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Msg  548897 of 548898  at  7/25/2022 12:55:52 PM  by


Article : A neuroscience image sleuth finds signs of fabrication in scores of Alzheimerís articles

 Blots on a Field?
A neuroscience image sleuth finds signs of fabrication in scores of Alzheimer’s articles, threatening a reigning theory of the disease
BYCHARLES PILLER / Science Magazine / July 21, 2022

Neuroscientist and physician Matthew Schrag found suspect images in dozens of papers involving Alzheimer’s disease, including Western blots (projected in green) measuring a protein linked to cognitive decline in rats.

A version of this story appeared in Science, Vol 377, Issue 6604.

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).

Schrag, 37, a softspoken, nonchalantly rumpled junior professor, had already gained some notoriety by publicly criticizing the controversial FDA approval of the anti-Aβ drug Aduhelm. His own research also contradicted some of Cassava’s claims. He feared volunteers in ongoing Simufilam trials faced risks of side effects with no chance of benefit.

So he applied his technical and medical knowledge to interrogate published images about the drug and its underlying science—for which the attorney paid him $18,000. He identified apparently altered or duplicated images in dozens of journal articles. The attorney reported many of the discoveries in the FDA petition, and Schrag sent all of them to the National Institutes of Health (NIH), which had invested tens of millions of dollars in the work. (Cassava denies any misconduct [see sidebar, below].)

But Schrag’s sleuthing drew him into a different episode of possible misconduct, leading to findings that threaten one of the most cited Alzheimer’s studies of this century and numerous related experiments.

The first author of that influential study, published in Nature in 2006, was an ascending neuroscientist: Sylvain Lesné of the University of Minnesota (UMN), Twin Cities. His work underpins a key element of the dominant yet controversial amyloid hypothesis of Alzheimer’s, which holds that Aβ clumps, known as plaques, in brain tissue are a primary cause of the devastating illness, which afflicts tens of millions globally. In what looked like a smoking gun for the theory and a lead to possible therapies, Lesné and his colleagues discovered an Aβ subtype and seemed to prove it caused dementia in rats. If Schrag’s doubts are correct, Lesné’s findings were an elaborate mirage.

Schrag, who had not publicly revealed his role as a whistleblower until this article, avoids the word “fraud” in his critiques of Lesné’s work and the Cassava-related studies and does not claim to have proved misconduct. That would require access to original, complete, unpublished images and in some cases raw numerical data. “I focus on what we can see in the published images, and describe them as red flags, not final conclusions,” he says. “The data should speak for itself.”

A 6-month investigation by Science provided strong support for Schrag’s suspicions and raised questions about Lesné’s research. A leading independent image analyst and several top Alzheimer’s researchers—including George Perry of the University of Texas, San Antonio, and John Forsayeth of the University of California, San Francisco (UCSF)—reviewed most of Schrag’s findings at Science’s request. They concurred with his overall conclusions, which cast doubt on hundreds of images, including more than 70 in Lesné’s papers. Some look like “shockingly blatant” examples of image tampering, says Donna Wilcock, an Alzheimer’s expert at the University of Kentucky.

The authors “appeared to have composed figures by piecing together parts of photos from different experiments,” says Elisabeth Bik, a molecular biologist and well-known forensic image consultant. “The obtained experimental results might not have been the desired results, and that data might have been changed to … better fit a hypothesis.”

“The immediate, obvious damage is wasted NIH funding and wasted thinking in the field because people are using these results as a starting point for their own experiments.”

Early this year, Schrag raised his doubts with NIH and journals including Nature; two, including Nature last week, have published expressions of concern about papers by Lesné. Schrag’s work, done independently of Vanderbilt and its medical center, implies millions of federal dollars may have been misspent on the research—and much more on related efforts. Some Alzheimer’s experts now suspect Lesné’s studies have misdirected Alzheimer’s research for 16 years.

“The immediate, obvious damage is wasted NIH funding and wasted thinking in the field because people are using these results as a starting point for their own experiments,” says Stanford University neuroscientist Thomas Südhof, a Nobel laureate and expert on Alzheimer’s and related conditions.

Lesné did not respond to requests for comment. A UMN spokesperson says the university is reviewing complaints about his work.

To Schrag, the two disputed threads of Aβ research raise far-reaching questions about scientific integrity in the struggle to understand and cure Alzheimer’s. Some adherents of the amyloid hypothesis are too uncritical of work that seems to support it, he says. “Even if misconduct is rare, false ideas inserted into key nodes in our body of scientific knowledge can warp our understanding.”

IN HIS MODEST OFFICE, steps away from a buzzing refrigerator, Schrag displays an antique microscope—an homage to predecessors who applied painstaking bench science to medicine’s endless enigmas. A small sign on his desk reads, “Everything is figureoutable.”

So far, Alzheimer’s has been an exception. But Schrag’s background has left him comfortable with the field’s contradictions. His father hails from a family of Mennonites, known for their philosophy of peacemaking—but joined the military. The family moved from Arizona to Germany to England before settling in Davenport, a tiny cow town in eastern Washington. After leaving the Air Force, Schrag’s dad became a nurse and worked in a nursing home. As a young teen, Schrag volunteered to visit dementia patients there. “I remembered being mystified by a lot of the strange behaviors,” he says. It was a formative experience “to see people struggling with such unfair symptoms.”

Home-schooled by his mom, Schrag entered community college at 16, like many of the town’s studious kids—including his teenage sweetheart and future wife, Sarah. They now live on a small ranch outside Nashville with their two young children and three aging horses that Sarah grew up with.

While prepping for medical school at the University of North Dakota, Schrag spent long hours in a neuropharmacology lab absorbing the patient rhythms of science. He repeated experiments over and over, refining his skills. These included a protein identification method known as the Western blot. It uses electricity to drive protein-rich tissue samples through a gel that acts like a sieve to separate the molecules by size. Distinct proteins, tagged and illuminated by fluorescent antibodies, appear as stacked bands.

In 2006, Schrag’s first publication examined how feeding a high-cholesterol diet to rabbits seemed to increase Aβ plaques and iron deposits in one part of their brains. Not long afterward, when he was an M.D.-Ph.D. student at Loma Linda University, another research group found support for a link between Alzheimer’s and iron metabolism. Encouraged, Schrag poured his energy into trying to confirm the connection in people—and failed. The experience introduced him to a disquieting element of Alzheimer’s research. With this enigmatic, complex disease, even careful experiments done in good faith can fail to replicate, leading to dead ends and unexpected setbacks.

One of its biggest mysteries is also its most distinctive feature: the plaques and other protein deposits that German pathologist Alois Alzheimer first saw in 1906 in the brain of a deceased dementia patient. In 1984, Aβ was identified as the main component of the plaques. And in 1991, researchers traced family-linked Alzheimer’s to mutations in the gene for a precursor protein from which amyloid derives. To many scientists, it seemed clear that Aβ buildup sets off a cascade of damage and dysfunction in neurons, causing dementia. Stopping amyloid deposits became the most plausible therapeutic strategy.

Hundreds of clinical trials of amyloidtargeted therapies have yielded few glimmers of promise, however; only the underwhelming Aduhelm has gained FDA approval. Yet Aβ still dominates research and drug development. NIH spent about $1.6 billion on projects that mention amyloids in this fiscal year, about half its overall Alzheimer’s funding. Scientists who advance other potential Alzheimer’s causes, such as immune dysfunction or inflammation, complain they have been sidelined by the “amyloid mafia.” Forsayeth says the amyloid hypothesis became “the scientific equivalent of the Ptolemaic model of the Solar System,” in which the Sun and planets rotate around Earth.

By 2006, the centenary of Alois Alzheimer’s epic discovery, a growing cadre of skeptics wondered aloud whether the field needed a reset. Then, a breathtaking Nature paper entered the breach.

It emerged from the lab of UMN physician and neuroscientist Karen Ashe, who had already made a remarkable series of discoveries. As a medical resident at UCSF, she contributed to Nobel laureate Stanley Prusiner’s pioneering work on prions—infectious proteins that cause rare neurological disorders. In the mid-1990s, she created a transgenic mouse that churns out human Aβ, which forms plaques in the animal’s brain. The mouse also shows dementia-like symptoms. It became a favored Alzheimer’s model.

By the early 2000s, “toxic oligomers,” subtypes of Aβ that dissolve in some bodily fluids, had gained currency as a likely chief culprit for Alzheimer’s—potentially more pathogenic than the insoluble plaques. Amyloid oligomers had been linked to impaired communication between neurons in vitro and in animals, and autopsies have shown higher levels of the oligomers in people with Alzheimer’s than in cognitively sound individuals. But no one had proved that any one of the many known oligomers directly caused cognitive decline.

In the brains of Ashe’s transgenic mice, the UMN team discovered a previously unknown oligomer species, dubbed Aβ*56 (pronounced “amyloid beta star 56”) after its relatively heavy molecular weight compared with other oligomers. The group isolated Aβ*56 and injected it into young rats. The rats’ capacity to recall simple, previously learned information—such as the location of a hidden platform in a maze—plummeted. The 2006 paper’s first author, sometimes credited as the discoverer of Aβ*56, was Lesné, a young scientist Ashe had hired straight out of a Ph.D. program at the University of Caen Normandy in France.

Ashe touted Aβ*56 on her website as “the first substance ever identified in brain tissue in Alzheimer’s research that has been shown to cause memory impairment.” An accompanying editorial in Nature called Aβ*56 “a star suspect” in Alzheimer’s. Alzforum, a widely read online hub for the field, titled its coverage, “Aβ Star is Born?” Less than 2 weeks after the paper was published, Ashe won the prestigious Potamkin Prize for neuroscience, partly for work leading to Aβ*56.

The Nature paper has been cited in about 2300 scholarly articles—more than all but four other Alzheimer’s basic research reports published since 2006, according to the Web of Science database. Since then, annual NIH support for studies labeled “amyloid, oligomer, and Alzheimer’s” has risen from near zero to $287 million in 2021. Lesné and Ashe helped spark that explosion, experts say.

The paper provided an “important boost” to the amyloid and toxic oligomer hypotheses when they faced rising doubts, Südhof says. “Proponents loved it, because it seemed to be an independent validation of what they have been proposing for a long time.”

“That was a really big finding that kind of turned the field on its head,” partly because of Ashe’s impeccable imprimatur, Wilcock says. “It drove a lot of other investigators to … go looking for these [heavier] oligomer species.”

As Ashe’s star burned more brightly, Lesné’s rose. He joined UMN with his own NIH-funded lab in 2009. Aβ*56 remained a primary research focus. Megan Larson, who worked as a junior scientist for Lesné and is now a product manager at Bio-Techne, a biosciences supply company, calls him passionate, hardworking, and charismatic. She and others in the lab often ran experiments and produced Western blots, Larson says, but in their papers together, Lesné prepared all the images for publication.

He became a leader of UMN’s neuroscience graduate program in 2020, and in May 2022, 4 months after Schrag delivered his concerns to NIH, Lesné received a coveted R01 grant from the agency, with up to 5 years of support. The NIH program officer for the grant, Austin Yang—a co-author on the 2006 Nature paper—declined to comment.

IN DECEMBER 2021, Schrag visited PubPeer, a website where scientists flag possible errors in published papers. Many of the site’s posts come from technical gumshoes who deconstruct Western blots for telltale marks indicating that bands representing proteins could have been removed or inserted where they don’t belong. Such manipulations can falsely suggest a protein is present—or alter the levels at which a detected protein is apparently found. Schrag, still focused on Cassava-linked scientists, was looking for examples that could refine his own sleuthing....

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