Jul 26, 2022 02:57 PM
https://www.science.org/content/blog-pos...es-it-mean
EXCERPTS: Late last week came this report in Science about doctored images in a series of very influential papers on amyloid and Alzheimer’s disease. That’s attracted a lot of interest, as well it should, and as a longtime observer of the field (and onetime researcher in it), I wanted to offer my own opinions on the controversy.
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. But don’t get your hopes up: from one point of view, 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. So that's not very comforting, either. We’ll start with some background and history, the better to appreciate the current furor in context. Those of you who know the field can skip ahead to later sections as marked, but your admission ticket is valid for the entire length of the ride if you want to get on here.
[...] There had been a lot of work (and a lot of speculation) about the possibility of there being hard-to-track-down forms of amyloid that were the real causative agent of Alzheimer’s. You can find plenty of papers from the late 1990s and early 2000s on the idea of pathogenic soluble amyloid oligomers, oligimerization state as correlated with disease, all that sort of thing. It was certainly not an unexplored idea.
But this 2006 paper did indeed get a lot of attention, because it took the idea further than many other research groups had. It was from the lab of Karen Ashe at Minnesota, highlighting work from Sylvain Lesné in her lab on a form of amyloid called AB*56. Isolating this species from a transgenic mouse model and injecting it into young rats caused them to start exhibiting memory defects in turn. Now that’s the kind of smoking gun you want to see, especially in a field as murky and tangled as this one. That paper has been cited well over 2000 times since then, and Lesné has since produced a large number of papers following up on this idea and its ramifications. He’s running his own research group now, naturally, and Ashe’s group has also continued to work on amyloid oligomers, as have (by now) many others.
But some of these later Lesné papers had been flagged on the PubPeer site for potential image doctoring...
[...] Science had Schrag’s findings re-evaluated by several neuroscientists, by Elisabeth Bik, a microbiologist and extremely skilled spotter of image manipulation, and by another well-known image consultant, Jana Christopher. Those last two even found more examples that Schrag himself had missed. Apparently everyone agrees that Lesné’s work is full of trouble. Phrases like “shockingly blatant” and “highly egregious” are quoted, and it looks like key parts of the experimental evidence in these papers is nothing more than cut-and-paste jobs assembled to show the desired result.
[...] What About Peer Review, Damn It All? Yeah, there’s that. The Lesné stuff should have been caught at the publication stage, but you can say that about every faked paper and every jiggered Western blot. When I review a paper, I freely admit that I am generally not thinking “What if all of this is based on lies and fakery?” It’s not the way that we tend to approach scientific manuscripts....
[,...] beta-Amyloid has been the dominant explanation for Alzheimer’s for decades. ... but every attempt to target it and slow the disease has failed in the clinic.
These failures, combined with the still-compelling reasons to think that amyloid is indeed a major part of the disease, have led to hypotheses that would square all these conflicting findings: perhaps amyloid really is the cause of Alzheimer’s, but not the form of amyloid we’ve been looking at...
[...] Lesné’s work now appears suspect across his entire publication record... The AB*56 work did not lead directly to any clinical trials on that amyloid species ... But it certainly did raise the excitement and funding levels in the area and gave people more reason to believe...
[...] Those trials have failed. But every single Alzheimer’s trial has failed. I think that any ultimate explanation of Alzheimer’s disease is going to have to include beta-amyloid as a big part of the story - but if attacking the disease from that standpoint is going to lead to viable treatments, we sure as hell haven’t been seeing it. We have to put money and effort down on other hypotheses and stop hammering, hammering, hammering on beta-amyloid so much. It isn’t working... (MORE - missing details)
EXCERPTS: Late last week came this report in Science about doctored images in a series of very influential papers on amyloid and Alzheimer’s disease. That’s attracted a lot of interest, as well it should, and as a longtime observer of the field (and onetime researcher in it), I wanted to offer my own opinions on the controversy.
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. But don’t get your hopes up: from one point of view, 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. So that's not very comforting, either. We’ll start with some background and history, the better to appreciate the current furor in context. Those of you who know the field can skip ahead to later sections as marked, but your admission ticket is valid for the entire length of the ride if you want to get on here.
[...] There had been a lot of work (and a lot of speculation) about the possibility of there being hard-to-track-down forms of amyloid that were the real causative agent of Alzheimer’s. You can find plenty of papers from the late 1990s and early 2000s on the idea of pathogenic soluble amyloid oligomers, oligimerization state as correlated with disease, all that sort of thing. It was certainly not an unexplored idea.
But this 2006 paper did indeed get a lot of attention, because it took the idea further than many other research groups had. It was from the lab of Karen Ashe at Minnesota, highlighting work from Sylvain Lesné in her lab on a form of amyloid called AB*56. Isolating this species from a transgenic mouse model and injecting it into young rats caused them to start exhibiting memory defects in turn. Now that’s the kind of smoking gun you want to see, especially in a field as murky and tangled as this one. That paper has been cited well over 2000 times since then, and Lesné has since produced a large number of papers following up on this idea and its ramifications. He’s running his own research group now, naturally, and Ashe’s group has also continued to work on amyloid oligomers, as have (by now) many others.
But some of these later Lesné papers had been flagged on the PubPeer site for potential image doctoring...
[...] Science had Schrag’s findings re-evaluated by several neuroscientists, by Elisabeth Bik, a microbiologist and extremely skilled spotter of image manipulation, and by another well-known image consultant, Jana Christopher. Those last two even found more examples that Schrag himself had missed. Apparently everyone agrees that Lesné’s work is full of trouble. Phrases like “shockingly blatant” and “highly egregious” are quoted, and it looks like key parts of the experimental evidence in these papers is nothing more than cut-and-paste jobs assembled to show the desired result.
[...] What About Peer Review, Damn It All? Yeah, there’s that. The Lesné stuff should have been caught at the publication stage, but you can say that about every faked paper and every jiggered Western blot. When I review a paper, I freely admit that I am generally not thinking “What if all of this is based on lies and fakery?” It’s not the way that we tend to approach scientific manuscripts....
[,...] beta-Amyloid has been the dominant explanation for Alzheimer’s for decades. ... but every attempt to target it and slow the disease has failed in the clinic.
These failures, combined with the still-compelling reasons to think that amyloid is indeed a major part of the disease, have led to hypotheses that would square all these conflicting findings: perhaps amyloid really is the cause of Alzheimer’s, but not the form of amyloid we’ve been looking at...
[...] Lesné’s work now appears suspect across his entire publication record... The AB*56 work did not lead directly to any clinical trials on that amyloid species ... But it certainly did raise the excitement and funding levels in the area and gave people more reason to believe...
[...] Those trials have failed. But every single Alzheimer’s trial has failed. I think that any ultimate explanation of Alzheimer’s disease is going to have to include beta-amyloid as a big part of the story - but if attacking the disease from that standpoint is going to lead to viable treatments, we sure as hell haven’t been seeing it. We have to put money and effort down on other hypotheses and stop hammering, hammering, hammering on beta-amyloid so much. It isn’t working... (MORE - missing details)