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Remembering the year with E.B. Lewis

2005; Wiley; Volume: 232; Issue: 3 Linguagem: Inglês

10.1002/dvdy.20331

1097-0177

Shigeru Sakonju,

Earth Systems and Cosmic Evolution

E.B. Lewis was not a household name among biologists back in 1981. Most molecular biologists had never heard of him. Some thought he used to be a well-known geneticist. One even called him a legend. A few have heard the rumors of his extraordinary homeotic mutants, but no one could tell what he was doing with them. One could read about Lewis's work in the paper he published in Nature in 1978, the only one during the previous 11 years. It contained fantastic ideas, although, truth be said, it was nearly impossible to follow the argument. No one I knew could name anyone who had worked with Lewis. No one around me had ever seen him or heard him talk. Was he a J.D. Salinger of genetics? A recluse in Howard Hughes' mode? E.B. Lewis was an enigma as I headed out West to his lab that summer. I had just finished my doctoral thesis at Johns Hopkins and planned to spend one year in his lab before joining Dave Hogness's lab at Stanford. The Ed Lewis who welcomed me to Caltech was no recluse. He was a man with a broad smile and cheerful disposition, who exuded kinetic energy from his compact body. We even wore the same kind of shoes, a pair of old Hush Puppies. He took me out to lunch at the Athenaeum, the dining club on campus, as he would many times during that year, and he introduced me to everyone we ran into. He immediately treated me as a colleague, as he did anyone who walked into his lab. Either out of his subversive attempt to breach exclusiveness or because that is just the way it was in the old halcyon days at Caltech, he once took me to an informal regular luncheon, which turned out to be attended by some of the biology faculty and visiting scientists. I was promptly banned from attending such future luncheons by a dominant figure on the faculty, for which Ed was embarrassed and apologetic. It was not just his sense of open social interaction that lingered from the old days. The top floor of Kerckhoff Laboratories where Ed worked looked and smelled as it must have in the days of Alfred Sturtevant, Calvin Bridges, and perhaps even T.H. Morgan. Ed occupied a large room on that floor. As you stepped into the room, you saw on your left Ed's cockpit where he sat to push his flies. The working surface at his microscope was lit by an ingenious home-made lighting system: a small desk lamp shining light through a round-bottom flask filled with a copper sulfate solution, which gave a bluish light that he liked working under. From the scope, he could swivel to the left to type letters and memos on his old typewriter. There was an old couch, a coffee table stacked full of papers, and a large aquarium for octopuses. A portrait of Sturtevant, his mentor, hung on the wall. A music stand stood with a sheet of flute music. The rest of the room was filled with dust-covered cardboard boxes and an assortment of clutter, which gave the room the appearance of a museum attic. Ed was to be found in this room after lunch until approximately 5 PM, and from midnight to the early hours of morning. He had two short stretches of sleep. He said he acquired this biphasic daily routine while he was an army weatherman during World War II. On most afternoons, Ed was busy running back and forth between the lab, the departmental office, the fly stock center, and the fly kitchen. He was not really running, of course. But because of his bouncing energy, it seemed as if he was running back and forth. When he returned at midnight, he settled in to work for several hours. This is a wonderful way to work, if you can pull it off. Your brain cells have just been invigorated by sleep. There are no visitors. No phone calls. There was of course no e-mail back then. You are totally undisturbed. Ed was very productive, although one was not quite sure what he was up to. Everyday one saw dozens of new vials in a holding rack by his chair, in which he was collecting virgins or setting up crosses. He kept most mutants he and other people in the lab found. If he was not interested in them, he knew who might be and suggested sending them to that person. He numbered every cross he set up (already in 5 digits at that time), and a mutant found in that cross would receive a new number. If more than one mutant were found, a decimal point would be added. In conversation, he referred to crosses and mutants using these numbers, which could be utterly bewildering to the uninitiated. During much of his career, Ed worked by himself. There were occasional visiting geneticists. But for whatever reason there had been only a few graduate students and postdocs. One suspects Ed's science may have been simply not fashionable enough during the heydays of phage and bacterial genetics (fashionable being one quality that all youngsters entering science understand well.) That year there were suddenly three postdocs in Ed's lab: Ian Duncan, a superb geneticist who was also well versed in molecular biology; Margit Lohs-Schardin, who had fate-mapped the Drosophila embryo using laser ablations; and me, a molecular biologist who could not tell a male from a female fly. There were also three technicians who kept the fly stocks for Ed and the Caltech stock center. Ed seemed bemused to have so many people in his lab. One consequence of this expanded laboratory was that when all of us were in, there was quite a racket from the sound we made from banging glass milk bottles against the table, to drop flies away from the foam caps. This noise grated on Ed's musical ears. He used to complain in private, “I don't understand why people have to bang them so hard. All you have to do is hold the bottle with one hand and gently tap it against the palm of your other hand.” And this he did; whenever Ed opened a fly bottle, some gently tapped flies would jump out, and he would be busy smashing them against the table with his palm. Ed showed curious idiosyncrasies for a geneticist. He did not like to count flies, during screens and even during recombination mapping. This, at first, seemed surprising for a man who spent a large part of his career fine-mapping pseudoalleles. In practice, however, it made sense. He counted bottles and estimated progeny numbers from them. For dominant gain-of-function mutations, which we were looking for at the time, the frequency was so low that the numbers would not be so meaningful anyway. For recombination mapping, Ed would estimate approximate map distances relative to the linked markers of known distances. It is clear he had nothing against denominators. A few years later Ed became enamored of an automatic fly counter, a high-tech gadget developed by a company that apparently saw a lucrative market among fly pushers. The machine consisted of a tube attached to a vacuum pump, and an electronic eye that counted flies as they flew along the tube at high speed toward a flytrap. Ed even set up a table at the Annual Drosophila Research Conference to demonstrate its usefulness and to herald the dawn of a new age in fly counting. The machine, I believe, was not a commercial success. Another idiosyncrasy was that Ed refused to do recessive lethal screens. Because F1 flies are individually crossed in vials, these screens require thousands of vials. Ed said that some years before, someone had done a huge F2 screen and caused so many problems in the fly kitchen that he would not allow himself or anyone else to do such screens. He had a very strong feeling about this. Dave Hogness said that he had once tried to persuade Ed to do a recessive lethal screen at the bithorax complex, and Dave apparently pushed him a bit too far, thereupon Ed banged on the table with his fist and exclaimed, “I WILL NOT DO F2 SCREENS!” And that was the end of that discussion. So a recessive lethal screen was not done until Gines Morata's group in Spain finally did it in 1985. Despite his protestations about overloading the fly kitchen, it is also possible that the real reason Ed refused to do a lethal screen at the bithorax complex is that he anticipated correctly what he was going to find: there would be only three lethal complementation groups—Ubx, iab-2, and iab-7—and EMS-induced mutations that disrupt other gene functions would occur at extremely low frequencies. But to dwell on these idiosyncrasies is to miss the point of what Ed really had to offer. In his Nobel lecture, Ed quotes Bertrand Russell on the power of using abstractions. This indeed was what I learned most from Ed that year. What makes genetics so wonderful is that abstract thinking and real life are so directly connected. Because Ed's models are abstract formulations of the phenotypes he had observed, he knew he could not be wrong. He had conviction that that is how life worked. That is why he called them “rules.” It did not much matter for these rules if gene functions were protein-coding sequences, cis-regulatory elements, or small RNAs. Of course he knew that molecules mattered in the end. But for him, molecules had to fit the rules he found, not the other way around. When Ed once talked about a model of transvection in which RNA polymerase jumped from one chromosome to another, I did not know if he was being serious or facetious. But as I learned more about his thought process, I realized that he did not let textbook images of how molecules should behave constrain his models. He just knew that something had to “jump” from one chromosome to another. Ed once told me about how Barbara McClintock had come to Caltech to give a seminar and how badly her story of transposable elements had been received. He said she was not treated nicely, and she never returned to Caltech after that. This incident clearly still pained him. I mention this anecdote because I think Ed understood that, as an abstraction, McClintock's idea had to be correct. And the notion that abstraction has power was what Ed really wanted to teach. In real life, Ed did not dwell in the abstract world. Ed infected us with his boyish delight in watching animals. He loved to visit tidal pools along the coast. He kept miniature octopuses in aquariums in his office and at home. On rare occasions when a pair began to mate, he would rush into the lab to grab anyone who was there to appreciate the display of graceful underwater dancing with him. A visitor to his house felt obliged to greet his beloved turtle, who was always wandering off somewhere among the shrubs and difficult to locate. And there were his wife Pam's praying mantis babies… Was it this joy in the living as much as his intellectual curiosity that kept Ed at his microscope all those years? Ed also took genuine delight in music. Playing the flute had been an important part of his life since his youth. He was pleased to learn that I played the piano and was able to accompany him. We began playing together on Sundays. He preferred music that was lively, which flute music tends to be, and played it just as he sets up his crosses: at good clipping tempo. One luxury Ed and Pam afforded themselves was to attend as many opera performances as possible in Los Angeles, San Diego, and San Francisco. They held season tickets at the San Francisco Opera and flew there just for the performances. During the last dinner I had with them, Ed and Pam animatedly told the entire complicated story line of the obscure opera Khovanshchina by Moussorgsky. Shortly before Ed was to leave for Stockholm to accept his Nobel Prize, I sent Ed a note of congratulations along with two books of poems by Seamus Heaney, who had won the Nobel Prize in Literature that same year. After a few months, I received this note from Ed: “Please excuse the delay in thanking you for the books of Heaney's poetry. I took the smaller one and he autographed it and wrote on the title page, ‘Home from home, In Stockholm, Hallelujah!’” Heany's choice of the word Hallelujah is ironic, because Ed was a profoundly nonreligious man. Yet somehow the word has an appropriate ring when remembering Ed, for his way of thinking, generosity, enthusiasm, and charm. Yes indeed, Hallelujah! I thank Ian Duncan, Howard Lipshitz, Ai Sakonju, and Gary Schoenwolf for helpful comments and editorial assistance.