December 2014
Volume 55, Issue 12
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Lecture  |   December 2014
Introducing Wolfgang Baehr, the 2014 Recipient of the Proctor Award
Investigative Ophthalmology & Visual Science December 2014, Vol.55, 8651-8652. doi:10.1167/iovs.14-16265
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      Samuel M. Wu; Introducing Wolfgang Baehr, the 2014 Recipient of the Proctor Award. Invest. Ophthalmol. Vis. Sci. 2014;55(12):8651-8652. doi: 10.1167/iovs.14-16265.

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      © ARVO (1962-2015); The Authors (2016-present)

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Wolfgang Baehr was born in Mannheim, Germany, and received a PhD in organic chemistry from the University of Heidelberg. He completed his postdoctoral training at the Max Planck Institute für Biophysikalische Chemie-Göttingen, where he studied DNA structure and initiation of transcription in bacteria. Wolfgang's career in vision research started in the laboratory of Meredithe Applebury at Princeton University, where he developed biochemical methods for the isolation of phototransduction proteins. In the mid-1970s, the study of phototransduction was in its infancy when the only known component was rhodopsin and Ca2+, rather than cGMP, was proposed as the secondary messenger. Wolfgang developed a novel method to isolate transducin and cGMP phosphodiesterase (PDE) from bovine rod outer segment membranes and determined their subunit compositions. Moreover, he identified PDEγ as the third PDE-subunit and determined the catalytic constant of PDE in the inactive and active states, thereby contributing key results to our understanding of phototransduction. These works have been cited frequently and remain cornerstones of photoreceptor biochemistry. 
In the early 1980s, Wolfgang moved to Purdue University and pioneered the application of molecular biology to phototransduction research by employing newly discovered technologies to sequence cDNAs encoding the proteins. Although most molecular biology tools available today were then unknown, Wolfgang used his organic chemistry knowledge to synthesize 12-mer oligonucleotide primers (key for priming the synthesis of opsin cDNA on its mRNA template by reverse transcription) one nucleotide at a time, via anhydrous ester condensation and silica-based TLC separation at a snail's pace of two nucleotides per week, completing a 12-mer in 6 weeks. Despite the painfully slow syntheses, these primers produced opsin cDNA, which proved to be an extremely useful agent to identify opsins of various species and to clone Drosophila Rh1, as well as mouse and frog rhodopsins. 
Wolfgang joined the Cullen Eye Institute, Baylor College of Medicine, in 1988. Major achievements of this period included the generation of the first transgenic mouse model for autosomal dominant retinitis pigmentosa based on the P23H mutation in the rhodopsin gene. The GHL-rhodopsin mouse line accurately mimics the human disease and is still used today for analysis of the unfolded protein response (UPR) as well as gene-based therapies. Other major breakthroughs include identification of Pde6b gene defects in the rd1 mouse and rcd1 Irish setter, and generation of animal models of recessive retinitis pigmentosa. One particularly outstanding achievement of Wolfgang's laboratory was the determination of the rd1 mutation. His group provided conclusive evidence that Clyde Keeler's rodless mouse (r), discovered in the 1920s as the first mouse model of retinal degeneration, carried a gene defect identical to that found in rd1. To demonstrate this finding, Wolfgang's lab extracted DNA from an archival microscope slide containing Keeler's 1924 r/r retinal tissue. Amplification and sequencing of r exon 7 unambiguously established that r and rd were allelic and carried the same nonsense mutation (Y347ter). They published this work in the Proceedings of the National Academy of Sciences in 1993 (including Dr Clyde Keeler, then alive, as co-author), nearly 70 years after Keeler's groundbreaking study of the rodless mouse in the same journal. 
Identification of GCAP1 and GCAP2 as Ca2+-dependent activators of photoreceptor guanylate cyclases was the beginning of a long-lasting collaboration with Kris Palczewski, then at the University of Washington in Seattle. Since 1994, Wolfgang and Kris have collaborated on more than 50 publications, exploring the structure and functions of GCAPs, which culminated in the identification of mutations in the high-affinity Ca2+ binding sites (EF hands) responsible for dominant cone dystrophies. 
In 1995, Wolfgang moved to the John A. Moran Eye Center, University of Utah, Salt Lake City, to continue his research on biochemistry/molecular biology of phototransduction and animal models of retinal degeneration, specifically cone dystrophies and retinitis pigmentosa. His lab identified a null mutation in the Gucy2e gene encoding guanylate cyclase 1 in rd chicken, an animal model for Leber Congenital Amaurosis (LCA) and the first mutant with a Gucy2e deletion. This research generated Gucy2f and Gucy2e/Gucy2f double knockout mouse lines and was eventually followed with gene therapy to cure the LCA phenotype in mice. Many gene knockouts (Rdh8, Rdh12, Rdh8/12, Lrat, Guca1a/Guca1b, Gucy2f, Gucy2e/ucy2f, Pde6d, Kif3a, Kif17, Cetn1, Cetn2, Cetn1/Cetn2, ab8, ab11, ab8/rab11 double knockouts) have followed, with the idea of modeling human retinal diseases, identifying disease mechanisms, and exploring treatment strategies. 
During the past several years, Wolfgang's lab has studied trafficking of phototransduction components (transducin, PDE, GRK1, pigments, channel subunits) in rods and cones. He has found that trafficking in cones requires the chromophore 11-cis-retinal, expression of guanylate cyclase and heterotrimeric kinesin-II proteins. Defects in these processes result in photoreceptor degeneration. Discoveries of outstanding importance are the identification of two lipid-binding proteins—the prenyl-binding protein PDEδ and the acyl-binding protein UNC119—and their roles in trafficking of transducin, PDE, and GRK1. PDEδ specifically interacts with prenylated proteins while UNC119 is an acyl-binding protein with specificity for the N-terminus of the transducin α-subunit. UNC119 plays a key role in returning transducin to the outer segments following light-induced translocation to the inner segments. Recently, Wolfgang's lab co-crystallized UNC119 with an acylated N-terminal transducin peptide, an important finding about a protein that may play key roles in protein trafficking and photoreceptor degeneration. 
Wolfgang has served as a member (and chair in 2000) of the ARVO-BI program committee, organizer of the ARVO Sunday Symposium in 1988, co-organizer of FASEB meetings (2001–2003) and pre-ARVO Vision Research symposia (1998–2012), as well as the senior editor of Vision Research (1998–2012). He was named a Fellow of ARVO in 2009. Since 1968, Wolfgang has published more than 170 articles, book chapters, reviews, and editorials—covering topics from inorganic and organic chemistry, biophysics, biochemistry, molecular biology, bacteriology, infectious diseases, to mouse and human genetics. He has made important contributions to our understanding of the basic biochemistry, molecular biology, and genetics of photoreceptors, as well as the molecular and genetic mechanisms of retina diseases. 
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