17 Oct 2024
A most sensible researcher’s fall from grace sends surprise waves during the medical group. Such is the case with neuropathologist Eliezer Masliah, who stands accused of picture falsification spanning 26 years. Masliah has printed greater than 800 papers. He is among the global’s main professionals on α-synuclein, a protein inquisitive about Alzheimer’s and Parkinson’s sicknesses and the objective of more than one medicine in scientific trials founded partly on his analysis.
Masliah’s preclinical knowledge have supported scientific trials focusing on α-synuclein.
Many micrographs display up more than one occasions underneath other labels, some in more than one publications; many western blots seem spliced.
Masliah can have acted on my own, however ratings of co-authors now query their collaborations.
Establishments that hired Masliah and his primary collaborators have refused to reply to questions concerning the topic.
On September 26, 2024, the Nationwide Institute on Ageing (NIA) introduced that Masliah have been got rid of from his place as medical director of the institute’s neuroscience department after a nine-month-long NIH investigation discovered “falsification and/or fabrication involving re-use and relabel of determine panels representing other experimental leads to two publications.”
The similar day, Science mag posted an investigative tale by which reporter Charles Piller and a group of picture analysts compiled a 286-page file of 132 papers that seem to include duplicated or doctored photographs and figures.
Alzforum has reviewed the file. It makes for wrenching studying. It main points how figures in every paper—occasionally one, occasionally 3 or extra—can have been manipulated, ceaselessly to turn the similar data underneath other labels. The file’s authors have posted the entire figures as feedback at the PubPeer web page. Masliah is the one co-author who seems on the entire puzzled papers. They run from 1997 to 2023, years Masliah was once hired on the College of California, San Diego, and NIA in Bethesda, Maryland.
Reuse, Recycle? Mouse hippocampi appear to include the similar picture cropped otherwise and printed as being from other samples. Panel G is categorised as coming from a non-transgenic mouse, while H is purportedly from a Nogo homozygous knockout. A number of dozen papers had been flagged for this sort of drawback. PubPeer.
On September 23, 2024, 3 days prior to his elimination and the Science article, Masliah opened the 2024 NIH Alzheimer’s Analysis Summit, talking after NIA director Richard Hodes. The NIH didn’t reply to questions on whether or not the convention organizers knew Masliah was once underneath an investigation that had concluded on September 15, 2024.
Two weeks after the allegations first seemed, the neurodegeneration analysis group continues to be reeling with disbelief. Many scientists spoke with Alzforum however had been unwilling to be quoted. In essence, they stated that the level of the manipulation took their breath away and made them deeply involved for the popularity of medical investigation of their box.
Already, the placement has drawn the attention of a U.S. congressional committee this is urging better transparency and different reforms on the NIH. “Those findings are deeply troubling and aggravate an already rising mistrust of the NIH’s medical analysis,” Cathy McMorris Rodgers (R-WA), chair of the Space Power and Trade Committee, in conjunction with two subcommittee chairs, stated in a commentary.
Masliah has now not commented publicly and didn’t reply to an interview request from Alzforum. The NIH, responding on behalf of NIA, stated it “does now not talk about body of workers issues” when requested whether or not Masliah continues to be hired on the institute. A spokesperson at UCSD, the place Masliah labored between 1990 and 2016 prior to transferring to NIA, would now not ascertain if it is carrying out its personal investigation however stated it “addresses all allegations based on college coverage and procedures.”
In the meantime, fear is operating during the group that suspicion will fall on Masliah’s lab participants or even some collaborators. Some are clarifying their collaborations (see remark from Takeshi Iwatsubo, underneath). Alzforum discovered that the 132 puzzled papers contain greater than 550 co-authors. They come with junior researchers, scientists at biotech corporations, lab technicians, and one of the vital maximum outstanding names in neurodegeneration analysis. “It is depressing to take into consideration it,” stated Samuel Gandy of Icahn College of Drugs at Mount Sinai in New York Town.
Double Imaginative and prescient? In those mind sections from α-synuclein transgenic and non-transgenic mice, small sections of pictures seem to be duplicated thru “cloning” the usage of picture manipulation device. Coloured packing containers point out duplicated areas inside of the similar panel. PubPeer.
Alzforum contacted 39 of Masliah’s former collaborators, inquiring for remark at the state of affairs and at the nature in their collaborations with him. About part didn’t reply. Others declined, announcing their interactions with Masliah’s lab have been minimum—sharing a reagent, for example, or hiring him as a expert to research samples. Many directed Alzforum to their institutional press places of work, which presented no data, or to school attorneys. NIH scientists who labored in Masliah’s department stated that they had been suggested to refer media requests at the topic to the company’s communications administrative center.
The few researchers who did talk with Alzforum at the file described Masliah as personable, hard-working, and the uncommon administrator who was once ready to run a big executive program whilst proceeding to provide his personal analysis. “I at all times had immense appreciate for Eliezer,” stated Benjamin Wolozin, Boston College. “Now not many of us are preferred via such a lot of others. We now have numerous nice scientists however many people have our character quirks.”
Wolozin stated he idea Masliah was once the easiest particular person to take over the neuroscience portfolio at NIA, which he did in 2016. “His judgment at the box of science was once remarkable,” Wolozin stated. Nonetheless, “What he did was once unacceptable and absolute grounds for dismissal,” Wolozin stated.
The NIA stated it began its misconduct evaluate procedure in Would possibly 2023 on the request of the Place of business of Analysis Integrity, which had gained allegations of information manipulation, and began its formal investigation in December 2023. NIA deputy director Amy Kelley is serving as appearing director of the neuroscience department.
Neither UCSD nor NIA would resolution questions past issuing boilerplate statements. “UC San Diego is dedicated to the absolute best moral and prison requirements within the behavior of study and we take allegations of study misconduct very severely,” the college wrote. An NIH spokesperson stated the company “takes allegations of study misconduct severely. NIH does now not talk about whether or not or now not a analysis misconduct continuing is going down and does now not touch upon NIH complaints.”
The NIH even declined to substantiate which two papers it had known as containing falsified knowledge, however issued a commentary announcing they “constitute early-stage analysis performed in mice on alpha-synuclein, a protein present in neurons. Whilst those research tell translational analysis in people, this is a very small piece of the entire analysis that contributes to the sphere of neurogenerative sicknesses.” The 2 articles, NIH stated, had been cited in different papers 18 and 11 occasions respectively. Further questions went unanswered.
Two? Or 132?
Commenters on PubPeer and the file’s authors flagged problems throughout a minimum of 132 papers on plenty of subjects. The issues vary from arguably minor to egregious. Examples come with a number of cases of questionable statistics, corresponding to lacking error bars or statistically not likely knowledge issues. In a single example, a photograph of a rat, categorised as a mouse, is used as an example conduct assays of mice’s purported reaction to an investigational remedy.
Ratted Out? An information determine on how antibodies in opposition to 3R tau reportedly stepped forward mouse conduct comprises a photograph of a rat, now not a mouse. The picture is the same to 1 illustrating Open Box Exploratory Locomotion for instance of rat phenotyping assays at the web page of UC Davis’s Rodent Habits Core ( No researchers from that establishment are indexed at the paper (Remark #3 on PubPeer web page,
The commonest considerations contain western blots that include duplicated bands or more than one photographs spliced in combination. Probably the most fresh papers comprises it sounds as if duplicated recording photographs from a kymograph, which presentations motion of lysosomes alongside axons. A number of dozen papers include histological photographs that seem in more than one determine panels categorised as coming from other animal traces or from other experimental remedy prerequisites, or sections of tissue that seem to have been cloned, circled, deleted or in a different way altered.
A number of an identical figures seem underneath other labels in more than one papers printed years aside in numerous journals, together with one this is categorised as a rat mind in a 2013 paper and a mouse mind in a 2015 paper. “Usually, when I am proven most of these photographs, I’ve an excessively tough time understanding if they’re duplicated,” stated George Perry, College of Texas at San Antonio. “On this specific case, I didn’t have a troublesome time.”
Wolozin has been inquisitive about investigating fraud instances prior to now. He stated that the number of alleged issues can be a spectrum starting from sloppiness to planned fraud. “It is going to be tricky for Eliezer to vindicate himself, as a result of in fraud instances, you’re presumed accountable till confirmed blameless,” he stated. Researchers accused of misconduct ceaselessly declare that they misplaced the unique knowledge; if a long time have handed because the paper got here out, this may well be true. “That creates a excessive bar,” Wolozin stated.
Wild Western? Ratings of publications include western blots that seem to have duplicated lanes or include more than one blots spliced in combination. The file’s authors enhanced the distinction to turn that packing containers display rapidly an identical lanes. From PubPeer.
Todd Golde, Emory College, Atlanta, was once unsurprised that NIH and UCSD have stayed silent. He famous that investigating even a unmarried e-newsletter can take months, and that the establishments have dozens of allegations to appear into. They might also face prison problems involving corporations that experience approved medicine in response to Masliah’s knowledge, Golde famous. In some instances, the NIH can pressure establishments to go back grant cash that has been spent on fabricated analysis.
Nonetheless, Golde stated, slowly appearing interior investigations at the back of closed doorways within the face of plentiful public knowledge suggesting misconduct can seem like a cover-up. Talking off the file, different main scientists expressed fear that the establishments will slow-walk, reduce, after which try to bury an inconvenient factor corresponding to this.
Golde thinks it’s unlucky that the issues had been published via a Science mag information tale as a substitute of via a magazine or establishment. “It is unhealthy for everyone as a result of it isn’t truthful to the sphere or the investigator,” he stated. “There may well be fair errors; all of us lead them to.”
Duplicating photographs, as is the case with lots of the papers, generally is a mistake. Establishments now have the duty of figuring out whether or not photographs had been deliberately manipulated and, if that is so, via whom. None of Masliah’s present and previous lab technicians Alzforum contacted, a few of whom seem on dozens of papers with him, spoke back, or did so handiest to request no additional touch.
The senior researcher is liable for knowledge produced in his or her lab. If truth be told, regardless that, “a few of them needed to had been complicit,” Wolozin stated. “It may well be complicit within the sense that they are afraid to tackle their boss.” Nonetheless, Wolozin suspects there will have to had been communicate. “How may just there now not be gossip about it? It’s mind-boggling,” he stated.
Many scientists are enthusiastic about papers they co-authored with Masliah. Doug Galasko, UCSD, co-authored 5 papers within the file. He stated he would categorize their issues as “misconduct.” Galasko stated that the scientific core on the Shiley-Marcos ADRC at UCSD, which he directs, principally labored in parallel with Masliah’s lab to review Lewy frame pathology in folks with Parkinson’s. Galasko, a neurologist, treated scientific knowledge whilst Masliah carried out pathology on post-mortem knowledge, they usually blended their findings. “I’d have noticed the general paper, however wouldn’t have long gone during the figures intimately,” he stated.
Galasko stated he had by no means heard Masliah’s knowledge puzzled publicly. “I don’t have any proof about reason or how any of this stuff came about,” he stated. “The level throughout such a lot of papers does lift critical questions.”
Different professors at UCSD who labored with Masliah declined to reply to questions concerning the respective roles their labs performed within the file’s publications. Paula Desplats, who seems on 19 of the flagged papers, stated she does “now not but have the entire main points.” Leslie Crews, who collaborated on 23 flagged papers, stated she was once “not able to remark at the moment,” bringing up paintings points in time. Each directed Alzforum to UCSD’s press administrative center, which refused to talk with the click.
Dora Video games labored at Athena Neurosciences, South San Francisco, till she retired in 2012. She doubts accusations of planned misconduct. “There might rather well had been oversights with the quantity of labor he was once doing,” she stated, including that she knew Masliah as a conscientious researcher. “I will be able to’t imagine that he would deliberately devote fraud or physician figures to misinform.” Video games had now not noticed the file on the time she spoke with Alzforum.
Video games labored with Masliah on an α-synuclein-targeting antibody referred to as prasinezumab, which is being advanced via Prothena Biosciences for Parkinson’s illness. She stated Masliah in my opinion analyzed Athena’s histology samples however was once blinded to that have been controls and that have been handled. “There have been numerous exams and balances in those experiments,” she stated. Video games seems on six papers indexed within the file; many of the considerations about them contain western blot manipulation.
Dot Dot Dot. Neuritic α-synuclein accumulation represented as darkish staining. This excerpt of a picture panel exemplifies more than one cases of alleged deletion or addition of such foci to Figures 2, 4, 9 of the paper. (From Remark 3 of six feedback on PubPeer web page
Every other common co-author is Robert Rissman. Of his 41 papers with Masliah, 15 are discussed within the file. Rissman to start with agreed to speak with Alzforum, announcing he was once “in a state of concern” compounded via his bearing in mind Masliah to be a mentor and private pal, however then directed us to USC’s press administrative center. Rissman had labored at UCSD since 2008, and in June 2024 took a place on the College of Southern California, Los Angeles.
USC stated they’re investigating Rissman’s paintings with Masliah. “USC takes any allegations of study integrity very severely,” the college stated. “In step with federal laws and USC insurance policies, this evaluate will have to be stored confidential. Consequently, we’re not able to offer any more data.”
USC continues to be carrying out an interior evaluate of Berislav Zlokovic, whose analysis into the function of the blood-brain barrier in AD and stroke drew public scrutiny in 2023 (see Science).
Now not all of Masliah’s many co-authors labored with him carefully. Markus Mandler, Tridem Bioscience, Vienna, is a co-author on 4 of the puzzled papers. They concerned growing immunotherapies in opposition to α-synuclein at AFFiRiS. Mandler stated that the Austria-based corporate, based in 2003 round immunotherapy approaches for Alzheimer’s and Parkinson’s sicknesses, would send immunization experiments and samples to UCSD for evaluation. “At no time all over this collaboration did we have now any suspicion that he could be manipulating knowledge, or that he could be the usage of manipulation to toughen his conclusions,” Mandler stated.
Mandler stated it will had been tricky to have noticed determine duplication with out image-analysis device that was once now not frequently used 10 years in the past. “In case you are now not fascinated about this type of factor, you could possibly additionally now not suppose that that is imaginable,” he stated. Mandler stated many different papers from different labs have since validated the papers’ total conclusion that focusing on α-synuclein has doable as an immunotherapy goal. “I am satisfied that the principle message of the paper remains legitimate,” he stated.
Mandler is not affiliated with AFFiRis, and AffiRis is not pursuing AD or PD. Certainly one of its two systems, AD02, was once terminated; the opposite, PD01, bought to AC Immune.
Martin Citron, UCB, Brussels, stated his corporate had reached an identical conclusions relating to a 2023 paper within the file on which Masliah was once credited as a contractor however now not a co-author (Value et al., 2023). The learn about examined an α-synuclein drug referred to as minzasolmin. UCB approved it from Neuropore Remedies, a San Diego-based corporate Masliah co-founded. The query comes to one panel of 7 in a determine appearing mouse hippocampi handled with the drug. UCB says that Masliah was once blinded to the animals’ remedy standing. The file’s authors imagine the staining within the keep watch over pattern seems suspiciously gentle. Citron and UCB disagree and stand via the paper’s conclusions. “There may be not anything that adjustments, undermines, or in a different way affects the validity or accuracy of the preclinical effects or at the ongoing scientific building program,” a UCB spokesperson stated.
Minzasolmin is in Segment 2 trials, with effects anticipated later this 12 months. Citron stated that the scientific knowledge outweighs preclinical mouse knowledge, and that the latter has been replicated in other places. “It will be very tricky for a unmarried investigator to misdirect a complete box,” he informed Alzforum, however added that the allegations are miserable. “On the finish of the day this is helping no one,” Citron stated.
“Essentially the most unforgivable phase is that if there may be medical misconduct and knowledge manipulation supporting therapeutics which might be transferring into scientific trials. That’s an enormous drawback,” Golde stated. “Other people could be put at needless possibility for one thing for which there isn’t medical proof.” The NIH paused a tribulation of an investigational stroke drug via USC’s Zlokovic; no such motion has been involved in Masliah’s paintings (Los Angeles Instances).
8 of the file’s papers fear cerebrolysin, a handled peptide extract from farm animals mind this is being administered for cerebrovascular prerequisites in Eu nations. Cerebrolysin isn’t authorized within the U.S. For instance, Rockenstein et al., 2015, has 13 flags, with picture overlap animations (PubPeer). For any other instance, see picture underneath.
All in One? In line with PubPeer Remark 2 to this paper, panels o, p, q seem to come back from the similar hippocampus. Panels o and q are printed to constitute other mouse traces handled with cerebrolysin; p purports to turn a vehicle-treated mouse. Coloured packing containers define the overlap; remark 3 hyperlinks to animation on PubPeer web page.
In line with the file, 4 of Masliah’s papers on preclinical fashions that supported the advance of prasinezumab seem to include manipulated photographs. The drug is in Segment 2. One learn about reported no efficacy after twelve months on prasinezumab, and critical opposed occasions in 7 % of handled sufferers; alternatively, subgroup analyses and a long-term extension trace at slower decline in sure teams after a number of years of remedy (Pagano et al., 2022). Researchers warning that it’s too quickly to affiliate the drug’s efficiency with doable manipulations in preclinical knowledge. “We truly want to see dialogue about how those effects had been replicated time and again in numerous tactics via unbiased folks,” Video games stated.
“Medical trials fail for lots of causes,” Wolozin stated, together with other mechanisms using the mouse phenotype and human illness, or now not sufficient antibodies entering the mind. “Those are issues that may handiest be taken care of out, sadly, in scientific trials.”
Coming: A Wave of Corrections and Retractions?
Journals by which the puzzled papers are printed at the moment are investigating the figures. Alzforum known 13 corrections to Masliah’s papers recently in PubMed, maximum made in accordance with older flags on PubPeer that precede via a number of years the present investigation via Science. No papers had been retracted so far.
One fresh correction considerations a 2022 paper in NPJ Vaccines that examined an α-synuclein vaccine referred to as PV-1950D in mice (Kim et al., 2023). In a touch upon PubPeer, the paper’s senior writer, Michael Agadjanyan, Institute for Molecular Drugs, Huntington Seaside, California, expressed marvel that he had now not been made conscious about the correction to 4 panels in a determine that contained duplicated photographs of hippocampi. Nor was once the correction entire: The file discovered one different panel within the determine was once just like one in a separate determine however have been circled 180 levels.
An e mail it sounds as if despatched via Masliah to NPJ Vaccines attributed the issue to “having more than one panels opened all over the assembling of the multi-panel determine and unintentionally now not the usage of the proper panel of hippocampus handled with PV-1950D within the erratum that was once submitted in 2023.” Masliah wrote he was once going to ship the magazine a completely corrected determine. Agadjanyan, in his indignation, shared the e-mail with Alzforum. Our requests to substantiate its authenticity with Masliah gained no reaction. The magazine’s managing editor declined to substantiate the correspondence, however did answer to mention that, on October 15, 2024, the magazine added a be aware of shock to the paper (Kim et al., 2024).
“I’m stunned and deeply bothered via the possible implications of Dr. Masliah’s medical misconduct,” Agadjanyan informed Alzforum, including that he’s actively taking a look into what this may imply for his prior collaboration. A few of the dozens of implicated papers, more than one examples exist the place corrections seem to have been partial, or irregularities had been therefore flagged within the corrections themselves (e.g. Dhungel et al. 2023 on PubPeer).
The newest correction to one in every of Masliah’s papers, which isn’t within the file or PubPeer, was once posted October 3, 2024. It involved a histological picture of a hippocampus that have been duplicated throughout two figures in a paper in EMBO Reviews (Maeda et al., 2016). Its senior writer, Lennart Mucke, College of California, San Francisco, seems on 47 papers with Masliah, seven of which can be within the file. “It will be beside the point for me to remark in this factor till I’ve advanced a greater working out of all main points concerned,” Mucke wrote to Alzforum.
One magazine—PLoS ONE—has up to now issued an expression of shock, a step generally taken prior to a retraction (Duka et al., 2013). The paper, about tau phosphorylation, on which Masliah was once a co-author, contained suspiciously an identical western blot bands, amongst different imaginable manipulations. “The authors didn’t reply to the worries that had been raised relating to those figures, and no underlying knowledge was once supplied for editorial evaluate,” the magazine editors wrote. The paper’s corresponding writer, Anita Sidhu, Georgetown College, Washington, D.C., didn’t reply to interview requests.
PLoS ONE posted its realize on December 5, 2023, the similar month by which the NIH introduced its investigation. The company would now not ascertain whether or not this paper was once some of the two it had known as containing falsified knowledge.
Alzforum requested the NIH why, given the handfuls of folks whose printed paintings might now face correction or retraction, it was once now not freeing extra details about its investigation. The company didn’t reply.
“One must now not condemn any one who was once operating with Masliah simply because [they were] operating with him,” Mandler stated. “Irrespective of who’s at fault, this a caution for the sphere that you simply truly want to at all times make very thorough evaluation and ensure the entirety is proper,” he added.
Perry blamed drive to put up thrilling knowledge in high-impact journals, slightly than replicating current knowledge. The file flags 3 papers within the Magazine of Alzheimer’s Illness, of which Perry is the senior editor. He stated he takes them severely however is not sure how his magazine will have stuck them previous. “We are responding to, slightly than on the lookout for, the issue. I believe that is what maximum journals are doing,” he stated. “To have image-analysis folks on board with the intention to do that, and the device, calls for slightly a dedication.”
Gandy has the same opinion that copy photographs in papers printed years aside could be unimaginable to identify “except there is AI keep watch over of each and every picture that enters the literature and compares it in opposition to each and every different picture within the literature.” That stated, the image-analysis device utilized by PubPeer sleuths no doubt may well be deployed via main journals to stop embarrassment later.
Wolozin was once stunned that Masliah’s publications include such a lot of duplicated photographs. “It kind of feels like he endured that previously during the virtual revolution,” Wolozin stated. “I am stunned that he don’t have idea he could be stuck in the future.”
5 of the roughly 130 papers had been lined on Alzforum once they got here out. One has two flags, for a picture and a western blot space (Masliah et al., 2001, PubPeer). One has two video animations for seven flags about western blots and microscopy photographs (Masliah et al., 2005, PubPeer). One has problematic western blots, a fourth has overlapping immunohistochemistry photographs categorised as coming from other Alzheimer’s sufferers in addition to doubtlessly cloned sections in electron micrographs (Rockenstein et al., 2007, PubPeer; Pickford et al., 2008, PubPeer). A 5th has a difficult western blot (Dziewczapolski et al., 2009, PubPeer).
General, Masliah’s case of alleged malpractice is probably the most intensive however now not the one fresh one in neurodegeneration analysis. But even so USC’s Zlokovic, Marc Tessier-Lavigne misplaced the presidency of Stanford over irregularities in his lab there and prior to now at Genentech (e.g., Would possibly 2014 information). Nobel laureate Tom Südhof of Stanford is protecting his profession with a devoted segment of his lab web page detailing adjustments in lab group and transparency (Südhof Laboratory Integrity Projects). Prion researcher Adriano Aguzzi of the College of Zurich is coping with public accusations (Blick information tale).
After years of controversy, Cassava, the corporate at the back of simufilam, in September 2024 was once fined $40 million via the Securities and Change Fee and its husband-and-wife management group let move. The College of Minnesota’s Sylvain Lesne has vanished from public view after allegations ensnared a 2006 Nature paper that had made an preliminary splash however was once by no means replicated via, nor influenced, different Alzheimer’s analysis labs (Jul 2022 information).
The NIH is attempting to handle the wider factor of reproducibility, e. g., with an initiative to toughen unbiased replication that comes with grants (e.g. this one). What else can scientists do? To proportion concepts, touch us.—Sara Reardon and Gabrielle Strobel
Sara Reardon is a contract author in Bozeman, Montana.
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Pickford F, Masliah E, Britschgi M, Lucin Okay, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T.
The autophagy-related protein beclin 1 presentations diminished expression in early Alzheimer illness and regulates amyloid beta accumulation in mice.
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No To be had Additional Studying