分子生物學 1958

論蛋白質的合成

法蘭西斯·克里克

基因的鹼基序列，是一份寫就蛋白質的密碼——而資訊，絕不會倒流出來。

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In depth · the introduction

在幫助找出 DNA 的形狀五年之後，法蘭西斯·克里克寫下了這個形狀「做什麼」的規則——並預言了一個誰都不曾見過的分子。

核心想法

DNA 寫就蛋白質。它那四個化學「字母」的順序，是一份密碼，而單單這個順序，就決定了串成蛋白質的那些積木——胺基酸——的次序。把序列定下來，蛋白質便會自己摺疊成能幹活的形狀。

克里克又加了第二條關於方向的規則。資訊從 DNA，流到一份工作副本，再到蛋白質，卻從不倒著走：一個造好的蛋白質，無法反過來去指定造它的那個基因的序列。他把這條規則，稱為「中心法則」。

它從哪裡來

1957 年，克里克在倫敦作了一場演講；次年，他把它寫成一篇論文——《論蛋白質的合成》。彼時的分子生物學，還是一堆彼此半連半斷的發現，而克里克，是它最大膽的理論家——樂於一路推理到結論，再逼著實驗去追上。

他最大膽的猜測是：必定存在一個小小的「配接器」分子，去搭起基因密碼與胺基酸之間的橋——因為這兩者，本無天然的化學吸引。他只憑邏輯就預言了它。也就在那一年，實驗者們找到了恰恰這樣一個分子——也就是我們如今所說的轉移 RNA。

它為何重要

這篇短短的論文，給了分子生物學一部憲章。它把一堆觀察，變成了一套單一的、單向的邏輯，並點名了緊隨其後的那個大謎題——「編碼問題」：DNA 裡三個字母的詞，如何對應到胺基酸。破解這套密碼的競賽——克里克本人也是贏家之一——是二十世紀科學的凱歌之一。

一個類比

把它想成一份鎖在圖書館裡的總藍圖（細胞核裡的 DNA）。你從不會把正本拿去車間；你複印一份工作副本（信使 RNA），帶著它走。在車間裡，一個個小小的翻譯員（配接器分子）各讀一個三字母的詞，去取來恰好對應的零件，機器便一件一件被裝起來。而這裡有一條單行規則：你能照藍圖把機器造出來，卻永遠無法從造好的機器上，把藍圖反讀回去。

它落在哪裡

它從華生與克里克 1953 年的結構停下的地方開始（見華生–克里克，1953）：雙螺旋揭示了 DNA 如何被複製；而這篇論文追問的是——複製，是為了什麼。它為 1960 年代遺傳密碼的破解搭好了舞台，又在逆轉錄被發現後得到修正，並活在你聽說過的工具裡——基因編輯（見 CRISPR，2012），以及把一份配方交到你自己細胞手裡的 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