An apparent fraud may have resulted in millions of dollars of public funding earmarked for Alzheimer’s research being wasted, delaying the discovery of a cure for the disease. Investigations conducted by neuroscientist Matthew Schrag, from Vanderbilt University, in the US state of Tennessee, and by the journal Science pointed to signs of altered or duplicated images in dozens of scientific articles, some of them important for the approval of the drug Simufilam, from Cassava Sciences pharmaceuticals.
Alzheimer’s disease, a type of neurodegeneration that mainly affects the memory of the elderly, is still incurable. Different interventions that reduce the risk have already been proposed: from drinking coffee to doing crossword puzzles and taking an annual dose of the flu vaccine. There is also a genetic component. When he had his genome sequenced in 2007, the co-discoverer of the DNA structure James Watson did not want to know if he carried genetic variants of predisposition to the disease, because “there is not much what we can do.”
One of the genetic bases proposed for Alzheimer’s involves the beta-amyloid protein, which accumulates in plaques in neurons, impairing their function. Different attempts to develop drugs based on this hypothesis have failed. With Simufilam came something new: apparent fraud.
Schrag was hired for a fee of thousand dollars as an investigator by the lawyer of two other neuroscientists interested in the Cassava Sciences bankruptcy, according to a report in the magazine Science. Schrag reviewed the scientific literature and found signs of doctored or duplicated images in dozens of articles, including those on which the drug’s approval depends. The investigation report was sent to the main research funding agencies in the United States.
One of the articles contested by Schrag’s investigation is a study published in the journal Nature in 2006 cited by more than two thousand other studies, according to the journal itself, which added a note of concern to the publication. The first author is Sylvain Lesné of the University of Minnesota. The article reports the discovery of a subtype of beta-amyloid that would cause dementia similar to Alzheimer’s in rodents. The year of publication marked one hundred years since the German neuropathologist Alois Alzheimer, who gives the name to the disease, observed the protein plaques in the brain of a patient suffering from dementia. That beta-amyloid plaques really are in patients is little doubt. The pressing question is whether they are the cause or consequence of degeneration.
“Shockingly obvious” fabrications
The detective scientist avoids the word fraud as he does not have access to possible original unpublished images, but points out that there are telltale signs of trouble.
Science conducted its own six-month investigation that corroborated Schrag’s findings and found reason to doubt more than 2006 images in Lesné’s studies, among others. Lesné did not respond to the magazine’s contact. In May of this year, he obtained approval for a research grant from the US government of more than US$70 thousand, valid for five years. A person responsible for approving the grant co-authored the study by 2006.
Elisabeth Bisk, molecular biologist and consultant in forensic image analysis, told the scientific journal that “the experimental results obtained may not have been as desired, and the data may have been tampered with to better fit a hypothesis”. For her, there are figures that look like montages made from images from different experiments. Some are “shockingly obvious” fabrications, commented Alzheimer’s expert Donna Wilcock of the University of Kentucky.
The images are mostly pictures of results from the test known as ” Western blot”, which shows the proteins as bands on gel blocks. No matter how careful you are in handling, it is very rare that two bands have the same shapes or imperfections, which would be an indication of manipulation. In Lesné’s studies, there are entire rows of identical bands.
If the suspicions are confirmed, tens to hundreds of millions of dollars in public research funding is wasted. In 2021 alone, the US National Institutes of Health (NIH) have invested 70 millions in research that mention beta-amyloid and Alzheimer’s. Scientists who propose different hypotheses to explain Alzheimer’s disease complain about an “amyloid mafia” that makes it difficult for them to access resources and form cartels in the main decision-making process for publishing articles — peer review.
Some, like John Forsayeth, professor of neurosurgery at the University of California, compare the beta-amyloid hypothesis to Ptolemaic models of the solar system that put the Earth at the center. When faced with problems with the idea that the planets revolve in circular orbits around the Earth, Ptolemaic astronomers, rather than abandoning it, proposed that the orbits did not at first look like circles because they were circles upon circles, or “epicycles.” . Great effort not to change his mind—like someone tampering with photos of proteins to defend a favorite hypothesis about Alzheimer’s disease.
Karen Ashe, a medical neuroscientist who collaborates with Lesné and co-author of the study by 2006, is reticent to completely rebut the problems found by Schrag, but went to an online forum where Schrag found the first clues to give alternative explanations. She provided some original images in higher resolution. But the images only heightened Schrag’s suspicions, providing more detail on the bands copied.
Another co-factor for Lesné is Denis Vivien, a cell biologist at the University of Caen in Normandy, in five of the suspicious articles. Vivien believes the articles will survive scrutiny, but confesses that he was already suspicious of his colleague. When they were working on an article that would be published in the journal Nature Neuroscience, Vivien found some photos prepared by Lesné suspicious and asked students to redo the experiment. Students failed to replicate the result. Confronted, Lesné denied that anything was wrong. Vivien says she removed the article from the publication’s wake “to preserve my scientific integrity” and broke contact with the contributor.
Despite being reluctant to assert certainty of fraud, Matthew Schrag muses: “You can cheat to get an article published. You can cheat to get a grant. cannot cheat to cure a disease. Biology doesn’t care.” He believes that beta-amyloid may still have something to do with the causes of Alzheimer’s. But the foundations are shaken.
Concerning the complaints against the “amyloid mafia”, the British psychologist Stuart Ritchie comments in his book of 2020 Science Fictions (“Science Fiction”, in free translation) that “the stories of bullying and intimidation that ensue when researchers challenge the amyloid hypothesis suggest an area in which bias has become collective, where new ideas don’t get the time they deserve, and where scientists routinely fail to apply the norm of organized skepticism to their own favored theories. .