On July 22, the journal Science published an investigative report that shook the industry.
The article questioned a number of papers by Sylvain Lessner, a rising star in the field of Alzheimer's disease research and a neuroscientist at the University of Minnesota Twin Cities, for alleged academic fraud, including one of the groundbreaking studies in the field: one in 2006 Article published in Nature. This paper belongs to the research category of the most mainstream "beta amyloid hypothesis" of Alzheimer's disease. "Science" magazine wrote that the article published in "Nature" was suspected of misleading the world's Alzheimer's disease research for 16 years, and the most immediate and obvious damage was the waste of NIH (National Institutes of Health). ) funding and thinking in the field.
Academic fraud was not uncommon. This time, people pay so much attention to this investigation in Science because it happened in a special time and atmosphere: the cause of Alzheimer's disease is still unclear, and the successive drug development battles have failed repeatedly. Over the years, skeptical scientists hope to break the theory's "monopoly" as the "amyloid beta hypothesis" that underpins it has been wobbly amid repeated clinical failures.
However, several neuroscientists told "China News Weekly" that even if these papers turned out to be fake, its impact on the Alzheimer's disease academia and pharmaceutical industry was not as serious as the outside world thought.
Suspected academic misconduct discovered by shorting companies
As the most common form of dementia, Alzheimer's disease (AD) is a degenerative disease of the central nervous system. The "Amyloid Beta Hypothesis" proposed in the 1990s is one of several hypotheses for the pathogenesis of Alzheimer's disease. The hypothesis states that Aβ plaques in brain tissue are the main cause of the disease.
In 2006, while working in the laboratory of renowned neuroscientist and University of Minnesota professor Karen Asia, Lesner published a paper titled "Specific β-amyloid associations in the brain" as the first author in the top journal "Nature". Impairing memory", the corresponding author of the article is Asia. In this study, Aβ oligomer form with a molecular weight of 56kD was isolated and purified from the brain tissue of aged AD model mice, and injected into young mice, and found that it can exert neurotoxicity.
In its commentary on the paper at the time, Nature called Aβ*56 the "number one suspect" of Alzheimer's disease. According to the Web of Science database, the paper is cited by approximately 2,300 scholarly articles — the fifth most cited report on Alzheimer's disease basic research published since 2006.
Wu Chengbiao, an associate professor at the Department of Neuroscience at the University of California, San Diego, told China News Weekly that before and after 2000, clinical trials have found that after removing amyloid beta plaques, the cognitive ability of patients deteriorated faster than that of the control group. People do not know that reason. A few years after 2000, well-known scholars such as the main promoter of the "β-amyloid hypothesis" and professor of Harvard Medical School, Dennis Selko, have speculated that soluble oligomers may be the culprit of the disease, but No one knows for sure what form this oligomer takes in an organism.
This article by Lesne is the first in vivo purification of soluble Aβ oligomer forms in an animal model and demonstrates the toxicity of Aβ oligomers. Wu Chengbiao said that many laboratories followed suit, hoping to find various Aβ oligomers.
Lesner officially joined the University of Minnesota in 2009 and was funded by the NIH to establish his own laboratory. Science reports that since then, NIH support for research with the key words "amyloid, oligomers and Alzheimer's disease" has risen from nearly zero to $287 million in 2021, experts say, Sylvain Lesner and Asia have contributed to this explosion of funding.
The alleged falsification of this paper has already emerged as early as the end of 2021.
In August 2021, Matthew Schrager, a neuroscientist at Vanderbilt University, got a call from a colleague asking if he was interested in a job. The job offers are two neuroscientists who want to short Cassava Sciences, a pharmaceutical company that suspects there may be something wrong with data on an investigational treatment for Alzheimer's disease. Schrager, who works on Alzheimer's disease, has previously been controversial for publicly criticizing an approved drug of this type.
In December 2021, Schrager visited PubPeer, an academic anti-counterfeiting website, in an attempt to investigate scientists associated with Cassava Sciences. In the process of unraveling, a new clue was unexpectedly discovered: the bands of the images seemed suspicious to Lesner on multiple papers as the first or corresponding author. In the end, Schrager identified more than 20 suspicious Rice papers, 10 of which were related to Aβ*56, including the one in Nature.
Earlier this year, Schrager raised his concerns with journals such as the NIH and Nature, arguing that images in several of Lesner's papers had been altered or reused. Science then stepped in and conducted a six-month investigation, finding Schrager's conclusions "convincing and reasonable."
Zhou Xianbo, the co-founder of Zhongze Medical Technology Co., Ltd., has been engaged in the research and development of new small molecule drugs in the field of tumor and central nervous system in the United States for many years. He returned to China in 2015 to start a business. He told China News Weekly that biological experiments are all done under specific conditions. But if a study leads people to work in a certain direction and makes a breakthrough, it can in turn verify that the study is meaningful.
Karen Asya responded on the website "Alzforum", an internationally renowned academic forum in the field of Alzheimer's disease. She said she could not comment on allegations that her former collaborator Lesne may have altered the images inappropriately. But she said, "I was shocked when I discovered that my collaborators may have misled me and the scientific community by manipulating the images." On July 14, Nature responded that it was investigating the paper and advised readers to exercise caution the results of the thesis.
If such a critical paper is finally confirmed to be the result of artificial modification, is there a dereliction of duty in the authoritative journal? Chen Xiqun, assistant professor of neurology at Massachusetts General Hospital at Harvard Medical School, told China News Weekly that although reviewers of journals can play a more important monitoring role in the review of papers, they cannot and should not be fully responsible for academic crackdowns. Task. Those deliberate academic misconduct may never be discovered by reviewers.
Has it overturned the theoretical foundations of the field?
If he hadn't seen the "Science" report from social media, Zhou Xianbo would have actually forgotten the paper in "Nature".
Many scholars interviewed said that the series of papers about Aβ*56 that were suspected of being fake did not actually shake the "amyloid beta hypothesis" as "Science" thought. A very important reason is that the oligomer of Aβ*56 is very unstable, and it is rarely reproduced in other laboratories.
Dennis Selko, a professor at Harvard Medical School, cited the Nature paper at least 13 times. But in two 2008 papers, Selko mentioned that he also did not find Aβ*56 in human body fluids or tissues. In an interview with China News Weekly, he said that the allegations made by the Science article against the papers published by Sylvain Lesner and others appear to be true. But he believes that even if the papers are fabricated, they have little impact on science and industry.
In 1985, Colin Masters, a professor at the University of Melbourne, Australia, was the first to isolate Aβ oligomers from plaques in the brains of AD patients. He pointed out that Aβ is also known as the "peptide from hell" because of its high hydrophobicity and aggregation, it is difficult to extract, purify and other operations. On the "Alzforum" website, he wrote that when Aβ*56 was first reported, we took a look and were a little surprised. In fact, we haven't seen them since. So our study never relied on these data.
A public search found that there were only 47 studies mentioning Aβ*56 in the paper titles and abstracts, including 11 follow-up reports from Lesner's lab after 2006. Zhou Xianbo told China News Weekly that the real mainstream research oligomers are Aβ*42 and Aβ*40, and the industry has not used Aβ*56 as the research and development target of new anti-AD drugs.
In a public response, Karen Asya countered that the Science article suggested that her study misled Alzheimer's researchers by encouraging the development of treatments for amyloid deposits. She divides Aβ into two general forms: type 1 and type 2, and writes that her lab and others have found that a specific form of type 1, Aβ*56 in her paper, damages small memory function in mice, but there are no clinical trials for type 1 Aβ.
Judging from the development history of the "beta amyloid hypothesis", it is not a "castle in the air" built on the suspected fake paper in 2006.
The first new Alzheimer's drug, aducanumab, approved in June 2021, was developed based on the beta amyloid theory.
In 1906, psychiatrists Eros Alzheimer's disease and Emil Kreepelin of the Munich University Hospital in Germany gave a presentation at an academic conference. They noted specific plaque-like changes and neurofibrillary tangles in the brain of a 51-year-old woman with dementia and psychotic symptoms at autopsy.
In 1984, researchers extracted amyloid beta (Aβ) from plaques in the brains of Alzheimer's patients. In 1992, after John Hardy, a member of the Royal Academy of Sciences and University College London, proposed the "amyloid cascade hypothesis" of Alzheimer's disease in the journal Science, the medical community began to focus on the study of the role of Aβ in Alzheimer's disease. Some pharmaceutical companies and scientific research institutions are also working on developing drugs targeting Aβ.
The β-amyloid cascade hypothesis is currently the mainstream hypothesis accepted by most scholars. Li Yanfeng, chief physician of the Department of Neurology at Peking Union Medical College Hospital, told China News Weekly that many current studies, including genetic, clinical and other basic research, have provided a variety of evidence to support this hypothesis. Some explanations for the pathogenesis proposed in the past, such as oxidative stress, neuroinflammation, infection, neurovascular mechanism, etc. in the pathogenesis of Alzheimer's disease, currently seem to be more based on the "Aβ cascade hypothesis". Replenish.
When the discovery of Aβ*56 was first reported by Sylvain Lesner et al in 2006, many, including him, felt that the study was unlikely to be meaningful or correct, Dennis Selko in reply "China News Weekly" wrote in the email. Still, he is on the side of the Aβ hypothesis, saying that the "unfortunate event" of the alleged falsification of the paper has not changed the overwhelming prevalence of amyloid beta in genetics, neuropathology, animal models, and even human clinical trials. evidence of. These lines of evidence suggest that lowering all forms of amyloid, including Aβ oligomers, improves disease, reduces neurofibrillary tangles, and delays AD clinical progression.
A mainstream hypothesis and more than 20 years of failed drug development history
In his investigative report in Science, Schrager pointed out that beta-amyloid oligomers may still have some function in Alzheimer's disease; after the 2006 paper was published, other researchers also found Aβ oligomers are associated with cognitive impairment in animal models. He hopes that people won't be timid about the field because of this, but also mentions that these (academic misconduct) findings may allow us to pause and rethink the foundation behind the whole theory.
It is undeniable that this alleged fraud will have a profound impact on the reputation of the "amyloid beta" theory. If it is placed in a larger context to observe, as Zhou Xianbo pointed out, the root cause is the continuous challenges and doubts faced by the "β-amyloid" hypothesis in recent years.
Since it was proposed in the 1990s, the entire field has been "monopolized" by the Aβ hypothesis for almost 30 years. Significant costs have been spent in industry and academia to verify whether Aβ is a good pharmaceutical target. Since the Aβ vaccine AN1792 entered the second clinical phase in 2000, a large number of Aβ-targeted drugs, including vaccines, γ-secretase/BACE1 inhibitors and Aβ antibodies, have emerged in more than 20 years, almost all of which have ended in failure.
Zhou Xianbo said that everyone feels that it is relatively safe to do mainstream research under the framework of big experts, but it is actually a kind of "intellectually lazy". At one time, big pharmaceutical companies basically only did large-scale phase III clinical trials related to amyloid, and at the same time, the failure of several large clinical trials has also occurred.
Zhou Xianbo said that in the past 20 years, after the industry experienced several relatively concentrated setbacks, many pharmaceutical companies have withdrawn from AD or even the entire field of central nervous system diseases. By 2020, there are only a handful of companies still developing central system drugs.
As early as 2018, when two high-profile clinical trials of Alzheimer's disease drugs failed, the journal Nature published a long article pointing out that the field may be going through a frustrating journey of discovery. But if the field is based on the wrong idea, researchers may be approaching the end of a dead end. "Amyloid beta is not the only potential cause, and it's time to explore other pathways."
At the time, the industry had confidence in an anti-AD drug that appeared to improve cognitive function in early trials in 2016. This is the first new Alzheimer's disease drug approved in June 2021: aducanumab, developed and produced by Biogen, an American biotechnology company. This drug was also developed based on the beta amyloid theory, but it further aggravated the doubts of the beta amyloid hypothesis in the academic and industrial circles.
Biogen has conducted two Phase III trials with durations of 2 to 3 years. After preliminary analysis, although the drug can effectively remove Aβ plaques, it cannot significantly slow down cognitive decline; in contrast, compared with the control group, the risk of cerebral edema and cerebral hemorrhage in the high-dose group increased by 31%. Therefore, Both trials were terminated in March 2019. A few months later, Biogen retrospectively analyzed the available clinical trial data and found that in one of the studies, the high-dose group showed a statistically significant result that the drug slowed cognitive decline. After several months of communication with the U.S. Food and Drug Administration (FDA), Biogen officially submitted a supplemental data application for aducanumab in July 2020.
In November 2020, the US FDA held a consultation meeting on aducanumab. In the final vote, only 1 of the 11 experts agreed to approve the drug for marketing, 8 of the remaining 10 experts objected, and 2 expressed uncertainty. But it was eventually approved through a special channel called "accelerated approval".
On December 17, 2021, the European Medicines Agency rejected the marketing authorization of aducanumab; 5 days later, the Japanese Ministry of Health also refused to approve the marketing application of aducanumab on similar grounds. On June 9 this year, Biogen voluntarily withdrew the regulatory review of aducanumab in Health Canada.
On June 16 this year, Roche announced the failure of a phase II clinical trial of its anti-AD drug. The clinical trial is designed to evaluate the potential of drug candidates to slow or prevent Alzheimer's disease in people with normal cognitive function but at a familial genetic risk for AD. The study recruited a total of 252 subjects in the South American country of Colombia for a period of 5 to 8 years, and the candidate drug was the amyloid beta-targeting crenezumab (crenezumab). The results showed that there was no significant difference in the efficacy of the treatment group and the placebo group, and the treatment with crenezumab did not delay cognitive decline and memory decline.
Time to explore new directions
In Zhou Xianbo's view, a particularly strange phenomenon is that proponents of the beta amyloid hypothesis have been looking for reasons for the failure of clinical trials, for example, we may be treating too late and should be given earlier; or Our drug target is wrong. If Aβ*42 and Aβ*40 are ineffective, we should try other oligomers, etc.
"People keep looking for evidence to support the beta-amyloid hypothesis, rather than finding evidence to disprove it and move on," he says, but now some scientists are growing tired of the narrative.
A neuroscientist told "China News Weekly" that in the field of Alzheimer's disease, from scientific research to drug development, different hypotheses are actually a bit like mountains, and Aβ is undoubtedly one of the strongest ones.
The Science article noted that during the fiscal year, the NIH spent about $1.6 billion on projects involving amyloid, about half of its total Alzheimer's research and development funding. Scientists studying other potential causes of Alzheimer's disease, such as neuroimmune and neuroinflammatory responses, complain that they are being sidelined by the powerful "amyloid clique."
However, Chen Xiqun, an assistant professor of neurology at the Massachusetts General Hospital of Harvard Medical School, pointed out that although beta amyloid is the mainstream theory of Alzheimer's disease, there have always been doubts about this theory, and there is also evidence that does not support this theory. It keeps accumulating, and in fact there is not only one voice in this field.
"In the 116 years since Alzheimer's disease was reported, there has actually been little progress in drug research and development. The treatments that can be used in doctors' toolboxes have not substantially progressed." Zhou Xianbo said that the entire Alzheimer's disease The field of disease is still at a relatively early stage and faces too many unknowns.
Chengbiao Wu, an associate professor in the Department of Neuroscience at the University of California, San Diego, who focuses on inherited neurodegenerative diseases of the elderly, believes that in addition to about 3% to 5% of Alzheimer's disease being entirely genetic, another 95% to 97% of sporadic cases , in fact, no one knows what caused it. In this case, clinging on to amyloid beta as a pharmaceutical target may have been wrong to begin with. In his view, AD is more of a syndrome than a disease that may not be cured by a single-target drug.
"I think the biggest unanswered question is, does beta amyloid deposition contribute to the onset of Alzheimer's disease, or is it a concomitant consequence of neuronal damage? If it's not the cause , then the drugs targeting amyloid beta may only treat the symptoms rather than the root causes." Chen Xiqun said, however, even so, it cannot be said that this theory has no scientific meaning. If it can be detected in the neuroperiphery of AD patients, it may still have a role as a biomarker.
Zhou Xianbo also emphasized that, except for the very small number of hereditary AD patients, more and more people now do not recognize beta amyloid as the cause, but consider it only a pathological feature. He further pointed out that age-related diseases are usually multifactorial causes, and it is difficult to find a definite causative factor like tumors. Aβ deposition, which in turn leads to tau fibrillary tangles, and then neuronal cell death, is well established. However, it is not clear what causes amyloid deposition. It may be caused by microorganisms and aging.
In a 2018 interview with the journal Nature, a neuroscientist said that some ideas may be more important than we think, but few people are delving into, and he supports funding those more novel ideas. There isn't much to add to the beta-amyloid hypothesis, he said, "it's time to cast a bigger net -- we need more diverse ideas to build on."
In the pharmaceutical world, this kind of Transformation is happening. According to public statistics, there are currently about 170 active Alzheimer's disease treatments in clinical trials around the world, including 22 in Phase III, 75 in Phase II, and 73 in Phase I. Only 31% of all clinical therapies under investigation target traditionally misfolded proteins, including amyloid beta and tau. The pharmaceutical targets for Alzheimer's disease are being decentralised, and pharmaceutical companies have begun to develop new anti-AD drugs targeting synaptic activity and more mechanisms such as nerve conduction and inflammation.
Another Harvard Medical School researcher also told "China News Weekly" that as far as he knows, some funds, such as the Alzheimer's Drug Discovery Foundation (Alzheimer's Drug Discovery Foundation), have studied the Aβ hypothesis and developed it based on it. The therapy is not interested, and now the focus is shifted to new directions such as neuroimmunity.
According to the report on the ADDF website, in the three years of 2017, 2018 and 2021, the proportion of anti-AD drugs targeting misfolded proteins in the first phase of clinical trials was 43%, 25% and 19%, respectively. %, is gradually decreasing, while the proportion of therapies targeting neuroprotective, inflammatory, genetic and epigenetic targets has increased significantly.
In recent years, with the arrival of an aging society, the global attention to Alzheimer's disease has increased, and funds are also pouring into this field. Zhou Xianbo said that everyone finally has the opportunity to make more efforts from different aspects. After so many setbacks and doubts about the beta amyloid hypothesis, he is optimistic about the future basic research and drug development of Alzheimer's disease.
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