Bai Yingnan felt a little wrong. I dont have any research fraud, she told the China Science Daily.
Embarrassed like Bai Yingnan, there is also a researcher in the field of cardiac stem cells. At a recent academic conference, several big colleagues asked him in secret: The news says that heart stem cell youre working on is fake?
Heart stem cell researchers in China are suspected of a pseudo-earthquake after Harvard Medical School recommended the withdrawal of 31 papers from Piero Anversa. According to an in-depth investigation by a reporter in the Chinese Science Journal, heart stem cell research in China focuses on preclinical studies of various types of stem cells for the treatment of heart disease, and has nothing to do with the differentiation of c-kit positive heart stem cells suspected of fraud. Nevertheless, the repeatability of experiments in this field should also be taken into account, and false positive results should be cautioned against hasty release.
C-kit in China
The cause of Bai Yingnans embarrassment is traced back to early 2010. Bai Yingnan, who finished her postgraduate study of EPCs, was recommended by a Japanese professor and sent to Anversa Laboratory as a visiting scholar by Fudan University.
Over the past three years, Bai Yingnan has been assigned to a team of researchers called Polina Goichberg to study the effect of ephrinA1 signaling pathway on the repair of myocardium by c-kit-positive cardiac stem cells. The Anversa lab has a clear division of labor, and my team is only responsible for the animal part of MI mice. Previous isolation and culture of c-kit-positive cardiac stem cells, and subsequent in vivo experiments to detect their migration, were conducted by other groups. Bai Yingnan said.
In 2011, the Journal Circulation Research published the labs research on ephrinA1, and the correspondent Anversa himself, with 16 authors, came in second. Between 2011 and 2015, four other papers on ephrin A1 were published, all bearing the name of Bai Yingnan.
At the end of 2012, Bai Yingnan returned to Sun Yat-sen Hospital of Fudan University without bringing back more information about C-kit-positive cardiac stem cells, and the focus of her life changed from scientific research to treatment. Unfortunately, I did not apply for the project, the relevant research work has stopped, and no papers have been published. She said.
In fact, c-kit-positive heart stem cells had been questioned by other research groups before faking the hammer. The focus of the doubt was that no differentiation of c-kit-positive cardiac stem cells was observed in repeated experiments.
According to the verification of Chinese papers by the reporter of China Science Journal, most of the researchers of heart stem cells come from medical schools in China, and they are most concerned about the clinical use of heart stem cells. Therefore, the research on C-kit positive cardiac stem cells is mainly focused on pre-clinical. It has been proved that effective stem cells cooperate with other factors, and solve the clinical problems such as how to transplant and homing. The more fundamental and controversial mechanism of action is lack of empirical research.
A review article published in Advances in Physiological Sciences in 2016 describes the current state of research on c-kit-positive cardiac stem cells, and the logic of its writing also reflects the thinking of domestic research in this field - easy use is the key. The role of c-kit-positive cardiac stem cells in heart diseases such as myocardial infarction and heart failure has been confirmed by a number of in vivo and in vitro experiments and clinical trials, but the mechanism of treatment is still controversial.
Since Anversa published the results that c-kit positive heart stem cells can differentiate into cardiomyocytes, Ge Junbo, director of Cardiology and academician of Chinese Academy of Sciences of Zhongshan Hospital affiliated to Fudan University, who has conquered heart disease for a lifetime, has sprouted the idea of trying new c-kit positive heart stem cells to treat heart disease.
Ge Junbo, a clinician, denied the possibility of clinical use of c-kit-positive cardiac stem cells when he learned the details from Anversas laboratory. Anversa proposes that a condition for obtaining c-kit-positive cardiac stem cells requires a myocardial biopsy of the left atrium, which requires an opening about 5mm deep in the left atrium, and the left atrium itself is only about 4mm thick, like a sheet of paper. At the time, I thought it was a risk of heart rupture, and it was hard to get approval from the ethics committee. Ge Junbo said.
In other words, the problem with c-kit-positive cardiac stem cells lies in the mechanism of action, and most domestic studies have skipped the validation mechanism and directly entered the lower reaches of the effect. If the researchers did not lie in the effect-observing experiment, a collective fraud suspected of having been falsified by c-kit-positive cardiac stem cells would not have occurred.
In addition to preclinical studies, few domestic studies focus on cell tracer technology. Previously, the flaws in cell tracing technology have become one of the controversial concerns about the differentiation of c-kit-positive cardiac stem cells. The commonly used cell tracer technology needs to stain the observed cells, and there is a certain error rate. At the same time, labeling C-kit-positive cardiac stem cells is less than 100 percent accurate and can leak to other types of cells. For example, when leaking into cardiomyocytes, the experimenter observes the offspring of cardiomyocytes and mistakes them for cells differentiated from c-kit-positive cardiac stem cells.
In recent years, Zhou Bin, a researcher at the Institute of Biochemistry and Cell Biology, Shanghai Academy of Health, Chinese Academy of Sciences, traced the genetic lineage of c-kit-positive cardiac stem cells. The results showed that c-kit-positive cells contributed very little to cardiac myocytes, whether in the physiological homeostasis of the heart or after myocardial infarction.
To verify the hypothesis, our team used real-time pedigree tracing to label non-cardiomyocytes and newly generated cardiomyocytes with fluorescent markers different from those of existing cardiomyocytes, demonstrating that c-kit-positive cardiac stem cells mainly contribute to coronary endothelial cells, not to the heart, in cardiac physiological homeostasis and injury repair. Muscle cells.
The idea of stem cell therapy for heart is cool?
Further, domestic research on stem cell therapy for heart disease is also suspected to be following the trend of academic fraud.
Huang Zheyong, professor of Cardiology at Zhongshan Hospital affiliated to Fudan University, told the Chinese Science Journal that the heart stem cells in the current news reports refer to the hearts own stem cells. The stem cells, which hope to treat heart disease, are more than c-kit positive cardiac stem cells.
Many adult adult organs contain some stem cells, which can be regenerated after being injured. For a long time, myocardial infarction or myocardial damage can not effectively self-repair is the consensus of the scientific community, so how to repair the injured heart, scientists need to overcome the problem.
Until 2003, Anversa published a paper saying that c-kit positive cardiac stem cells were found in the heart. C-kit is a receptor on the surface of cells, and Anversa claims to have discovered and named heart stem cells with this marker.
Since then, several research groups have repeated Anversas experiments and questioned the results, all around c-kit-positive heart stem cells. The latest advances came in August when Zhou Bin published an experiment in the Journal Circulation that showed no heart stem cells.
Ge Junbo said: The discovery of c-kit positive cells is indeed a bright spot, but the latest pedigree tracing technology found that adult heart non-cardiomyocytes do not transdifferentiate into cardiomyocytes, that is, no matter what kind of dry markers,hearts own cellsdo not have the ability to regenerate myocardium. Its really frustrating.
In theory, however, repairing damaged hearts can use stem cells from other sources as well as stem cells from the heart itself. For example, mesenchymal stem cells (MSC), induced pluripotent stem cells (IPS), embryonic stem cells (ES). These stem cells are not derived from the heart, but have been shown to be effective in repairing myocardium in some experiments or clinical trials, and the specific mechanism is still being explored.
For example, Huang Zheyong introduced that for MSC, initially researchers were confident that injecting MSC directly into necrotic myocardium could differentiate into new myocardial cells, thereby replacing necrotic myocardium. But its not as good as it seems. Injected MSCs stay in the myocardium very little, survive less, and those that survive in a small amount cant differentiate into cardiomyocytes.
In recent years, scientists have also proposed a new hypothesis that the benefits of MSC transplantation do not stem from cell regeneration, but from the paracrine production of some cytokines after MSC enters the human body, interacting with normal myocardial cells, improving the healing process of myocardial infarction, which may bring some benefits to patients with myocardial infarction.
Therefore, the papers on the first page of the Chinese database, which were searched by heart stem cells and sorted by citation, were all focused on the experiment of bone marrow MSC, and had nothing to do with c-kit positive heart stem cells.
ES and IPS are becoming another way to treat heart disease. In recent years, Ma Yue, a researcher in the Institute of Biophysics of the Chinese Academy of Sciences, led a research team to design a new method of myocardial differentiation. In vitro experiments, human ES can be efficiently differentiated into atrial and ventricular myocytes within 14 days. These cells have electrophysiological characteristics of atrial and ventricular myocytes during embryonic period. This result makes it possible to produce human atrial and ventricular myocytes in large quantities in the laboratory. Myocardial infarction occurs in the left ventricle, which determines that ventricular myocytes are the most suitable cells for cell transplantation in the treatment of myocardial infarction.
Theoretically, the nature of the adult cell itself as aninternal causedetermines that through any adult cell transdifferentiation into cardiomyocytes to achieve the goal of repairing the myocardium is not realistic. In the past, adult cells have been shown to beeffectivein many ways because they act asexternal factors to assist the heart in improving its function, such as paracrine. But Ma Yue explained, ES and IPS differentiated ventricular myocytes have contractile function, can directly improve the function of the heart, become the heart repairinternal cause.
In his view, the future direction of development will be the combination of internal and external factors, basic research and clinical research still need a lot of joint efforts.
From this point of view, the domestic heart stem cell research is still focused on the right path and will not be lost because of a stem cell type of fake.
Be vigilant to release false positive results
In summary, the great earthquake of academic fraud did not happen. However, as well as academic fraud, it is a phenomenon that cardiac stem cell research and even the whole field of stem cells and life sciences are too eager for quick success and instant benefit.
All want to make history. This is the assessment of heart stem cell research by Charles Murry of the University of Washington in Seattle, who has questioned the Anversa experiment.
The biggest driver of Anversas data fraud is its reputation and economic success as a major discoverer of new science. No one can resist such temptation.
Xue Tian, a professor at the College of Life Sciences at the University of Science and Technology in China, said the United States had been a swarm of bees eager to apply the results to clinical practice. A number of cattle in the cardiovascular field in the United States have invested a lot of manpower and material resources, and the National Institutes of Health have also invested a lot of research funds in the next 10 years to study its theory and potential applications.
There is a claim in the scientific community that extraordinary discoveries require extraordinary evidence. The whole field of cardiovascular science has not really followed this principle, and the criteria for judging scientific evidence have been lowered for the sake ofMajor scientific discoveries. Xue Tian told the China Science Journal.
In his view, although it is impossible to prove that Chinese researchers are suspected of fraud, the articles published by Chinese researchers show the characteristics of low-end repetitive research.
Under the premise of academic integrity, the research on cardiac stem cells both at home and abroad shows the phenomenon of eagerness to succeed while neglecting strict scientific research standards, which deserves academic reflection.
In addition, taking one-off story and false positive as major scientific advances has also become an important reason why the field of life sciences has repeatedly become the scene of major traffic accidents in recent years.
A domestic life scientist told the China Science Journal that European and American scientists frequently reported significant advances in life sciences around 2003. It was difficult for Chinese scholars to compare with them at that time and the research could not be published in top journals. We have a joke that if you want to send CNS [Cell, Nature, Science], youre going to validate the big progress and write negative results. He said.
The concept of experimenter retrogression put forward by the philosopher of science, Collins, can more or less explain the phenomenon that a large number of achievements in the field of life science can not be repeated. When the experimental system gives the correct answer, you know that the experimental system is effective, but only after trusting the experimental system, you know what the correct answer is. A CAS academician, who declined to be named, said that, like many life sciences, stem cell research is still at the forefront of science, and some researchers pursue major scientific discoveries without paying enough attention to the repeatability of experimental data. Especially some tutors do not do experiments for a long time, the data produced by students can not be grasped, resulting in many papers are actually described as aone-off story,the results can not be repeated. Researchers call for discoveries in life sciences, including stem cells, to be significant, but academic integrity should be emphasized first, and scientific rigour should also be given priority. Source: Science Editor: Han Jiapeng _NN9841
The concept of experimenter retrogression put forward by the philosopher of science, Collins, can more or less explain the phenomenon that a large number of achievements in the field of life science can not be repeated. When the experimental system gives the correct answer, you know that the experimental system is effective, but only after trusting the experimental system, you know what the correct answer is.
A CAS academician, who declined to be named, said that, like many life sciences, stem cell research is still at the forefront of science, and some researchers pursue major scientific discoveries without paying enough attention to the repeatability of experimental data. Especially some tutors do not do experiments for a long time, the data produced by students can not be grasped, resulting in many papers are actually described as aone-off story,the results can not be repeated.
Researchers call for discoveries in life sciences, including stem cells, to be significant, but academic integrity should be emphasized first, and scientific rigour should also be given priority.