Edward B. Lewis 1918–2004

Ed Lewis, who died on 21 July aged 86, was an example of that rare and underfunded breed, the scientific loner. From the moment he arrived at Caltech in August 1939, bringing his own project with him, to the last years of his life, feted and honoured as a Nobel laureate, he pursued his own ideas, working for the most part alone. Early on in his career he became convinced that he had evidence to support Calvin Bridges’ hypothesis that new genes arise from old by a process of tandem duplication followed by divergence. He lived to see that belief vindicated, although not in the way that he (or anyone else) had anticipated. In the process, not only the dark prehistory of evolution but also the molecular basis of embryogenesis was illuminated. The key that unlocked both these areas was the bithorax complex, a gene cluster in Drosophila melanogaster that Lewis discovered and dissected. Lewis was born on May 20, 1918, in Wilkes Barre, Pennsylvania, the second of two sons. A child of the depression, the family struggled to make ends meet after his father, a watchmaker, was thrown out of work. His childhood hobbies were playing the flute and building terraria and aquaria. Both lasted a lifetime: visitors to Caltech might be introduced to a baby octopus, and his fellow night owls would catch the sweet sound of the flute in the hours between midnight and dawn. Typically, his entrance into Drosophila genetics was selfgenerated. Reading his way through the town library he came across diagrams illustrating the sex-linked inheritance of white eyes in Drosophila and discovered that you could buy cultures for $1 each. (It was the fact that the breeding “could be expressed symbolically... almost like algebra” that appealed to him.) His parents, who tolerated large snakes in his bedroom, seem to have drawn the line at flies, and it was his high school biology teacher who gave him space and freedom to work after school hours. Here he teamed up with a schoolfriend, Ed Novitski. Their supplier put them in touch with Calvin Bridges, who “wrote long letters back to us, about how to grow the flies, and sent us more mutants”. Their most notable success in high school was Novitski’s discovery of the mutant heldout in 1935, later to be rediscovered and renamed decapentaplegic. The two friends went to different universities but were reunited three years later as graduate students at Caltech. Lewis went first to Bucknell College for a year, on a music scholarship, and then to the University of Minnesota, chosen for its low out-of-state fees. Here he was helped financially by his elder brother and, by taking exams for courses he had not attended, graduated in Biostatistics in two years. He was also given space in the Drosophila laboratory of C.P. Oliver and began the study of multiple allelic series that led him to the bithorax complex. Oliver had observed the occasional appearance of wild-type flies in crosses between two alleles of a rough-eyed mutant, lozenge, but was unable to decide whether this represented crossing over within an allelic series (unheard of at the time) or reverse mutation. What was needed was the reciprocal crossover, the double mutant. Lewis began working on another pair of rough-eyed mutants: Star, a well-known dominant, and a new mutation found by Novitski that was thought to be a recessive allele of Star. At Minnesota, crosses between the two produced only a single wild-type fly, but on his arrival at Caltech he decided to continue the search. As Lewis has pointed out, this was a high-risk project, looking for rare events. In the event it was spectacularly successful. By a complicated feat of genetics Lewis succeeded in isolating the double mutant and in the process discovered the cis–trans position effect, in which two mutant alleles in trans (on opposite chromosomes) show a far more extreme phenotype than when they are in cis (on the same chromosome). He was also able to locate Star and its new allele, now named asteroid, to one of the ‘doublets’ that Bridges had observed in the salivary gland chromosomes. Bridges had suggested that these represented cytological evidence for the tandem duplication of genes, and Lewis decided he now had the genetic evidence: two closely linked genes with similar effects. “Because that's what I was after, looking for tandem duplications established in the species that Bridges said were in evidence in the salivary gland chromosomes.” The interactions between Star and asteroid he interpreted as evidence of their recent evolution. In December 1941, the United States went to war and the paper detailing these results was not published until 1945. By that time Lewis was in the Pacific, as weather officer on one of the command ships anchored in Okinawa. (His ‘postdoc’ had been a one-year MSc in meteorology.) He had already decided that after the Ed Lewis at the 1951 Cold Spring Harbor symposium on genes and mutations. (Courtesy of the Cold Spring Harbor Laboratory Archives.)