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生物学 1953

核酸的分子结构

詹姆斯·沃森 与 弗朗西斯·克里克

DNA 是一座双螺旋,它成对的「字母」悄然解释了生命如何自我复制。

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In depth · the introduction

DNA 是一架拧转的梯子,梯级是成对的化学「字母」——而正是这种配对,让生命得以复制自己。

核心想法

DNA 是携带「如何构建并运转一个生命」之指令的分子。沃森与克里克弄清了它的形状:一座双螺旋,像一架沿着长度被轻轻拧转的梯子。两侧是长长的化学骨架;梯级则是四种「字母」——A、T、G、C——的配对。最关键的发现是:这些字母只能以唯一的方式配对:A 永远配 T,G 永远配 C。

正是这一条简单的规则,悄然回答了生物学最古老的问题之一:生命如何复制自己?把梯子从中间拉开,每一条孤零零的半边,都会自动「拼写」出它缺失的另一半必须是什么。原本一架梯子的地方,便长出两架一模一样的梯子。每一次细胞分裂,发生的正是这件事——在你体内,每天都有亿万次。

它是如何诞生的

到 1950 年代初,人人都知道 DNA 携带着遗传,却没人知道它的形状。这场竞赛,在两所英国实验室之间展开。在剑桥的卡文迪许实验室,詹姆斯·沃森与弗朗西斯·克里克,用硬纸板和金属丝搭起一个个实体模型,寻找一种能与化学相吻合的形状。在伦敦国王学院,罗莎琳·富兰克林与莫里斯·威尔金斯,则用 X 射线照射 DNA 纤维,为它的结构拍照。

两条线索揭开了谜底。富兰克林那张清晰得惊人的 X 射线照片——「51 号照片」——一眼便显出 DNA 是一座尺寸确定的螺旋。而化学家埃尔温·查戈夫早已发现,DNA 中 A 与 T 的含量总是相等,G 与 C 的含量也总是相等。沃森与克里克于是看出了拼合之道:一座双螺旋,A 永远配 T、G 永远配 C。他们的解释,1953 年在《自然》上仅占了一页。富兰克林的数据对此至关重要,却只被一句带过;她于 1958 年去世,而 1962 年的诺贝尔奖,授予了沃森、克里克与威尔金斯。

它为何重要

这篇仅一页的论文,开创了分子生物学。一旦我们明白生命的指令是用四个字母的密码写成的,我们便能开始解读它,并最终编辑它——由此通向现代遗传学、DNA 指纹鉴定、基于基因的医学,以及像 CRISPR 这样能有意改写密码的工具。

一个可以想象的画面

想象一条拉链。一侧的每一颗齿,在另一侧都只有唯一一颗能与之咬合。把拉链拉开,任何一半都精确地告诉你:缺失的那一半,原本必然是什么。DNA 的字母,就是这些齿——A 只与 T 咬合,G 只与 C 咬合——所以单单一条链,就是它配对链的一份完整配方。这正是为什么一架梯子,能变成两架一模一样的梯子。

可交互的 DNA:为左右两侧各选一个碱基,看 A–T 与 G–C 如何配对(各有两个或三个氢键),而错配则无法成键;接着把双螺旋梯子拉开,每一半都重建出自己的互补链,一架梯子于是变成两架。

它的位置

一个世纪以前,孟德尔已经表明,性状以一个个离散、隐藏的「因子」代代相传,但那些因子是抽象的——没人知道它们究竟由什么构成。这一结构,给了基因一具身躯:螺旋之上、一段用四个字母写成的密码。从这里,一条线径直通向人类基因组计划,通向今天能编辑基因的医学。

The original document
Original source text
J. D. Watson & F. H. C. Crick · Nature 171 (1953): 737–738
We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.
A structure for nucleic acid has already been proposed by Pauling and Corey. … In our opinion this structure is unsatisfactory for two reasons: (1) We believe that the material which gives the X-ray diagrams is the salt, not the free acid. … (2) Some of the van der Waals distances appear to be too small.
We wish to put forward a radically different structure for the salt of deoxyribose nucleic acid. This structure has two helical chains each coiled round the same axis. … We have made the usual chemical assumptions, namely, that each chain consists of phosphate di-ester groups joining β-D-deoxyribofuranose residues with 3′,5′ linkages. The two chains (but not their bases) are related by a dyad perpendicular to the fibre axis.
The novel feature of the structure is the manner in which the two chains are held together by the purine and pyrimidine bases. … They are joined together in pairs, a single base from one chain being hydrogen-bonded to a single base from the other chain, so that the two lie side by side.
One of the pair must be a purine and the other a pyrimidine for bonding to occur. … If it is assumed that the bases only occur in the structure in the most plausible tautomeric forms, it follows that only specific pairs of bases can bond together. These pairs are: adenine (purine) with thymine (pyrimidine), and guanine (purine) with cytosine (pyrimidine).
It has been found experimentally that the ratio of the amounts of adenine to thymine, and the ratio of guanine to cytosine, are always very close to unity for deoxyribose nucleic acid.
It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.
We are much indebted to Dr. Jerry Donohue for constant advice and criticism. … We have also been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr. M. H. F. Wilkins, Dr. R. E. Franklin and their co-workers at King's College, London.
Cavendish Laboratory, Cambridge · April 2, 1953