RETROSPECTIVE RETROSPECTIVE Walter Jakob Gehring: A master of developmental biology Markus Affoltera,1 and Kurt Wüthrichb,c about modern DNA research, and then aGrowth and Development, Biozentrum der Universität Basel, CH-4056 Basel, Switzerland; moved to the newly founded “Biozentrum” bInstitut für Molekularbiologie und Biophysik, Eidgenössiche Technische Hochschule c at the University of Basel in 1972. With Hönggerberg, CH-8093 Zürich, Switzerland; and Department of Integrated Structural and a solid background of cloning techniques, Computational Biology, The Scripps Research Institue, La Jolla, CA 92037 Walter and collaborators established the first Drosophila gene bank in Europe, and with Alfred Tissiere’s group at the University of With Walter J. Gehring’sdeathinBaselon and transdetermination his thesis subject. At Geneva identified and characterized several May29,2014,thescientificcommunitylost that time, his interest was caught by a Dro- genes from this bank (1). Now, Walter’sma- one of the pioneers of molecular develop- sophila mutant, which carried an extra leg jor aim—to clone developmental regulatory mental biology. Walter will be missed by instead of the antenna on the fly head. The genes—was coming closer. After an extended a large community of friends and colleagues, gene mutated in this stock later turned out to walk along the chromosome, the Antp gene but he lives on in the work of the many be Antennapedia (Antp), a homeotic gene re- of Drosophila was cloned in 1983 (2). The big scientists whom he had mentored and who sponsible for the formation of the fly seg- surprise came when it turned out that Antp now work in his and related fields. ment on which the second leg pair is formed. shared a 180-bp segment with other home- Walter J. Gehring, born in Zurich in 1939, Walter called this remarkable Drosophila fly otic genes found in Drosophila (3) and “ ” became interested in developmental biology Nasobemia. In his own words, Nasobemia other organisms, including humans (4). early on in his life as he watched beautiful accompanied Walter through his life, and The homeobox was born, and it turned butterflies emerging out of rather ugly pupae cloning of the underlying gene and finding out that this stretch of DNA coded for the stored in a cardboard box given to him out how mutation of a single gene could give DNA-binding “homeodomain” of a wide by his uncle. Walter went on to study bird rise to a new, fully developed structure in the variety of proteins. migration for his diploma work, and then wrongplace,wasamajoraimofhisresearch Walter Gehring was the initiator of an pursued doctoral studies with Ernst Hadorn, from this point onward. important episode in structural biology, which an eminent developmental geneticist teaching After obtaining his doctoral degree at the involved M.A. as his postdoctoral student at the University of Zürich. Drosophila mel- University of Zürich, Walter Gehring joined and K.W. as an external collaborator. Be- anogaster was Walter’s experimental system, the laboratory of Alan Garen at Yale to learn cause 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’sbroad 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 pro- tein structure determination by NMR. The following week, Walter called K.W. to in- quire 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, be- cause his laboratory was used to work with at most micrograms of the Antp homeodomain.

Author contributions: M.A. and K.W. wrote the paper.

Walter J. Gehring speaking at a developmental biology meeting at the Biozentrum in 2009. 1 To whom correspondence should be addressed. Email: Markus. Image courtesy of the Biozentrum of the University of Basel (Basel). [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1413434111 PNAS Early Edition | 1of2 Downloaded by guest on September 30, 2021 Nonetheless, after two years of hard work, Subsequent to the homeobox success story, Royal Society of London and the US National Walter and his collaborators drove to Walter Gehring’s laboratory again gained Academy of Science. Zurich and personally handed 12 milligrams broad attention, both in scientific circles as Walter was a well-read zoologist, hands- of the Antp homeodomain to the NMR well as in the general public, with the discov- on marine biologist, and passionate bird spectroscopists. The structure was deter- ery that flies and mammals share a gene called watcher. In Banyuls-sur-mer he taught a bi- mined with homonuclear NMR, lifting PAX6, which is involved in the formation of ennial two-week course on marine biology. Walter’s enthusiasm to the next level: that facetted eyes in flies, and lens eyes in mice and These two weeks included molecular biology is, to have a go at determination of the humans (8). Moreover, when inappropriately experiments, cultural excursions, and experi- homeodomain–DNA complex, which would expressed, this single gene was capable of in- encing the local cuisine. An excellent dinner also be a novel achievement in NMR struc- ducing ectopic eye structures on all appen- with good wine, entertaining stories and ture determination. This next step required dages in flies, and so did the ectopic jokes—as well as lively scientific discus- isotope labeling of the homeodomain with expression of the human gene (9)! This was sions—was Walter’s preferred way to spend 13Cand15N. According to well-documented one of the most dramatic and spectacular an evening! It was also to a large extent in and often repeated statements by Walter, demonstrations of the power of a develop- Banyuls-sur-mer that Walter wrote the regu- the expense for the isotopes made this the mental master control gene, and represented lar updates of Zoologie, a textbook that he most expensive single experiment in his ca- the basis for Walter’shypothesisthatdifferent coauthored with Rüdiger Wehner. Until his reer, and there was apparently a lot of ex- eye structures in different species originated death, Walter also continued to work at the citement in his laboratory during this from a common ancestral eye structure under Biozentrum, planning new experiments and protein preparation. In due time, Walter the control of PAX6 in a primitive animal. maintaining himself a significant collection of drove to Zurich and personally handed Walter Gehring’s outstanding contribu- fly stocks. Ongoing studies of Walter’sgroup the labeled homeodomain preparation to tions were recognized by numerous presti- address the molecular aspects of vision; he the NMR spectroscopists. When it turned gious awards, including the Jeantet Prize wanted to test a number of hypotheses re- out that the structure of the homeo- for Medecine (1987), the Gairdner Award garding the emergence of vision in evolution domain–DNA complex contained features (1987), the Kyoto Prize for Basic Science (10). Walter Gehring will not see the results that had been predicted by him and col- (2000), and the Balzan Prize for Develop- of these latest studies, which he initiated, but leagues in his laboratory, Walter’s enthusi- mental Biology (2002). Walter was elected the research will go on and his memory will asm had no limits. This collaborative to several national academies, including the be with us while this happens. project, which resulted in the structure determination of the Antp homeodomain (5), its DNA complex (6), and a variety of 1 Schedl P, et al. (1978) Two hybrid plasmids with D. melanogaster Comparison with prokaryotic repressors. Cell 59(3): variant Antp homeodomains and several DNA sequences complementary to mRNA coding for the major heat 573–580. shock protein. Cell 14(4):921–929. 6 Gehring WJ, et al. (1994) Homeodomain-DNA recognition. Cell different wild-type homeodomains (see, for 2 Garber RL, Kuroiwa A, Gehring WJ (1983) Genomic and cDNA 78(2):211–223. example, ref. 7), was a great experience and clones of the homeotic locus Antennapedia in Drosophila. EMBO J 7 Qian YQ, et al. (1994) Nuclear magnetic resonance solution resulted in lasting friendships among those 2(11):2027–2036. structure of the fushi tarazu homeodomain from Drosophila and 3 McGinnis W, Levine MS, Hafen E, Kuroiwa A, Gehring WJ comparison with the Antennapedia homeodomain. J Mol Biol involved. It also provided a unique oppor- (1984) A conserved DNA sequence in homoeotic genes of the 238(3):333–345. tunity to apply the then new NMR method Drosophila Antennapedia and bithorax complexes. Nature 8 Quiring R, Walldorf U, Kloter U, Gehring WJ (1994) Homology of 308(5958):428–433. the eyeless gene of Drosophila to the Small eye gene in mice and for macromolecular structure determination 4 McGinnis W, Garber RL, Wirz J, Kuroiwa A, Gehring WJ (1984) Aniridia in humans. Science 265(5173):785–789. with a highly visible, front-line biology A homologous protein-coding sequence in Drosophila homeotic 9 Halder G, Callaerts P, Gehring WJ (1995) Induction of ectopic eyes project. The biomolecular NMR commu- genes and its conservation in other metazoans. Cell 37(2): by targeted expression of the eyeless gene in Drosophila. Science 403–408. 267(5205):1788–1792. nity owes a lot to Walter Gehring for his 5 Qian YQ, et al. (1989) The structure of the Antennapedia 10 Gehring WJ (2014) The evolution of vision. Wiley Interdiscip Rev adventurous initiation of this work. homeodomain determined by NMR spectroscopy in solution: Dev Biol 3(1):1–40.

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