给Nature的信（英文版）

《自然》杂志资深编辑建议我把投诉给贵刊的质疑信贴在颜宁博士2014和2015年两篇葡萄糖转运蛋白论文下面的评论栏，以便读者可以看到我的质疑。

这是经过了一年多与贵刊打交道后到目前为止的最新进展。虽然杂志的《评论》是读者自己注册后便可贴上去的，但我的评论需要经过编辑审查。我只能投诉颜宁博士没引用我们的论文，因为负责此事的资深编辑认为我们的论文应该被引用。其它方面，他说由于颜宁的论文是受到了同行审查的，我可以贴论文里的哪些缺陷，但不能有misconduct/fool the readers/misleading the scientifc community 等字眼，否则当即被删除。事实上，有这类指控内容的，我都贴不上，因为给我设计了专门的只要我 log in 就消失了“发送”键的页面。

科学论文打假，在西方往往需要漫长的过程。然而，到了上周，我的质疑信就可以贴在《评论》栏了，还是资深编辑告诉我的。我经过了周末的思考后，本周一才贴上去的，而且有“发送键”。已经贴在那里6天了。《自然》杂志的《评论》栏是公开的网站，是希望更多读者看到。我保有资深编辑给我的信。

那么，我就可以把此信在网络上公开了。因为总有网友提议要把英文版贴出来，知道我质疑颜宁论文造假/欺骗的内容是什么。毕竟这一科学发现被列为“十大科学进展”，也令颜宁博士获得了贵校终身冠名讲席教授的职位、美国科学院院士称号，也获得了中华人民共和国百万元级别的科学荣誉奖“Seek Truth Award”（中文：求是奖）。

我把此信附在下面。《自然》杂志下面的评论栏里也有，我本来是贴在2014论文下面的，是资深编辑看了后建议质疑哪篇的就分开贴在哪篇的评论里。下面的版本是我的质疑信，分开贴在了《自然》杂志2014 和 2015 两篇论文的下面评论栏目里。

这也是科普内容，科学家们读了我的质疑信后便会去读原论文，对比研究，验证我的质疑是否有理有据，有没有冤枉颜宁博士，同时对“十大科学进展”之一的科学知识有了掌握，等于直接科普世界科学界“十大科学进展”的内容。

然而，质疑是一方观点，应该有反方的答疑。一年多了，不论是在中文世界还是在英文世界，我都没收到颜宁博士对质疑的答疑（“碰瓷”不是科学用语）。估计是杂志社不让我看到。那就需要更多的科学家们进行探索真相。这就需要更多的科学家有知情权，了解我质疑的内容，并亲自看原文，以确定质疑是不是应该得到答疑、我的质疑是否有道理。

我不知道谁是颜宁论文的审稿人，但我知道中国国内媒体当年公开发表了三位美国著名科学家对颜宁论文的高度评价，都是美国科学院院士，有一位诺贝尔奖得主。显然，他们是看过颜宁2014年发表的葡萄糖载体（她称之为转运蛋白）论文的。载体和转运蛋白，也是从英文翻译过来的，一个是carrier, 一个是transporter，至今二者通用。

科学真理都是在质疑中被矫正、鉴定出来的。真理是不怕质疑的。

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Dear Nature,

I am writing to you with a concern about Dr. Nieng Yan, a Member of the U.S. National Academy of Sciences (NAS). I believe she is guilty of scientific misconduct, and I have evidence to prove it.

1.Misleading the scientific community—-“latch gate” theory

In the paper, she identified an “latch” which was one of her two main findings, and she thoroughly explained her latch gate finding (the other main finding was “the Glut1 working model”).

In Fig.3 and Fig. 5, she named it an ICH domain and explained the ICH domain function as: “The ICH domain serves as a latch that tightens the intracellular gate.”(p.123) “Because of the extensive interactions between TMD and ICH, the ligand-free protein may prefer an outward-open conformation.” (p.124)

In fact, the XylE and Glut1 are transporters belonging to the Facilitated Diffusion Superfamily, whose function (direction and efficiency) solely depends on the substrate concentration gradient across the membrane, and functionally no sided-ness. This means the glucose can be transported from one side of the membrane to the other and vice versa. It is impossible for a “facilitated diffusion transporter” to have a “LATCH GATE” to maintain the out-facing direction.  If so, they are no longer “Diffusion Transporters.”  Instead, they are “GATED CHANNELS.”

If Dr. Nieng Yan’s “outward-open latch” theory was true, then the glucose transporters COULD NOT RELEASE accumulated glucose into the extracellular space adjacent to the blood capillary, because the “Latch Gate” would make the transporter bear outward-open conformation with the inside closed by the latch, so that the glucose inside could not get into the translocation pathway of the transporter.

In nature, glucose transporters DO release accumulated glucose into the extracellular space adjacent to the blood capillary by facilitated diffusion.

In addition, if the latch had no function, then it should have been eliminated during the 3 billion years of transporter evolution.

Apparently, Dr. Nieng Yan never did a biochemical assay for any Facilitated Diffusion Superfamily transporters and merely assumed that the glucose was transported only from outside to inside of the cells, and that the glucose concentration inside was always lower than outside, thus devising an artificial “outward-open conformation latch gate” theory without any scientific data to support it. The reviewers should have caught that, because in the paper, she mentioned that the XylE and Glut1 are members of the facilitated diffusion superfamily.

She found the ICH latch domain from a crystallized symporter (XylE), and she predicted that “substrate-free uniporters have a preferred open conformation” (P.124), which means that all of the uniporters should no longer be “Facilitated Diffusion Superfamily” members.

How can such an illogical and unrealistic “theory”, without any biochemical analysis or any scientific data support, be accepted by Nature reviewers, thus misleading the scientific community?

I don’t know the answer. However, if I were to guess, I can imagine two possibilities.  (A) Some reviewers may not be in the transporter field and have never done any biochemical assay in order to know that the facilitated diffusion transporters functionally have no sidedness, and therefore these reviewers just trusted Dr Nieng Yan. (B). A reviewer might have been in the transporter field,  and perhaps, this reviewer might have been reluctant to challenge Dr. Nieng Yan’s scientific work, due to fear of losing funding from the  Chinese government by collaboration.  

2.Fooling the scientific community

The “four conformational structures” described in the paper to prove her major scientific contribution cannot prove the working model. When the transporter (also called carrier) was in occluded inward-facing conformation (which means a glucose molecule was inside the transporter), Dr. Nieng Yan presented it as evidence that the glucose had entered the transporter from inside the cell (see Fig 5). However, the glucose could have been transported from outside the cell during crystallization. That is why we have to use radioactive labeled substrates in our experiments  [Runtao Yan & Peter C Maloney (JHU),1993 Cell, 75:37-44; 1995 PNAS, 92:5973-5976].

A simple example can illustrate this point. Suppose I show a picture of a man on a boat on the north bank of a river, and then assert that the man had boarded the boat from the north bank, a skeptic could question my inference, since the man might have ferried from the south to the north bank.

Does this represent Dr. Nieng Yan’s level of logical thinking, or is she being deliberately deceptive? She should know that her “four conformational structures” cannot prove the working model of a transporter. How could she possibly ascertain whether the glucose was from the inside the cell, or transported from outside? It would be impossible for her to distinguish without radioactively labeling the substrate.

3.Deceiving and fabricating

Even if the “four-conformation structures” proposed in the paper could prove that to be the working model of a transporter (which, in fact it could not), Dr. Nieng Yan did not find the four structures. In her paper, she claimed that the four structures are required for a complete transport cycle. However, there are only two crystal structures of E. coli xylose transporter (proton co-transporter, i.e. symporter), and one human glucose transporter Glut-1(uniporter). Even after combining the symporter and uniporter together, she only obtained THREE structures. When she presented “A working model of Glut1” (written in bold-faced typesetting) from Fig. 5, her conclusion was based on the “Predicted data” from Fig 5’s detailed descriptions (written in small typeset). In other words, her work should be presented as a “Predicted working model of Glut1” instead of an actual “working model of Glut1”. The essence of this wording is deceptive.

It is impossible for Dr. Nieng Yan to propose a working model for Glut1 while lacking the basic experimentation of the “four conformation structure” cycle.   She clearly stated in her paper that (1) “the conformational switch from inward-facing to outward-facing of symporters remains to be elucidated”; and (2) The outward-open structure remains to be captured. 

4.Did not disclose the source of the “published biochemical data”

Since she did not obtain four crystal structures and had no way to identify the working model based on only three structures, she tried to fix the problem by providing more “evidence” in her discussion section, where she said, “On the basis of our structural analysis and published biochemical data, we propose a working model for Glut1” (P124 ). If she thought she did not need to provide appropriate references because the biochemical experiments were done in her lab, then she should not have used the term “Predicted” in Fig.5.

No matter who may ultimately have performed the experiment, the fact is that the cystine-scan method created by RuntaoYan/Peter C Maloney was the only biochemical method to identify the membrane transport working model (1995 PNAS, 92:5973-5976).

5.Deceiving her colleagues in 2015 Nature paper

Dr. Nieng Yan also deceived her scientific colleagues when she wrote in her 2015 Nature paper (Nature 526, 391–396) that occluded inward-facing conformation was the evidence that a glucose molecule inside the carrier had entered from the inside of the cell, and occluded outward-facing conformation was the evidence that the glucose molecule must have entered from outside the cell. She should have known better, with a background of having studied transporters. To return to my earlier boating illustration, if there is no ticket to check, how could you know where the man boarded?   (Just like if you do not use radioactive labeling!)