饶毅教授曾在2002年10月写过一篇《二十一项值得获诺贝尔生理或医学奖的工作及科学家》，我当时在转发给友人时加了一些注解。我对饶毅教授所列的21项中的10项左右表示赞同，而其余则认为希望渺茫：

http://xys.dxiong.com/xys/ebooks/others/science/report/21xiang.txt

考虑到本客栈对生物和化学有兴趣的网友不多，就不必重复我的一一点评了。今年在看了世界杯和ICM2006之后预测有点上瘾，索性再预测一下马上就要揭晓的诺贝尔奖得主，限于专业只对医学奖和化学奖发表看法。

* 将在10月2日宣布的医学奖：我看好饶毅文章中的第9项工作，但我估计的最佳组合是Alfred G. Knudson和Robert Weinberg两人分享。第三个获奖者存在的可能性不大，若有则可能是饶毅文章中的第14项中提及的Judah Folkman，总的主题是肿瘤研究。若真是这3人得奖，则前两人各得1/4而Folkman可得1/2。我的选择除了工作重要性之外，还考虑到Knudson已经80多岁，诺贝尔委员会要抓紧时间。。。Knudson在生物医学领域的声望相当之高，应该是许多该得还未得者中呼声较高者。

* 将在10月4日宣布的化学奖：我猜想今年还会像2003年那样给生物化学类，很可能是饶毅文章中的第8项工作---Roger Y. Tsien （钱永健）和 Douglas C. Prasher。Tsien发明钙染料，Prasher发现绿色荧光旦白GFP。其中钱永健是钱学森留在美国的堂弟之子，我曾于2003年初在Princeton听过他的报告，印象非常深刻，堪称华裔生物化学家的骄傲。

由于诺贝尔奖从提名开始的过程50年之内完全保密，以上预测纯属乱猜，作为茶余饭后的消遣。

我也来预测一下文学奖我猜是村上春书成就不用说了，和平奖我想应该颁给黎巴嫩总理西尼乌拉，此君曾在以色列军队和黎巴嫩真主党的冲突中含泪恳请联合国斡旋停火，为国家的和平做出了不可限量的贡献

今天随便用Google看一下网上有没有其他人也在预测2006年诺贝尔奖，结果还真有一个公司专门靠此来打知名度：

http://scientific.thomson.com/nobel/pressrel/

他们预测的依据主要是论文被引用的次数，不见得有多管用。其中医学奖有一个众人皆知的风向标---Lasker奖，Thomson公司基本上用历届Lasker奖来预测。我还是坚持原来的看法，但我也认为在Knudson和Weinberg以外最有希望得医学奖的该是2001年的3位Lasker奖得主Mario Capecchi, Martin Evans和Oliver Smithies（姑且称他们三人为“第二梯队”吧）：

http://www.laskerfoundation.org/awards/library/2001basic.shtml

而化学奖的预测难度要大许多，我还是认为今年生物化学家的几乎要高于有机化学家。另外前天《纽约时报》一篇关于诺贝尔奖历史的文章很有意思：

http://www.nytimes.com/2006/09/26/health/26docs.html

Alfred Nobel and the Prize That Almost Didn’t Happen

没想到饶毅文章中的最后一项---RNA干扰---今年就能得奖。RNA干扰自1998年发现以来其应用和机理研究一直非常火爆，短短几年之内其生物化学机理到2005年已经大致阐明。不过以诺贝尔委员会一贯的谨慎态度，这项发现完全可以再等上若干年，何况两位得奖者都还不到50岁：

http://nobelprize.org/nobel_prizes/medicine/laureates/2006/

看来已经80多岁的Knudson还要继续等下去。RNA干扰得奖是迟早的事情，可惜做了最初铺垫性工作的Ken Kemphues没有得到承认（尤其是在第三个名额空缺的情况下），看来生物学界对于一个原创发现“第一步”的定义有时无法达成共识。

数学就不一样了，虽然Fields奖是保密的，但是很多人还是事先就知道了。比如这次的Tao和Perelman，闭着眼睛也猜得到这两人。

仔细读了一下今年医学奖委员会主席---Karolinska学院教授Bertil Daneholt写的"Advanced Information":

http://nobelprize.org/nobel_prizes/medicine/laureates/2006/adv.html

可以看出Ken Kemphues（其铺垫性工作是复旦留美学生郭苏做的）未能分享荣誉的关键原因是：

"。。。but remarkably sense RNA（24）could also silence genes, but the results were inconsistent and the effects usually modest. However, due to the fact that both sense and antisense RNA could cause silencing, Mello argued that the mechanism could not just be a pairing of antisense RNA to mRNA, and he coined the term RNA interference for the unknown mechanism (25)."

(24). Guo, S and Kemphues, KJ (1995). Par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Sex/Thr kinase that is asymmetrically distributed. Cell 81, 611-620.

(25). Rocheleau, CE, Downs WD, Lin, R, Wittman, C, Bei, Y, Cha, YH, Ali, M, Priess JR and Mello, CC (1997), Wnt signaling and an APC-relatred gene specify endoderm in early C. elegans embryos. Cell 90, 707-716.

其中就关键的评论是“but the results were inconsistent and the effects usually modest”，委员会因此认为此项发现真正的“第一步”是Mello实验室1997年文章中的“大胆假设”加上Fire和Mello两个小组合作并于1998年完成的“小心求证”：

(22). Fire, A, Xu, S, Montgomery, MK, Kostas, SA, Driver, SE, and Mello, CC (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806-811.

获得2006年诺贝尔医学奖的工作就是这篇1998年的Nature论文。换个角度看，如果Kemphues能在其1995年论文的讨论部分大胆猜测一下郭苏的实验对照组用的sense RNA也能导致gene silencing的原因，提出双链RNA也有可能抑制基因表达，那么Kemphues就有可能分享荣誉。看来Kemphues没能对郭苏意外发现的重要性有足够的认识，因为这不属于他的实验室研究的主攻方向---线虫的胚胎发育。

Since I have only read papers referring to Guo & Kemphues (1995) rather than the original paper itself, I spent some time to examine it for fact checking. My guess was correct that Kemphues didn't put out any hypothesis for the surprising "sense RNA effect", here are some excerpts from the "Results" section of the 1995 Cell paper (p.613):

"Surprisingly, injection of in vitro synthesized sense RNA from the cDNA ZC22 also induced par-1 phenotypes at a high frequency among the progeny of the injected worms. It is not clear what accounts for this effect. ... Thus, the antisense and sense effects appear to be separable and probably involve different mechanisms. The basis for the sense effect is under investigation and will not be discussed further."

Kemphues' conservative attitude as shown in the wording "... will not be discussed further" is really a pity. After publishing this paper, Kemphues didn't appear to ask his student Guo Su to put serious efforts into pursuing along this direction. Guo was an excellent graduate student and she published many papers during her graduate career. The Kemphues lab had at least a 2-year window to conduct the "investigation" on the "sense effect", but they seemed to view it too much digression from the main research theme. Instead, Craig Mello caught the opportunity and wisely coined the term "RNAi" in his lab's 1997 Cell paper.

So after reading the original papers, I think the decision made by the Nobel Assembly is correct --- only Mello and Fire should be recognized as the main discoverers of RNAi. Wikipedia even traced the history of RNA interference back to a 1990 discovery in plant biology:

http://en.wikipedia.org/wiki/RNAi

The title of the celebrated 1998 Nature paper also carries a lot of convincing power: "Potent and specific genetic interference by double-stranded RNA in C. elegans". In this regard, it is fair to describe the observation of Guo & Kemphues in 1995 with the injection of single-stranded sense RNA as "moderate". The key to the success of the RNAi technology was the conception of using "double-stranded RNA", Fire and Mello are the only principal investigators to come up with this idea and confirm it with convincing experimental data.

今天化学奖也揭晓了，颁给生物化学这一点算是猜对了，但是Roger Kornberg这个人选实在没有想到。“真核细胞转录及其调控机制”这个课题非常重要，作为“将门虎子”的Roger Kornberg也在该领域做出了重大贡献，但该领域有另外两人已经得过Lasker奖：

http://www.laskerfoundation.org/awards/library/2003basic.shtml

http://www.laskerfoundation.org/awards/library/1997basic.shtml

而Roger Kornberg至今还未得过Lasker奖。显然今天的消息将会让Roeder和Ptashne无比沮丧，奈何自古“人生长恨水长东”。:-)究竟是结构生物学在技术上的优越，还是因为Roger的老爸Arthur之余威（这位1959年医学奖得主还健在，今年88岁高龄），恐怕没人能够说得清楚。至少Roger一人独得这项荣誉和1987年利根川进一人独得“阐明抗体多样性机理”的荣誉同样令人惊讶，某些政治家难免又要高呼“友邦人士，莫名惊诧”，呵呵。