客观评论：傅新元的贡献够诺贝尔奖吗?

网上盛传“美国科学界的钩心斗角”（作者：老中汲取），描绘Indiana大学教授傅新元在美国的遭遇。围绕他和洛克菲勒大学Darnell教授的斗争，绘声绘色地勾勒了一条主线。这条主线的人事斗争，八九不离十。但是，其中的科学贡献，有三点不太对。

第一， Darnell能不能得诺贝尔奖，不一定。他做RNA剪接，做了很久，发现很早，但是，缺了临门一脚，输给Sharp，周芷和Roberts，Darnell自己认输。他做STAT，发现新的信号转导蛋白，从细胞膜直接进入细胞核，作用方式新颖。没有STAT，他不太可能获得美国国家科学奖和Lasker奖。STAT确实是他一生最重要的发现。

但是，Darnell的工作，可以得奖，也可以不得奖。信号转导有几个更重要、更经典的通路，还没有得奖。日本科学家发现PKC，英国科学家发现磷酸肌醇，都还没有得奖。日本人已经去世。Darnell的工作比一般信号转导更重要，但是，并不比PKC和磷酸肌醇更重要。

所以，Darnell和诺贝尔奖：可得可不得。如果得奖，也可以和其他人合得。合得，有名额限制，只能三人。

第二， 傅新元最重要的工作，不是“老中汲取”说的1992年PNAS，是1990年的PNAS。Darnell实验室84年就开始做beta干扰素诱导基因转录的机理。已经知道增强子序列。Darnell实验室的Pine1990年纯化到了ISGF2，但是它的结构不新颖，功能不重要。
傅新元1992年纯化到了ISGF3，结构新颖，功能重要。这其中，不是傅新元有先见之明。在没有拿到以前，并不能预测ISGF2和3哪个更重要。如果知道3重要，Pine就会选择做3，不做2了。只要做出来以后，才知道哪个更重要。

这样看，Darnell的贡献毫无疑问：不管是2重要，还是3重要，都是他实验室的工作，他必定会发现其中重要的蛋白。所以，Darnell的地位不可动摇。

傅新元做出了关键的一项，是临门一脚。在Darnell实验室，确实最突出。如果他1990到1992年不分心，1992年的论文，就是1991年，而且Schindler就不会和他分PNAS。

Darnell做干扰素基因诱导，并不是第一个。哈佛大学的Maniatis，83年就开始了，不过，Maniatis做gamma干扰素。主意一样的，方法大同小异。最后这条路，出了东西，但是意义比不上Darnell的beta干扰素。这，基本上是随机的差别，没办法预料。所谓运气。

傅新元自己实验室的工作，也很不错，但是就是发《细胞》、《科学》，也还没有超越最早那PNAS。

第三， 因为傅新元最重要的工作是Darnell工作的一部分，给傅新元多少功劳，取决于Darnell的态度。

历史上，老师学生一道得奖有先例。青霉素分离提纯是Florey实验室的Chain做的，他们师徒和Fleming合得诺贝尔奖。Levi-Montacini和她的学生Cohen共同得奖。她发现神经生长需要某种活性，他会生化技术，分离提纯了神经生长因子，一种新型的蛋白质。

但是，Levi－Montacini必需Cohen的技术。Darnell实验室，如果没有傅新元，其他人，或迟或早，也能分离纯化STAT。这不否认傅新元的功劳，如果Darnell和他关系好，可以多让他做一些，多给他功劳。如果Darnell和他关系不好，和他竞争，他就得不到足够的功劳。

客观地总结，临门一脚的大功劳，归傅新元。但是，该不该得奖，要打两个问号。

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Kessler DS, Levy DE, Darnell JE Jr. Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes.
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Pine R, Decker T, Kessler DS, Levy DE, Darnell JE Jr. Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary tranxxxxional activator of either.
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Interferon-stimulated gene factor 2 (ISGF2) was purified from HeLa cells treated with alpha interferon. The factor, a single polypeptide of 56 kilodaltons (kDa), bound both to the central 9 base pairs of the 15-base-pair interferon-stimulated response element (ISRE) that is required for tranxxxxional activation of interferon-stimulated genes and to the PRD-I regulatory element of the beta interferon gene. ISGF2 was a phosphoprotein, and dephosphorylation in vitro reduced its DNA-binding activity. However, conditions that changed the amount of ISGF2 did not change the phosphorylated isoxxxxs in vivo. ISGF2 in unstimulated cells existed in trace amounts and was induced by both alpha interferon and gamma interferon as well as by virus infection. Plasmid-bearing Escherichia coli clones encoding ISGF2 were selected with antibody against purified ISGF2. Sequence analysis revealed that the ISGF2 protein was the same as that encoded by the cDNA clone IRF-1, which has been claimed to activate tranxxxxion of interferon genes. We show that tranxxxxion of the ISGF2 gene was induced by alpha interferon, gamma interferon, and double-stranded RNA. However, ISGF2 was neither necessary nor sufficient for induced tranxxxxion of the beta interferon gene, while the factor NF kappa B was clearly involved.

Fu XY, Kessler DS, Veals SA, Levy DE, Darnell JE Jr.
ISGF3, the tranxxxxional activator induced by interferon alpha, consists of multiple interacting polypeptide chains.
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Interferon-stimulated gene factor 3 (ISGF3) is the ligand-dependent tranxxxxional activator that, in response to interferon treatment, is assembled in the cell cytoplasm, is translocated to the nucleus, and binds the consensus DNA site, the interferon-stimulated response element. We have purified ISGF3 and identified its constituent proteins: a DNA-binding protein of 48 kDa and three larger polypeptides (84, 91, and 113 kDa), which themselves do not have DNA-binding activity. The multisubunit structure of ISGF3 most likely reflects its participation in receiving a ligand-dependent signal, translocating to the nucleus, and binding to DNA to activate tranxxxxion.

Shuai K, Schindler C, Prezioso VR, Darnell JE Jr. Activation of tranxxxxion by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein.
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Interferon-gamma (IFN-gamma) induces the tranxxxxion of the gene encoding a guanylate binding protein by activating a latent cytoplasmic factor, GAF (gamma-activated factor). GAF is translocated to the nucleus and binds a DNA element, the gamma-activated site. Through cross-linking and the use of specific antibodies GAF was found to be a 91-kilodalton DNA binding protein that was previously identified as one of four proteins in interferon-stimulated gene factor-3 (ISGF-3), a tranxxxxion complex activated by IFN-alpha. The IFN-gamma-dependent activation of the 91-kilodalton DNA binding protein required cytoplasmic phosphorylation of the protein on tyrosine. The 113-kilodalton ISGF-3 protein that is phosphorylated in response to IFN-alpha was not phosphorylated nor translocated to the nucleus in response to IFN-gamma. Thus the two different ligands result in tyrosine phosphorylation of different combinations of latent cytoplasmic tranxxxxion factors that then act at different DNA binding sites.

Fu XY. A tranxxxxion factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s).
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Interferon-stimulated gene factor 3 (ISGF3), the primary tranxxxxion factor induced by interferon alpha, is a complex of four (113, 91, 84, and 48 kd) proteins. This paper reports that the 113, 91, and 84 kd (ISGF3 alpha) proteins of ISGF3 contain conserved SH2 and SH3 domains. A specific interferon alpha-induced cytoplasmic protein tyrosine kinase(s) can xxxx a transient complex with ISGF3 alpha proteins. These ISGF3 alpha proteins can be immunoprecipitated by anti-phosphotyrosine antibodies only after interferon alpha treatment. Phosphoamino acid analyses of 32P-labeled ISGF3 alpha proteins confirm that ISGF3 alpha proteins are directly tyrosine phosphorylated both in vitro and in vivo in response to interferon alpha, and this tyrosine phosphorylation can be inhibited by staurosporine and genistein. Phosphatase treatment of these ISGF3 alpha proteins results in inhibition of ISGF3 complex xxxxation in vitro. These observations indicate that interferon alpha-induced direct tyrosine phosphorylation of ISGF3 alpha proteins is necessary for activation of the tranxxxxion factor ISGF3.

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Goodbourn S, Zinn K, Maniatis T. Human beta-interferon gene expression is regulated by an inducible enhancer element.
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Fan CM, Maniatis T. A DNA-binding protein containing two widely separated zinc finger motifs that recognize the same DNA sequence.
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