分子生物学 1958

论蛋白质的合成

弗朗西斯·克里克

基因的碱基序列，是一份写就蛋白质的密码——而信息，绝不会倒流出来。

Choose your version

In depth · the introduction

在帮助找出 DNA 的形状五年之后，弗朗西斯·克里克写下了这个形状「做什么」的规则——并预言了一个谁都不曾见过的分子。

核心想法

DNA 写就蛋白质。它那四个化学「字母」的顺序，是一份密码，而单单这个顺序，就决定了串成蛋白质的那些积木——氨基酸——的次序。把序列定下来，蛋白质便会自己折叠成能干活的形状。

克里克又加了第二条关于方向的规则。信息从 DNA，流到一份工作副本，再到蛋白质，却从不倒着走：一个造好的蛋白质，无法反过来去指定造它的那个基因的序列。他把这条规则，称为「中心法则」。

它从哪里来

1957 年，克里克在伦敦作了一场演讲；次年，他把它写成一篇论文——《论蛋白质的合成》。彼时的分子生物学，还是一堆彼此半连半断的发现，而克里克，是它最大胆的理论家——乐于一路推理到结论，再逼着实验去追上。

他最大胆的猜测是：必定存在一个小小的「适配器」分子，去搭起基因密码与氨基酸之间的桥——因为这两者，本无天然的化学吸引。他只凭逻辑就预言了它。也就在那一年，实验者们找到了恰恰这样一个分子——也就是我们如今所说的转移 RNA。

它为何重要

这篇短短的论文，给了分子生物学一部宪章。它把一堆观察，变成了一套单一的、单向的逻辑，并点名了紧随其后的那个大谜题——「编码问题」：DNA 里三个字母的词，如何对应到氨基酸。破解这套密码的竞赛——克里克本人也是赢家之一——是二十世纪科学的凯歌之一。

一个类比

把它想成一份锁在图书馆里的总蓝图（细胞核里的 DNA）。你从不会把正本拿去车间；你复印一份工作副本（信使 RNA），带着它走。在车间里，一个个小小的翻译员（适配器分子）各读一个三字母的词，去取来恰好对应的零件，机器便一件一件被装起来。而这里有一条单行规则：你能照蓝图把机器造出来，却永远无法从造好的机器上，把蓝图反读回去。

它落在哪里

它从沃森与克里克 1953 年的结构停下的地方开始（见沃森–克里克，1953）：双螺旋揭示了 DNA 如何被复制；而这篇论文追问的是——复制，是为了什么。它为 1960 年代遗传密码的破解搭好了舞台，又在逆转录被发现后得到修正，并活在你听说过的工具里——基因编辑（见 CRISPR，2012），以及把一份配方交到你自己细胞手里的 mRNA 疫苗。

The original document

Original source text

F. H. C. Crick · Symp. Soc. Exp. Biol. XII (1958), 138–163 · from a lecture to the Society for Experimental Biology, University College London, September 1957

Two general principles

Crick frames the whole problem of protein synthesis around the order of the amino acids, and proposes two ideas to govern it. He is candid that both are, at this point, hypotheses — a theorist's scaffold for facts not yet in hand.

The Sequence Hypothesis

In its simplest form it assumes that the specificity of a piece of nucleic acid is expressed solely by the sequence of its bases, and that this sequence is a (simple) code for the amino acid sequence of a particular protein.

One linear sequence dictates another: the order of bases along the nucleic acid fixes the order of amino acids along the chain — and that order alone, Crick argues, is enough to determine how the protein folds and what it does.

The Central Dogma

This states that once ‘information’ has passed into protein it cannot get out again. In more detail, the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible.

Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.

The claim is specifically about sequence information. It permits the flows we now call replication and transcription and translation, and forbids the reverse — protein dictating the sequence of a nucleic acid or of another protein.

The adaptor hypothesis

Because an amino acid has no obvious chemical affinity for the bases that supposedly specify it, Crick reasons there must be an intermediary: a set of small ‘adaptor’ molecules, very likely containing nucleotides, each of which base-pairs with the code on one side and carries its own amino acid on the other — with a special enzyme to load each one. He expects about twenty such adaptors. The molecule he is describing, still hypothetical here, is transfer RNA.

[ … ]

What is left open

The coding problem — exactly how a run of bases is parsed into amino acids — Crick leaves explicitly unsolved, the central puzzle he hands to the next decade. He is equally frank about how much of the rest is informed guesswork, sketching where in the cell synthesis happens (on RNA-rich particles) while marking the speculation as speculation.

Medical Research Council Unit, Cavendish Laboratory, Cambridge · 1958