In August 2021, a citizen’s petition was filed against the company Cassava Science, accusing them of egregious misconduct and data falsification. The topic of this misconduct: an Alzheimer’s disease drug that was poised to continue to phase 3 clinical trials. The petition called for a pause in trial progression to prevent patients from being treated with a drug based on potentially fraudulent research.
Alzheimer’s disease is a devastating progressive form of dementia that is steadily rising in prevalence in our society. Despite decades of research on this disease, scientists have still had little to no success in finding an effective treatment. Much of the research in the field has been focused on abnormal aggregations of the protein amyloid beta (B) that forms plaques in the brains of patients and are thought by many to cause disease formation. However, Cassava Science claimed that they had found a novel target for Alzheimer’s disease, a protein called Filamin A, which they stated was involved in amyloid B signaling. They developed their drug, Simufilam, in order to stabilize this protein and prevent disease progression.
Cassava scientists repeatedly claim to have conducted seemingly undoable experiments
Shortly after the original petition, several whistleblowers came forward regarding false data published by Cassava Science. They state that “Cassava scientists repeatedly claim to have conducted seemingly undoable experiments.” On top of the methodology concerns, the preclinical data has come under scrutiny for potential falsification of images, particularly Western blot data.
Western blot is a technique used by scientists that can detect the presence of a particular protein. Bands of proteins are identified both by how far they travel down a gel and if they are recognized by an antibody that can detect the presence of that protein. Although incredibly useful when used correctly, as most scientists do, it is also one of the most common techniques where data falsification has been discovered in research. Manipulation of a gel can often be detected by scientific sleuths. In a paper examining the prevalence of problematic figures’ in biomedical research, investigators found 782/20,261 (3.8%) papers with Western blot data examined had at least one inappropriate duplication in the image. At least half of the images seem to show purposeful signs of data manipulation.
This is an incredibly alarming finding in the scientific literature. Researchers depend on the trail of knowledge from those that came before them in order to guide them down their own new avenues of research. How can scientists trust the preceding literature if the possibility of fraud is prevalent and growing?
Fortunately, scientific misconduct and hoaxes are receiving growing attention from journals. And with this new awareness, hopefully there will be more stringent review of papers before publishing to keep the literature to high standards. In line with this, the number of retracted articles has increased in recent years along with increasing transparency about the process from editors. Although retracted papers do not always result from scientific misconduct, fraud does account for about 60% of these incidences. Additionally, relatively few authors are the culprit for a large number of retractions related to misconduct. Data published by Cassava Science has led to several paper retractions, most of which are from just two authors affiliated with the company.
Unfortunately, when it rains, it pours, and the hits just kept coming in the Alzheimer’s disease research field. During the investigation into Cassava Science, expert examiners were led to a 2006 Alzheimer’s disease paper published by Sylvain Lesné in the lab of Karen Ashe. This paper claimed to have identified a novel oligomer (variant) of amyloid B that when injected into mice can lead to memory decline even in the absence of neurodegeneration. However, the examiners found bands in the Western blot that appear to have been duplicated, meaning the band identifying the oligomer of interest could have been falsified. Subsequent investigation has found 20 of Lesné’s published papers from his time as a PI seem to contain suspect images, half of which concern his identified oligomer.
Although this incident of misconduct is egregious and evident, the magazine article that widely publicized this finding (‘Blots on a Gel?’ written by Charles Piller in Science magazine) opted for sensationalism over fact. Piller claimed that this likely erroneous find has “misdirected Alzheimer’s research for 16 years.” He makes it seem as if the entire field of amyloid B research is problematic due to this one paper.
However, the amyloid B hypothesis predates this one paper by over a decade, with the original seminal papers published in 1991-1992. Several of the most distinguished scientists in the field have fought back over this slander of the prevalent amyloid B hypothesis, stating that this one instance of misconduct does not eliminate decades of work and properly conducted research. Although individual scientists may have wasted time and money trying to replicate a result generated from probable misconduct, there are no clinical trials targeting this oligomer and it has not been propagated by the literature due to lack of confirmation. Therefore, the amyloid B hypothesis is not under any serious threat. Despite this, numerous media outlets have picked up the story and misconstrued it with clickbait headlines such as “Leading Alzheimer’s theory undermined: Did tampering waste 16 years of research?”
Unfortunately, scandals such as these can undermine the public’s trust in research and the health care system. Information gets picked up by the media and stretched well beyond the original context. This can completely mislead even the savviest of readers.
Perhaps, all of this came at the perfect time for Lesné’s amyloid B misconduct to be used as a scapegoat for mounting frustrations due to negative data in Alzheimer’s disease clinical trials. Recently, several monoclonal antibody drugs targeting amyloid B plaques have gone through phase 3 clinical trials. Despite robust ability to clear plaques, evidence for slowed cognitive decline has been minimal. One of these drugs, lecanemab, had a phase 3 trial that ran for 18 months and enrolled nearly 1800 patients with early-stage Alzheimer’s disease. This drug decreased amyloid plaques in the brain and led to a statistically significant slowing in cognitive decline. This sounds like ground-breaking news; however, the decline was only a 0.45 improvement out of an 18-point scale. Therefore, despite statistical significance, there remain many questions regarding the clinical meaningfulness of this data. Additionally, there were safety concerns due to brain swelling and small brain bleeds. This has left many scientists, patients, families and caregivers wondering if the risks are worth the rewards and where the field should go from here.
Where does that leave us readers, scientists, and science enthusiasts? It can be hard to reconcile egregious misconduct in the biomedical sciences. In a world of publish or perish, one can perhaps understand where a desperate scientist could get the idea to falsify their data. However, we as a scientific field have to demand better of ourselves and those around us. Research integrity is not only important, but vital to the safety of patients, the advancement of treatments and the validity of the scientific field. We must pressure journals to better validate articles before publishing. And as always, we must be cautious of the information given to us and be thorough in our critique of any media we consume. Despite the scandals, scientists remain strong in their conviction to continue advancing treatments and knowledge in the Alzheimer’s disease field. These instances of misconduct can and will be overcome.
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