JAMES WATSON and Francis Crick earned scientific immortality by elucidating the structure of the genetic code. DNA, they showed, is a double helix formed of the base pairs of adenine and thymine (referred to as A and T for short), and of cytosine and guanine (C and G).



For some 3.5 billion years the Watson and Crick base pairs, as they are known, have been faithfully replicated by DNA polymerases, the enzymes that copy DNA. But now, for the first time since life began, a third, artificial base pair is being replicated. (RNA, which is used in various intermediate stages by many organisms, and also by viruses, substitutes another molecule, uracil for thymine, but the two are very similar.)







The unnatural molecule is 3-fluorobenzene (3FB for short), which forms a pair with itself. In Floyd Romesberg's lab at the Scripps Research Institute in La Jolla, California, 3FB-3FB joins the natural base pairs of A-T and C-G. It is the first step, says Dr Romesberg, in the expansion of the genetic code.



Why there are only two base pairs is an open question, and one which evolutionary biologists and geneticists want to answer. With Dr Romesberg's modified DNA, they might get a chance to do so. Other unnatural base pairs have been made before, notably by a Japanese group led by Shigeyuki Yokoyama, now at the Genomic Sciences Centre in Saitama. But unlike those other unnatural base pairs, the Scripps researchers say 3FB can be well replicated by DNA polymerases.



However, typos do creep into the copy when the unnatural base pair is included. A mistake typically occurs once in every 1,000 base pairs that are copied, compared with around one in 10m bases of natural DNA. But Dr Romesberg is confident he can improve the copy quality. He presented his research this week at a meeting of the American Chemical Society, in San Diego.



One way to improve copying fidelity is to evolve polymerase enzymes better able to replicate the unnatural DNA. That is one of the projects Dr Romesberg's lab is working on. If and when these enzymes are perfected, the way will be open to make simple organisms engineered to carry the new base pair.



Since such organisms (simple yeasts or bacteria) would carry a brand-new genetic code, they would in effect be new life forms. Organisms with more than the standard two base pairs would be able to make more than the standard 20 amino acids. Thus, such organisms could make novel, unnatural proteins.



That might help evolutionary biologists answer the question of why, for billions of years, and in every form of life on earth, only two base pairs are used. It might be that the two base-pair system is the best. Or it might be a simple accident which occurred when life began.



In any case, expanding the genetic code of simple organisms could lead to radical new applications for medicine and biotechnology, and to useful information storage and retrieval systems based on DNA.

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