Shock the medical world!The classic papers 16 years ago were suspected of fraud. Has the drug research and development misleaded?

Author:Look at the think tank Time:2022.08.03

On July 22, "Science" magazine published a survey report that caused internal vibration.

The article questioned the new star in the research field of Alzheimer's disease and the neuros scientist Silwan Rice, a neuroscience of the Double City of the University of Minnesota, was suspected of academic fraud, including one of the foundations in the field: one article: One article Published an article on the top issue "Nature" in 2006. This paper belongs to the research category of Alzheimer's most mainstream "β amyloid protein hypothesis". "Science" magazine wrote that the article published in "Nature" was suspected of misleading the study of Alzheimer's disease in the world for 16 years. ) Funding and thinking in this field.

Academic fraud is not uncommon. This time, people attach great importance to this survey of "Science" because it happened in a special time point and atmosphere: the cause of Alzheimer's disease is still unclear, and the successful development of drug development has repeatedly defeated. Over the years, the "β amyloid -like protein hypothesis", as its supporting theory, has begun to shake in continuous clinical failures, and scientists who are suspicious to break the "monopoly" of this theory.

However, a number of neurosciences told reporters that even if these papers were finally proven to be fraud, its impact on Alzheimer's academic and pharmaceutical circles was not as serious as the outside world thought.

Wen | Peng Danni

This article is reproduced from the WeChat public account "China News Weekly" (ID: chinanewsweekly). The original first published on July 30, 2022. The original title was "Alzheimer's Disotropic Thesis was suspected of fraud. Has the drug research and development misleaded? ", Does not mean looking at the view of the think tank.

Suspected academic misconduct found due to space

As the most common type of dementia, Alzheimer's disease (AD) is a degenerative central nervous system disease. The "β amyloid -like protein hypothesis" proposed in the 1990s was one of the hypothesis of several major pathogenesis of Alzheimer's disease. The hypothesis believes that Aβ plaques in brain tissue are the main causes of this disease.

In 2006, while working at the well -known neurologist and Professor Karen Asia Laboratory at the University of Minnesota, Ricene published the "Nature" in the top journal "Nature" and published the "specific β amyloid protein in the brain The paper of damage to memory, the author of the article is Asia. The study is separated from the brain tissue of the elderly AD model mice and purifies the Aβ oligopoly with a molecular weight of 56kd and injected it into the young mice and found that it can exert neurotoxicity.

"Nature" said in a commentary on this paper that Aβ*56 was the "number one suspect" of Alzheimer's disease. According to the Web of Science database, this paper was quoted by about 2,300 academic articles -it was the fifth quotation of Alzheimer's basic research report published since 2006.

In fact, Wu Chengbiao, an associate professor of the Department of neuroscience at the University of California San Diego, told reporters that around 2000, clinical trials have found that the patient's cognitive ability worsens faster than the control group. Essence A few years after 2000, well -known scholars such as Dennis Saierko, a professor of "β amyloid protein hypothesis" and a professor at Harvard Medical College of the United States, have guess that soluble widows may be the culprit of the disease, but No one knows exactly what this oligopoly is in the organism.

This article in Risne is the first time in the animal model, which is purified in the body for the first time in the body. Wu Chengbiao said that many laboratories followed the trend, hoping to find a variety of Aβ clusters.

Lesne officially joined the University of Minnesota in 2009 and was funded by NIH to establish his own laboratory. "Science" reported that since then, the support of the National Institute of Health's research on keywords is "starch protein, oligopoly, and Alzheimer's disease" each year from nearly 0 to US $ 287 million in 2021 Experts said that Silwan Rice and Asia helped this explosive growth of funds.

The dissertation was suspected of fraud to the end of 2021.

In August 2021, Matthew Schrag, a neuroscience at the University of Van Dandburg, received a call from a peer and asked if he was interested in a job. The two neurologists are provided. They want to be short -term medical company Cassava Sciences, suspecting that one of the research data of one Alzheimer's disease in the research can have some problems. Schrag is committed to studying Alzheimer's disease and has previously caused controversy for publicly criticizing a drug that has been approved for listing.

In December 2021, Schrag visited Pubpeer, an academic counterfeit website, trying to investigate scientists related to Cassava Sciences. During the process of drawing cocoon, a new clue was unexpectedly discovered: Lesne as the first author or communication author, the image of the image seemed to be suspicious. In the end, Schrag has determined more than 20 suspicious Rice's papers, of which 10 are related to Aβ*56, including the article "Nature". Earlier this year, Schrag asked his doubts to NIH and Nature and other journals. He believed that there was a change or reuse of pictures of many papers in the Lesne thesis. Subsequently, Science involved in and carried out a half -year investigation that Schrag's conclusion was "convincing and reasonable."

Zhou Xianbo, co -founder of Zhongze Pharmaceutical Technology Co., Ltd., has developed a small molecular drug in the field of tumors and central nervous systems in the United States for many years. He returned to China in 2015 and was also the director of the Alzheimer Research Center of Washington Clinical Research Institute in the United States. He told reporters that, in fact, even if it was published in the top journal, when the Dato Pharmaceutical Factory conducted experiments based on these papers, it was found that more than 50%of them were not duplicated. Because biological experiments are made under specific conditions. But if a study drives people's work in a certain direction and breakthroughs, in turn, it can verify that this study is meaningful.

But if it is academic fraud, the nature is completely different.

Dennis Purcer participated in the investigation process of Science magazine, and found 12-15 experimental images "except tampering without other explanations", including one of the most critical "Nature" paper Show the image of Aβ*56 that is purified. The reporter sent an email to Silwan Rice and Karen Asia, hoping to verify and interview related issues, but as of July 30, the two did not respond.

Kellen Asia responded on the "ALZFORUM" website in Alzheimer's "ALZFORUM" website. She said that she could not comment on the allegations of her former collaborators, Ricene, might not have modified the image. But she said, "When I found that my collaborators might mislead the image of the scientific community by tampering with the image, I was very shocked." On July 14, "Nature" responded to investigating the paper and suggested that readers treat them with caution to treat them with caution. The result of the paper.

If such a key papers are finally confirmed to be a result of human modification, is there a negligence of authoritative journals for review? Chen Xiqun, assistant professor of neurology at the Massachusetts General Hospital of Harvard Medical College, told reporters that although the magazine reviewer can play a more important supervisory role in the thesis review, they cannot and should not fully assume the task of academic counterfeiting. Those conscious academic inconsistencies may never be able to discover it.

She believes that academics are not just academic issues, but morality and even legal issues. The increasingly stringent and complicated publishing requirements, whether it is the author or the magazine, it is a burden on time and resources, and it may not be the ultimate solution. After all, "the laboratory cannot be moved to the magazine" " More importantly, it relies on scholars' integrity, system, and norms to work together.

Is the theoretical foundation in the field?

If it wasn't for the report of "Science" from social media, Zhou Xianbo had actually forgotten the paper in "Nature".

Several interviewees said that this series of papers about Aβ*56, which questioned fraud, did not actually shake the "β amyloid protein hypothesis" as "Science". One of the very important reasons is that Aβ*56 This oligopoly is very unstable, and it is rarely repeated in other laboratories.

Dennis Purcer, a professor at Harvard University School of Medicine, quoted at least 13 papers of "Nature". But in the two papers in 2008, Purcera mentioned that he did not find Aβ*56 in human body fluids or tissues. He said in a response to the reporter that the allegations of the papers published by Silwan Lesne and others seem to be real. But he believes that even if these papers are artificially fake, it has a small impact on science and industry.

In 1985, the University of Melbourne, Professor of Melbourne, Australia, and others were first separated from AD patients with AD β 寡. He pointed out that Aβ is also known as "peptide from hell" because it has high hydrophobicity and aggregation, and it is difficult to extract and purify it. On the "ALZFORUM" website, he wrote that when Aβ*56 was originally reported, we looked at it and were a little surprised. In fact, we have never seen them since then. So our research has never rely on these data.

Public retrieval found that there were only 47 research on Aβ*56 in the title and summary, including the follow -up reports of 11 Rice laboratory after 2006. Zhou Xianbo told reporters that the vertical polymers of the real mainstream research are Aβ*42 and Aβ*40, and the industry does not use Aβ*56 as a target for R & D AD drugs.

Karen Asia refuted in public response, and the article "Science" hinted that her research was encouraged to develop researchers in the field of Alzheimer's disease by encouraging the development of therapy for starch -like deposition. She divides Aβ into two general forms: type 1 and type 2. She wrote that her laboratory and others found that a special form of type 1, that is, Aβ*56 in her papers will damage the small minor small The memory function of the rat, but there is no clinical trial for type 1 Aβ. From the perspective of the development history of "β amyloid -like protein hypothesis", it is not based on the "Air Tower" that was built on this suspected counterfeit paper in 2006.

In 1906, Eros Alzheimer, a psychiatrist at the University of Munich, Germany, and Emir Krepelin reported in an academic conference. They noticed that a 51 -year -old female patient with dementia and psychiatric symptoms changed the special plaques in the brain and the nerve -ray fiber tangled.

In 1984, the researchers extracted β amyloid protein (Aβ) from the plaques in the patients of Alzheimer's disease. In 1992, after the Royal Academy of Sciences and the University of London, John Hardy, the University of London, the University of London, in the "Science" magazine that the "starch -like protein -grade hypothesis" of Alzheimer's onset, the medical community began to focus on studying Aβ in Alz In the role of Hemo's disease, some pharmaceutical companies and scientific research institutions are also committed to developing drugs for Aβ.

β amyloid -like protein -grade hypothesis is the mainstream hypothesis currently accepted by most scholars. Li Yanfeng, chief physician of the Department of Neurology, Beijing Union Hospital, told reporters that many studies, including genetic genes, clinical and other basic studies, providing various evidence to support this hypothesis. In the past, some explanations of the pathogenesis, such as the oxidation stress, neuritis, infection, neuroma vascular mechanism of Alzheimer's disease, etc. At present, it seems that it is more about the "Aβ -Class hypothesis". Replenish.

In 2006, when Silvan Rice and others reported the discovery of Aβ*56 for the first time, many people, including him, felt that this study was unlikely to be meaningful or correct. The reporter's email wrote. However, he still stood on the side of the Aβ hypothesis. He said that the "unfortunate incident" of the dissertation suspected of fraud has not changed β amyloid protein in genetics, neurology, animal models, and even human clinical trials. evidence of. These evidence shows that reducing all forms of starch protein, including Aβ oligoplasty, can improve the disease, reduce the tangling of neurotransmal fibers, and delay the clinical progress of AD.

A mainstream hypothesis and more than 20 years of drug research and development failure history

Schrag pointed out in the survey report of Science that β amyloid protein cluster may still have some functions in Alzheimer's disease; after the 2006 paper was published, some researchers also found that Aβ oligomes are related to the cognitive ability of animal models. He hopes that people will not be timid to related fields because of this incident, but also mentioned that the discovery of these (academic misconduct) may allow us to suspend their pace and reintegrate the foundation behind the theory.

It is undeniable that the suspected fake incident will have a profound impact on the reputation of the theory of "β amyloid". If it is placed in a larger background to observe, as Zhou Xianbo pointed out, the root cause is the continuous challenges and doubts faced by the "beta starch -like protein" hypothesis in recent years.

Since its proposal in the 1990s, the entire field has been "monopolized" by Aβ hypothesis for almost 30 years. It costs a lot of costs in the industrial and academic fields to verify whether Aβ is a good pharmaceutical target. Since the Aβ vaccine AN1792 has entered the second phase of the clinic in 2000, a large number of Aβ target drugs emerging in more than 20 years, including vaccines, γ-secretion enzyme/BACE1 inhibitors, and Aβ antibodies, almost all ended in failure.

Zhou Xianbo said that everyone thinks that doing mainstream research under the framework of experts seems to be relatively stable. In fact, it is a kind of "Intellectually Lazy (intellectual laziness)." The large pharmaceutical factory basically only did large -scale clinical trials related to starch -like protein. At the same time, the failure of several large clinical trials had also appeared.

Zhou Xianbo said that in the 20 years, after several concentrated frustrations in the industry, many pharmaceutical companies withdrew from AD and even the entire central nervous disease field. Around 2020, companies that are still developing central system drugs have been counted.

As early as 2018, when the clinical trials of Alzheimer's drugs that received much attention declared failed, the "Nature" magazine published a long article pointed out that the field may be experiencing a frustrating discovery journey. However, if this field is based on the foundation of the wrong thoughts, researchers may be approaching the end of the dead alley. "Β starch -like protein is not the only potential cause, it is time to explore other paths."

At that time, the industry was confident in a anti -AD drug, because it seemed to be effective in improving cognitive functions in early trials in 2016. This is the first Alzheimer's new drug approved in June 2021: Aducanumab, which is developed and produced by Bo Jian, a US biotechnology company, is developed and produced. This drug is also based on the development of β amyloid -like protein, but further exacerbates the skepticism of β amyloid protein hypothesis in the academic and industry. Bo Jian has conducted two III trials of 2 to 3 years. After preliminary analysis, although the medicine can effectively remove Aβ plaques, it cannot significantly slow down the decline in cognitive; in contrast, the risk of cerebral edema and cerebral hemorrhage by high doses of cerebral edema and cerebral hemorrhage have increased by 31%. Two tests were terminated in March 2019. A few months later, Bo Jian's retrospective analysis of the obtained clinical trial data found that one of them studied a statistically significant result in the high -dose group, that is, drugs can slow down cognitive decline. After several months of communication with the Food and Drug Administration (FDA), Bo Jian officially submitted the supplementary data application for Aduca Metabu in July 2020.

In November 2020, the US FDA held a consultation meeting on Aduca Mipide. In the last voting voting, only one of the 11 experts agreed to approve the listing of the drug, and 8 of the remaining 10 experts opposed it, and the two were uncertain. But it was finally approved through the special channel of "accelerated approval".

"Any hypothesis can bring the listing of new drugs, it is definitely worth celebrating, but the listing of Aduca Mubiokabu just makes the field think that this target may not be satisfactory." The clinical trial data of the drug shows that its efficacy is uncertain, and the side effects of toxicity are more serious.

On December 17, 2021, the European Medicine Administration rejected the listing license of Aduca Metase; 5 days later, the Ministry of Health of Japan also refused to approve the application for the listing of Aduca Midurate for a similar reason. On June 9 this year, Bo Jian took the initiative to withdraw the regulatory review of Aduca Mipida in Canada.

In the explanation of the continuous failure of clinical trials, "Nature" wrote that the most commonly mentioned reason is that these drugs are administered too late, and Aβ deposition has caused irreversible damage of the brain. Brain PET scan shows that plaques may begin to form in the decades when cognitive symptoms appear, and the level of β amyloid protein may be stable when patients enter clinical trials.

On June 16 this year, Roche Pharmaceutical announced that its clinical II trials failed. Among people with normal cognitive function but family AD genetic risks, the clinical trial aims to evaluate the potential of candidate drugs to slow down or prevent Alzheimer's disease. Study a total of 252 subjects in Columbia, South America, for 5-8 years. CENEZUMAB, Crenezumab, which targeted β amyloid proteins. The results showed that the efficacy of the treatment group and the placebo group was not significantly different, and the treatment of Cranet's treatment monoclonal anti -antibody treatment failed to delay the decline in cognitive decline and memory decline.

It's time to explore the new direction

In Zhou Xianbo's view, a particularly strange phenomenon is that the fans of β amyloid -like protein hypothesis have been looking for reasons for the failure of clinical trials. For example, we may be treated too late and should be administered earlier; or Our drug targets are not right. If Aβ*42, Aβ*40 is invalid, try other oligoplasts and so on.

"Everyone keeps looking for evidence to support β starch protein hypothesis, instead of finding evidence that can overthrow it, and then continue to move forward." He said, but now, some scientists are getting more and more tired of this narrative.

A neuroscience scholar told reporters that in the field of Alzheimer's disease, from scientific research to drug development, in fact, different hypothesis is a bit like a mountain, and Aβ is undoubtedly one of the strong one.

The article "Science" pointed out that in this fiscal year, NIH spent about $ 1.6 billion in projects involving amyloid protein, accounting for about half of its total research and development of Alzheimer's disease. Study other potential causes of Alzheimer's disease, such as scientists who have neurotomorphic reactions and neural inflammation reactions, complaining that they are crowded out by the powerful "starch protein group".

Chen Xiqun, assistant professor of neurology at Harvard Medical College Massachusetts General Hospital, pointed out that although β amyloidin is the mainstream theory of Azheimer's disease, there has always been questioning of this theory. In fact, there is not only one sound in this field.

"Since Alzheimer's disease has been reported in 116 years, the history of drug research and development has been very small. Now the treatment methods that doctors can use in the toolbox of doctors have not made great progress in essence." Zhou Xianbo said that the entire Alz Sea The field of dexiated disease is still in a relatively early stage, facing too many unknown.

Wu Chengbiao, an associate professor of the Department of Neuroscience of the Department of Neuroscope, University of California, who pays attention to genetic elderly neurotic disease, believes that in addition to about 3-5%of Alzheimer's disease is completely inherited, 95-97%of ex -transmission cases. Actually Everyone does not know what causes it. In this case, it may be wrong from the beginning. In his opinion, AD is not so much a disease. It is better to be a syndrome and may not be cured by drugs with a single target. "I think the biggest unsolved problem is that it is β amyloid -like protein deposition that causes the onset of Alzheimer's disease, or is it a companion of a neurons after the onset? Then, for β amyloid -like drugs, it may be just cure for the standard rather than the root cause. "Chen Xiqun said, but even so, it cannot be said that this theory has no scientific significance. If it can be detected in the nerves of AD patients, it may still have the function of biomarkers.

Zhou Xianbo also emphasized that, in addition to the very small part of the hereditary AD patients, more and more people do not recognize β amyloid protein as a cause, but believe that it is just a pathological characteristics. He further pointed out that age -related diseases are usually the cause of multiple factors, and it is difficult to find a certain pathogenic factor like tumor. Aβ is deposited, which causes the fiber tangue of TAU protein, and then causes nerve cells to die, which is recognized by everyone. However, what causes starch -like protein precipitation is unclear, and it may be possible for microorganisms and aging.

A neurologist said in an interview with "Nature" magazine in 2018 that some ideas may be more important than what we imagine, but few people have studied, and he supports funding to support those new ideas. He said that there is not much to add for β amyloid -like protein hypotheses. "It's time to sprinkle a larger net: we need more thoughts as a basis."

In the pharmaceutical industry, this transformation is happening. According to public statistics, about 170 active Alzheimer's disease therapy is currently undergoing clinical trials, including 22 clinical phase 3, 75 clinical phase 2, and 73 clinical phase 1. In all clinical therapies, only 31%of the targets are traditional error folding proteins, including β amyloid proteins and tau proteins. Alzheimer's pharmaceutical target is being decentralized. Pharmaceutical companies have begun to develop anti -AD drugs for more mechanisms such as synapses, neurotiating, and inflammation.

Another researcher at the Harvard University School of Medicine also told reporters that according to his understanding, some funds, such as Alzheimer's Drug Discovery Foundation, have already been interested in the Aβ hypothesis and based on its development therapy. Now transfer the focus to new directions such as neuromanosis.

According to reports on the ADDF website, in the three years of 2017, 2018 and 2021, the therapy for targeting error folding proteins in global anti -AD drugs, 43%, 25%, and 19%in the first phase of clinical trials. At the same time, the proportion of therapy for neural protection, inflammation, genetic and epigenetic targets has increased significantly.

In recent years, with the advent of aging society, the world's emphasis on Alzheimer's disease has increased, and funds are pouring into this field. Zhou Xianbo said that everyone finally has the opportunity to make more efforts from different aspects. After experiencing so many setbacks and doubts about β amyloid protein hypotheses, he was optimistic about the basic research and drug research and development of Alzheimer's disease in the future.

(Intern Du Yin also contributed to this article)

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