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Sylvain Lesné

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Sylvain E. Lesné (born 1974) is a French neuroscientist and associate professor at the Department of Neuroscience at the University of Minnesota (UMN) Medical School, known for his research into Alzheimer's disease. He is the primary author of a controversial 2006 Nature paper, "A specific amyloid-β protein assembly in the brain impairs memory".[1] Lesné's work in the 2006 publication and others has been investigated since June 2022 on charges that he manipulated images to inflate the role of Aβ*56 in Alzheimer's.[2] Retracted in 2024,[3] the paper was foundational in the hypothesis that one specific toxic oligomer of the amyloid beta protein, known as Aβ*56, caused memory impairment in Alzheimer's, aligned with the prevailing amyloid hypothesis.

Karen Ashe, the senior author of the 2006 Nature paper – and all authors except Lesné – agreed to retract the paper which, according to Retraction Watch, makes it the second most highly cited paper ever retracted.[2] Responses from other researchers indicated that, while the allegations were significant, the overall impact on amyloid research was small and most Alzheimer's research was not compromised.[4] Other researchers disagreed, and expressed concerns that the doctored images raised doubts about the amyloid hypothesis.[2] As of June 2024 Lesné is still a professor at UMN.[2]

Personal life and education

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Sylvain E. Lesné was born in 1974[5] and raised in Luc-sur-Mer, a small town in the Normandy region in northwestern France.[6] His parents are Bertrand and Marie Carmen Lesné.[7]

Lesné holds a master's degree in biochemistry and has a PhD with a major in neuroscience from the University of Caen Normandy.[8] His doctoral thesis (2002) was "Régulation d'expression et du métabolisme d'APP au cours des pathologies dégénératives" (Regulation of APP expression and metabolism during degenerative pathologies).[9]

Jill Caroline, a Minnesota psychologist and special educator, and Lesné were married in Beauvoir-sur-Mer, France on August 14, 2010.[7]

Early career

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Denis Vivien, a French cell biologist and neuroscience professor who oversaw Lesné's doctoral work[10] and published with Lesné, says Lesné produced some immunostaining images which Vivien thought suspect; others were unable to replicate Lesné's data. Vivien withdrew a paper that was to be published with Lesné, and told Le Monde in 2022 that he had long ago ceased having any personal or scientific contact with Lesné.[11][12]

University of Minnesota

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After graduating from university, Lesné was hired in 2002 as a post-doctoral research associate[8] by Karen Ashe at the University of Minnesota.[11] The Minneapolis Star Tribune described Ashe as a "distinguished professor considered by many to be on the short list for a Nobel Prize for her work".[13] Ashe in turn has described Lesné as her "brilliant postdoctoral fellow"; he had claimed to have developed a means of measuring amyloid beta (Aβ) oligomer proteins separately inside and outside of cells.[11][12] Dennis J. Selkoe, another Alzheimer's researcher, has questioned this method, saying that "it made no biochemical sense".[11]

Since 2009,[14] Lesné has had a laboratory at the UMN funded by National Institutes of Health (NIH).[11][15] He received $774,000 in NIH grants to study Aβ*56 through 2012, in addition to over $7 million for Alzheimer's research through 2022.[14][a]

Lesné was named an associate professor in the Neuroscience Department in 2016, and given tenure according to the Lesné Lab website.[16] He was an associate director at the UMN's N. Bud Grossman Center for Memory Research and Care, where Ashe serves as director.[6][17][18] As of 2024, he is a scholar at the UMN's Institute for Translational Neuroscience.[6][19]

Alzheimer's research

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Lesné is the lead author, with Ashe and others as co-authors, of a controversial 2006 report published in Nature.[20] The paper, "A specific amyloid-β protein assembly in the brain impairs memory", suggested the Aβ*56 oligomer (known as amyloid beta star 56 and Abeta*56)[14] as a cause of Alzheimer's disease.[11][21] The study proposed that Aβ*56 was responsible for the memory deficits that occur in Alzheimer's.[20] According to the Star Tribune, images from the study showed the Aβ*56 protein growing as mice began to decline and age with dementia.[13]

Science says it was the fifth-highest cited paper in Alzheimer's research as of early 2022, with approximately 2,300 other articles citing it.[11] The Guardian says the paper was "highly influential" and calls it "one of the most cited pieces of Alzheimer's disease research in the last two decades", writing that it has "dominated the field" of research.[20] The Atlantic likens publication in Nature to a "career high-water mark", reflecting especially important findings.[22] The Daily Telegraph states that the "seminal research paper" led to increased drug research funding worldwide.[23] For the paper, Lesné was listed as of May 13, 2022 at UMN Medical School's Wall of Scholarship recognizing faculty who "must have first or last author credits on a publication that has been cited at least 1,000 times".[24][25][b]

Other scientists have not been able to replicate the results specific to Aβ*56 and whether it exists is questioned;[11][20] several Alzheimer's researchers stated in July 2022 on the website Alzforum that they have long been skeptical of the Aβ*56 findings.[22][26] Frédéric Checler, a lab director at the Institute of Molecular and Cellular Pharmacology [fr] in Sophia Antipolis, France, told Le Monde in 2022 that the 2006 Nature publication raised suspicions early on, saying: "It is extremely difficult to obtain a pure aggregate protein, and to be certain that its nature remains the same after its purification."[12]

2022 investigation

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A July 2022 publication in Science authored by Charles Piller questioned the authenticity of Western blot images used in Lesné's research;[11] Piller's report alleges, based on a six-month investigation,[23] that images may have been doctored to emphasize the role of Aβ*56 in Alzheimer's.[14] Matthew Schrag, a Vanderbilt University neuroscientist,[11] raised concerns in a whistleblower report that images were falsified,[23] casting doubt on the association between the Aβ*56 protein and dementia symptoms.[13] Schrag told USA Today the images had similarities to what one would expect from software like Photoshop.[27]

The editors of Nature responded with a July 14, 2022 note stating that they were aware of and investigating the concerns and that "readers are advised to use caution when using results reported therein".[1][14] The NIH, where Schrag lodged the whistleblower report, is also investigating the matter, and could decide to pass it on the United States Office of Research Integrity if the complaints are found valid.[23]

Lesné is the leading researcher overseeing or instigating the work in about ten disputed studies as of 2022;[14][20][28] as of May 2023, according to the Minneapolis Star Tribune, images have been questioned on 20 articles he has authored.[29] Another journal, Science Signaling, has issued two expressions of concern,[c][d] and two other journals,The Journal of Neuroscience[e] and Brain,[f] have issued corrections on articles associated with Lesné and his UMN co-workers.[6][28] Retraction Watch states that Ashe co-authored some of the disputed papers, and that the authors in the disputed work do not overlap except for two from UMN Department of Neuroscience.[28] On the corrected paper in Brain, Ashe and Lesné are the senior and first authors.[11] Piller did not find the same image inconsistencies in other work published by Ashe or Vivien without Lesné as a co-author.[11]

Lesné's work in the 2006 publication and others has been investigated since June 2022.[2][20] Alzheimer's researcher John Forsayeth commented that Ashe had been guilty of a "major ethical lapse" in oversight of data and Dennis Selkoe, a Harvard Medical School neurologist, said he did not understand how Ashe failed to "hyperscrutinize" data considering reactions to the 2006 Nature report. Piller writes that Lesné's work was already being queried before his investigation, when other researchers were unable to replicate the results.[11]

As of June 2024, Lesné had not commented;[2][10][27] he is still a professor at UMN.[2] Ashe stated via email in 2022 that "it is devastating to discover that a colleague may have misled me and the scientific community ... [it is also] distressing that a major scientific journal has blatantly misrepresented the implications of my work."[14][g] The Daily Telegraph states that the "authors of the Minnesota paper have defended their original findings" and support the role of amyloid as a cause of Alzheimer's.[23] USA Today reported that Ashe had started the process to retract the Nature paper, but that had not been done as of July 29, 2022 because six of the eight co-authors would not sign off on the request.[27] She stated via email that "... the figures in question were manipulated in a way that made them look nicer but did not affect one word in the paper".[27] Defending the work, she said that the image adjustments "should not have occurred", but called them "non-material" and "inconsequential" to the research overall.[10]

2024 retraction

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In May 2023, the Star Tribune reported that the senior author of the study, Karen Ashe, was using new techniques to re-do the work reported in the 2006 Nature study, this time without Lesné, and that she stated "it's my responsibility to establish the truth of what we've published".[29] Ashe's new article was published in March 2024 in the journal iScience.[30]

In May 2024, Ashe announced that the 2006 publication would be retracted, although she stated that the manipulated images did not affect the study's conclusions; according to Retraction Watch, this makes it the most highly cited paper ever retracted.[2] The only co-author who did not agree with retraction was Lesné.[2][31] Nature published retraction of the article on June 24, 2024, noting that the edited images showed "excessive manipulation, including splicing, duplication and the use of an eraser tool".[3][31]

Impact on Alzheimer's research

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Responses from some researchers indicated that, while the allegations were significant, the overall impact on amyloid research was small and most Alzheimer's research was not compromised.[32] Other researchers disagreed, and expressed concerns that the doctored images raised doubts about the amyloid hypothesis.[2]

If studies were manipulated, Jeremy Olson stated in the Star Tribune that "thinking on the causes of the disease and dementia" could change.[14] Olson wrote that the allegations "wouldn't scuttle the entire theory of amyloid proteins", but "Selkoe told Science that they undercut the existence of the Aβ*56 protein that is central to Lesné's research."[13] A Massachusetts General Hospital researcher, Rudolph E. Tanzi, said the alleged manipulation "had virtually zero effect on progress" in Alzheimer's research and characterized statements about its effect on the overall field and the amyloid hypothesis as "hyperbole".[27]

USA Today states that experts have "downplayed" the impact the Nature paper had on drug discovery research.[27] Alzheimer's researchers or organizations from Australia,[33] France,[12] and the UK[23][27][34] state that the general theory behind the amyloid hypothesis remains valid. Selkoe, who Science describes as "a leading advocate of the amyloid and toxic oligomer hypotheses", opined that the "broader amyloid hypothesis remains viable" and referred to the alleged image manipulation as "what really looks like a very egregious example of malfeasance that's squarely in the Aβ oligomer field".[11]

Sara Imarisio of Alzheimer's Research UK said:[23]

"These allegations are extremely serious. ... The amyloid protein is at the centre of the most influential theory of how Alzheimer's disease develops in the brain. But the research that has been called into question is focused on a very specific type of amyloid, and these allegations do not compromise the vast majority of knowledge built up during decades of research into the role of this protein in the disease."[23]

The U.S. National Institute on Aging issued a statement saying:[35]

... the Aβ*56 oligomer was one of many being explored at the time ... immunotherapies targeting Aβ monomers (a single 'unit' of Aβ), other types of oligomers, and the longer amyloid fibrils have been the focus of studies ... there is still a strong scientific rationale for continuing to explore approaches that target different aspects and collections of the amyloid protein.[35]

Legacy

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Writing in The Atlantic, David Grimes comments that the Lesné matter exemplifies the publish or perish dilemma, in which pressure to publish in academia can lead to wasted research dollars and inaccurate findings.[22] A National Public Radio broadcast on the show All Things Considered linked instances of scientific misconduct to competition for funding.[36]

Notes

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  1. ^ See Reporter.nih.gov Advanced search for NIH grants totaling $7,997,415 with Lesné listed as principal investigator.
  2. ^ The UMN Medical School Wall of Scholarship webpage does not list Lesné as of July 28, 2022.
  3. ^ Expression of concern June 21, 2022 for Amar F, Sherman MA, Rush T, Larson M, Boyle G, Chang L, Götz J, Buisson A, Lesné SE (May 2017). "The amyloid-β oligomer Aβ*56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation". Sci Signal. 10 (478). doi:10.1126/scisignal.aal2021. PMC 5859319. PMID 28487416.
  4. ^ Expression of concern June 21, 2022 for Alfonso SI, Callender JA, Hooli B, Antal CE, Mullin K, Sherman MA, Lesné SE, Leitges M, Newton AC, Tanzi RE, Malinow R (May 2016). "Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease". Sci Signal. 9 (427): ra47. doi:10.1126/scisignal.aaf6209. PMC 5154619. PMID 27165780.
  5. ^ Erratum June 15, 2022 for Larson ME, Sherman MA, Greimel S, Kuskowski M, Schneider JA, Bennett DA, Lesné SE (July 2012). "Soluble α-synuclein is a novel modulator of Alzheimer's disease pathophysiology". J Neurosci. 32 (30): 10253–66. doi:10.1523/JNEUROSCI.0581-12.2012. PMC 3425439. PMID 22836259.
  6. ^ Erratum May 13, 2022 for Lesné SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, Ashe KH (May 2013). "Brain amyloid-β oligomers in ageing and Alzheimer's disease". Brain. 136 (Pt 5): 1383–98. doi:10.1093/brain/awt062. PMC 3634198. PMID 23576130.
  7. ^ See also Ashe's July 22 response posted on the Alzheimer Research Forum, referencing "allegations about images that may have been inappropriately altered by my former co-worker Dr. Sylvain Lesné".[26]

References

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  1. ^ a b Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (March 2006). "A specific amyloid-beta protein assembly in the brain impairs memory". Nature. 440 (7082): 352–7. Bibcode:2006Natur.440..352L. doi:10.1038/nature04533. PMID 16541076. S2CID 4407385. Archived from the original on July 22, 2022. Retrieved July 22, 2022. (Retracted, see doi:10.1038/s41586-024-07691-8, PMID 38914864) See lay summary: "Aβ Star is Born? Memory Loss in APP Mice Blamed on Oligomer", Alzheimer Research Forum, March 17, 2006.
  2. ^ a b c d e f g h i j Piller C (June 4, 2024). "Researchers plan to retract landmark Alzheimer's paper containing doctored images". Science. Retrieved June 4, 2024.
  3. ^ a b Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (June 24, 2024). "Retraction Note: A specific amyloid-β protein assembly in the brain impairs memory". Nature. 631 (8019): 240. doi:10.1038/s41586-024-07691-8. ISSN 1476-4687. PMID 38914864.
  4. ^ See Piller 2022, Alltucker & Weintraub 2022, Olson 2022a, Olson 2022b, Layt 2022, Morin & Cabut 2022, Knapton 2022,Alzheimer's_Society 2022 and Hodes 2022.
  5. ^ "Lesné, Sylvain (1974–....)". idref.org (in French). Agence bibliographique de l'enseignement supérieur. Retrieved July 24, 2022.
  6. ^ a b c d "People: Sylvain Lesné". The Lesné Laboratory. 2017. Archived from the original on June 2, 2024. Retrieved June 2, 2024.
  7. ^ a b "Caroline-Lesne". Forum Communications Company. September 18, 2010. Archived from the original on July 27, 2022. Retrieved July 27, 2022.
  8. ^ a b Lesné SE (2013). "Breaking the Code of Amyloid-β Oligomers" (PDF). International Journal of Cell Biology. 2013. OMICS Group Conferences: 950783. doi:10.1155/2013/950783. PMC 3773433. PMID 24072999. Archived from the original (PDF) on July 27, 2022. Retrieved July 27, 2022.
  9. ^ Lesné, Sylvain; Vivien, Denis (January 2002). Régulation d'expression et du métabolisme d'APP au cours des pathologies dégénératives [Regulation of APP expression and metabolism during degenerative pathologies]. theses.fr (These de doctorat) (in French). Retrieved 24 July 2022. Lesné's doctoral thesis catalogue entry on theses.fr, with abstract.
  10. ^ a b c Olson J (July 30, 2022). "University of Minnesota researcher seeks to sustain Alzheimer's findings amid image scandal". Star Tribune. Archived from the original on July 31, 2022. Retrieved July 31, 2022.
  11. ^ a b c d e f g h i j k l m n Piller C (July 21, 2022). "Blots on a field?". Science. 377 (6604): 358–363. Bibcode:2022Sci...377..358P. doi:10.1126/science.add9993. PMID 35862524. S2CID 250953611. Archived from the original on August 28, 2022.
  12. ^ a b c d Morin H, Cabut S (July 25, 2022). "Recherche sur la maladie d'Alzheimer : des soupçons d'inconduites scientifiques" [Research on Alzheimer's disease: suspicions of scientific misconduct]. Le Monde (in French). Retrieved July 25, 2022. 'Je ne souhaite pas épiloguer sur le cas de Sylvain Lesné, avec qui j'ai décidé de stopper toutes relations scientifiques et personnelles depuis bien longtemps', écrit le chercheur au Monde. ... Le chercheur se souvient d'ailleurs qu'à sa publication, l'article avait suscité des réticences dans la communauté, pas tant pour une suspicion de manipulations de données que pour des raisons techniques. 'Il est extrêmement difficile d'obtenir une protéine agrégée pure, et d'être certain que sa nature reste la même après sa purification', souligne-t-il. ['I do not wish to dwell on the case of Sylvain Lesné, with whom I decided to stop all scientific and personal relations a long time ago,' writes the researcher to Le Monde. ... The researcher also remembers that when it was published, the article had aroused reluctance in the community, not so much for a suspicion of data manipulation as for technical reasons. 'It is extremely difficult to obtain a pure aggregate protein, and to be certain that its nature remains the same after its purification', he underlines.]
  13. ^ a b c d Olson J (July 21, 2022). "Review questions key work by University of Minnesota on Alzheimer's". Star Tribune. Archived from the original on July 24, 2022. Retrieved July 24, 2022.
  14. ^ a b c d e f g h Olson J (July 22, 2022). "University of Minnesota scientist responds to fraud allegations in Alzheimer's research". Star Tribune. Archived from the original on July 26, 2022. Retrieved July 26, 2022.
  15. ^ "The Lesné Laboratory". Sylvain Lesné. August 2016. Archived from the original on July 27, 2022. Retrieved July 27, 2022.
  16. ^ "Promotion & Tenure to Associate Professor". The Lesné Lab. May 25, 2016. Archived from the original on April 23, 2021. Retrieved July 28, 2022.
  17. ^ Wroge L (February 3, 2015). "With aging population, Alzheimer's a main focus". Minnesota Daily. Archived from the original on 8 February 2015. Retrieved July 22, 2022.
  18. ^ "Team". N. Bud Grossman Center for Memory Research and Care: University of Minnesota. 20 February 2015. Archived from the original on July 12, 2017. Retrieved July 30, 2022.
  19. ^ "Scholars". Institute for Translational Neuroscience: University of Minnesota. 28 March 2018. Archived from the original on June 2, 2024. Retrieved June 2, 2024.
  20. ^ a b c d e f Glenza J (July 23, 2022). "Critical elements of leading Alzheimer's study possibly fraudulent". The Guardian. Archived from the original on July 23, 2022. Retrieved July 23, 2022.
  21. ^ Lerner M (February 13, 2012). "Dr. Karen Ashe: Stalking Alzheimer's". Star Tribune. Archived from the original on October 17, 2016. Retrieved July 22, 2022.
  22. ^ a b c Grimes DR (July 29, 2022). "What an Alzheimer's Controversy Reveals About the Pressures of Academia". The Atlantic. Archived from the original on July 29, 2022. Retrieved July 29, 2022.
  23. ^ a b c d e f g h Knapton S (July 21, 2022). "'Manipulated' Alzheimer's data may have misled research for 16 years". The Daily Telegraph. Archived from the original on July 22, 2022. Retrieved July 23, 2022.
  24. ^ "Wall of Scholarship". University of Minnesota. 13 March 2018. Archived from the original on May 13, 2022. Retrieved July 28, 2022.
  25. ^ "Honored at the UMN Wall of Scholarship". The Lesné Lab. November 5, 2015. Archived from the original on April 23, 2021.
  26. ^ a b "Sylvain Lesné, Who Found Aβ*56, Accused of Image Manipulation". Alzheimer Research Forum (alzforum.org). July 22, 2022. Archived from the original on July 29, 2022. Retrieved July 29, 2022.
  27. ^ a b c d e f g Alltucker K, Weintraub K (July 29, 2022). "Investigation into pivotal Alzheimer's study raises questions on suspected disease culprit". USA Today. Retrieved July 29, 2022.
  28. ^ a b c Marcus A (June 21, 2022). "Papers on Alzheimer's slapped with expressions of concern". Retraction Watch. Archived from the original on June 30, 2022. Retrieved July 23, 2022.
  29. ^ a b Olson J (May 13, 2023). "University of Minnesota researcher seeks to put tarnished Alzheimer's discoveries back on track". Star Tribune. Retrieved May 14, 2023.
  30. ^ Liu P, Lapcinski IP, Hlynialuk CJ, Steuer EL, Loude TJ, Shapiro SL, Kemper LJ, Ashe KH (March 2024). "Aβ∗56 is a stable oligomer that impairs memory function in mice". iScience. 27 (3): 109239. doi:10.1016/j.isci.2024.109239. PMC 10905009. PMID 38433923.
  31. ^ a b Olson J (June 24, 2024). "Landmark University of Minnesota papers on Alzheimer's disease and stem cells retracted". Star Tribune. Retrieved June 25, 2024.
  32. ^ See Piller 2022, Alltucker & Weintraub 2022, Olson 2022a, Olson 2022b, Layt 2022, Morin & Cabut 2022, Knapton 2022,Alzheimer's_Society 2022 and Hodes 2022.
  33. ^ Layt S (July 25, 2022). "Alleged Alzheimer's research fraud won't derail search for cure". The Sydney Morning Herald. Retrieved July 26, 2022.
  34. ^ "Explaining the amyloid research study controversy" (Press release). Alzheimer's Society. July 25, 2022. Retrieved July 28, 2022.
  35. ^ a b Hodes, Richard J. (July 29, 2022). "NIA statement on amyloid beta protein dementia research". National Institute on Aging. Retrieved September 1, 2022.
  36. ^ Crann T, Bui N (July 28, 2022). "'It's about a bad system': Fraud and fabrication in scientific research – How competition and limited funding can lead to dishonesty". All Things Considered. Minnesota Public Radio. Retrieved July 30, 2022.
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