. [0] the grad student who pushed through this paper is a huge scientific hero. [1] there are some subtleties though.
  - throwawaymaths 4y ago
    I guess I should post a positive example of what the field (should be/should have been) doing: https://onlinelibrary.wiley.com/doi/full/10.1002/pro.2339 https://onlinelibrary.wiley.com/doi/full/10.1002/pro.2339 Ms. Murray (aforementioned hero) is doing a startup these days so if you are or know any VCs that talk a good game about funding science then see if they'll throw some money her way.
- zosima 4y ago
  It hasn't been ruled out, but as Derek Lowe mentions, there is a good amount of genetic evidence that increased cleaving of APP and thus more amyloid-beta leads to earlier, faster and more severe Alzheimer's. And certain mutations in the amyloid-beta producing APP-cleavage machinery leads to familial dominant Alzheimer's, where the carriers will almost certainly develop early Alzheimer's. So there is not many ways around APP/amyloid-beta having some role in Alzheimer's pathology.
- atombender 4y ago
  Definitely hasn't been ruled out. Researchers have hypothesized that the amyloid plaques are a protective mechanism; unfortunately, we still don't know why they form. One hot area of research is currently focused on herpesviruses such as HSV1. Here [1] is a paper summarizing some of that research. The thing about viruses is that they are weird things with unexpected behaviours. For example, we are still learning about Epstein-Barr (EBV, which is another type of herpesvirus); only this year did researchers come to suspect that EBV could be responsible for MS. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234998/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234998/
lazide 4y ago
Good write up on a very disturbing case of blatant academic fraud. Some of the methods mentioned that were used to discover it are pretty simple - prior compression artifacts showing borders around sub areas of a large graph, indicating cutting and pasting of elements, etc. What I don’t get, is why the underlying data doesn’t get included and any graphs just generated from that? Why have an actual embedded image and that’s all good?
- sooheon 4y ago
  Western blots are analog -- the captured image is the underlying data.
  - gspr 4y ago
    Could one imagine imagining equipment cryptographically signing the images they spit out? (Sorry if this is a super naive HN-esque comment – the topic is far outside my field, and I don't mean to actually suggest this as a solution, I'm just curious.)
    - _Wintermute 4y ago
      That's definitely possible. These sort of images are typically re-arranged to fit nicely in a figure for publication. It's now more common that any figure that has a western blot within it, you also have to provide the raw unaltered image. Though this wasn't standard practice at the time. As someone in the field, western blots are terrible for a number of reasons. Even if you get nice bands and you're honest about what you show. The companies that make the antibodies for these commonly sell people duds that will bind to a number of unknown things, and people blindly trust that since the website said it's specific for protein-XYZ, that's what they're measuring.
- searine 4y ago
  This type of data is 'old school' molecular biology. Creating those blots is a grind. It takes hundreds of hours to set up those experiments and they often don't work, or go wrong, and you have to do it all over again. The people who are good at making these are usually the people who aren't really up to date with the whole 'computers' thing. Yes, there would a hundred ways to easily verify the provenance of data from an image of a blot all the way to publication. However, this area of research is very slow to incorporate the latest computer tech.
chaosfox 4y ago
the silver lining, I hope, is that this will highlight how important independent verification and reproduction of results is in academia, people "know" that but funding for it is still scarce as its always more exciting to try to find something new than to validate a known result.
- mhh__ 4y ago
  Independent verification is why scientific fraud is so dangerous. On the one hand you'll eventually get caught, but only after potentially millions has been spent on said catching.
- debacle 4y ago
  No one at any point in the funding cycle benefits from asking questions. In fact, for most of the people in a position to ask the kinds of questions that need to be asked, they risk their entire career when they do so. The entire industry has issues.
- LatteLazy 4y ago
  Isn't that exactly what has NOT happened here? Some combination of: * People not checking * People checking and joining the fraud * People checking, not joining the fraud and then getting their work suppressed.
- Obi_Juan_Kenobi 4y ago
  Replication is far from trivial. It's still worth pursuing, but it's easy to overlook how challenging it can be to successfully execute scientific procedures. Labs generally specialize, as there's a long learning curve to climb before you can reliably execute even 'bedrock' molecular biology protocols like immunoassays. Small ambiguities in protocol can lead to failure, and there's always simple human error involved that can tank a result. Generally you'll have positive controls available to tell you whether a protocol was successfully executed, but there are cases where that's simply not practical. In the end, 'failure to replicate' does not necessarily mean there was anything wrong with the original work. Positively concluding that requires a lot of additional work that could explain the discrepancy.
lettergram 4y ago
To quote someone I know in Alzheimer research - “I’m pretty sure it’s all fake” It’s funny because more than once I’ve had conversations off-the-record with people who had the same concerns. What I think is most troubling is how long it took and how many papers support the claims. In other words, there are thousands of papers supporting beta-amyloid and/or building off the data / theory. All of that data and everyone conducting that data should be in question. Yes, sometimes you’ll see correlations even though the mechanism is not what you’d expect. That said, for 16 years? Lol No, in reality, this should indicate there is systemic fraud in the industry. I don’t think everyone’s a fraud, it’s as much about what doesn’t get published as what does get published. How does this happen? I commented on incentives prior here: https://news.ycombinator.com/reply?id=32213123 https://news.ycombinator.com/reply?id=32213123 I personally don’t see how we can advance science with the current credentialing and paper citation == academic success we’ve seen grow the last 50 years. In many ways, fundamental research has stalled, with applications of research advancing (giving us the illusion of advancing the fundamentals). To fix this problem, an overhaul is needed. Most importantly, the gate keeping mechanisms should be removed.
- kurupt213 4y ago
  What’s one of the first things they teach when dealing with statistical analysis? Correlation is not causation
- beanjuice 4y ago
  What do you mean by "the gate keeping mechanisms" should be removed? Do you mean the difficulty of publishing? Or tenure? Or degrees?
  - voakbasda 4y ago
    All of those gate keeping mechanisms have systemic issues and need to be reformed at the very least. "Removed" might be a bit strong, but I definitely see how one could reach that perspective. Regardless, they certainly have lost the credibility to claim any monopolistic authority over the domains they purport to serve.
beanjuice 4y ago
Pubpeer is an incredible project [0], and unless I am mistaken, you could say that this finding may not have occurred without it. For those that do not know, it is a website (with browser extension) which allows a comment section for academic publication, with anonymous comment, for posting critique and questions about papers. I suggest all of my peers to install the extension, as a pre-warning system for poor quality papers. This paper in question can be found here [1], and it is a good example of what simple image processing techniques can be used to verify, or question claims. It is unfortunate that while things like NMR, XRD, SEM/TEM images, and Western blots are commonly faked, and found out- not all science is based off of verifiable data at the reader's end. [0] https://pubpeer.com/static/about https://pubpeer.com/static/about [1] https://pubpeer.com/publications/8FF7E6996524B73ACB4A9EF5C0AACF https://pubpeer.com/publications/8FF7E6996524B73ACB4A9EF5C0A...
stuckinhell 4y ago
Interesting article. From an non-researchers perspective, I find a couple points extremely disturbing. - The failure to notice and act on the faked data in the Lesné papers is still a disgrace, and there’s plenty of blame to go around among other researchers in the field as well as reviewers and journal editorial staffs. - Every single Alzheimer’s trial has failed. I strongly suspect there is more fraud, just because of human nature. It looks multiple checkpoints are failing. We also have the replication crisis going on. It's pretty clear at this point incentives are misaligned at every level of the research pipeline. It's a bad time for this highly public research failure. The general public's faith in experts is dropping, and maybe for good reason. As the economy, and quality of life deteriorates, I think we will see the public demand "results" from experts.
- matthewdgreen 4y ago
  It's also possible that Alzheimer's is an incredibly challenging disease and the tools we have to deal with it are suboptimal. People have a hard time distinguishing failure from malice, unfortunately. It's understandable to want someone to blame.
  - AbrahamParangi 4y ago
    One way for something to be extremely challenging is for it to be impossible
  - stuckinhell 4y ago
    I agree. However I also think, we are seeing evidence of malice, greed, and maybe desperation in these acts of scientific fraud. Experts need to quickly define what malice in their respective fields means. Then most importantly they need to act on it and restore integrity, discipline, and show results. Otherwise the general public will define it and act on it themselves.
  - naasking 4y ago
    It is a hard disease to study for sure. The hardest part of it is that there's no effective test for it, you just have to check for a somewhat vague constellation of symptoms over a person's entire lifespan. I think a big part of the obsession with the amyloid plaques hypothesis is that it was the only issue that was consistent among patients that they could actually test for, so rather than continuing the harder work of searching in the dark for something better, researchers latched onto exploring how and why that was associated with Alzheimer's. And it makes sense in a way, there's obviously something going on and figuring out why the plaques are produced should provide some mechanistic insight into what's going on. And that's true, in the same way that capturing all of the EM emissions from a laptop will provide some insight into what's going on inside the laptop, but that information will likely only be useful if you already have a good mechanistic model of a laptop's inner workings (people have successfully read data across an air gap this way). I suspect that's what will happen with amyloid plaques as well, ie. plaques will only make sense retrospectively.
tomelders 4y ago
> He was originally hired by two other neuroscientists who also sell biopharma stocks short I'm blown away by this investment strategy. What a brilliant way to monetise exposing fraud. Get your proof, short the stock, publish your proof, profit!
- meepmorp 4y ago
  Doing well by doing good
- pjbk 4y ago
  Unfortunately it's more common than you think... I remember this case in particular from some years ago: https://www.legalreader.com/st-jude-medical-files-lawsuit-against-medsec-and-muddy-waters/ https://www.legalreader.com/st-jude-medical-files-lawsuit-ag...
  - JumpCrisscross 4y ago
    > Unfortunately it's more common Why is calling out fraud unfortunate? With respect to St. Jude, Muddy Waters was at least partially right [1]. [1] https://www.hipaajournal.com/fda-confirms-muddy-waters-claims-st-jude-medical-devices-can-hacked-8642/ https://www.hipaajournal.com/fda-confirms-muddy-waters-claim...
    - DiggyJohnson 4y ago
      Presumably GP is not saying that the calling out of fraud is unfortunate, but that the fraud itself is unfortunate.
      - pjbk 4y ago
        Precisely, sorry if it was not clear enough. Pointing vulnerabilities and betting on the side to effectively become a stakeholder raises some concerns on your true intentions, even if it could be legal to do so.
- 323 4y ago
Imnimo 4y ago
People want to point the finger at structural problems with academia to explain why this wasn't caught earlier. But what about industry? Didn't they have a huge incentive to catch this sort of thing before they spend boatloads of money on clinical trials, and didn't they have some level of immunity to concerns about tenure committees and journal editors? If this was so easy to catch if it weren't for the troubling incentives of academia, why did drug companies still spend billions on it?
- xiande04 4y ago
  > why did drug companies still spend billions on it? Because they made even more off it.
  - throwawaymaths 4y ago
    No, they lost money on it. Clinical trials aren't cheap.
  - deleted 4y ago
    [deleted]
  - PeterisP 4y ago
    How? They aren't getting revenue until they can sell a drug that has passed clinical trials, and no clinical trials have been successful for Alzheimer's.
    - t90z 4y ago
  - jcranmer 4y ago
    Only one drug has been even provisionally approved--Aduhelm--and that approval is so mired in controversy that everyone is refusing to pay for it, so I doubt its company has made even a million dollars in revenue off of it. No, Alzheimer's has been a multibillion dollar sinkhole for drug development cash with absolutely nothing to show for it.
endominus 4y ago
Worth rereading; "Time to assume that health research is fraudulent until proven otherwise?" from no less a source than the British Medical Journal [0]. Another example; 5-HTTPLPR studies [1] in psychiatric research (over 450, "proving" the effects of the gene on basically every psychological malady) stretching all the way back to 1996. [0]: https://blogs.bmj.com/bmj/2021/07/05/time-to-assume-that-health-research-is-fraudulent-until-proved-otherwise/ https://blogs.bmj.com/bmj/2021/07/05/time-to-assume-that-hea... [1]: https://slatestarcodex.com/2019/05/07/5-httlpr-a-pointed-review/ https://slatestarcodex.com/2019/05/07/5-httlpr-a-pointed-rev...
- gilrain 4y ago
  Unfortunately, this has become a rational precaution. Capitalism has thoroughly undermined humanity’s greatest tool.
  - MattPalmer1086 4y ago
    Well, the problem is one of misaligned incentives rather than capitalism per se. From the BMJ article: "Researchers progress by publishing research, and because the publication system is built on trust and peer review is not designed to detect fraud it is easy to publish fraudulent research. The business model of journals and publishers depends on publishing, preferably lots of studies as cheaply as possible. They have little incentive to check for fraud and a positive disincentive to experience reputational damage—and possibly legal risk—from retracting studies. Funders, universities, and other research institutions similarly have incentives to fund and publish studies and disincentives to make a fuss about fraudulent research they may have funded or had undertaken in their institution—perhaps by one of their star researchers." Capitalism is certainly the economic context we operate in, but I'd hardly say it is the root cause of most of the above, which could apply equally in other economic funding models.
Flankk 4y ago
Where is the "trust science" crowd when stuff like this goes down. It's strangely quiet in here. Shouldn't they be here telling us how this is a mistake because the editorial and peer review process prevents this? Something about how science brought us all of technology? Oh, that was actually capitalism? Oh great science, where great minds get paid by industry to submit their doctored conclusions to a journal, attached with a small bribe.
- cm42 4y ago
  We'll have to wait until someone breaks it down into a rhyming Harry Potter reference or something.
- Jaygles 4y ago
  I've never understood "trust science" as "blindly trust scientists". I've always understood it as "trust the scientific process", which is sensible in my opinion, as the process is designed to determine truths. When people falsify results, what they are doing isn't really a product of the scientific process, they are just committing fraud.
  - Flankk 4y ago
    So they're still here, and they're brain dead.
  - scarmig 4y ago
    Particularly for heavily politicized topics, "trust the science" usually means something like "trust that the people that the media has designated as scientific authorities always follow the scientific process, understand statistics, and are objective searchers for truth; moreover, don't try to substitute your expertise for theirs." The scientific community can't simply no-true-scotsman every claim pushed with the banner of Science that turns out to be false or fraud if it wants the true claims to be considered seriously.
- betenoire 4y ago
  Seriously? Science is a process, not a result, and science is literally revealing the fraud here.
hindsightbias 4y ago
That the cycle of science works slowly. Slower than to be applicable in your lifespan.
VikingCoder 4y ago
So the University of Minnesota faked Alzheimer's research and injected Linux kernel bugs on purpose? [1] Not feeling so proud as an alumni today. [1]: https://news.ycombinator.com/item?id=26887670 https://news.ycombinator.com/item?id=26887670
- deleted 4y ago
  [deleted]
criddell 4y ago
Is there a new leading theory?
renewiltord 4y ago
Amusing. Second-hand experience[0] with "exciting science areas" led me to this belief already. It's one of those interesting things. For folks outside of science, they think most of this stuff is backed. You can see it in the fact that people will quote "there is evidence that X is Y" using some random study, commonly on HN. There's a common reaction to this sort of thing where people act like it is some betrayal of a sacred pact, etc. etc. but there is so much fake science out there that it is really hard to believe that there is actually some betrayal and it's not just the reality of the field. And always there'll be some guy who comes up with a "I've never heard of this and neither has any of the ten guys I talked to about it". Just do the math. At a 10% fake rate (which I would consider extraordinary) there's a 1 in 3 chance that you wouldn't detect it with just independent observations of you and 10 friends (and that's assuming you and your friends are independent here, which is very generous). At a 5% fake rate (which is still horrible), there's a 1 in 10 chance that even you and 40 of your friends would not detect it. The thing with not-so-rare things is that you can fail to detect it through sheer chance. 0: https://news.ycombinator.com/item?id=25926188 https://news.ycombinator.com/item?id=25926188 P.S. hn.algolia.com is excellent. I managed to find this comment in a couple of seconds on it.
- bhk 4y ago
  The "I've never heard of this ..." comment can also be explained by the possibility that the person making the comment is one of the fraudsters. This adds 10% to the 1/3 chance in your example. So no matter how high the rate of fraud is, we would expect to hear comments like this.
  - renewiltord 4y ago
    I did not think about that, but you are right (with appropriate maths modifications)
rbanffy 4y ago
In this age of politically-motivated scientific disinformation, the one thing we don't need is fraudulent science. We need to be able to trust which drugs and vaccines work, anc which don't. We need to be able to trust the predictions about global warning and the societal impact of it so we can chart the optimum path with as little disruption and suffering as we can. In short, we cannot afford not to be rational, not to ground our decisions in hard facts and solid models. Scientists like Lesné should be detected much earlier in their careers.
- arbitrage 4y ago
  The situation in Academia is similar to child abuse in the Churches. These people often are detected early, and get shuffled around. A lot of people know about this problem, have for a long time. A lot of people continue to do nothing about it.
pvg 4y ago
Recent big threads yesterday and a few days ago with 250+ comments each: https://news.ycombinator.com/item?id=32212719 https://news.ycombinator.com/item?id=32212719 https://news.ycombinator.com/item?id=32183302 https://news.ycombinator.com/item?id=32183302 And a danglist with more https://news.ycombinator.com/item?id=32213973 https://news.ycombinator.com/item?id=32213973
- hprotagonist 4y ago
  Not a dupe, per se. Derek Lowe's summaries of current events are themselves valuable and aren't just "hey look, [this thing]!".
  - pvg 4y ago
    HN dupes are mostly by value rather than by reference and there's also a kind of topic repetition limit even when the there's more commentary on the topic.
  - dang 4y ago
    That's a good point. I call this sort of post either a follow-up or a quasidupe, depending on how dupey (?) it is. The problem is that the HN discussions on a topic cluster tend to be much the same, even if the article itself isn't. But I've taken the [dupe] stigma off this one now.
- dang 4y ago
  Might as well keep it updated I suppose. Two decades of Alzheimer’s research was based on deliberate fraud - https://news.ycombinator.com/item?id=32212719 https://news.ycombinator.com/item?id=32212719 - July 2022 (295 comments) Potential fabrication in research threatens the amyloid theory of Alzheimer’s - https://news.ycombinator.com/item?id=32183302 https://news.ycombinator.com/item?id=32183302 - July 2022 (236 comments) Alzheimer’s amyloid hypothesis ‘cabal’ thwarted progress toward a cure (2019) - https://news.ycombinator.com/item?id=31828509 https://news.ycombinator.com/item?id=31828509 - June 2022 (307 comments) How an Alzheimer’s ‘cabal’ thwarted progress toward a cure - https://news.ycombinator.com/item?id=21911225 https://news.ycombinator.com/item?id=21911225 - Dec 2019 (382 comments) The amyloid hypothesis on trial - https://news.ycombinator.com/item?id=17618027 https://news.ycombinator.com/item?id=17618027 - July 2018 (43 comments) Is the Alzheimer's “Amyloid Hypothesis” Wrong? (2017) - https://news.ycombinator.com/item?id=17444214 https://news.ycombinator.com/item?id=17444214 - July 2018 (109 comments)
sudden_dystopia 4y ago
This sounds just like cholesterol to me. Yes, beta amyloids are correlated with Alzheimer’s and cholesterol is correlated to cardiac issues. But correlation is not causation. Why is their seemingly no mainstream discussion that perhaps these correlations are simply the markers of an underlying biological function that has become disregulated and leads to the presence of higher amyloid/cholesterol/etc? When we try to treat cancer, do we focus on the symptoms, or do we try to obliterate the cancer? As far as I can tell, we aren’t looking for the “cancer”, we are trying to treat symptoms.
- _Wintermute 4y ago
  > Why is their seemingly no mainstream discussion that perhaps these correlations are simply the markers of an underlying biological function that has become disregulated and leads to the presence of higher amyloid That's a discussion point pretty much every time the amyloid hypothesis is mentioned in the scientific literature. I'm not sure where you're going to get information about the pathophysiology of Alzheimer's disease, but it doesn't really strike me as a "mainstream" topic where they're going to discuss the finer details or debates.
  - throwawaymaths 4y ago
    > That's a discussion point pretty much every time the amyloid hypothesis is mentioned in the scientific literature I don't feel like that's true. Back when I was a grad student doing this research it was striking to me how little that was in the literature considering how much we said it internally.
holyknight 4y ago
I think the main issue is that papers and studies with negative results are almost never published. There should be some procedure in place that ensures that papers will always be published no matter what is the result. This decision shouldn't be in the hands of the researchers and even less so on the investors. Direct investor oversight over the research is very concerning. With the current method we can only blindly trust that scientist will be willing to sacrifice their career to publish a research that could potentially bury their investor. This makes absolutely no sense and will almost always end in conflict of interest. I don't know the answer, but the current status quo is deeply flawed and needs to change quickly.
deleted 4y ago
[deleted]
A4ET8a8uTh0 4y ago
From the article: << Now Cassava is a story of their own, and I have frankly been steering clear of it, despite some requests. To me, it’s an excellent example of a biotech stock with a passionate (and often flat-out irrational) fan club. I wonder if this is part of the issue. It is now something of a social club, where allegiance is to the clan. I initially wondered if it is the function of the internet, but the I remembered that various cliques existed way before that. Internet just put a spotlight on it. The only real question is whether the current club can be reformed.
temporalparts 4y ago
Ask HN: What do you think about a law that criminalizes faking and doctoring data for their research? Clearly we need greater punitive consequences for these types of behavior that's becoming an epidemic in research.
- arbitrage 4y ago
  Effectively, it's the same reason why the death penalty does not deter crime from happening. The threat of career-ending shame & humiliation is remote and unlikely. As another poster said much further up-thread, there is more fraud going on that doesn't get detected. Criminal penalties in this realm are a bit draconian. More punishment & punity is not the answer.
- UweSchmidt 4y ago
  That makes it even harder to call out bad science. You hate how your colleague cut corners but do you want to testify against them in court in your free time and have them sent to jail? I'd go the opposite way and give job security to anyone who is doing solid science to remove some of the weird incentives. There is upside to be amazing and win prizes or get better positions, but there is also space for people to "just" reproduce, or generally do important but non-glamorous stuff.
CommanderData 4y ago
Wasn't HSV also implicated in Alzheimer's. Seeing most of the world is infected with cold sores I wonder if we should question this research too?
jtdev 4y ago
pcrh 4y ago
Here is a lengthy response from more than 20 researchers in the field [0]. In brief, the claims made in the article above are exaggerated. As someone who works in the field, and who is skeptical of the amyloid hypothesis, I agree. [0] https://www.alzforum.org/news/community-news/sylvain-lesne-who-found-av56-accused-image-manipulation https://www.alzforum.org/news/community-news/sylvain-lesne-w...
- jeremyjh 4y ago
  It’s so shocking that they don’t want their field to be discredited.
  - pcrh 4y ago
    Not really. There is plenty of criticism of the amyloid hypothesis within the field, and even specifically of the oligomer variant thereof that Schrag focused on. You can even read that criticism in the link I provided. Schrag's investigation did not (in my opinion) discover any fraud in the Lesné paper, even if the paper perhaps over-states its case. The amyloid hypothesis has several very strong strands of evidence in its favor, specifically that it is (currently) the only way to reconcile the indisputable genetic and pathological evidence for mutations in the genes APP and presenilin both producing early-onset Alzheimer's disease. Amyloid is derived from the action of presenilin on APP. Until an alternate way of reconciling this observation is found, the amyloid hypothesis will always have supporters.
- gausswho 4y ago
  Having read it, I don't recognize anything that suggests the Science article is an exaggeration. Perhaps there's something in the comments you're referring to, but if so can you be more specific?
  - pcrh 4y ago
    Scientists are often very circumspect in how they phrase things, but this particular phrasing in the main article is notable: >“This is not a real scientific problem, but it is most unfortunate for general science credibility,” Selkoe wrote to Alzforum. Edit: I should add that the "oligomers" described in the Lesne article have been found by other researchers, see [0] [0] https://scholar.google.co.uk/scholar?hl=en&as_sdt=0%2C5&q=Aβ*56&btnG= https://scholar.google.co.uk/scholar?hl=en&as_sdt=0%2C5&q=Aβ...
brighamyoung 4y ago
It probably means that the Bredesen protocol is the cure for Alzheimers. He has a literally proven track record of success with hundreds of patients.
jmyeet 4y ago
I'm not in academia but here's what I don't understand. Generlaly, my understanding was that important results typically get replicated by other institutions and teams. Not necessarily to prove that initial result but to work out the limits of whatever the conclusion was. Imagine you discovered that ibuprofen could reduce the risk of stroke by 30%, for example. You would have other teams that might start playing with the factors and asking different questions like: - What if we raise or lower the dosage? - Waht if we mix that with other medications? In doing so you'd get further confirmation of the original result. You'd think there'd be some similar studies done of the original result but that doesn't seem to have been the case or this fraud would've been discovered already. So for anyone who does know about how this works, why didn't this happen?
- photochemsyn 4y ago
  One neglected issue here is the role of government funding agencies and universities in controlling who gets funded. It's common practice for universities to encourage their own researchers to get government positions at funding agencies, where they can help shepherd grants back to their parent institutions, for example. Something like this seems to have gone on with Alzheimer's funding - some people involved with the source lab ended up directing funding at the federal level. So, if you're a researcher who decides to publish refutation of a fundamental claim by the leading stars in the field, you risk getting on a funding blacklist, and your grant review doesn't get approved. Hence, the safer thing to do is simply ignore the research you suspect to be fraudulent and take your own research in a different direction. There's also the concept that they don't want to discredit the entire field by exposing fraud and thereby risk Congress spiking the funding entirely or something like that. Incidentally, a lot of the silence on the very plausible notion that Sars-CoV2 escaped from a lab, and that its transmissibiliy and virulence likely were increased in the lab as a consequence of various gain-of-function (well-meaning I suppose) research techniques (serial passage, CRISPR engineering, etc.), appears to be due to similar concerns (i.e. researcher who even discuss the possiblity might run afoul of people like Fauci and cohort who still control virology research funding).
- jcranmer 4y ago
  > You'd think there'd be some similar studies done of the original result but that doesn't seem to have been the case or this fraud would've been discovered already. As Derek Lowe says, this did happen: > I could be wrong about this, but from this vantage point the original Lesné paper and its numerous follow-ups have largely just given people in the field something to point at when asked about the evidence for amyloid oligomers directly affecting memory. I’m not sure how many groups tried to replicate the findings, although (as just mentioned) when people did it looks like they indeed couldn’t find the 56 oligomer. And judging from the number of faked Westerns, that’s probably because it doesn’t exist in the first place. But my impression is that a lot of labs that were interested in the general idea of beta-amyloid oligomers just took the earlier papers as validation for that interest, and kept on doing their own research into the area without really jumping directly onto the 56 story itself. The bewildering nature of the amyloid-oligomer situation in live cells has given everyone plenty of opportunities for that! The expressions in the literature about the failure to find *56 (as in the Selkoe lab’s papers) did not de-validate the general idea for anyone - indeed, Selkoe’s lab has been working on amyloid oligomers the whole time and continues to do so. Just not Lesné’s oligomer. In other words, the result was tried to be replicated a few times, and no one could replicate it. But the groups working in this space were already pursuing similar paths before this paper, and the results were taken not as a "target this one specific thing and you'll be golden" but rather "here's more evidence that targeting this class of thing is useful in this place." I'll also point out that by the time you're talking dosage questions, you're generally tackling clinical trials (phase II trials are meant to establish the dosing regime), which is far downstream of work that gets published academically.
scaredginger 4y ago
When you have problems like this, they must be viewed from a systemic perspective. The truth is that our modern institutions of science are fraught with perverse incentives; people battling for funding, feeling pressure to publish and going to war over a few scarce tenured positions. I don't know how we solve this, but I think reforming academia with some well-placed regulation and an increase in publicly funded research would be a place to start.
ta8645 4y ago
Just another reminder that scientific consensus should not be blindly accepted with religious fervour.
tomohawk 4y ago
This is why censoring people on social media platforms when they disagree with "the experts" is so dangerous. Science is not about listening to experts. It's about the data, and about falsifiable theories.
UIUC_06 4y ago
Re solutions: now do Project Veritas. If you're a whistleblower and you're not getting shunned by "respectable" people, you're probably doing something wrong.
peter303 4y ago
Two reasons why this hypothesis may not be true: 1) Universal failure of plaque-reduction drug trials. 2) Numerous post-mortem counter-examples: dementia w/o plaques and plaques without dementia.
joe_the_user 4y ago
"First off, I’ve noticed a lot of takes along the lines of “OMG, because of this fraud we’ve been wasting our time on Alzheimer’s research since 2006”. That’s not really the case, as I’ll explain..." I'm not seeing the explanation. The Amyloid hypothesis was weakening in 2006 and a series of apparently ground-breaking but actually fake results gave new life over a significant period of time. Yes the author says: "the main inaccuracy in that statement is that we’ve been actually been wasting our time in Alzheimer’s research for even longer than that." but the problem is testing a false hypothesis and discarding isn't a waste of time, it's how science should work. Fraud and forgone failures, of course, are how science shouldn't work. And yes, there's lot of fraud around but I don't see how this isn't especially damaging.
- nl 4y ago
  > I'm not seeing the explanation. It's in there: > But my impression is that a lot of labs that were interested in the general idea of beta-amyloid oligomers just took the earlier papers as validation for that interest, and kept on doing their own research into the area without really jumping directly onto the 56 story itself. The bewildering nature of the amyloid-oligomer situation in live cells has given everyone plenty of opportunities for that! The expressions in the literature about the failure to find 56 (as in the Selkoe lab’s papers) did not de-validate the general idea for anyone - indeed, Selkoe’s lab has been working on amyloid oligomers the whole time and continues to do so. So labs wanted to work on this for their own reasons, not because of this result. > Did the 56 Work Lead to Clinical Trials? > That’s a question that many have been asking since this scandal broke a few days ago. And the answer is that no, I have been unable to find a clinical trial that specifically targeted the AB56 oligomer itself So there weren't even any wasted clinical trials. Basically his point is that maybe this drew some extra researchers into that area, but it was a worthwhile area anyway. The fact that nothing worked isn't particularly relevant because nothing has worked for Alzheimer's anyway.
  - mkl 4y ago
    You can escape the *s with \ (i.e. \*56) to fix the formatting of *56.

250 points by hprotagonist 4y ago

How did we rule out an underlying pathology that triggers toxic buildup of these substances, either as a byproduct or even as a defense mechanism (perhaps to isolate / destroy neurons that are infected). It would seem that if cognitive decline were caused by some neurological disease and the body were fighting that, it might cause all kinds of dangerous looking things to happen to neurons. And, if you do dangerous things to neurons, perhaps you also get cognitive decline.

lazide 4y ago
It hasn’t been ruled out, it just hasn’t been able to be identified either. Some research is ongoing related to viral infection from some common viral species for instance. The problem is that we have non-destructive and reliable way to image or sample the brain at the resolutions necessary to see what is going on right now. If you can’t see or sense what’s happening until it’s too late, it’s really hard to figure out what is going on. If doing post-Mortem brain biopsies (most common way) for Alzheimer’s patients and the plaques is the equivalent of picking through the wreckage of a lost war, it’s pretty hard to figure out who was the enemy and who was collateral damage.
- mitjam 4y ago
  There are some but research into viral origins or other competing ideas seem to be marginalized and underfunded, I don‘t have first hand insights into it but read about it here https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarted-progress-toward-cure/ https://www.statnews.com/2019/06/25/alzheimers-cabal-thwarte... and elsewhere.
- throwawaymaths 4y ago
  > we have non-destructive I think you meant to say we don't have non-destructive?
  - lazide 4y ago
    Thank you, yes. I can’t edit my comment anymore. :(
throwawaymaths 4y ago
We didn't rule it out. I worked in an Alzheimer's lab about 15 years ago. In our outside voice for Grant committees, publications, etc. We acknowledged the amyloid hypothesis but internally almost every other group meeting the postdocs and grad students disclaimed that we still couldn't rule out "common factor X". It was also morbid humor we would say "oh maybe the amyloid hypothesis is wrong" whenever something strange would come up. We only about 10% joking. It's nice to see that skepticism has finally bubbled up across the field. I like to think we were one of the more honest groups in the field -- I have post-publication corrections on my papers, the lab issued an 11-page retraction (with cautions about what not to do experimentally) when it turned out one of our lab's major findings was an artifact [0]. It's worth noting WHY the amyloid hypothesis sticks around, it's because the prion hypothesis is extremely well supported by the data (even though I think pruisner is a shady dude), so it's not a stretch to think that other amyloid diseases work in a similar way [1]. [0] the grad student who pushed through this paper is a huge scientific hero. [1] there are some subtleties though.
- throwawaymaths 4y ago
  I guess I should post a positive example of what the field (should be/should have been) doing: https://onlinelibrary.wiley.com/doi/full/10.1002/pro.2339 https://onlinelibrary.wiley.com/doi/full/10.1002/pro.2339 Ms. Murray (aforementioned hero) is doing a startup these days so if you are or know any VCs that talk a good game about funding science then see if they'll throw some money her way.
zosima 4y ago
It hasn't been ruled out, but as Derek Lowe mentions, there is a good amount of genetic evidence that increased cleaving of APP and thus more amyloid-beta leads to earlier, faster and more severe Alzheimer's. And certain mutations in the amyloid-beta producing APP-cleavage machinery leads to familial dominant Alzheimer's, where the carriers will almost certainly develop early Alzheimer's. So there is not many ways around APP/amyloid-beta having some role in Alzheimer's pathology.
atombender 4y ago
Definitely hasn't been ruled out. Researchers have hypothesized that the amyloid plaques are a protective mechanism; unfortunately, we still don't know why they form. One hot area of research is currently focused on herpesviruses such as HSV1. Here [1] is a paper summarizing some of that research. The thing about viruses is that they are weird things with unexpected behaviours. For example, we are still learning about Epstein-Barr (EBV, which is another type of herpesvirus); only this year did researchers come to suspect that EBV could be responsible for MS. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234998/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234998/

lazide 4y ago

Good write up on a very disturbing case of blatant academic fraud. Some of the methods mentioned that were used to discover it are pretty simple - prior compression artifacts showing borders around sub areas of a large graph, indicating cutting and pasting of elements, etc. What I don’t get, is why the underlying data doesn’t get included and any graphs just generated from that? Why have an actual embedded image and that’s all good?

sooheon 4y ago
Western blots are analog -- the captured image is the underlying data.
- gspr 4y ago
  Could one imagine imagining equipment cryptographically signing the images they spit out? (Sorry if this is a super naive HN-esque comment – the topic is far outside my field, and I don't mean to actually suggest this as a solution, I'm just curious.)
  - _Wintermute 4y ago
    That's definitely possible. These sort of images are typically re-arranged to fit nicely in a figure for publication. It's now more common that any figure that has a western blot within it, you also have to provide the raw unaltered image. Though this wasn't standard practice at the time. As someone in the field, western blots are terrible for a number of reasons. Even if you get nice bands and you're honest about what you show. The companies that make the antibodies for these commonly sell people duds that will bind to a number of unknown things, and people blindly trust that since the website said it's specific for protein-XYZ, that's what they're measuring.
searine 4y ago
This type of data is 'old school' molecular biology. Creating those blots is a grind. It takes hundreds of hours to set up those experiments and they often don't work, or go wrong, and you have to do it all over again. The people who are good at making these are usually the people who aren't really up to date with the whole 'computers' thing. Yes, there would a hundred ways to easily verify the provenance of data from an image of a blot all the way to publication. However, this area of research is very slow to incorporate the latest computer tech.

chaosfox 4y ago

the silver lining, I hope, is that this will highlight how important independent verification and reproduction of results is in academia, people "know" that but funding for it is still scarce as its always more exciting to try to find something new than to validate a known result.

mhh__ 4y ago
Independent verification is why scientific fraud is so dangerous. On the one hand you'll eventually get caught, but only after potentially millions has been spent on said catching.
debacle 4y ago
No one at any point in the funding cycle benefits from asking questions. In fact, for most of the people in a position to ask the kinds of questions that need to be asked, they risk their entire career when they do so. The entire industry has issues.
LatteLazy 4y ago
Isn't that exactly what has NOT happened here? Some combination of: * People not checking * People checking and joining the fraud * People checking, not joining the fraud and then getting their work suppressed.
Obi_Juan_Kenobi 4y ago
Replication is far from trivial. It's still worth pursuing, but it's easy to overlook how challenging it can be to successfully execute scientific procedures. Labs generally specialize, as there's a long learning curve to climb before you can reliably execute even 'bedrock' molecular biology protocols like immunoassays. Small ambiguities in protocol can lead to failure, and there's always simple human error involved that can tank a result. Generally you'll have positive controls available to tell you whether a protocol was successfully executed, but there are cases where that's simply not practical. In the end, 'failure to replicate' does not necessarily mean there was anything wrong with the original work. Positively concluding that requires a lot of additional work that could explain the discrepancy.

lettergram 4y ago

To quote someone I know in Alzheimer research - “I’m pretty sure it’s all fake” It’s funny because more than once I’ve had conversations off-the-record with people who had the same concerns. What I think is most troubling is how long it took and how many papers support the claims. In other words, there are thousands of papers supporting beta-amyloid and/or building off the data / theory. All of that data and everyone conducting that data should be in question. Yes, sometimes you’ll see correlations even though the mechanism is not what you’d expect. That said, for 16 years? Lol No, in reality, this should indicate there is systemic fraud in the industry. I don’t think everyone’s a fraud, it’s as much about what doesn’t get published as what does get published. How does this happen? I commented on incentives prior here: https://news.ycombinator.com/reply?id=32213123 https://news.ycombinator.com/reply?id=32213123 I personally don’t see how we can advance science with the current credentialing and paper citation == academic success we’ve seen grow the last 50 years. In many ways, fundamental research has stalled, with applications of research advancing (giving us the illusion of advancing the fundamentals). To fix this problem, an overhaul is needed. Most importantly, the gate keeping mechanisms should be removed.

kurupt213 4y ago
What’s one of the first things they teach when dealing with statistical analysis? Correlation is not causation
beanjuice 4y ago
What do you mean by "the gate keeping mechanisms" should be removed? Do you mean the difficulty of publishing? Or tenure? Or degrees?
- voakbasda 4y ago
  All of those gate keeping mechanisms have systemic issues and need to be reformed at the very least. "Removed" might be a bit strong, but I definitely see how one could reach that perspective. Regardless, they certainly have lost the credibility to claim any monopolistic authority over the domains they purport to serve.

beanjuice 4y ago

Pubpeer is an incredible project [0], and unless I am mistaken, you could say that this finding may not have occurred without it. For those that do not know, it is a website (with browser extension) which allows a comment section for academic publication, with anonymous comment, for posting critique and questions about papers. I suggest all of my peers to install the extension, as a pre-warning system for poor quality papers. This paper in question can be found here [1], and it is a good example of what simple image processing techniques can be used to verify, or question claims. It is unfortunate that while things like NMR, XRD, SEM/TEM images, and Western blots are commonly faked, and found out- not all science is based off of verifiable data at the reader's end. [0] https://pubpeer.com/static/about https://pubpeer.com/static/about [1] https://pubpeer.com/publications/8FF7E6996524B73ACB4A9EF5C0AACF https://pubpeer.com/publications/8FF7E6996524B73ACB4A9EF5C0A...

stuckinhell 4y ago

Interesting article. From an non-researchers perspective, I find a couple points extremely disturbing. - The failure to notice and act on the faked data in the Lesné papers is still a disgrace, and there’s plenty of blame to go around among other researchers in the field as well as reviewers and journal editorial staffs. - Every single Alzheimer’s trial has failed. I strongly suspect there is more fraud, just because of human nature. It looks multiple checkpoints are failing. We also have the replication crisis going on. It's pretty clear at this point incentives are misaligned at every level of the research pipeline. It's a bad time for this highly public research failure. The general public's faith in experts is dropping, and maybe for good reason. As the economy, and quality of life deteriorates, I think we will see the public demand "results" from experts.

matthewdgreen 4y ago
It's also possible that Alzheimer's is an incredibly challenging disease and the tools we have to deal with it are suboptimal. People have a hard time distinguishing failure from malice, unfortunately. It's understandable to want someone to blame.
- AbrahamParangi 4y ago
  One way for something to be extremely challenging is for it to be impossible
- stuckinhell 4y ago
  I agree. However I also think, we are seeing evidence of malice, greed, and maybe desperation in these acts of scientific fraud. Experts need to quickly define what malice in their respective fields means. Then most importantly they need to act on it and restore integrity, discipline, and show results. Otherwise the general public will define it and act on it themselves.
- naasking 4y ago
  It is a hard disease to study for sure. The hardest part of it is that there's no effective test for it, you just have to check for a somewhat vague constellation of symptoms over a person's entire lifespan. I think a big part of the obsession with the amyloid plaques hypothesis is that it was the only issue that was consistent among patients that they could actually test for, so rather than continuing the harder work of searching in the dark for something better, researchers latched onto exploring how and why that was associated with Alzheimer's. And it makes sense in a way, there's obviously something going on and figuring out why the plaques are produced should provide some mechanistic insight into what's going on. And that's true, in the same way that capturing all of the EM emissions from a laptop will provide some insight into what's going on inside the laptop, but that information will likely only be useful if you already have a good mechanistic model of a laptop's inner workings (people have successfully read data across an air gap this way). I suspect that's what will happen with amyloid plaques as well, ie. plaques will only make sense retrospectively.

tomelders 4y ago

> He was originally hired by two other neuroscientists who also sell biopharma stocks short I'm blown away by this investment strategy. What a brilliant way to monetise exposing fraud. Get your proof, short the stock, publish your proof, profit!

meepmorp 4y ago
Doing well by doing good
pjbk 4y ago
Unfortunately it's more common than you think... I remember this case in particular from some years ago: https://www.legalreader.com/st-jude-medical-files-lawsuit-against-medsec-and-muddy-waters/ https://www.legalreader.com/st-jude-medical-files-lawsuit-ag...
- JumpCrisscross 4y ago
  > Unfortunately it's more common Why is calling out fraud unfortunate? With respect to St. Jude, Muddy Waters was at least partially right [1]. [1] https://www.hipaajournal.com/fda-confirms-muddy-waters-claims-st-jude-medical-devices-can-hacked-8642/ https://www.hipaajournal.com/fda-confirms-muddy-waters-claim...
  - DiggyJohnson 4y ago
    Presumably GP is not saying that the calling out of fraud is unfortunate, but that the fraud itself is unfortunate.
    - pjbk 4y ago
      Precisely, sorry if it was not clear enough. Pointing vulnerabilities and betting on the side to effectively become a stakeholder raises some concerns on your true intentions, even if it could be legal to do so.
323 4y ago

Imnimo 4y ago

People want to point the finger at structural problems with academia to explain why this wasn't caught earlier. But what about industry? Didn't they have a huge incentive to catch this sort of thing before they spend boatloads of money on clinical trials, and didn't they have some level of immunity to concerns about tenure committees and journal editors? If this was so easy to catch if it weren't for the troubling incentives of academia, why did drug companies still spend billions on it?

xiande04 4y ago
> why did drug companies still spend billions on it? Because they made even more off it.
- throwawaymaths 4y ago
  No, they lost money on it. Clinical trials aren't cheap.
- deleted 4y ago
  [deleted]
- PeterisP 4y ago
  How? They aren't getting revenue until they can sell a drug that has passed clinical trials, and no clinical trials have been successful for Alzheimer's.
  - t90z 4y ago
- jcranmer 4y ago
  Only one drug has been even provisionally approved--Aduhelm--and that approval is so mired in controversy that everyone is refusing to pay for it, so I doubt its company has made even a million dollars in revenue off of it. No, Alzheimer's has been a multibillion dollar sinkhole for drug development cash with absolutely nothing to show for it.

endominus 4y ago

Worth rereading; "Time to assume that health research is fraudulent until proven otherwise?" from no less a source than the British Medical Journal [0]. Another example; 5-HTTPLPR studies [1] in psychiatric research (over 450, "proving" the effects of the gene on basically every psychological malady) stretching all the way back to 1996. [0]: https://blogs.bmj.com/bmj/2021/07/05/time-to-assume-that-health-research-is-fraudulent-until-proved-otherwise/ https://blogs.bmj.com/bmj/2021/07/05/time-to-assume-that-hea... [1]: https://slatestarcodex.com/2019/05/07/5-httlpr-a-pointed-review/ https://slatestarcodex.com/2019/05/07/5-httlpr-a-pointed-rev...

gilrain 4y ago
Unfortunately, this has become a rational precaution. Capitalism has thoroughly undermined humanity’s greatest tool.
- MattPalmer1086 4y ago
  Well, the problem is one of misaligned incentives rather than capitalism per se. From the BMJ article: "Researchers progress by publishing research, and because the publication system is built on trust and peer review is not designed to detect fraud it is easy to publish fraudulent research. The business model of journals and publishers depends on publishing, preferably lots of studies as cheaply as possible. They have little incentive to check for fraud and a positive disincentive to experience reputational damage—and possibly legal risk—from retracting studies. Funders, universities, and other research institutions similarly have incentives to fund and publish studies and disincentives to make a fuss about fraudulent research they may have funded or had undertaken in their institution—perhaps by one of their star researchers." Capitalism is certainly the economic context we operate in, but I'd hardly say it is the root cause of most of the above, which could apply equally in other economic funding models.

Flankk 4y ago

Where is the "trust science" crowd when stuff like this goes down. It's strangely quiet in here. Shouldn't they be here telling us how this is a mistake because the editorial and peer review process prevents this? Something about how science brought us all of technology? Oh, that was actually capitalism? Oh great science, where great minds get paid by industry to submit their doctored conclusions to a journal, attached with a small bribe.

cm42 4y ago
We'll have to wait until someone breaks it down into a rhyming Harry Potter reference or something.
Jaygles 4y ago
I've never understood "trust science" as "blindly trust scientists". I've always understood it as "trust the scientific process", which is sensible in my opinion, as the process is designed to determine truths. When people falsify results, what they are doing isn't really a product of the scientific process, they are just committing fraud.
- Flankk 4y ago
  So they're still here, and they're brain dead.
- scarmig 4y ago
  Particularly for heavily politicized topics, "trust the science" usually means something like "trust that the people that the media has designated as scientific authorities always follow the scientific process, understand statistics, and are objective searchers for truth; moreover, don't try to substitute your expertise for theirs." The scientific community can't simply no-true-scotsman every claim pushed with the banner of Science that turns out to be false or fraud if it wants the true claims to be considered seriously.
betenoire 4y ago
Seriously? Science is a process, not a result, and science is literally revealing the fraud here.

hindsightbias 4y ago

That the cycle of science works slowly. Slower than to be applicable in your lifespan.

VikingCoder 4y ago

So the University of Minnesota faked Alzheimer's research and injected Linux kernel bugs on purpose? [1] Not feeling so proud as an alumni today. [1]: https://news.ycombinator.com/item?id=26887670 https://news.ycombinator.com/item?id=26887670

deleted 4y ago
[deleted]

criddell 4y ago

Is there a new leading theory?

renewiltord 4y ago

Amusing. Second-hand experience[0] with "exciting science areas" led me to this belief already. It's one of those interesting things. For folks outside of science, they think most of this stuff is backed. You can see it in the fact that people will quote "there is evidence that X is Y" using some random study, commonly on HN. There's a common reaction to this sort of thing where people act like it is some betrayal of a sacred pact, etc. etc. but there is so much fake science out there that it is really hard to believe that there is actually some betrayal and it's not just the reality of the field. And always there'll be some guy who comes up with a "I've never heard of this and neither has any of the ten guys I talked to about it". Just do the math. At a 10% fake rate (which I would consider extraordinary) there's a 1 in 3 chance that you wouldn't detect it with just independent observations of you and 10 friends (and that's assuming you and your friends are independent here, which is very generous). At a 5% fake rate (which is still horrible), there's a 1 in 10 chance that even you and 40 of your friends would not detect it. The thing with not-so-rare things is that you can fail to detect it through sheer chance. 0: https://news.ycombinator.com/item?id=25926188 https://news.ycombinator.com/item?id=25926188 P.S. hn.algolia.com is excellent. I managed to find this comment in a couple of seconds on it.

bhk 4y ago
The "I've never heard of this ..." comment can also be explained by the possibility that the person making the comment is one of the fraudsters. This adds 10% to the 1/3 chance in your example. So no matter how high the rate of fraud is, we would expect to hear comments like this.
- renewiltord 4y ago
  I did not think about that, but you are right (with appropriate maths modifications)

rbanffy 4y ago

In this age of politically-motivated scientific disinformation, the one thing we don't need is fraudulent science. We need to be able to trust which drugs and vaccines work, anc which don't. We need to be able to trust the predictions about global warning and the societal impact of it so we can chart the optimum path with as little disruption and suffering as we can. In short, we cannot afford not to be rational, not to ground our decisions in hard facts and solid models. Scientists like Lesné should be detected much earlier in their careers.

arbitrage 4y ago
The situation in Academia is similar to child abuse in the Churches. These people often are detected early, and get shuffled around. A lot of people know about this problem, have for a long time. A lot of people continue to do nothing about it.

pvg 4y ago

Recent big threads yesterday and a few days ago with 250+ comments each: https://news.ycombinator.com/item?id=32212719 https://news.ycombinator.com/item?id=32212719 https://news.ycombinator.com/item?id=32183302 https://news.ycombinator.com/item?id=32183302 And a danglist with more https://news.ycombinator.com/item?id=32213973 https://news.ycombinator.com/item?id=32213973

hprotagonist 4y ago
Not a dupe, per se. Derek Lowe's summaries of current events are themselves valuable and aren't just "hey look, [this thing]!".
- pvg 4y ago
  HN dupes are mostly by value rather than by reference and there's also a kind of topic repetition limit even when the there's more commentary on the topic.
- dang 4y ago
  That's a good point. I call this sort of post either a follow-up or a quasidupe, depending on how dupey (?) it is. The problem is that the HN discussions on a topic cluster tend to be much the same, even if the article itself isn't. But I've taken the [dupe] stigma off this one now.
dang 4y ago
Might as well keep it updated I suppose. Two decades of Alzheimer’s research was based on deliberate fraud - https://news.ycombinator.com/item?id=32212719 https://news.ycombinator.com/item?id=32212719 - July 2022 (295 comments) Potential fabrication in research threatens the amyloid theory of Alzheimer’s - https://news.ycombinator.com/item?id=32183302 https://news.ycombinator.com/item?id=32183302 - July 2022 (236 comments) Alzheimer’s amyloid hypothesis ‘cabal’ thwarted progress toward a cure (2019) - https://news.ycombinator.com/item?id=31828509 https://news.ycombinator.com/item?id=31828509 - June 2022 (307 comments) How an Alzheimer’s ‘cabal’ thwarted progress toward a cure - https://news.ycombinator.com/item?id=21911225 https://news.ycombinator.com/item?id=21911225 - Dec 2019 (382 comments) The amyloid hypothesis on trial - https://news.ycombinator.com/item?id=17618027 https://news.ycombinator.com/item?id=17618027 - July 2018 (43 comments) Is the Alzheimer's “Amyloid Hypothesis” Wrong? (2017) - https://news.ycombinator.com/item?id=17444214 https://news.ycombinator.com/item?id=17444214 - July 2018 (109 comments)

sudden_dystopia 4y ago

This sounds just like cholesterol to me. Yes, beta amyloids are correlated with Alzheimer’s and cholesterol is correlated to cardiac issues. But correlation is not causation. Why is their seemingly no mainstream discussion that perhaps these correlations are simply the markers of an underlying biological function that has become disregulated and leads to the presence of higher amyloid/cholesterol/etc? When we try to treat cancer, do we focus on the symptoms, or do we try to obliterate the cancer? As far as I can tell, we aren’t looking for the “cancer”, we are trying to treat symptoms.

_Wintermute 4y ago
> Why is their seemingly no mainstream discussion that perhaps these correlations are simply the markers of an underlying biological function that has become disregulated and leads to the presence of higher amyloid That's a discussion point pretty much every time the amyloid hypothesis is mentioned in the scientific literature. I'm not sure where you're going to get information about the pathophysiology of Alzheimer's disease, but it doesn't really strike me as a "mainstream" topic where they're going to discuss the finer details or debates.
- throwawaymaths 4y ago
  > That's a discussion point pretty much every time the amyloid hypothesis is mentioned in the scientific literature I don't feel like that's true. Back when I was a grad student doing this research it was striking to me how little that was in the literature considering how much we said it internally.

holyknight 4y ago

I think the main issue is that papers and studies with negative results are almost never published. There should be some procedure in place that ensures that papers will always be published no matter what is the result. This decision shouldn't be in the hands of the researchers and even less so on the investors. Direct investor oversight over the research is very concerning. With the current method we can only blindly trust that scientist will be willing to sacrifice their career to publish a research that could potentially bury their investor. This makes absolutely no sense and will almost always end in conflict of interest. I don't know the answer, but the current status quo is deeply flawed and needs to change quickly.

deleted 4y ago

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A4ET8a8uTh0 4y ago

From the article: << Now Cassava is a story of their own, and I have frankly been steering clear of it, despite some requests. To me, it’s an excellent example of a biotech stock with a passionate (and often flat-out irrational) fan club. I wonder if this is part of the issue. It is now something of a social club, where allegiance is to the clan. I initially wondered if it is the function of the internet, but the I remembered that various cliques existed way before that. Internet just put a spotlight on it. The only real question is whether the current club can be reformed.

temporalparts 4y ago

Ask HN: What do you think about a law that criminalizes faking and doctoring data for their research? Clearly we need greater punitive consequences for these types of behavior that's becoming an epidemic in research.

arbitrage 4y ago
Effectively, it's the same reason why the death penalty does not deter crime from happening. The threat of career-ending shame & humiliation is remote and unlikely. As another poster said much further up-thread, there is more fraud going on that doesn't get detected. Criminal penalties in this realm are a bit draconian. More punishment & punity is not the answer.
UweSchmidt 4y ago
That makes it even harder to call out bad science. You hate how your colleague cut corners but do you want to testify against them in court in your free time and have them sent to jail? I'd go the opposite way and give job security to anyone who is doing solid science to remove some of the weird incentives. There is upside to be amazing and win prizes or get better positions, but there is also space for people to "just" reproduce, or generally do important but non-glamorous stuff.

CommanderData 4y ago

Wasn't HSV also implicated in Alzheimer's. Seeing most of the world is infected with cold sores I wonder if we should question this research too?

jtdev 4y ago

pcrh 4y ago

Here is a lengthy response from more than 20 researchers in the field [0]. In brief, the claims made in the article above are exaggerated. As someone who works in the field, and who is skeptical of the amyloid hypothesis, I agree. [0] https://www.alzforum.org/news/community-news/sylvain-lesne-who-found-av56-accused-image-manipulation https://www.alzforum.org/news/community-news/sylvain-lesne-w...

jeremyjh 4y ago
It’s so shocking that they don’t want their field to be discredited.
- pcrh 4y ago
  Not really. There is plenty of criticism of the amyloid hypothesis within the field, and even specifically of the oligomer variant thereof that Schrag focused on. You can even read that criticism in the link I provided. Schrag's investigation did not (in my opinion) discover any fraud in the Lesné paper, even if the paper perhaps over-states its case. The amyloid hypothesis has several very strong strands of evidence in its favor, specifically that it is (currently) the only way to reconcile the indisputable genetic and pathological evidence for mutations in the genes APP and presenilin both producing early-onset Alzheimer's disease. Amyloid is derived from the action of presenilin on APP. Until an alternate way of reconciling this observation is found, the amyloid hypothesis will always have supporters.
gausswho 4y ago
Having read it, I don't recognize anything that suggests the Science article is an exaggeration. Perhaps there's something in the comments you're referring to, but if so can you be more specific?
- pcrh 4y ago
  Scientists are often very circumspect in how they phrase things, but this particular phrasing in the main article is notable: >“This is not a real scientific problem, but it is most unfortunate for general science credibility,” Selkoe wrote to Alzforum. Edit: I should add that the "oligomers" described in the Lesne article have been found by other researchers, see [0] [0] https://scholar.google.co.uk/scholar?hl=en&as_sdt=0%2C5&q=Aβ*56&btnG= https://scholar.google.co.uk/scholar?hl=en&as_sdt=0%2C5&q=Aβ...

brighamyoung 4y ago

It probably means that the Bredesen protocol is the cure for Alzheimers. He has a literally proven track record of success with hundreds of patients.

jmyeet 4y ago

I'm not in academia but here's what I don't understand. Generlaly, my understanding was that important results typically get replicated by other institutions and teams. Not necessarily to prove that initial result but to work out the limits of whatever the conclusion was. Imagine you discovered that ibuprofen could reduce the risk of stroke by 30%, for example. You would have other teams that might start playing with the factors and asking different questions like: - What if we raise or lower the dosage? - Waht if we mix that with other medications? In doing so you'd get further confirmation of the original result. You'd think there'd be some similar studies done of the original result but that doesn't seem to have been the case or this fraud would've been discovered already. So for anyone who does know about how this works, why didn't this happen?

photochemsyn 4y ago
One neglected issue here is the role of government funding agencies and universities in controlling who gets funded. It's common practice for universities to encourage their own researchers to get government positions at funding agencies, where they can help shepherd grants back to their parent institutions, for example. Something like this seems to have gone on with Alzheimer's funding - some people involved with the source lab ended up directing funding at the federal level. So, if you're a researcher who decides to publish refutation of a fundamental claim by the leading stars in the field, you risk getting on a funding blacklist, and your grant review doesn't get approved. Hence, the safer thing to do is simply ignore the research you suspect to be fraudulent and take your own research in a different direction. There's also the concept that they don't want to discredit the entire field by exposing fraud and thereby risk Congress spiking the funding entirely or something like that. Incidentally, a lot of the silence on the very plausible notion that Sars-CoV2 escaped from a lab, and that its transmissibiliy and virulence likely were increased in the lab as a consequence of various gain-of-function (well-meaning I suppose) research techniques (serial passage, CRISPR engineering, etc.), appears to be due to similar concerns (i.e. researcher who even discuss the possiblity might run afoul of people like Fauci and cohort who still control virology research funding).
jcranmer 4y ago
> You'd think there'd be some similar studies done of the original result but that doesn't seem to have been the case or this fraud would've been discovered already. As Derek Lowe says, this did happen: > I could be wrong about this, but from this vantage point the original Lesné paper and its numerous follow-ups have largely just given people in the field something to point at when asked about the evidence for amyloid oligomers directly affecting memory. I’m not sure how many groups tried to replicate the findings, although (as just mentioned) when people did it looks like they indeed couldn’t find the 56 oligomer. And judging from the number of faked Westerns, that’s probably because it doesn’t exist in the first place. But my impression is that a lot of labs that were interested in the general idea of beta-amyloid oligomers just took the earlier papers as validation for that interest, and kept on doing their own research into the area without really jumping directly onto the 56 story itself. The bewildering nature of the amyloid-oligomer situation in live cells has given everyone plenty of opportunities for that! The expressions in the literature about the failure to find *56 (as in the Selkoe lab’s papers) did not de-validate the general idea for anyone - indeed, Selkoe’s lab has been working on amyloid oligomers the whole time and continues to do so. Just not Lesné’s oligomer. In other words, the result was tried to be replicated a few times, and no one could replicate it. But the groups working in this space were already pursuing similar paths before this paper, and the results were taken not as a "target this one specific thing and you'll be golden" but rather "here's more evidence that targeting this class of thing is useful in this place." I'll also point out that by the time you're talking dosage questions, you're generally tackling clinical trials (phase II trials are meant to establish the dosing regime), which is far downstream of work that gets published academically.

scaredginger 4y ago

When you have problems like this, they must be viewed from a systemic perspective. The truth is that our modern institutions of science are fraught with perverse incentives; people battling for funding, feeling pressure to publish and going to war over a few scarce tenured positions. I don't know how we solve this, but I think reforming academia with some well-placed regulation and an increase in publicly funded research would be a place to start.

ta8645 4y ago

Just another reminder that scientific consensus should not be blindly accepted with religious fervour.

tomohawk 4y ago

This is why censoring people on social media platforms when they disagree with "the experts" is so dangerous. Science is not about listening to experts. It's about the data, and about falsifiable theories.

UIUC_06 4y ago

Re solutions: now do Project Veritas. If you're a whistleblower and you're not getting shunned by "respectable" people, you're probably doing something wrong.

peter303 4y ago

Two reasons why this hypothesis may not be true: 1) Universal failure of plaque-reduction drug trials. 2) Numerous post-mortem counter-examples: dementia w/o plaques and plaques without dementia.

joe_the_user 4y ago

"First off, I’ve noticed a lot of takes along the lines of “OMG, because of this fraud we’ve been wasting our time on Alzheimer’s research since 2006”. That’s not really the case, as I’ll explain..." I'm not seeing the explanation. The Amyloid hypothesis was weakening in 2006 and a series of apparently ground-breaking but actually fake results gave new life over a significant period of time. Yes the author says: "the main inaccuracy in that statement is that we’ve been actually been wasting our time in Alzheimer’s research for even longer than that." but the problem is testing a false hypothesis and discarding isn't a waste of time, it's how science should work. Fraud and forgone failures, of course, are how science shouldn't work. And yes, there's lot of fraud around but I don't see how this isn't especially damaging.

nl 4y ago
> I'm not seeing the explanation. It's in there: > But my impression is that a lot of labs that were interested in the general idea of beta-amyloid oligomers just took the earlier papers as validation for that interest, and kept on doing their own research into the area without really jumping directly onto the 56 story itself. The bewildering nature of the amyloid-oligomer situation in live cells has given everyone plenty of opportunities for that! The expressions in the literature about the failure to find 56 (as in the Selkoe lab’s papers) did not de-validate the general idea for anyone - indeed, Selkoe’s lab has been working on amyloid oligomers the whole time and continues to do so. So labs wanted to work on this for their own reasons, not because of this result. > Did the 56 Work Lead to Clinical Trials? > That’s a question that many have been asking since this scandal broke a few days ago. And the answer is that no, I have been unable to find a clinical trial that specifically targeted the AB56 oligomer itself So there weren't even any wasted clinical trials. Basically his point is that maybe this drew some extra researchers into that area, but it was a worthwhile area anyway. The fact that nothing worked isn't particularly relevant because nothing has worked for Alzheimer's anyway.
- mkl 4y ago
  You can escape the *s with \ (i.e. \*56) to fix the formatting of *56.