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生物學 1953

核酸的分子結構

詹姆斯·沃森 與 法蘭西斯·克里克

DNA 是一座雙螺旋,它成對的「字母」悄然解釋了生命如何自我複製。

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In depth · the introduction

DNA 是一架擰轉的梯子,梯級是成對的化學「字母」——而正是這種配對,讓生命得以複製自己。

核心想法

DNA 是攜帶「如何構建並運轉一個生命」之指令的分子。沃森與克里克弄清了它的形狀:一座雙螺旋,像一架沿著長度被輕輕擰轉的梯子。兩側是長長的化學骨架;梯級則是四種「字母」——A、T、G、C——的配對。最關鍵的發現是:這些字母只能以唯一的方式配對:A 永遠配 T,G 永遠配 C。

正是這一條簡單的規則,悄然回答了生物學最古老的問題之一:生命如何複製自己?把梯子從中間拉開,每一條孤零零的半邊,都會自動「拼寫」出它缺失的另一半必須是什麼。原本一架梯子的地方,便長出兩架一模一樣的梯子。每一次細胞分裂,發生的正是這件事——在你體內,每天都有億萬次。

它是如何誕生的

到 1950 年代初,人人都知道 DNA 攜帶著遺傳,卻沒人知道它的形狀。這場競賽,在兩所英國實驗室之間展開。在劍橋的卡文迪許實驗室,詹姆斯·沃森與法蘭西斯·克里克,用硬紙板和金屬絲搭起一個個實體模型,尋找一種能與化學相吻合的形狀。在倫敦國王學院,羅莎琳·富蘭克林與莫里斯·威爾金斯,則用 X 射線照射 DNA 纖維,為它的結構拍照。

兩條線索揭開了謎底。富蘭克林那張清晰得驚人的 X 射線照片——「51 號照片」——一眼便顯出 DNA 是一座尺寸確定的螺旋。而化學家埃爾溫·查戈夫早已發現,DNA 中 A 與 T 的含量總是相等,G 與 C 的含量也總是相等。沃森與克里克於是看出了拼合之道:一座雙螺旋,A 永遠配 T、G 永遠配 C。他們的解釋,1953 年在《自然》上僅佔了一頁。富蘭克林的數據對此至關重要,卻只被一句帶過;她於 1958 年去世,而 1962 年的諾貝爾獎,授予了沃森、克里克與威爾金斯。

它為何重要

這篇僅一頁的論文,開創了分子生物學。一旦我們明白生命的指令是用四個字母的密碼寫成的,我們便能開始解讀它,並最終編輯它——由此通向現代遺傳學、DNA 指紋鑑定、基於基因的醫學,以及像 CRISPR 這樣能有意改寫密碼的工具。

一個可以想像的畫面

想像一條拉鏈。一側的每一顆齒,在另一側都只有唯一一顆能與之咬合。把拉鏈拉開,任何一半都精確地告訴你:缺失的那一半,原本必然是什麼。DNA 的字母,就是這些齒——A 只與 T 咬合,G 只與 C 咬合——所以單單一條鏈,就是它配對鏈的一份完整配方。這正是為什麼一架梯子,能變成兩架一模一樣的梯子。

可互動的 DNA:為左右兩側各選一個鹼基,看 A–T 與 G–C 如何配對(各有兩個或三個氫鍵),而錯配則無法成鍵;接著把雙螺旋梯子拉開,每一半都重建出自己的互補鏈,一架梯子於是變成兩架。

它的位置

一個世紀以前,孟德爾已經表明,性狀以一個個離散、隱藏的「因子」代代相傳,但那些因子是抽象的——沒人知道它們究竟由什麼構成。這一結構,給了基因一具身軀:螺旋之上、一段用四個字母寫成的密碼。從這裡,一條線徑直通向人類基因組計劃,通向今天能編輯基因的醫學。

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