为《细胞研究》鼓掌：有关耿美玉为通讯作者的论文事件

       中国出版的英文的学术刊物《细胞研究

》(Cell Research)，在引进曾任美国《细胞》杂志编辑成员之一的李党生后，他带领的编辑部不断进取，并与《自然出版集团》合作而国际化，显著提高。

       2019年10月，《细胞研究》杂志发表Wang等的论文，前四位作者为绿谷药厂成员，责任通讯作者为中国科学院上海药物研究所耿美玉研究员。

       不少人私下质疑这一论文，但公开质疑的很少。

       有鉴于此，2020年3月14日，在迹象显示中国新冠肺炎疫情基本控制的情况下，笔者致信《细胞研究》。《细胞研究》杂志的主编被笔者另外质疑有过学术问题，有利益冲突，所以被要求不能参与此事。经过与编辑部多次沟通，包括编辑委员会成员的全部国际成员，也包括编辑部与其国际合作者(自然出版集团)，最后于2020年7月6日，按国际学术常规，全文发表笔者来信。

       这是我国比较罕见的按国际学术规则，公开发表严肃质疑性质的来信。为我国科学界引入了理性辩论、合理质疑、负责任地批评的学风。

       《细胞研究》这一举措，表明：我国也有学术刊物，不仅希望卓越，而且希望有道德、有原则。

       以上为简要说明，以下是《细胞研究》信件的翻译：

应该更正一位作者忽略引用以前文献

事涉：Wang et al. Cell Res 29, 787-803 (2019)

作为《细胞研究》的编委，此信提供对《细胞研究》2019年10月期Wang et al.1论文读者所需要的必需信息。

应该注意，该文的通讯作者耿美玉博士，此前发表过GV971或与之密切相关的12篇论文，其中包括体外和体内实验。因为Wang et al. (2019)论文对它们一篇都没有引用，所以列在此以便读者知情。7篇论文是GV971的原始论文2-8，其他是综述或相关文章9-13。

总结而言，耿博士以前文章号称GV971可以治疗动物模型的巴金森病2，GV971可以直接与β淀粉样肽直接结合4, 9，GV971 可以保护神经细胞免受β淀粉样肽的毒性4, 5， GV971可以减轻β淀粉样肽注射到脑内导致的记忆缺失6，GV971 可以直接抑制过氧化氢诱导的神经细胞死亡3, GV971 可以减轻东莨菪碱导致的大鼠记忆缺失3， GV971 可在体外作用于星型胶质细胞8 ，GV971 可与神经细胞内的蛋白质相结合7。这些效果是直接作用于Aβ肽, 或直接作用于神经细胞、或神经胶质细胞，全部都是在神经系统内，而现在Wang et al. 1 等的论文号称GV 971 在阿兹海默症的动物模间接通过肠道微生物和炎症起作用。这些作用在药物靶标、有效部位、治疗机理上有如此惊人的差别，以致引起对可信性的潜在关注。读者不应该没有注意，虽然通常存在多个靶点意味着副作用，而作者们却号称GV971的所有靶标和作用都帮助治疗阿兹海默症。

我自己对中外生物医学历史都有研究（如以中文发表过中国青蒿素、三氧化二砷研究的科学史14，也以英文在国际刊物发表过肾上腺素的科学史研究文章15），我从未看过一个药物有如此多的靶标共同治疗一个疾病。

《细胞研究》的引文是简略版，更详细的文献为

1)    Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, Xie Z, Chu X, Yang J, Wang H, Chang S, Gong Y, Ruan L, Zhang G, Yan S, Lian W, Du C, Wang D, Zhang Q, Lin F, Liu J, Zhang H, Ge C, Xiao S, Ding J and Geng M (2019) Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Research 29:787-803.

2)    Dong XL, Geng MY, Guang HS and Xie JX (2003) Effects of marine acidic oligose on dopamine release from striatum and amygdala in the rat models of Parkinson’s disease. Chinese Journal of Marine Drugs (中国海洋药物杂志) 9(5):9-12.

3)    Fan Y, Hu J, Li J, Yang Z, Xin X, Wang J, Ding J and Geng M (2005) Effect of acidic oligosaccharide sugar chignon scopolamine-induced memory impairment in rats and its related mechanisms.Neuroscience Letters 374:222-226.

4)    Geng MY (2007) Protective effect of marine-derived oligosaccharide as a candidate anti-AD drug and its related mechanisms. Chinese Pharmacologist 24:7. 

5)    Guo X, Geng M and Du D (2005) Glucose transporter 1, distribution in the brain and in neural disorders: its relationship with transport of neuroactive drugs through the blood-brain barrier.Biochemical Genetics 43: 175-187.

6)    Hu JF, Geng MY and Zhang JT (2003) The relationship between senile plaques, neurofibrillary tangles and sulfated polysaccharides. Chinese Pharmacology Bulletin (中国药理学通报) 19:(1)12-16.

7)    Hu J, Geng M, Li J, Xin X, Wang J, Tang M, Zhang, J, Zhang X and Ding J (2004) Acidic oligosaccharide sugar chain, a marine-derived acidic oligosaccharide, inhibits the cytotoxicity and aggregation of amyloid beta protein. Journal of Pharmacological Sciences95:248-255. 

8)    Jiang R-W, Du X-G, Zhang X, Wang X, Hu D-Y, Meng T, Chen Y-L, Geng M-Y and Shen J-K (2013) Synthesis and bioassay of b-(1,4)-D-mannans as potential agents against Alzheimer’s disease. Acta Pharmacologica Sinica 34:1585-1591.

9)    Kong L-N, Geng M-Y, Mu L, Xin X-L, Yang N, and Zuo P-P (2005) Effects of acidic oligose on differentially expressed genes in the mice model of Alzheimer’s disease by microarray. Acta Pharmaceutica Sinica 40:1105-1109.

10) Liu M, Nie Q, Xin X and Geng M (2008) Identification of AOSC-binding proteins in neurons.Chinese Journal of Ocenology and Limnology26:394-399.

11) Nie Q, D X-G and Geng M-Y (2011) Small molecule inhibitors of amyloid b peptide aggregation as a potential therapeutic strategy for Alzheimer’s disease. Acta Pharmacologica Sinica 32:545-551.

12) Wang S, Li J and Geng M (2005) Inflammatory mechanisms of Alzheimer’s disease and the anti-inflammatory effects of sugar-related substances.Progresses in Physiological Sciences 36:67-70.

13) Wang S, Li J, Xia W and Geng M (2007) A marine-derived acidic oligosaccharide sugar chain specifically inhibits neuronal cell injury mediated by b -amyloid-induced astrocyte activation in vitro.Neurological Research 29:96-102.

14) Rao Y, Li RH and Zhang DQ (2013) from poison to drug: the discovery of arsenic trioxide treatment of acture promyelocytic leukemia. Science in China (Life Sciences) 56:495-502 doi:10.1007/s11427–13-4487-z

15) Rao Y (2019) The first hormone: adrenaline. Trends in Endocrinology and Metabolism 30:331-334. 

附：《细胞研究》发表信的原文

Brief Communications Arising 

Omission of previous publications by an author should be corrected 

Arising from: X. Wang et al. Cell Res 29, 787-803 (2019) 

Cell Research (2020) 0:1; https://doi.org/10.1038/s41422-020-0344-3

As a member of the Editorial Board of Cell Research, I am writing to provide essential information to readers of the Wang et al.1 paper on GV971 published in the October 2019 issue of Cell Research. 

It should be noted that the corresponding author of the paper, Dr. Meiyu Geng, has previously published 12 papers on or closely related to GV971, including both in vitro and in vivo studies. Because not a single one of these papers was cited in Wang et al. (2019), they are listed here so that the readers would be aware of them. Seven papers are original research papers on GV971,2-8 while others are reviews or related papers.9-13

To summarize, previous papers by Dr. Geng have claimed that GV971 can treat Parkinson’s disease in animal models,2 that GV971 can directly bind to amyloid β peptides,4, 9 that GV971 can protect neurons from amyloid β toxicity,4, 5 that GV971 can ameliorate memory loss caused by amyloid β peptide injection into the brain,6 that GV971 can inhibit H2O2 induced neuronal death directly,3 that GV971 can attenuate scopolamine induced memory impairment in rats,3 that GV971 can act on astrocytes in vitro8 and that GV971 can bind to proteins inside neurons.7 While those effects were directly on the Aβ peptide, or directly on neurons or glial cells, all inside the nervous system, Wang et al. 1now claim that GV 971 works on Alzheimer’s animal model indirectly through regulating gut microbiomes and inflammation. These effects are so strikingly different with regard to drug target(s), location of effective sites and therapeutic mechanisms that they raised a potential concern of credibility. It should not escape the attention of readers that, while usually the existence of diverse targets means side effects, the authors claim all targets and effects of GV971 are helping to alleviate the Alzheimer’s disease. 

In my own study of the history of biomedical research, ranging from that in China which includes but is not limited to, the discovery of the antimalaria drug artemisinin and the anti-leukemia drug arsenic trioxide 14, to that in the rest of the world 15, I have never come across a single drug with so many targets for curing or alleviating one disease. 

Correspondence: Yi Rao 

References

1. Wang X, et al. Cell Res 29, 787-803 (2019).

2. Dong X, Geng M, Guang H & Xie J. Chin. J. Mar. Drugs (Article in Chinese) 9, 9-12 (2003).

3. Fan Y, et al. Neurosci. Lett. 374, 222-226 (2005). 

4. Hu J, et al. J. Pharmacol. Sci. 95, 248-255 (2004).

5. Jiang R, et al. Acta Pharmacol. Sin. 34, 1585-1591 (2013).

6. Kong L, et al. Yao Xue Xue Bao (Article in Chinese) 40, 1105-1109 (2005).

7. Liu M, Nie Q, Xin X & Geng M. Chin. J. Ocenol. Limnol. 26, 394-399 (2008).

8. Wang S, Li J, Xia W & Geng M. Neurol. Res. 29, 96-102 (2007).

9. Geng M, Zhongguo Yao Li Tong Xun (Article in Chinese) 24, 8 (2007).

10. Guo X, Geng M & Du D. Biochem. Genet. 43, 175-187 (2005).

11. Hu JF, Geng MY & Zhang JT. Zhongguo Yao Li Xue Tong Bao (Article in Chinese) 19, 12-16 (2003).

12. Nie Q, Du X & Geng M. Acta Pharmacol. Sin. 32, 545-551 (2011).

13. Wang S, Li J & Geng M. Sheng Li Ke Xue Jin Zhan36, 67-70 (2005).

14. Rao Y, Li RH & Zhang DQ. Sci. China Life Sci. 56, 495-502 (2013).

15. Rao Y. Trends Endocrinol. Metab. 30, 331-334 (2019).