Directed Mutation: A Current Perspective

The publication in 1988 of the paper "The origin of mutants" by Cairns, Overbaugh and Miller, with its message that mutations could be "directed" towards those conferring a beneficial phenotype, reawakened the neo-Darwinist-Lamarckian debate concerning the origin of genetic variation which had waged well into the twentieth century. Six years on, the (often emotional) controversy generated by the paper still persists. Two contrasting reviews published last year, one by Foster, the other by Lenski & Mittler, present, respectively, arguments for and against directed mutagenesis. However before these can be properly appreciated it is helpful to review some of the background to the debate. The most convenient starting point is the fluctuation test introduced by Luria and Delbrueck in 1943, with which they were able to demonstrate that, using resistance to phage T1 as a marker, mutations occurred randomly during the growth of bacteria, quite independently of the presence of the selective agent. (Nowadays this is usually interpreted as reflecting the built-in error frequency with which nucleotides are inserted into DNA during replication.) However, the conclusion that was almost universally drawn from the experiments was much stronger, namely, that all spontaneous mutations occurred in this way. As can be seen from the following comments made at the annual Cold Spring Harbor symposium in 1946, Delbrueck had strong reservations about the generality of this interpretation.