Source: [Science Network]
A Nature paper that has been cited more than 2,300 times is suspected of fraud.
In the early morning of July 22, Beijing time, Science published a six-month investigation report, claiming that there may be academic misconduct in more than 20 papers published by neurologist Sylvain Lesné of the University of Minnesota, USA, including this pioneering paper published in Nature in 2006.
This involves one of the most cited research on Alzheimer's disease (commonly known as " Alzheimer's ") this century. As soon as the news came out, it caused a stir in the academic community. "The most direct and obvious damage is the wasting of the funds of NIH (National Institutes of Health ) and thinking in this field, because people use these results as the starting point for their experiments." The worst effect of
may be that it has misled Alzheimer's disease research around the world for 16 years.
traces the root cause and discovers that the foundational research is suspected of fraud
In August 2021, Matthew Schrag, a neurologist and doctor at Vanderbilt University in the United States, realized that he might fall into the vortex of academic misconduct.
His colleague wants him to contact a lawyer who is investigating an experimental drug for Alzheimer's disease, Simufilam. Cassava Sciences, the developer of the drug, claims it can improve cognitive ability in part because it repairs a protein that blocks the deposition of beta amyloid (Aβ) in the brain.
You should know that the "amyloid hypothesis" is one of the major pathogenesis hypotheses of Alzheimer's disease. The hypothesis suggests that Aβ plaques in brain tissue are the main cause of this devastating disease that tortures tens of millions of people around the world. Many research hotspots are mostly based on this hypothesis to develop new drugs.
The lawyer submitted a petition to US Food and Drug Administration (FDA) to suspend two phase III clinical trials of Cassava Sciences on Simufilam drug, and believes that some of the studies behind the drug may be "fraudulent".
Schrag, 37, has previously gained fame for publicly criticizing the FDA for approving the anti-Aβ drug Aduhelm, and his own research also refuted some of the claims made by Cassava Sciences. He is concerned that more than 1,800 volunteers who are participating in Simufilam drug trials will face the risk of side effects and will not get any benefits.
Therefore, he used his technical and medical knowledge reserves to investigate public images of drugs and their basic sciences. He found tampered or repeated images and suspicious data in dozens of journal papers. He then sent all investigation files to the NIH, which has invested tens of millions of dollars in the study.
In December 2021, Schrag visited PubPeer, an academic anti-counterfeiting website, to try to investigate scientists related to Cassava Sciences.
When searching for "Alzheimer's Disease" on PubPeer, posts about several papers on The Journal of Neuroscience caught Schrag's attention. The post commented that several bands in the paper seemed to be repeated. Schrag used software tools to confirm this speculation and found similar problems with other blots in the same paper.
Three of the papers listed Lesné, which Schrag had never heard of, as the first author or the corresponding author of . As a result, Lesné entered Schrag's investigation vision. Schrag soon discovered that another Lesné paper was also questioned on PubPeer, so he expanded his search to the unlabeled Lesné paper.
Finally, Schrag stumbled upon this groundbreaking paper published in Nature in 2006, which is the foundation of many other papers. It also seems to contain multiple tampered images.
His discovery threatens one of the most cited Alzheimer's disease studies and countless related experiments this century. If Schrag's suspicion is correct, then Lesné's research is a well-designed mirage.
The so-called key pathogenic substance, many scholars said that they had not found
Nature recently added editorial notes and have begun to investigate the doubts encountered by the article
Nature The first author of this pioneering paper is Lesné, and the corresponding author is his supervisor - Karen Ashe, a famous neuroscientist and professor at the University of Minnesota . This study provides strong support for the controversial "amyloid hypothesis".
Ashe has achieved a series of achievements. She has been a resident at UC San Francisco and contributed to Nobel Prize winner Stanley Prusiner’s pioneering work on prions .
In the mid-1990s, Ashe created a transgenic mouse that could produce large quantities of human Aβ, a substance that forms plaques in the brains of animals. The mouse also showed symptoms similar to dementia, which became a popular model of Alzheimer's disease.
In the brains of genetically modified mice, the scientific research team discovered a previously unknown oligomer , named Aβ*56. The team isolated Aβ*56 and injected it into the juvenile mice, and found that the juvenile mice's ability to recall simple, previously learned information has decreased.
Ashe touted Aβ*56 on his personal website as "the first substance found in the field of Alzheimer's disease research that has been shown to cause memory disorders." An editorial in Nature stated that Aβ*56 is the "number one suspect" of Alzheimer's disease. Less than two weeks after the paper was published, Ashe won the prestigious Neuroscience Potan Gold Award.
According to data from the Web of Science database, this paper by Nature has been cited by about 2,300 academic papers, which is more than the other four basic Alzheimer's disease research reports published since 2006. Since then, NIH’s support for “amyloid, oligomers and Alzheimer’s disease” research has risen from zero to $287 million in 2021.
Sylvain Lesné and Karen Ashe. Image source: Science
This research not only helped Ashe continue to advance, but also made Lesné's career develop better and better. In 2009, Lesné joined the University of Minnesota with a NIH-funded laboratory, and Aβ*56 remains the main focus of research.
In 2020, Lesné became a leader in the University of Minnesota's graduate program in neuroscience. Just four months after Schrag conveyed his concerns to the NIH, Lesné received a coveted R01 grant from the agency, which lasted for up to five years. Austin Yang, an NIH official in charge of the project and one of the co-authors of the 2006 Nature paper, declined to comment.
In the 16 years since the publication of this landmark paper, Lesné and Ashe have published many papers on the research, respectively or jointly. However, only a few other research groups reported findings of Aβ*56.
Ashe rejected an interview with Science via email, writing, “I still have confidence in Aβ*56” and mentioned her ongoing work on studying the structure of Aβ oligomers. "We have achieved preliminary results. I am still excited about this work and believe it may explain why Aβ therapy is still effective, despite the recent failure of treatment for amyloid plaques."
But in fact, sporadic evidence of Aβ*56's role in Alzheimer's disease has attracted attention before the Schrag investigation.
For a long time, Donna Wilcock, an Alzheimer's disease expert at the University of Kentucky, has been skeptical about the Aβ*56 study that claims to be used "purified". This oligomer is notoriously unstable and will spontaneously convert to other oligomer types. She noted that even after purification, multiple types may exist in the sample, so it is hard to say that any cognitive decline is caused by Aβ*56 alone. Moreover, there is another important premise, that is, Aβ*56 must exist.
In fact, Wilcock and others said that some labs have tried it but failed to find Aβ*56, and few people have published these findings. Because journals are often not interested in negative results, researchers may not be willing to refute a well-known researcher.
Interestingly, Dennis Selkoe, the main advocate of the "amyloid hypothesis", , Harvard University , cited this Nature paper at least 13 times. But in two 2008 papers, Selkoe mentioned that he did not find Aβ*56 in human body fluids or tissues.
These findings seem to illustrate the problem. In science, once you publish your data, if it is not prone to repeat, you will worry that it is incorrect or untrue. At present, there is little clear evidence that Aβ*56 exists.
images have been tampered with, and the research may mislead the entire field. The 6-month investigation has provided strong support for Schrag's suspicion and raised questions about Lesné's research.
Science invited renowned independent image analysts and top Alzheimer's disease researchers to review Schrag's investigation archives, including neurologist George Perry from the University of Texas San Antonio and UC San Francisco Dr. John Forsayeth. They agreed with Schrag's overall conclusions and questioned hundreds of images, including more than 70 of Lesné's previous papers.
Schrag pointed out that the version published on Nature shows the cutting traces. Some bands look unusually similar. Image source: Science
molecular biologist and famous academic anti-counterfeiter Elisabeth Bik said, "These seem to be images that the author synthesized by pieced together some of the images from different experiments." She also said, "The experimental results obtained may not be the expected results, and the data may have been changed to better fit a hypothesis." Denis Vivien, a cell biologist at
, said he worked with Lesné to write a paper on Aβ for Nature Neuroscience. During the final revision, he saw that the images provided by Lesné were suspicious, so he asked other students to repeat the findings, but failed. He questioned Lesné, but Lesné denied misconduct. Despite his lack of "iron evidence", Vivien withdraws the paper before publication to maintain his scientific integrity and cut off all ties with Lesné.
Selkoe, in accordance with the requirements of Science, consulted Schrag's investigation archives on Lesné's paper and stated that the investigation results were credible. He didn't see PS traces in every suspicious image, but he said, "There are definitely at least 12 or 15 images, and I don't think there is any explanation other than manipulation." Selkoe said that an image showing purified Aβ*56 in that Nature paper showed "very worrying" traces of tampering.
5 years later, the same image appeared again in another different paper, co-authored by Lesné and Ashe.
In short, Schrag identified more than 20 suspicious Lesné papers, 10 of which were related to Aβ*56. In the report submitted to the NIH, Schrag identified the stake: the archive is only a small part of what is readily seen when reviewing public data, and the suspicious work has been cited thousands of times, so it is very likely that it will mislead the entire field of research.
In the year, NIH spent about $1.6 billion on projects involving amyloid, accounting for about half of Alzheimer's total funding. "The most direct and obvious damage is the wasting of NIH funds and thinking in the field, because people use these results as the starting point for their own experiments," said Nobel Prize winner Thomas Südhof. "What's more serious is that some experts now suspect that Lesné's research has misled 16 years of research on Alzheimer's disease.
Schrag shared NIH's response to Science, which stated that complaints considered credible will be sent to the Office of Research Integrity (ORI) under the Department of Health and Human Services for review. The institution can then instruct the funded university to conduct an investigation before the final ORI review, a process that can take years. NIH told Science that they would take scientific research misconduct seriously, but declined to comment.
At present, Lesné still has not responded to reporters' request for comment. A spokesman for the University of Minnesota said the school is reviewing complaints about Lesné's work.A spokesperson for
Nature said the magazine took the concerns raised by people about its paper seriously, but did not comment on it other than that. A few days after the Science was investigated, Nature issued a statement saying it was investigating Lesné's paper published in 2006 and recommended that its results be treated with caution. Holden Thorp, editor-in-chief of
Science, said that these magazines have conducted more and more censorship of images, and “2017 should be the beginning of more focus on this issue, not just us, but the scientific publishing industry as a whole.”
Selkoe is more worried that in this era of increasing doubts and attacks, the Lesné incident may further weaken public trust in science. But he said scientists must prove that they can detect and correct rare, obvious misconduct. "We need to announce these cases and warn the world."
reference link:
https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease
https://www.nature.com/articles/nature04533
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