Shoulder Hopping on Giants

Editorial by Walter Schaffner on the early years with Charles Weissmann and Max L. Birnstiel

Before Max Birnstiel moved eastward to found the IMP in Vienna, I had the privilege to work with him in Zürich in his Institute of Molecular Biology II. Why II? Because there was also Molecular Biology I, of course. One may wonder why there were, to begin with, two Institutes of Molecular Biology in our relatively small university. That had to do with two outstanding scientists who had a great impact on the development of molecular biology and far beyond: Charles Weissmann and Max L. Birnstiel. Each one of them was recruited back to Switzerland by the renowned Zoologist Ernst Hadorn, and each one had his own vision of how to do science - hence the unconventional solution of twin institutes. Since I had done my diploma with Ernst Hadorn, the Ph.D. with Charles Weissmann, and later was a group leader with Max Birnstiel, I may present here some of my recollections of exciting early years in research, which I presented in a similar form at the 1997 celebration of 30 years of molecular biology in Zürich.

Anyone asking my mother about me in 1970, before I joined Charles Weissmann, would have heard the story of a great achiever, having completed studies in Zoology with the eminent Professor Hadorn in the minimal time with excellent marks. It was to no avail. Once in molecular biology, it soon dawned on me that just about everything was going to be different from the idyllic times I had enjoyed before. The very first priority was no longer to do solid but low-budget research, evident from the seemingly infinite supply of materials in the stockroom, but to produce results, even more evident from the different style of the new boss, who acted in a permanent 100,000 Volt show. Charles Weissmann made absolutely sure that the tough training to follow in his lab started from the beginning. He would not tolerate any fault in thought or experiment, and anyone's weaknesses were exposed pitilessly, be it with scolding or a sarcastic joke. For the latter he could draw from an endless stock to comment on any situation, either in science or in ordinary life. My first two thesis projects, one after the other, never got anywhere, and I felt so low that I seriously started wondering why the automatic doors at the Hönggerberg Cafeteria would still open for me. But I was determined to go on, to find new solutions, and with time the excellent scientific environment began to have its impact. My third project finally worked out well, namely a novel method for determining protein in dilute solutions. Though Schaffner-Weissmann never toppled the Lowry assay, it filled a niche and also allowed me to supply friends and relatives with the most exotic stamps from the more than 2000 reprint requests we received. The fourth project, the primary structure determination of a small parasitic RNA molecule that was replicated in the test tube by bacteriophage Q beta replicase, even made it into the Guinness Book of Records and helped to alert Max Birnstiel, who had shortly before founded his own Institute of Molecular Biology II, to my existence. He offered me a group leader position. Equipped from the Weissmann lab with several up-to-date molecular biology techniques, an unquenchable enthusiasm, and countless jokes, I thought that I had finally captured the essence of successful research. However, with Max Birnstiel almost everything was different once again. To begin with, he did not like the jokes. Max was also not into any public showdown of wit and eloquence that would redden your face and hoarsen your voice. Since Charles's demanding presence could bring almost anyone at times to the brink of mental exhaustion, I should have been glad to get a change of lifestyle with Max. Instead, I developed serious Molbio-I-withdrawal symptoms. Max was so unbelievably quiet (everything being relative, mind you). He liked discussions in his office rather than in public, and often astonished us the next morning with elegant solutions that had occurred to him at home. For example, one of the problems of injecting DNA into a frog oocyte nucleus was that the needle had to be inserted blindly due to the opacity of the yolk. Max simply introduced a short centrifugation step, after which the nucleus was floating on the cytoplasm as a pale white spot.

Now, even a half-blind beginner was able to inject hundreds of oocytes, giving his lab an edge over others. Furthermore, for Max's studies of RNA processing, the separation of RNA from nuclei and cytoplasm was a prerequisite but was also a major task. Max, perhaps while eating his favored Nüsslisalat mit Ei (salad garnished with boiled egg), just thought of dumping the tube with oocytes into boiling water, which solidified both nucleus and cytoplasm, keeping the RNA intact, and hence the subsequent separation of the two compartments was a piece of cake. However, I should add that Max did not boil any oocytes himself; for the realization of his ideas he always relied on skilled collaborators, including, at one time, even Hamilton 0. Smith, with whom he developed the Smith-Birnstiel technique of restriction site mapping.

In fact, I never saw Max do an experiment, in defiance of the myth that a good boss always has to keep his hands on the pipette as much as on his office phone. Like Charles, he had a sense for the most worthwhile experiment and went for it with the same uncompromising determination. Besides maintaining a scientific productivity second to none, Max was a bonvivant with an impressive expertise in Bordeaux wines, French cuisine, and cigars.

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

(Published as an Editorial in Biological Chemistry, Vol. 380, pp. 109-110, February 1999 - Copyright © by Walter de Gruyter & Co - Berlin -New York)