E. B. Lewis and the bithorax complex: part II. From cis-trans test to the genetic control of development.

AS discussed in Part I of this Perspectives (see the April tion, by means of the elegant cis-trans comparison devised by Lewis.” Benzer called this unit the “cistron”; issue of Genetics), E. B. Lewis’s early studies of the BX-C revealed a series of five bithorax complex molecular biologists came to view the cistron as the nucleotide sequence encoding a single polypeptide. (BX-C) “pseudoalleles” separable by recombination and by function, with the map order: bx Cbx Ubx bxd pbx. Thus, Lewis’s interpretation of the cis-trans test was turned on its head. In the new model, the BX-C mutaLewis found pronounced cis-trans position effects among these pseudoalleles. He interpreted these positions no longer necessarily defined separate but functionally interacting genes. Molecular biologists began tion effects in terms of a model in which the BX-C pseudoalleles define separate genes and in which these to tell Lewis that “I was simply dealing with missense and nonsense mutants within a protein and that all we genes function to control sequential biochemical reactions occurring along the chromosome. were doing was mapping sites within a single protein coding unit!” (quoted in Lawrence 1992). A sense of the difficulties Lewis encountered in this new scientific THE BX-C AND THE GENE CONCEPT climate can be gauged from a 1963 letter by Max Delbrück to a former member of Lewis’s laboratory (Rhoda “The original problem of defining the unit of heredity, which almost 50 years ago was designated ‘the gene,’ Grell). Delbrück wrote: “I then plunged into the bithorax saga for which Lewis very kindly sent me his has not yet been solved,” wrote M. Demerec in his introduction to the 1951 Cold Spring Harbor symposium latest manuscript. . . . I must say I am puzzled by the apparent agreement in his analysis between the two ways volume containing Lewis’s first comprehensive description of the BX-C system (Demerec 1951). Only 2 years of subdividing this gene complex, to wit by recombination on the one hand and by function on the other later, Watson and Crick’s model for the double-helical structure of DNA initiated a revolution in the gene hand. I strongly suspect that there is something wrong here in the analysis.” concept. With this molecular model in mind, Benzer embarked on his fine structure analysis of the rII region In fact, there was nothing wrong with Lewis’s analysis. What was lacking was an understanding of the complex, of phage T4. This work demonstrated that recombination occurs within genes and led to the conclusion: “The modular organization of cis-regulatory and coding regions making up many metazoan genes. The genetic classical ‘gene,’ which served at once as the smallest element of genetic recombination, of mutation, and of interactions that struck some of Lewis’s contemporaries as bizarre oddities can now be seen as manifestations function, is no longer adequate. These units require separate definition” (Benzer 1957, p. 70). The first two of the elaborate, long-range, cis-regulatory mechanisms governing animal development. This realization would units Benzer called the “recon” and “muton”; each of these could be resolved to one or a few DNA nucleotides. have to wait until the 1980s. In the meantime, there were compelling reasons for Lewis to reject the singleThe unit of function was much larger and “can be defined genetically, independent of biochemical informaprotein-coding models presented to him by molecular biologists. One was the recovery of rearrangements broken between Ubx and bxd (see above), which had full 1 Corresponding author: Department of Biology, Washington Univerfunction of bx and Ubx , but appeared almost comsity, 1 Brookings Dr., St. Louis, MO 63130. pletely defective for bxd and pbx. Such rearrangements E-mail: [email protected] were readily understood in terms of the Lewis model, 2Present address: 227 Union St., Brooklyn, NY 11231. E-mail: [email protected] but were difficult to rationalize in terms of the single-