客觀評論：傅新元的貢獻夠諾貝爾獎嗎?

網上盛傳“美國科學界的鈎心鬥角”（作者：老中汲取），描繪Indiana大學教授傅新元在美國的遭遇。圍繞他和洛克菲勒大學Darnell教授的鬥爭，繪聲繪色地勾勒了一條主線。這條主線的人事鬥爭，八九不離十。但是，其中的科學貢獻，有三點不太對。

第一， Darnell能不能得諾貝爾獎，不一定。他做RNA剪接，做了很久，發現很早，但是，缺了臨門一腳，輸給Sharp，周芷和Roberts，Darnell自己認輸。他做STAT，發現新的信號轉導蛋白，從細胞膜直接進入細胞核，作用方式新穎。沒有STAT，他不太可能獲得美國國家科學獎和Lasker獎。STAT確實是他一生最重要的發現。

但是，Darnell的工作，可以得獎，也可以不得獎。信號轉導有幾個更重要、更經典的通路，還沒有得獎。日本科學家發現PKC，英國科學家發現磷酸肌醇，都還沒有得獎。日本人已經去世。Darnell的工作比一般信號轉導更重要，但是，並不比PKC和磷酸肌醇更重要。

所以，Darnell和諾貝爾獎：可得可不得。如果得獎，也可以和其他人合得。合得，有名額限制，只能三人。

第二， 傅新元最重要的工作，不是“老中汲取”說的1992年PNAS，是1990年的PNAS。Darnell實驗室84年就開始做beta干擾素誘導基因轉錄的機理。已經知道增強子序列。Darnell實驗室的Pine1990年純化到了ISGF2，但是它的結構不新穎，功能不重要。
傅新元1992年純化到了ISGF3，結構新穎，功能重要。這其中，不是傅新元有先見之明。在沒有拿到以前，並不能預測ISGF2和3哪個更重要。如果知道3重要，Pine就會選擇做3，不做2了。只要做出來以後，才知道哪個更重要。

這樣看，Darnell的貢獻毫無疑問：不管是2重要，還是3重要，都是他實驗室的工作，他必定會發現其中重要的蛋白。所以，Darnell的地位不可動搖。

傅新元做出了關鍵的一項，是臨門一腳。在Darnell實驗室，確實最突出。如果他1990到1992年不分心，1992年的論文，就是1991年，而且Schindler就不會和他分PNAS。

Darnell做干擾素基因誘導，並不是第一個。哈佛大學的Maniatis，83年就開始了，不過，Maniatis做gamma干擾素。主意一樣的，方法大同小異。最後這條路，出了東西，但是意義比不上Darnell的beta干擾素。這，基本上是隨機的差別，沒辦法預料。所謂運氣。

傅新元自己實驗室的工作，也很不錯，但是就是發《細胞》、《科學》，也還沒有超越最早那PNAS。

第三， 因為傅新元最重要的工作是Darnell工作的一部分，給傅新元多少功勞，取決於Darnell的態度。

歷史上，老師學生一道得獎有先例。青黴素分離提純是Florey實驗室的Chain做的，他們師徒和Fleming合得諾貝爾獎。Levi-Montacini和她的學生Cohen共同得獎。她發現神經生長需要某種活性，他會生化技術，分離提純了神經生長因子，一種新型的蛋白質。

但是，Levi－Montacini必需Cohen的技術。Darnell實驗室，如果沒有傅新元，其他人，或遲或早，也能分離純化STAT。這不否認傅新元的功勞，如果Darnell和他關係好，可以多讓他做一些，多給他功勞。如果Darnell和他關係不好，和他競爭，他就得不到足夠的功勞。

客觀地總結，臨門一腳的大功勞，歸傅新元。但是，該不該得獎，要打兩個問號。

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Levy D, Larner A, Chaudhuri A, Babiss LE, Darnell JE Jr. Interferon-stimulated tranxxxxion: isolation of an inducible gene and identification of its regulatory region.
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Levy DE, Kessler DS, Pine R, Reich N, Darnell JE Jr. Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative tranxxxxional control.
Genes Dev. 1988 Apr;2(4):383-93.

Kessler DS, Levy DE, Darnell JE Jr. Two interferon-induced nuclear factors bind a single promoter element in interferon-stimulated genes.
Proc Natl Acad Sci U S A. 1988 Nov;85(22):8521-5.

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.
Mol Cell Biol. 1990 Jun;10(6):2448-57.
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.
Proc Natl Acad Sci U S A. 1990 Nov;87(21):8555-9.

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.
Science. 1992 Dec 11;258(5089):1808-12.
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).
Cell. 1992 Jul 24;70(2):323-35.
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.

Zinn K, Mellon P, Ptashne M, Maniatis T. Regulated expression of an extrachromosomal human beta-interferon gene in mouse cells.
Proc Natl Acad Sci U S A. 1982 Aug;79(16):4897-901.

Zinn K, DiMaio D, Maniatis T. Identification of two distinct regulatory regions adjacent to the human beta-interferon gene.
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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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Keller AD, Maniatis T. Identification and characterization of a novel repressor of beta-interferon gene expression.
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