View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Developmental Cell Obituary Walter Jakob Gehring (1939–2014) Walter J. Gehring died in renamed the ‘‘homeobox,’’ a Basel, Switzerland on May term still used today. The 29, 2014 from the injuries of unexpected finding that inver- a car accident on May 1 in tebrates and vertebrates Lesbos, Greece. With his share similar developmental passing, the scientific com- control genes was startling, munity loses one of the pio- and subsequent studies even neers in the field of molecular showed that similar cell types developmental biology and a use similar transcriptional mentor of many scientists regulators in very different working in this and in related organisms. fields. Beyond these important Walter started his scientific implications for the field, the career in the laboratory of homeobox also provided a Ernst Hadorn, an eminent probe to clone numerous developmental biologist work- genes from any given organ- ing at the University of Zu¨ rich. ism without the requirement He worked on a phenomenon of prior information or molec- known as transdetermination, ular tools such as probes the occasional respecification or antibodies. DNA hybridiza- of Drosophila imaginal disc tion turned out to be the tissue upon growth in the perfect discovery tool for abdomen of adult flies. At developmental control genes some point during Walter’s harboring highly conserved Walter J. Gehring PhD, Hadorn’s secretary DNA-binding domains. Within Walter J. Gehring talking about eye evolution during a birthday anniversary showed Walter a funny-look- symposium organized at the Biozentrum in Basel in March 2014. Photograph a few months, the number of ing fly, which, upon closer in- courtesy of the Biozentrum. cloned homeobox genes ex- spection, had a leg in place of ceeded by far the number of the antenna on the head. Wal- labs working in the field. A ter called the mutation causing this pheno- available for these genes. David Hog- new area in molecular developmental type ‘‘Nasobemia,’’ and this was the begin- ness’s lab at Stanford had established biology was born! ning of a lifelong connection to master ‘‘chromosomal walking’’ as a new con- Of course, the significance of the regulators in development. cept to isolate genes. The identification homeobox did not escape the attention For his postdoctorate, Walter joined of desired DNA clones relied on the avail- of Ed Lewis, who pioneered the genetic Alan Garen’s lab at Yale, where he wanted ability of genetically and cytologically analysis of the homeotic genes in to learn more about the novel, emerging well-defined chromosomal rearrange- Drosophila. As Lewis mentioned in a techniques of DNA cloning. After his ments with a breakpoint in the gene of in- note he added to a shipment of flies to appointment to the Biozentrum in Basel terest. Using this technique, it took Basel: ‘‘Dear Walter, you made the in 1972, Walter’s lab established the first 3.5 years to identify the Antennapedia homeobox our flying carpet.’’ European DNA bank of Drosophila (Antp) gene, which was finally published The next big step that Walter wanted to (instead of calling it a gene ‘‘library,’’ the in 1983 (Garber et al., 1983), concomi- undertake was to ‘‘redesign’’ the body term used in the US, Walter insisted with tantly with similar studies from Thom plan of the fruit fly by the inappropriate a big smile that, being in Switzerland, it Kaufmann’s lab (Scott et al., 1983). expression of the Antp gene in head tis- would be much better to call it a gene The molecular characterization of sue, more precisely in the antennal disc. ‘‘bank’’!). In a fruitful collaboration with Antp changed the field of molecular Although there was ample indirect evi- Alfred Tissie` re’s lab in Geneva, the heat developmental biology in a most dramatic dence that Antp did specify the second shock genes were cloned (Schedl et al., manner. Not only were sequence homol- thoracic leg in flies and that inappropriate 1978) and subsequently analyzed, putting ogies identified between Antp and other expression might lead to antenna- the lab in the spotlight for establishing a homeotic loci (called H-box homology; toward-leg transformation (such as in the proof of principle for gene identification McGinnis et al., 1984a), but the Gehring dominant Nasobemia mutant), Walter from the gene bank. lab also identified short stretches of wanted to do the key experiment and Identifying developmental control sequence homology (180 bp) in genomic directly demonstrate that a single gene genes in the bank was the ultimate goal DNA from many different animal species could transform a tissue to a large degree for Walter. This remained a difficult task, (McGinnis et al., 1984b). Walter insisted (Schneuwly et al., 1987). As Walter however, because there were no probes that the H-box, due to its importance, be mentioned in his correspondence with 120 Developmental Cell 30, July 28, 2014 ª2014 Elsevier Inc. Developmental Cell Obituary the Nature editors during the publication imental side of the experiment did not he proposed that the different eye types procedure, ‘‘I want to see molecular evi- advance, Walter decided that at least originated monophyletically and subse- dence,’’ in addition to genetic evidence. the control should be analyzed in detail quently diversified by divergent, parallel, It is fair to say that this statement reflects to finish up the project. Upon sequencing, or convergent evolution (Gehring, 2014). one of the major driving forces in Walter’s database analyses spat out homologies He still had a number of ongoing collabo- scientific approach and vision: the quest between this DNA fragment and the rations, and he wanted again to find for molecular evidence of biological mouse gene small eye (sey), the human molecular evidence for his hypotheses. observations. gene Aniridia (these genes were also Walter was a passionate scientist. He Ever since Walter had been in Alan referred to as PAX6), and some PAX put science in front of everything else Garen’s lab, he was interested in DNA- genes in flies. Moreover, the cDNA clone in life. His enthusiasm was infectious binding proteins, suspecting that, similar hybridized to sequences on the fourth and his talks were highly stimulating. to bacteria, such proteins would play chromosome in flies, in a region where Recently, at the hospital in Basel, his im- key roles in developmental processes. the eyeless (ey) mutation had been map- mediate concerns were for his collabora- Despite many attempts to purify such pro- ped. Ey mutant flies have little or no eye tors; they needed to be alerted that he teins from extracts, not much progress structures left on their head. Based on would not answer his email for a while was made. To Walter’s delight, it turned this analogy, the astounding hypothesis but that the research efforts should out that the homeobox indeed codes for could be envisioned that facet eyes in flies continue during his absence. In addition, the DNA-binding domain of Hox proteins, and lens eyes in vertebrates could use the a manuscript to be published in PNAS the homeodomain. Now Walter wanted to same transcription factor, PAX6, as a had to be proofread, such that its publica- know more about the interaction of home- master regulator. It indeed turned out tion could proceed quickly and without odomain proteins with DNA. At a Swiss that this was the case (Quiring et al., delay. meeting in 1986, he heard a talk by Kurt 1994). Walter was also an incredible mentor. Wu¨ thrich, from the ETH in Zu¨ rich, who What followed this discovery was what For his 60th,70th, and 75th birthday had started to establish methods to Walter himself would claim as his most anniversaries, respectively, a symposium determine the structure of proteins using stimulating scientific period. Walter al- was organized in Basel, and all former col- NMR spectroscopy. Although these ways had a somewhat simplistic idea of laborators were invited. More than 100 of NMR studies were really just developing things. Although he knew about the them made their way again this year, (a protein of the size of the homeodomain complexity of life, he favored simple hy- when his 75th birthday was celebrated had not been structurally analyzed at that potheses, and he now wanted to demon- from March 21 to 22, and Walter time) and several tens of milligrams of strate the role of PAX6 (ey in flies) in eye concluded the symposium with a scienti- pure protein were required to start the formation in the adult by inducing ey and fic lecture (see picture) and two dinner collaboration (protein expression and pu- subsequently eye formation in different speeches in the evening. It was again a rification were not as easy as they are tissues in the fly. The arguments in favor fantastic weekend, and all of the partici- today), Walter decided that this would of such a result, which Walter used to pants were shocked to hear only 10 weeks be an interesting and promising way to keep the students handling the project later the unbelievable news that Walter go, and he put a PhD student on the proj- on track, were the successful formation had passed away. ect. After a bit more than 2 years of work, of antennal legs by misexpression of Walter loved Greece, its culture, and its the three-dimensional structure of the Antp (he called this the ‘‘Schneuwly’’ cuisine. He attended all 18 previous Antennapedia homeodomain was solved experiment) and the occurrence of trans- EMBO conferences in Crete, at which by the Wu¨ thrich group, first in the determination toward eye structure from every other year roughly 100 Drosophila absence, and later in the presence, of several imaginal discs, as he and others researchers gather to discuss the newest DNA (Gehring et al., 1994).