诺奖得主、iPS细胞之父山中伸弥又道歉了！其研究所论文存在严重造假！

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这两天美国政府“关门”，作为联邦雇员笔者正好干些正经事。因为突然一日得知母校两位杰出师长仙逝，所以咬着洗牙的疼痛一日完成两篇悼念文章和一个新闻报道。

还没休息，就又有科友来“麻烦”来了：又报告笔者早就预计会发生的事情：诺奖得主、iPS细胞之父山中伸弥的研究所会论文造假，他又道歉了。

日本京都大学iPS研究所助教论文被曝存在捏造

2018年01月22日 18:21 中国新闻网

中新网1月22日电 据日媒22日报道，日本京都大学22日发布消息称，京大iPS细胞研究所特定据点助教山水康平的论文存在捏造和篡改。

日本京都大学称，被指捏造的iPS细胞研究所的论文于去年发表，内容为成功利用iPS细胞在体外培养出具有防止有害物质进入大脑的“血脑屏障”功能的结构体。

据悉，2017年8月，日本东京大学具有世界级影响力的著名细胞生物学家渡边嘉典被证实存在学术不端行为，他在发表的5篇论文中使用了造假的图片和图表。

出于科学的严谨，笔者还专门让“孤狗”用“鹰文”搜索，结果发现：诺奖得主、iPS细胞之父山中伸弥领导的iPS细胞研究所去年发表的一篇论文于称成功利用iPS细胞在体外培养出具有防止有害物质进入大脑的“血脑屏障”功能的结构体，但这篇论文的12个图竟然有11个是伪造的！

为此，山中伸弥在新闻发布会上公开道歉。

2018-01-23

Unstable work seen as a factor as Kyoto University admits iPS researcher falsified data in paper

KYOTO – Research misconduct at a leading iPS cell research institute, headed by Nobel Prize winner Shinya Yamanaka, has once again shaken confidence in the quality of Japan’s science.

But experts contacted by The Japan Times on Tuesday said that unstable employment conditions faced by scientists are behind the seemingly endless string of research-related scandals in the nation.

Kyoto University announced Monday that Kohei Yamamizu, 36 — a specially appointed assistant professor at its Center for iPS Cell Research and Application (CiRA) who was involved in research to generate a brain structure in vitro using iPS cells — had falsified 11 of 12 figures used in his paper that was published last year in the U.S. academic journal Stem Cell Reports.

Shinya Midori, a Tokyo-based science writer and author of a book about Yamanaka’s research, said that even at a venerable research institute like CiRA, scientists are under enormous pressure to show results before their contract terms end, or risk seeing their careers come to a halt.

“I think CiRA is doing relatively well when it comes to winning research funds. Yet, it is difficult to cover costs (to promote more researchers in permanent positions) as the scale of research centers have become bigger,” he said.

According to Kyoto University, 90 percent of roughly 300 scientists, research assistants, and administrative staff employed at CiRA as of March 2017 were on fixed-term contracts.

Another expert, Iekuni Ichikawa, executive director at the Association for the Promotion of Research Integrity, also said that excessive pressures among researchers to compete for permanent positions reflect a “poor balance” between fixed-term researchers and those in permanent roles.

Yamamizu reportedly admitted the fabrications and falsifications, claiming they were “to make the paper look better.” His term at CiRA was set to end in March 2018.

“As CiRA Director, I feel a strong responsibility for not having been able to prevent research misconduct at our institute and sincerely apologize to all who support us and our research activities,” Yamanaka said in a statement released Monday, adding that the organization will decide how to reprimand Yamamizu and other researchers, including Yamanaka. He said the research misconduct found this time has no direct influence on any ongoing or planned clinical research involving iPS cells.

The scandal involving the elite life science research body follows misconduct found at the University of Tokyo last year. The nation’s top university announced that fabrications and falsifications of data and images were detected in five papers supervised and coauthored by two researchers at its Institute of Molecular and Cellular Biosciences.

Midori said Yamanaka’s research center has been especially careful about avoiding academic dishonesty after misconduct over the research of Stimulus-Triggered Acquisition of Pluripotency (STAP) cells conducted by Haruko Obokata came to light in 2014.

Still, preventing misconduct by an individual researcher was difficult, especially after the scale of the research institute grew, he said.

“I think the pressure is felt by all researchers. But it’s not right to fabricate research results so as to favor themselves,” he said.

On the other hand, stepping up surveillance on dishonest practices may not always be a good thing for the future of academia as a whole, because good research often comes from academic freedom, Midori said.

“Once a strict checking system is set, researchers who are not engaged in misconduct also need to go through the same process. It’s always difficult to find a fair way to check research integrity while giving enough freedom to researchers,” he said.

Ichikawa also said researchers need to realize that, given the widespread use of the internet, even the slightest tampering of research data can be easily caught by people online.

“I think researchers need to realize that their work is always watched by outsiders from the moment they publish,” he said.

而一年前，山中伸弥就因为另一个原因深切道歉过。

2017-01-24

Kyoto University to halt provision of iPS cells after reagent misuse

KYOTO – Kyoto University will suspend its supply of induced pluripotent stem (iPS) cells for clinical use after a wrong reagent was possibly used to create such cells.

The suspension is “a very tough decision,” Shinya Yamanaka, director of the university’s Center for iPS Cell Research and Application, or CiRA, told a news conference on Monday.

“We deeply reflect on and apologize for” the possible misconduct, Yamanaka said.

No iPS cells provided by the university have been used on human bodies.

The university last November found a mislabeled tube containing a reagent that has nothing to do with creating iPS cells, during the process of making the cells. The cause of the problem has yet to be identified.

The suspicious iPS cells, made from blood taken from umbilical cords, were supplied for 23 projects at a total of 13 domestic universities and research institutions.

Of the distributed iPS cells, few were for clinical use.

No malfunction has been confirmed among any of the distributed iPS cells, according to Kyoto University.

The suspension of the supply of the iPS cells is expected to delay related research for up to one year.

The university aims to resume the program this summer. It will continue to supply iPS cells for nonclinical use and those derived from peripheral blood.

当时，笔者就发表过下面这篇文章：《日本诺奖得主山中伸弥道歉：这不是第一次，也绝不是最后一次》。

笔者在这篇文章里明确指出：

不听高人言，吃亏是自然。为什么这样说呢？因为我2007年就告诉我山中伸弥，所谓的“诱导多能干细胞”(induced pluripotent stem cell)就是“错编程干细胞”(incorrectly programed stem cell)，即“人造癌细胞”(man-made cancer cells)。

在我国留美学者刘实博士看来，iPS细胞的诱导过程和肿瘤的发生过程非常相似，而iPS细胞是将“激活”的癌基因（而且还不止一个）转入了体细胞，因此其致瘤性也就不足为奇。2008年刘实的观点以综述形式在美国《干细胞和发育》杂志发表，对iPS细胞的安全性提出自己的见解和担忧：指望在iPS细胞诱导配方中去除Myc来使其免于致瘤性的想法可能只是“良好的愿望”，因为其他基因的致瘤性也不能忽视。比如已有研究表明Oct-3/4基因在人类乳腺癌干细胞和膀胱癌中高度表达；曾经被认为是抑癌基因的KLF4也被重新定为癌基因；Nanog的过度表达也和白血病相关等。2008年8月Yamanaka  在《科学》杂志对刘实进行感谢，因为刘实对其发表在《科学》杂志上的无致癌性iPS细胞理论提出了质疑，而Yamanaka继续对那些iPS细胞进行观察后也确实发现了异常。Yamanaka在《自然·生物技术》上发表的新文章就是在接受刘实批评的基础上进行了比较系统化的iPS细胞致癌性研究后得出的。

而笔者对iPS细胞之父山中伸弥的科学质疑与批判是他一出道就开始的，参见笔者的一系列博客文章。

其中一些内容还被一些大众媒体广为传播。

《科学》网站登刘实就iPS研究致诺贝尔奖得主山中伸弥的公开质疑信

2012/11/01 来源：生物探索

导读	《科学》网站登刘实就iPS研究获诺贝尔奖致山中伸弥的公开信。刘实在公开信中要求山中伸弥明确答复他是否真的实现了将末端分化的成年体细胞转化为胚胎干细胞样的多能干细胞，同时请山中伸弥去斯德哥尔摩领奖前思考并回答一些关键问题。

10月30日《科学》网站发表新闻“Japanese Paper That Fell For False Stem Cell Claim Takes Corrective Action”（日本报纸因登虚假干细胞成果而采取纠错行动）。

在该新闻下。刘实贴出了他今日发给iPS细胞之父、今年的诺贝尔医学奖得主之一的日本人山中伸弥的公开信。

【背景】

对于这一惊人的声称，当时科学界都持谨慎态度，因为大家还没从韩国黄禹锡干细胞造假的阴影走出。

2007年《自然》杂志发表山中伸弥的第二篇iPS细胞论文，同期发表的另一iPS细胞论文则是美国科学大腕“夜里喜”（Jaenisch的音译）团队做出的。而当年创刊的《细胞-干细胞》杂志也发表了“夜里喜”以前的学生所做的另一个iPS细胞研究论文。这三篇论文的同时发表立刻造成了轰动效应，令科学界的主流不得不折服iPS重编程确有“返老还童”的魔力。

然而，对生命本质及发育过程有独到见解的刘实（详情和详情2）对这些iPS细胞论文所声称的将末端分化成年体细胞转化为与胚胎干细胞不可区别的多能干细胞表示怀疑，并明确指出所谓的iPS细胞就是错编程的干细胞或者说是人造癌细胞。这样的细胞不是不可与胚胎干细胞相区别，而是肯定有区别。这样的细胞不是安全和道德的胚胎干细胞替代品，用他们做细胞疗法是有致癌危险的（详情）。

山中伸弥在2007年答复刘实投给《自然》的批评文章时斩钉截铁地说他从未声称过将末端分化的成年体细胞转化为胚胎干细胞样的多能干细胞，并同意刘实提出的iPS细胞可能来自于本身就存在的干细胞或前细胞的观点。山中伸弥于2008年在《科学》发表更正时更是点名感谢刘实对其发表在《科学》的“无癌症风险”iPS细胞论文的批驳。

刘实对iPS细胞研究中表现出的一系列伪科现象的批驳发表在众多的论文中，其中有世界第一篇经过同行评审而于2008年发表在干细胞研究老牌主流杂志《干细胞与发育》上的综述。该综述发表后成为该杂志下载量最多的论文，两年之内被下载6500余次。

从2008年开始，刘实每年都给诺贝尔奖评委会发信，揭示iPS细胞研究的虚伪面并要求评委排除影响因子的影响而不错奖一个子虚乌有的发现。因为最新的实验报告实际上已完全证明刘实关于iPS细胞就是将干细胞错编程为人造癌细胞的基本判断，刘实今年更是两次给诺贝尔奖评委会发信。

然而，一个诺贝尔奖的悲剧还是发生了：山中伸弥竟因“发现成熟细胞可被重编为多能”而得了2012年的诺贝尔医学奖。对此，刘实已在《科学》网站发表多篇评论，认为诺贝尔奖被错误地发给了一个想像中的发现。

现在，刘实更是直接致（电子）信给山中伸弥，要求他明确答复他是否真的实现了将末端分化的成年体细胞转化为胚胎干细胞样的多能干细胞，同时请山中伸弥去斯德哥尔摩领奖前思考并回答一些关键问题。

刘实给山中伸弥的信现还以公开信的方式发布在《科学》的网站上。全文如下：

Open Letter to Yamanaka on His Nobel Prize-Winning iPS Work

就诺贝尔奖给iPS研究致山中伸弥的公开信

October 30, 2012

2012年10月30日

Dear Dr. Yamanaka,

亲爱的山中博士，

As a solid scientist who was once publicly thanked by you in Science for correctly criticizing your invalid claim of cancer-free iPS cells, I am writing to you again to repeat my challenge to your now accepted claim of inducing terminally differentiated cells into pluripotent stem cells that are indistinguishable from embryonic stem cells (ESCs).

作为一个曾因正确批评你无效的“不致癌iPS细胞”而被你在《科学》点名公开感谢的扎实科学家，我再次给你写信重复我对你现已接受的诱导末端分化细胞为与胚胎干细胞不可区别的多能干细胞的声称的挑战。

In response to my Communications Arising questioning the origin of iPS cells reported on your 2007 Nature paper you stated that “We agree that the origin of iPS cells may be tissue stem or progenitor cells co-existing in fibroblast cultures”. You even declared that“We have never claimed that we generated iPS cells from terminally differentiated cells.” Furthermore, with reference to my proposed single-cell tracking experiments, you stated that “I agree that the experiments you[r] proposed are important.”

在回复我对你2007年《自然》论文的iPS细胞来源的质疑时，你说“我们同意iPS细胞可能起源于纤维母细胞培养中共存的组织干细胞或前细胞”。你甚至于宣布“我们从未声称过从末端分化细胞产生iPS细胞”。而且，针对我提出的单个细胞跟踪实验，你说“我同意你提出的实验是重要的”。

Now, a Nobel Prize was awarded to you “for the discovery that mature cells can be reprogrammed to become pluripotent” which in fact refers to a claim made for you that you have advanced “a significant step toward delineating the minimal set of factors required to confer the developmental potential of an embryonic stem(ES) cell onto a terminally differentiated somatic cell” or, in popular term, you have found a “simple switch turns cells embryonic”.

现在，一个诺贝尔奖因为你“发现成熟细胞可被重编为多能”而奖给了你。这实际上是相信了一个为你制造的声称：你在阐明赋予末端分化体细胞以胚胎干细胞样发育潜能的最低因素上迈了一个显著的步伐。用通俗的话说，你发现了将细胞变为胚胎样的简单开关。

Apparently, you are very happy to accept these assessments and most likely will go to Stockholm to accept the Nobel Prize. But, before you do that, you need to think carefully the following points:

很明显，你是非常乐意接受这些评价而且很可能会去斯德哥尔摩领诺贝尔奖。但在你做那之前，你需要仔细考虑下面几点：

First, are you sure now you have achieved reprogramming terminally differentiated non-stem adult/mature cells into ESC-like pluripotent stem cells? If so, what are the evidences you have reported for that claim?

第一，你现在可明确你实现了重编末端分化非干细胞的成年/成熟细胞为胚胎干细胞样的多能干细胞吗？

Second, have you done the single-cell tracking experiments that I proposed to you back in 2007 and were considered as important by you then? If yes, what are the results? If not, why not?

第二，你做了我2007年就给你提出的而你也认为重要的单个细胞跟踪实验吗？如果做了，结果如何？如果没做，是因什么？

Third, what is your opinion about Jaenisch group’s new findings that only a very small fraction (0.01%) of donor cells can be turned into (fully) reprogrammed iPSCs and, more significantly, iPSCs can be sorted out according to some stemness markers without using any generic “Yamanaka” factors?

第三，你怎么看待Jaenisch团队的新发现：只有很小一部分（0.01%）供体细胞可被变为完全重编程的iPS细胞。更为重要的是，不用标准的“山中”因子也可根据干性标志筛选出iPS细胞。

Fourth, do you still think that iPS cells are not intrinsically cancerous cells and thus can be safely used for achieving cancer-free cell therapy?

第四，你仍然认为iPS细胞不是本能的癌化细胞而且可被安全地用于无癌发生的细胞疗法吗？

Fifth, do you still think that the observed rejection of syngenic iPS cells by animals with normal immunity is a questionable finding and syngenic iPS cells should have a natural advantage against immune rejection?

第五，你仍然认为被观察到的免疫正常的动物排斥自体来源的iPS细胞是可疑的发现而且自体来源的iPS细胞就应当具有天然的避免免疫排斥的优点吗？

I think your answers to above questions will help you to reach a safe conclusion on whether or not you should accept the Nobel Prize.

我想你对上述问题的回答将有助于你做出一个是否接受诺贝尔奖的安全结论。

Honestly, if I were you, I will ask the Nobel Prize Assembly to delay the award until I have obtained at least some solid evidence that I can indeed reprogram any mature/adult differentiated non-stem cells back into ESC-like cells.

老实地说，如果我是你，我会要求诺贝尔大会推迟发奖，直到我至少获得了一些扎实的证据表明我确实能够重编任何成年/成熟的非干细胞为胚胎干细胞样的细胞。

Sincerely,

诚挚的，

Shi V. Liu

刘实

在笔者看来，虽然山中伸弥因为成功的“返老还童”欺骗得到了诺贝尔奖，但最终纸是包不住火的，即使他也成功地躲过学术不端的指控：iPS Cell Pioneer Cleared Of Misconduct In Research Methods Photos and Images 。

但他最后还是逃不脱笔者对其iPS细胞研究的严肃科学质疑：

Stem Cells and Development

iPS Cells: AMore Critical Review

To cite this article:
Shi V. Liu. Stem Cells and Development. June 2008, 17(3): 391-398. https://doi.org/10.1089/scd.2008.0062

Published in Volume: 17 Issue 3: June 24, 2008
Online Ahead ofEditing: April 21, 2008

·        Full Text PDF (76.9KB)

·        Full Text PDF with Links (184.4 KB)

Author information

Shi V. Liu

Eagle Institute of MolecularMedicine, Apex, NC 27502.

ABSTRACT

Over the past 20 months, reports claiming the generation ofinduced pluripotent stem (iPS) cells with characteristics identical to those ofembryonic stem (ES) cells from nonembryonic tissue have captured greatattention in both the scientific community and the general public. In the lightof the continuing controversy over the use of ES cells, these reports haveprofound ramifications. This review calls into question the validity of manyclaims made in these reports—claims that have led to the rapid and prematureacceptance of using iPS cells as a viable alternative to using normal stemcells for regenerative therapy. How convincing is the evidence supporting thevarious claims made for the iPS cells? Are there other more plausibleexplanations for the same observations? What are these iPS cells? Are theyreally safe for therapeutic use? Should the iPS technique be considered, in theabsence of any direct evidence for induction and reprogramming,as a realistic alternative for somatic cell nuclear transfer (SCNT) to generate ES-likecells? This review attempts to encourage reflections on and offer alternativeviews for key aspects of iPS cells and studies.

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笔者相信，若干年后，山中伸弥忽悠不下去的时候，

他或许会再道歉一次：对不起，（引用刘实之语）所谓的“诱导多能干细胞”(induced pluripotent stem cell)就是“错编程干细胞”(incorrectly programed stem cell)，即“人造癌细胞”(man-made cancer cells)。

高人刘实，您说对了！