H. Ronald Kaback 1936–2019
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obituary H. Ronald Kaback 1936–2019 lmost exactly a year ago, I wrote an that Δμ~Hþ is indeed the driving force for article about my peerless mentor the accumulationI of many substrates3, and ARon Kaback, highlighting not only Mitchell himself regarded Ron’s results as the his extraordinary scientific contributions first piece of conclusive evidence in favor of but also his enormous and inspiring impact his chemiosmotic hypothesis, which became as a mentor1. Although Ron had by then widely accepted as a result of these findings. been facing health challenges for quite Ron had shown that Mitchell was right. some time, it is still surreal and painful After the lacY gene, which encodes lac that this obituary is being written so soon permease, was cloned and sequenced4, Ron’s thereafter. H. Ronald Kaback, distinguished group purified lac permease to homogeneity, professor in the Department of Physiology reconstituted it into proteoliposomes and at UCLA, died on 20 December 2019. showed it to be fully functional5. From Ron was without a doubt one of the most there, Ron’s group began to determine the original, creative and influential American roles of specific amino acid residues in lac biochemists of the last few decades. His permease, replacing them by site-directed research focused on transport across mutagenesis and eventually demonstrating biological membranes, a field he truly that only nine residues are essential to the pioneered. He was passionate about science activity of the protein. In quick succession, to a degree that almost defies description. Ron pioneered studies of helix packing using Ron’s name is virtually synonymous with thiol crosslinking between two cysteine Credit: Antonio De la Vieja the most extensively investigated membrane residues engineered onto a functional transport protein in the world: the lac transporter lacking native cysteines. Using permease of Escherichia coli. is emblematic of what Ron’s mind was a battery of site-directed techniques — Ron was born in Philadelphia in 1936. capable of. Kabackosomes were Ron’s most including second-site suppressor analysis After graduating from high school in his important scientific contribution during the coupled with chemical modification, thiol hometown, he attended Haverford College, early part of his career. crosslinking, excimer fluorescence, the where he was a biology major interested in After graduating from Einstein, Ron engineering of Mn(ii) binding sites onto the sports (particularly football). Ron benefited worked, starting in 1964, in Earl Stadman’s protein, electron paramagnetic resonance, greatly from a special program that brought enzymology laboratory at the National and chemical cleavage and identification world-renowned scientists, including Nobel Institutes of Health (NIH) as a way to meet of monoclonal antibody epitopes — he laureates, to Haverford to lecture and his Selective Service requirement without generated a helix-packing model6 with a interact with just seven biology majors. As having to be drafted and sent to Vietnam. resolution of ~4 Å. Ultimately, in 2003, Ron Ron himself said, one of the main driving In Stadman’s laboratory, he continued and his collaborators determined7 the crystal forces for his interest in science was his pushing the transport field forward using structure of a conformationally restricted desire to prove to his skeptical professors his membrane vesicles. Ron was later offered lac permease mutant in the inward-facing that he could be a football player and a position of his own at the NIH, and in conformation at a resolution of ~3.5 Å. go on to medical school “without being 1970, he moved to the newly founded Roche He went on to investigate the alternating intellectually compromised.” Ron published Institute of Molecular Biology in Nutley, access mechanism and to determine the his first paper at Haverford, from which New Jersey, where he was able to pursue his protein’s structure in the outward-facing he graduated in 1958. He then enrolled at research without having to apply for grant conformation using nanobodies8. Ron the Albert Einstein College of Medicine funds. His final move came in 1989, when recently reported on an engineered occluded in New York, where, as a medical student, Ron became an Investigator at the Howard apo intermediate of the protein. His quest he developed his own strand of research Hughes Medical Institute and Professor of to answer key questions about the structure in the laboratory of Adele Kostellow. Ron Physiology at UCLA, where he spent the rest and mechanism of the lac permease generated the first osmotically sealed of his career. was relentless. membrane vesicles from bacteria. These In the 1960’s, one issue of great Unsurprisingly, Ron received numerous vesicles, which came to be known as contention in bioenergetics was Peter honors over the course of his career. He was kabackosomes, are capable of transporting Mitchell’s chemiosmotic hypothesis, elected to the American Academy of Arts solutes just as well as intact cells do — but which states that the transmembrane and Sciences in 1986 and to the National they make for a much better controlled electrochemical gradient of protons Academy of Sciences in 1987. He received experimental system because they lack (Δμ~Hþ ) is the driving force for oxidative the Lewis S. Rosenstiel Award (1973), the cytoplasm and so do not metabolize any phosphorylation,I active transport, the 3M Life Sciences Award (shared with Peter substrates they accumulate. Astonishingly, functioning of the flagellar motor, and C. Nowell, in 1993), the Anatrace Membrane Ron faced a great deal of resistance to the other cellular processes. Most transport Protein Award (2007), the Distinguished publication of his seminal kabackosomes scientists, Ron very much included, were Alumni Award from the Albert Einstein paper, which only saw the light of day steadfast opponents of Mitchell’s hypothesis, College of Medicine (2009) and the Peter much later thanks to his determination and Ron set out to prove Mitchell wrong Mitchell Memorial Medal (2012), to name and persistence2. This brilliant idea, experimentally using his vesicles. Ironically, but a few. Ron published over 440 papers in which revolutionized transport research, Ron’s experiments actually demonstrated many of the leading international journals. NATURE STRUCTURAL & MOLECULAR BIOLOGY | VOL 27 | MARCH 2020 | 223–224 | www.nature.com/nsmb 223 obituary Major symposia were organized in his honor decades, Ron pushed the field of membrane Ron’s legacy. Ron’s death is an incalculable to celebrate his 60th and 80th birthdays, in transporters from the phenomenological loss for the scientific community at large, Villefranche-sur-Mer, France, and Bethesda, to the biochemical and even to the atomic but his powerful legacy will endure. He will Maryland, USA, respectively; both were level. By combining detailed biochemical not be forgotten. ❐ moving events attended by large numbers and biophysical studies, he gained an of former trainees and colleagues who came unparalleled mechanistic understanding Nancy Carrasco from far and wide. of all the types of reactions that lactose Department of Molecular Physiology and Biophysics, Ron Kaback gave countless lectures and permease mediates: active transport, Vanderbilt University, Nashville, TN, USA. seminars around the world, and he always facilitated diffusion, efflux, exchange and e-mail: [email protected] cut a unique figure wherever he went. counterflow. The approaches developed in He was known not only for his brilliance, Ron’s laboratory have been applied directly Published online: 27 February 2020 intelligence, talent and creativity but also to many important human transporters https://doi.org/10.1038/s41594-020-0392-x for his wit, his sense of humor and, in to elucidate their physiological and his younger years, for his Afro and cigar pathophysiological roles. References smoking. Ron was unconventional in Ron’s lifelong companion was his wife, 1. Carrasco, N. J. Gen. Physiol. 151, 97–99 (2019). 2. Kaback, H. R. & Kostellow, A. B. J. Biol. Chem. 243, many ways, and he never went unnoticed. Molly (known as Teenchy) Schreibman, 1384–1389 (1968). He was loyal to and supportive of his whom he first met in high school and who 3. Ramos, S., Schuldiner, S. & Kaback, H. R. Proc. Natl Acad. Sci. trainees, colleagues and friends to a fault, supported him and his career in myriad USA 73, 1892–1896 (1976). and for life. He seemed like an unceasing ways, all while pursuing her own careers as 4. Büchel, D. E., Gronenborn, B. & Müller-Hill, B. Nature 283, 541–545 (1980). idea-generating machine — and although a medical technician and later as a teacher. 5. Newman, M. J., Foster, D., Wilson, T. H. & Kaback, H. R. J. Biol. not all his ideas were good, reasonable or They had three children: Elizabeth, George Chem. 256, 11804–11808 (1981). feasible, his ceaselessness ultimately yielded and Josh. Ron’s numerous trainees continue 6. Kaback, H. R., Sahin-Toth, M. & Weinglass, A. B. Nat. Rev. Mol. Cell Biol. 2, 610–620 (2001). plenty of ideas that were actually great to do research at many different institutions 7. Abramson, J. et al. Science 301, 610–615 (2003). and bore valuable fruit. Over the last six around the world and are a vital part of 8. Jiang, X. et al. Proc. Natl Acad. Sci. USA 113, 12420–12425 (2016). 224 NATURE STRUCTURAL & MOLECULAR BIOLOGY | VOL 27 | MARCH 2020 | 223–224 | www.nature.com/nsmb.