Walter Jakob Gehring: A master of developmental biology

With Walter J. Gehring’s death in Basel on May 29, 2014, the scientific community lost one of the pioneers of molecular developmental biology. Walter will be missed by a large community of friends and colleagues, but he lives on in the work of the many scientists whom he had mentored and who now work in his and related fields.

Walter J. Gehring speaking at a developmental biology meeting at the Biozentrum in 2009. Image courtesy of the Biozentrum of the University of Basel (Basel).

Walter J. Gehring, born in Zurich in 1939, became interested in developmental biology early on in his life as he watched beautiful butterflies emerging out of rather ugly pupae stored in a cardboard box given to him by his uncle. Walter went on to study bird migration for his diploma work, and then pursued doctoral studies with Ernst Hadorn, an eminent developmental geneticist teaching at the University of Zürich. Drosophila melanogaster was Walter’s experimental system, and transdetermination his thesis subject. At that time, his interest was caught by a Drosophila mutant, which carried an extra leg instead of the antenna on the fly head. The gene mutated in this stock later turned out to be Antennapedia (Antp), a homeotic gene responsible for the formation of the fly segment on which the second leg pair is formed. Walter called this remarkable Drosophila fly “Nasobemia.” In his own words, Nasobemia accompanied Walter through his life, and cloning of the underlying gene and finding out how mutation of a single gene could give rise to a new, fully developed structure in the wrong place, was a major aim of his research from this point onward.

After obtaining his doctoral degree at the University of Zürich, Walter Gehring joined the laboratory of Alan Garen at Yale to learn about modern DNA research, and then moved to the newly founded “Biozentrum” at the University of Basel in 1972. With a solid background of cloning techniques, Walter and collaborators established the first Drosophila gene bank in Europe, and with Alfred Tissiere’s group at the University of Geneva identified and characterized several genes from this bank (1). Now, Walter’s major aim—to clone developmental regulatory genes—was coming closer. After an extended walk along the chromosome, the Antp gene of Drosophila was cloned in 1983 (2). The big surprise came when it turned out that Antp shared a 180-bp segment with other homeotic genes found in Drosophila (3) and other organisms, including humans (4). The homeobox was born, and it turned out that this stretch of DNA coded for the DNA-binding “homeodomain” of a wide variety of proteins.

Walter Gehring was the initiator of an important episode in structural biology, which involved M.A. as his postdoctoral student and K.W. as an external collaborator. Because this work is less prominent in records about Walter than his contributions to molecular and cell biology, we describe here this part of his scientific life in some detail, as it is a nice illustration of Walter’s broad interest and unbeatable enthusiasm. On March 21, 1986, Walter and K.W., who had not met previously, listened to each other’s plenary lectures at the 18th Union of Swiss Societies for Experimental Biology (USGEB) Meeting in Basel. Walter talked about the homeobox and K.W. about protein structure determination by NMR. The following week, Walter called K.W. to inquire about possible interest to determine the structure of the Antp homeodomain with the then new and little proven NMR method. After being informed that milligram quantities of the highly purified protein would be needed, Walter apparently nurtured some doubts about the wisdom of his initiative, because his laboratory was used to work with at most micrograms of the Antp homeodomain. Nonetheless, after two years of hard work, Walter and his collaborators drove to Zurich and personally handed 12 milligrams of the Antp homeodomain to the NMR spectroscopists. The structure was determined with homonuclear NMR, lifting Walter’s enthusiasm to the next level: that is, to have a go at determination of the homeodomain–DNA complex, which would also be a novel achievement in NMR structure determination. This next step required isotope labeling of the homeodomain with ¹³C and ¹⁵N. According to well-documented and often repeated statements by Walter, the expense for the isotopes made this the most expensive single experiment in his career, and there was apparently a lot of excitement in his laboratory during this protein preparation. In due time, Walter drove to Zurich and personally handed the labeled homeodomain preparation to the NMR spectroscopists. When it turned out that the structure of the homeodomain–DNA complex contained features that had been predicted by him and colleagues in his laboratory, Walter’s enthusiasm had no limits. This collaborative project, which resulted in the structure determination of the Antp homeodomain (5), its DNA complex (6), and a variety of variant Antp homeodomains and several different wild-type homeodomains (see, for example, ref. 7), was a great experience and resulted in lasting friendships among those involved. It also provided a unique opportunity to apply the then new NMR method for macromolecular structure determination with a highly visible, front-line biology project. The biomolecular NMR community owes a lot to Walter Gehring for his adventurous initiation of this work.

Subsequent to the homeobox success story, Walter Gehring's laboratory again gained broad attention, both in scientific circles as well as in the general public, with the discovery that flies and mammals share a gene called PAX6, which is involved in the formation of facetted eyes in flies, and lens eyes in mice and humans (8). Moreover, when inappropriately expressed, this single gene was capable of inducing ectopic eye structures on all appendages in flies, and so did the ectopic expression of the human gene (9)! This was one of the most dramatic and spectacular demonstrations of the power of a developmental master control gene, and represented the basis for Walter’s hypothesis that different eye structures in different species originated from a common ancestral eye structure under the control of PAX6 in a primitive animal.

Walter Gehring’s outstanding contributions were recognized by numerous prestigious awards, including the Jeantet Prize for Medecine (1987), the Gairdner Award (1987), the Kyoto Prize for Basic Science (2000), and the Balzan Prize for Developmental Biology (2002). Walter was elected to several national academies, including the Royal Society of London and the US National Academy of Science.

Walter was a well-read zoologist, hands-on marine biologist, and passionate bird watcher. In Banyuls-sur-mer he taught a biennial two-week course on marine biology. These two weeks included molecular biology experiments, cultural excursions, and experiencing the local cuisine. An excellent dinner with good wine, entertaining stories and jokes—as well as lively scientific discussions—was Walter’s preferred way to spend an evening! It was also to a large extent in Banyuls-sur-mer that Walter wrote the regular updates of Zoologie, a textbook that he coauthored with Rüdiger Wehner. Until his death, Walter also continued to work at the Biozentrum, planning new experiments and maintaining himself a significant collection of fly stocks. Ongoing studies of Walter’s group address the molecular aspects of vision; he wanted to test a number of hypotheses regarding the emergence of vision in evolution (10). Walter Gehring will not see the results of these latest studies, which he initiated, but the research will go on and his memory will be with us while this happens.