Download Article (PDF)

Editorial

Shoulder Hopping on Giants

Before Max Birnstiel moved eastward (and upward – see structure determination of a small parasitic RNA molecule his Guest Editorial) to found the IMP in Vienna, I had the that was replicated in the test tube by bacteriophage Q␤ privilege to work with him in Zürich in his Institute of Mole- replicase, even made it into the Guinness Book of Records cular Biology II. Why II? Because there was also Molecular and helped to alert Max Birnstiel, who had shortly before Biology I, of course. One may wonder why there were, to founded his own Institute of Molecular Biology II, to my begin with, two Institutes of Molecular Biology in our rela- existence. He offered me a group leader position. tively small University. That had to do with two outstanding Equipped from the Weissmann lab with several up-to- scientists who had a great impact on the development date molecular biology techniques, an unquenchable en- of molecular biology in Zürich and far beyond: Charles thusiasm, and countless jokes, I thought that I had finally Weissmann and Max L. Birnstiel. Each one of them was re- captured the essence of successful research. However, cruited back to Switzerland by the renowned Zoologist with Max Birnstiel almost everything was different once Ernst Hadorn, and each one had his own vision of how to again. To begin with, he did not like the jokes. Max was do science – hence the unconventional solution of twin in- also not into any public showdown of wit and eloquence stitutes. Since I had done my diploma with Ernst Hadorn, that would redden your face and hoarsen your voice. the Ph.D. with Charles Weissmann, and later was a group Since Charles’s demanding presence could bring almost leader with Max Birnstiel, I may present here some of my anyone at times to the brink of mental exhaustion, I should recollections of exciting early years in research, which I have been glad to get a change of lifestyle with Max. In- presented in a similar form at the 1997 celebration of 30 stead, I developed serious Molbio-I-withdrawal symp- years of molecular biology in Zürich. toms. Max was so unbelievably quiet (everything being Anyone asking my mother about me in 1970, before I relative, mind you). He liked discussions in his office rather joined Charles Weissmann, would have heard the story of than in public, and often astonished us the next morning a great achiever, having completed studies in Zoology with elegant solutions that had occurred to him at home. with the eminent Professor Hadorn in the minimal time For example, one of the problems of frog oocyte injection with excellent marks. It was to no avail. Once in molecular was that the needle had to be inserted blindly due to the biology, it soon dawned on me that just about everything opacity of the yolk. Max simply introduced a short cen- was going to be different from the idyllic times I had en- trifugation step, after which the nucleus was floating on joyed before. The very first priority was no longer to do sol- the cytoplasm as a pale white spot. Now, even a half-blind id but low-budget research, evident from the seemingly in- beginner was able to inject hundreds of oocytes, giving his finite supply of materials in the stockroom, but to produce lab an edge over others. Furthermore, for Max’s studies of results, even more evident from the different style of the RNA processing, the separation of RNA from nuclei and new boss, who acted in a permanent 100000 Volt show. cytoplasm was a prerequisite but was also a major task. Charles Weissmann made absolutely sure that the tough Max, perhaps while eating his favored Nüsslisalat mit Ei training to follow in his lab started from the beginning. He (salad garnished with boiled egg), just thought of dumping would not tolerate any fault in thought or experiment, and the tube with oocytes into boiling water, which solidified anyone’s weaknesses were exposed pitilessly, be it with both nucleus and cytoplasm, trapping the RNA intact, and scolding or a sarcastic joke. For the latter he could draw hence the subsequent separation of the two compart- from an endless stock to comment on any situation, either ments was a piece of cake. However, I should add that in science or in ordinary life. Max did not boil any oocytes himself; for the realization of My first two thesis projects, one after the other, never his ideas he always relied on skilled collaborators, includ- got anywhere, and I felt so low that I seriously started won- ing, at one time, even Hamilton O. Smith, with whom he dering why the automatic doors at the Hönggerberg Cafe- developed the Smith-Birnstiel technique of restriction site teria would still open for me. But I was determined to go mapping. on, to find new solutions, and with time the excellent In fact, I never saw Max do an experiment, in defiance of scientific environment began to have its impact. My third the myth that a good boss always has to keep his hands on project finally worked out well, namely a novel method for the pipette as much as on his office phone. Like Charles, determining protein in dilute solutions. Though Schaffner- he had a sense for the most worthwhile experiment and Weissmann never toppled the Lowry assay, it filled a niche went for it with the same uncompromising determination. and also allowed me to supply friends and relatives with Besides maintaining a scientific productivity second to the most exotic stamps from the more than 2000 reprint none, Max was a bonvivant with an impressive expertise in requests we received. The fourth project, the primary Bordeaux wines, French cuisine, and cigars. 110 Editorial

My initial scepticism turned into unreserved admiration schedl demonstrated that the upstream promoter region (which I tried not to reveal to him). One of the memorable of the H2A gene could be inverted yet retain transcription- events I remember vividly was Max’s introduction of DNA al activity. Our own young group in Molecular Biology II, in- cloning into his lab. He and John Telford had managed to cluding Julian Banerji, Sandro Rusconi, Frank Weber, Di- isolate in pure form five clustered histone genes from a sea dier Picard and Jean de Villiers, followed a different route urchin, which represented the first protein-coding genes by working out transient mammalian cell transfection. In isolated from a multicellular organism, by repeated densi- parallel to others, including Pierre Chambon, we studied ty gradient centrifugation, a method perfected by them. the Simian virus 40 control region and thereby discovered But then, just when it looked like years of undisturbed rich the enhancer effect, i.e., the activation of transcription in harvest would lie ahead of them, DNA cloning arrived on cis over long distances by a segment of DNA termed the scene. Max realized at once the potential of this new- enhancer. We also found, in parallel to Susumu Tonegawa fangled method. Instead of lamenting and indulging in re- and Michael Neuberger, the first cellular, cell type-specific sentment, he called everyone to the coffee room. There he enhancer in the immunoglobulin heavy chain gene locus. disclosed to us that his own centrifugation technique, (The question of how a gene is activated has kept us busy even if it might later be referred to as the classical tech- since then). nique of gene isolation, was about to be superseded by In 1987, Max left Zürich in order to build, from scratch, a gene cloning, and that every effort of the lab had to go into new Institute of Molecular Pathology in Vienna – which adopting and exploiting this new technique. Many of the turned out to be yet another smashing success of his. And early studies on eukaryotic genes were subsequently what happened in Zürich? After turning down an offer from done with cloned histone genes. the Biocenter in Basel, I became Max’ successor and was Max sent me to Fred Sanger in Cambridge, UK, so I able to attract Markus Noll to Molecular Biology II. Re- could familiarize myself with that new DNA sequencing cently, the two Institutes were fused to a single Molecular technique, and later on baited me back from Cold Spring Biology Institute, and Konrad Basler will soon become Harbor Laboratory with an irresistible offer of an assistant Charles Weissmann’s successor. Thus it seems safe to professorship in his institute. After my return from the U.S. say that the two giants have made deep and lasting foot- in 1978, Max gave me all the freedom I needed to follow my prints. own projects, while sparing me from administrative duties. Walter Schaffner While Max and his group mainly used the oocyte injection Institut für Molekularbiologie technique to define Pol III promoters and RNA processing, Universität Zürich-Irchel they also did groundbreaking work on Pol II genes. His- CH-8057 Zürich tone genes, of course; for example, he and Rudi Gros- Switzerland