Science, Blots on a field? (potential fabrication in Alzheimer's research), 2022, Charles Piller

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Article: Science, Blots on a field ?, Charles Piller

First para:

"In August 2021, Matthew Schrag, a neuroscientist and physician at Vanderbilt University, got a call that would plunge him into a maelstrom of possible scientific misconduct. A colleague wanted to connect him with an attorney investigating an experimental drug for Alzheimer’s disease called Simufilam.

The drug’s developer, Cassava Sciences, claimed it improved cognition, partly by repairing a protein that can block sticky brain deposits of the protein amyloid beta (Aβ), a hallmark of Alzheimer’s.

The attorney’s clients—two prominent neuroscientists who are also short sellers who profit if the company’s stock falls—believed some research related to Simufilam may have been “fraudulent,” according to a petition later filed on their behalf with the U.S. Food and Drug Administration (FDA)."

Online version of the Science article available here: https://www.science.org/content/art...mages-threatens-key-theory-alzheimers-disease
 
Solid article. Data fabrication is always bad, but particularly despicable when peoples’ lives are at stake.

“You can cheat to get a paper. You can cheat to get a degree. You can cheat to get a grant. You can’t cheat to cure a disease,” he says. “Biology doesn’t care.”
 
Reading comments about this elsewhere and overall the outrage is over nearly 2 decades lost on a wasted hypothesis, and all I can think of is how it pales in comparison to how chronic illness has been botched. It's a similar scandal except 10x longer and 10x more people, usually in the prime of our lives. Except there never was any evidence at all, didn't have to fake anything, there literally never was any, people just believe it, in fact need evidence against it.

Because 2 people didn't fail, an entire system failed. Hundreds of people were involved in validating and approving research based on this and they all failed at their duties, either they all saw nothing or failed to have the courage to say it.

And that same system fails us every day, for even worse reasons. There literally is no evidence for psychosomatic anything, it's not even a case of falsified evidence, it's the complete absence of it.

And yet there are probably barely a handful of people in all of academia who get this, most would never look at the scandalous denial of chronic illness and see any valid comparison, even though on the whole it's the same failure, just far worse. And this scandal is horrible, I'm not diminishing it, if anything it emphasizes how criminal everything done to us has been.

No one ever calls out the emperor's naked butt until everyone else does it. The system is at fault, it needs top to bottom reform, and yet hardly anyone could even acknowledge that, every mistake is its own little unique snowflake, which is why this whole damn system is so mediocre and dysfunctional that you can fake your way to billions in wasted funding and, let's be honest here, nothing will happen to the people responsible.

No incentives to do the right thing. Zero consequences for fraud. Great system, delivering exactly as much as it's built to.
 
One of the researchers involved - Dr Karen Ashe - has responded in what I assume is the Alzheimer's equivalent of S4ME. From the first comment in this post.

Regarding Charles Piller’s article in Science, I cannot comment on the allegations about images that may have been inappropriately altered by my former co-worker Dr. Sylvain Lesné, because he is now under formal investigation at the University of Minnesota. However, I will comment on his scientific statements, because his description of my scientific thesis is inaccurate.
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I have consistently expressed concerns that drugs targeting plaques were likely to be ineffective. Based on my published work (Liu et al., 2015; Ashe, 2020), it is clear that there are two general forms of Aβ, type 1 and type 2. One particular form of type 1 (referred to in our papers as Aβ*56 and in the Science article as “toxic oligomers”) was shown by my lab and others to impair memory function in mice. The type 2 form of Aβ is the one found in amyloid plaques. It is this latter form that drug developers have repeatedly but unsuccessfully targeted. There have been no clinical trials targeting the type 1 form of Aβ, the form which my research has suggested is more relevant to dementia.
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article conflated two distinct issues: a) the frustrations regarding the difficulties of drug development in Alzheimer’s; and b) a specific accusation of scientific misconduct relating to a set of papers about one particular aspect of the Aβ hypothesis.
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We previously reported that Aβ*56 is an SDS-stable Aβ assembly that impairs memory function in Tg2576 mice (Lesné et al., 2006). Dr. Peng Liu and other colleagues in my lab have gone on to confirm and extend these findings; we classified Aβ oligomers into two types, type 1 and type 2, that differ in structure, spatial distribution, and temporal expression, and hypothesized that type 1 are formed by primary nucleation and type 2 by secondary nucleation (Liu et al., 2015).
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Based on these data, I hypothesize that Aβ*56 is a metastable type 1 oligomer, which can make it frustratingly elusive. Its detection must be conducted with care
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A major focus of our current work is to determine the secondary and quaternary biophysical structures of type 1 oligomers, which may help explain why current Aβ therapies which target type 2 oligomers may not have been as effective as once hoped. Another focus is to develop monoclonal antibodies against type 1 oligomers, which could pave a path forward toward new Aβ therapeutics.
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Jaybee00 said:
https://www.science.org/content/blog-post/faked-beta-amyloid-data-what-does-it-mean


Faked Beta-Amyloid Data. What Does It Mean?
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Note to readers: for a quick summary, skip to the last section (The Big Picture).

There is a thought-provoking comment under the piece, too: https://www.science.org/content/blo...oid-data-what-does-it-mean#comment-5928242790
I've worked in preclinical discovery research in the biotech/pharma industry for over 20 years. Whenever I present our data at meetings I'm required to put up the obligatory disclosures that I'm a paid employee and the insinuation is that our work should be taken with a grain of salt because we are probably company shills in it for the money. The academic researchers can claim purity because they aren't corrupted by financial incentives.

However, throughout my career I've often noticed that when I try and replicate studies performed by other biotech companies I generally find results similar to the published data. Sometimes the data is noisier, not as robust, or compounds aren't as potent as claimed - but the overall result is qualitatively similar. Ironically, I've often had more trouble replicating data from academic labs. Sometimes we just don't see any evidence that the proposed pathways work as claimed. Maybe they are just better scientists, with true expertise in their field. Whatever the cause, if it persists we often drop the project and move on to something else that looks more promising.

I've speculated (without any evidence, just my anecdotal observations) that the incentives are different and drive this behavior. In industry, any drug I work on will get passed on to other scientists in the company - biochemists, cell biologists, in vivo pharmacologists, tox specialists, and eventually the true test will come in clinical trials. Falsifying data won't help my career much if the drug fails in everyone else's hands. In academia, the incentive to publish novel data drives grant funding and academic appointments. There is a clear incentive to produce grandiose new findings.

Maybe we need to rethink the disclosures at meetings. Maybe we need to rethink how we approve grant funding. Maybe we should revisit the academic appointment process at most academic research centers. And we absolutely need to stop relying upon data that hasn't been replicated in independent labs.

End of rant.
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