Accusations of image manipulation and manipulation of Alzheimer’s disease research may tarnish the University of Minnesota, but a bigger question looms amid the race for a treatment.
What about the landmark U Alzheimer discoveries that are still relevant?
Researchers, who wondered if the images in the U studies had been manipulated, said they could undermine a key 2006 discovery: a protein called abeta star 56, which independently caused memory loss in mice and looked like the long-awaited smoke gun behind a disease. Alzheimer’s. U’s research lead, Dr. Karen Ash, responded that her colleague, Sylvain Lesne, was wrong to alter the images, but she defended the discovery.
“While editing the selected images should not have occurred, the edits are immaterial, insignificant and have no effect on the search results,” she said.
Investigations by the U and the National Institutes of Health — which have funded much of the research — will assess irregularities by Lesné or other authors, while scientific journals determine whether studies with suspicious images require corrections or retractions.
Behind the controversy is a troubling neurological disease that affects 6 million Americans and is expected to grow as the population ages. This condition prevents thinking cells, and nerve cells, from performing cognitive or memory functions, or from transmitting signals that tell muscles and organs what to do.
While many of the research papers are in question, the 2006 study in Nature is gaining the most attention because it detected abeta star 56 or Aβ*56. Some researchers have been dismissive due to difficulties in replicating the results, but there is little question about the study’s impact. . The paper has been cited thousands of times by the scientists who used it as a basis for pursuing Alzheimer’s disease research.
“We wouldn’t be where we actually are today in terms of understanding,” said Maria Carrillo, chief science officer with the Alzheimer’s Association, without this study and related research. However, as the organization prepared its conference in San Diego next week, it said the scheduled presentations were evidence that research has outpaced this discovery.
However, she said rooting out academic wrongdoing is still important. “We discipline ourselves. If we can’t count on that, then everything unfolds.”
The research paper was built on the theory that the disease is linked to amyloid, which are proteins that can build up abnormally in plaques and possibly block nerve cells. The researchers targeted the soluble forms, rather than the solid plaques, that can build up for years before the symptoms of dementia that come with age appear.
U researchers have found an association between Aβ*56 and cognitive problems in middle-aged mice that have been genetically bred to produce amyloid plaques. Then they purified the protein and injected it into the young mice, which led to memory problems due to their inability to navigate a water maze.
At the time, Nature hailed the discovery that “Aβ*56 impairs memory independent of plaque or neuronal loss” as a “suspected star” in the search for Alzheimer’s treatments. Today, a warning sign has been placed on the paper to treat its findings with caution until a review of the disputed images is complete.
Much of the Western blots are being investigated, which use electrical charges to separate proteins and a chemical process to create visual representations of them. The size and thickness of the chemical bands produced on the film correspond to the amount of protein and, therefore, whether it is involved in a disease.
Single blot blasting in the Nature paper showed a difference proving the presence of Aβ*56 in mice showing amnesia. However, Dr. Matthew Schrag, an Alzheimer’s researcher in Tennessee, found linear changes around the bands suggesting they may be cut and glued. Some bands also appeared duplicates. Another spot showed clusters of identical peripheral points around the bands that suggested image editing.
Schrag conducted the review outside of his work at Vanderbilt University, posted his concerns on the academic website PubPeer and contributed to Science’s investigation of Lesné in July. Expert reviewers endorsed the concerns.
“This is a very sad example of human fragility and irregularities,” said Dr. Dennis Silko, a neuroscientist at Harvard Medical School. A supporter of the amyloid link to Alzheimer’s agreed that some of the U images appeared to be manipulated.
The science article suggested that Lesne manipulated the images before joining Ash’s team as a research assistant in 2002 and was promoted as an assistant professor in his own lab in 2009. Lesne’s doctoral education supervisor at the University of Caen-Normandy in France told the magazine to withdraw a newspaper prior to publication because he was skeptical The images produced by Lesny.
Lesné did not respond to requests for comment for this story.
U has had this problem before, requesting in 2008 to recall a landmark paper on adult stem cells after finding it contained manipulated images.
Schrag said he had not found studies of manipulated images in which Ash was author without Lisney, but concerns extend well beyond their 16-year-old research. He found tags on manipulated images in a 2013 study in the journal Brain in which researchers at U University confirmed their findings in human tissue about Aβ*56 as a precursor to Alzheimer’s disease. The images released this year as a patch look so different that Schrag wonders if they are from the same experience.
The spots mean little to the untrained eye, said Elizabeth Beck, a San Diego-based microbiologist turned forensic image consultant. She agreed that some of the photographs in Lesny’s papers appeared to have been tampered with.
“A science paper is not like a children’s book, where the pictures are only there to enlighten the whole story,” she said. “It’s different. Pictures in my opinion are data.”
The now-disputed Nature paper has influenced years of research. Federal funding for Alzheimer’s disease has increased in general, but specifically for studies targeting amyloid.
Dr. Ronald Petersen, director of the Alzheimer’s Disease Research Center at the Mayo Clinic, said the research was necessary because amyloid is part of the Alzheimer’s puzzle, but increased focus has slowed other key-cut studies. Immune reactions and cardiovascular disease also affect Alzheimer’s disease along with tau, a protein that can build up abnormally within nerve cells.
Variation appears in drug development. Aduhelm gained federal approval last year as a treatment for Alzheimer’s that breaks down amyloid plaques, although some doctors are skeptical whether it also slows cognitive decline. Three doses of monoclonal antibodies midway through clinical trials; All amyloid target.
Trials of other compounds targeting amyloid have failed. Asch said it was unfair to label the disputed U papers for such failures because they contained classes of the amyloid protein that were different and easier to replicate than Aβ*56.
Ash said she has expressed doubts that drugs that target those proteins will work, and that they are not linked to amyloid as the main cause of Alzheimer’s disease. Her research explored Tao and other possible causes.
Carrillo of the Alzheimer’s Association said limited funding for years has forced conservative rulings to support research in areas such as amyloid where there was early evidence. The increases have bolstered bolder exploration, and predicts that Alzheimer’s therapies that target tau and inflammation will emerge behind the current wave of amyloid-targeting.
She said that Aβ*56 was “somewhat irrelevant” to current drug studies, so the idea that the debate over U could undermine ongoing discoveries is “overrated and exaggerated.”