In Focus pubs.acs.org/acschemicalbiology
Carlos F. Barbas III (1964−2014): Visionary at the Interface of Chemistry and Biology Christoph Rader,*,† David J. Segal,*,‡ and Doron Shabat*,§ †
Department of Cancer Biology and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, United States ‡ Genome Center, Department of Biochemistry and Molecular Medicine, and MIND Institute, University of California, Davis, 451 Health Science Drive, Davis, California 95616, United States § Department of Organic Chemistry, School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel
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novo generation, affinity maturation, and humanization of therapeutic mAbs for AIDS and cancer. Since 1992, Barbas also served as director and instructor of an annual Cold Spring Harbor Laboratory course on phage display. Rather than settling with a career in antibody engineering, Barbas immediately recognized and harnessed the power of phage display for the tailoring of zinc finger transcription factors to selectively bind unique addresses in the genome with subnanomolar affinity,3 allowing activation and inhibition of genes at will.4 His widely adopted zinc finger modular assembly methods led to the creation of targetable nucleases and recombinases in his and other laboratories.5 On the basis of these fundamental contributions, Barbas is considered a pioneer of the modern field of genome engineering for the treatment of human diseases. Despite his achievements in protein engineering, Barbas remained a chemist at heart, and his laboratory was a melting pot of synthetic biologists and synthetic chemists who often teamed up to explore new frontiers in chemical biology. Fueled by his early interest in utilizing natural aldolases for synthetic chemistry6 and Lerner’s pioneering work on catalytic antibodies, Barbas used a revolutionary strategy dubbed reactive immunization to create the now also renowned mAb 38C2, which by virtue of a uniquely reactive lysine residue catalyzes a range of aldol, retro-aldol, and other reactions at enzymatic rates that rival natural aldolases, but with much broader scope with respect to the chemical diversity of its substrates.7 In addition to its utilization as a catalyst for stereoselective carbon−carbon bond formation and cleavage in synthetic chemistry, Barbas showed that mAb 38C2 has therapeutic potential through prodrug activation8 and chemical programming.9 On the basis of the latter concept, Barbas founded the company CovX, which was acquired by Pfizer in 2008 and advanced several programs built on chemically programmed mAb 38C2 to phase I and II clinical trials for the treatment of cancer and diabetes. Barbas founded two more companies invested in therapeutic antibodies: Prolifaron, which was acquired by Alexion Pharmaceuticals in 2000, and Zyngenia. More recently, Barbas discovered a new set of facile and stable protein/small molecule conjugation methods for tyrosine and cysteine residues that are applicable to the generation of bispecific antibodies and antibody-drug conjugates.10
n a recent Saturday evening, family, friends, and colleagues of Carlos F. Barbas III gathered at his house on Mount Soledad in La Jolla, California, to celebrate his life. As the sun set over the Pacific Ocean and a supermoon rose in the eastern sky, a eulogy speaker remembered Barbas with the words “The flame that burns twice as bright burns half as long.” Barbas died of cancer at the age of 49 on June 24, 2014. He was a singularity of incredible intelligence and intuition, which gifted him with an exciting professional and private life. Here we reflect on his 25-year career in synthetic biology, in synthetic chemistry, and at the boundaries of these disciplines. Barbas double majored in chemistry and physics at Eckerd College (St. Petersburg, Florida). After earning his Ph.D. with Chi-Huey Wong at Texas A&M University (College Station, Texas) and postdoctoral studies with Stephen J. Benkovic at Pennsylvania State University (University Park, Pennsylvania) and Richard A. Lerner at The Scripps Research Institute (La Jolla, California), he joined the faculty of The Scripps Research Institute at the age of 26.
Photo courtesy of Roger R. Beerli.
The year was 1991, and it marked an exciting time in the nascent field of antibody engineering. Teaming up with Lerner, Dennis R. Burton, and others, Barbas developed a phage display technology1 that was successfully applied to the discovery of human monoclonal antibodies (mAbs), including the now legendary mAb b12 that broadly and efficiently neutralized HIV-1 and has served as a trailblazer for AIDS vaccine design.2 Postdocs from all over the world flocked to the Barbas laboratory to learn phage display and expand its use to the de © 2014 American Chemical Society
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like reagents: a serum-stable alternative to maleimide-based protein conjugation. Angew. Chem., Int. Ed. 52, 12592−12596. (11) List, B., Lerner, R. A., and Barbas, C. F., 3rd (2000) Prolinecatalyzed direct asymmetric aldol reactions. J. Am. Chem. Soc. 122, 2395−2396. (12) (a) Notz, W., Tanaka, F., and Barbas, C. F., 3rd (2004) Enamine-based organocatalysis with proline and diamines: the development of direct catalytic asymmetric Aldol, Mannich, Michael, and Diels-Alder reactions. Acc. Chem. Res. 37, 580−591. (b) Barbas, C. F., 3rd (2008) Organocatalysis lost: modern chemistry, ancient chemistry, and an unseen biosynthetic apparatus. Angew. Chem., Int. Ed. 47, 42−47.
The utility of mAb 38C2 and other aldolase antibodies for catalytic asymmetric synthesis prompted the surprising discovery of much smaller organic catalysts, such as the amino acid proline,11 sparking the birth of modern organocatalysis, to which Barbas made key contributions over the past 15 years and even suggested a role of this chemistry in the prebiotic asymmetric synthesis of chiral amino acids, carbohydrates, and other building blocks of life.12 In addition to his nearly 350 publications, of which more than a quarter have already been cited more than 100 times and which have approximately 30,000 overall citations, Barbas is named inventor on nearly 60 issued patents. While his ingenious ideas will live on in many laboratories across the world, one is left to imagine what his brilliant mind would have created in another 25 years.
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AUTHOR INFORMATION
Corresponding Authors
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REFERENCES
(1) Barbas, C. F., 3rd, Kang, A. S., Lerner, R. A., and Benkovic, S. J. (1991) Assembly of combinatorial antibody libraries on phage surfaces: the gene III site. Proc. Natl. Acad. Sci. U.S.A. 88, 7978−7982. (2) Burton, D. R., Pyati, J., Koduri, R., Sharp, S. J., Thornton, G. B., Parren, P. W., Sawyer, L. S., Hendry, R. M., Dunlop, N., Nara, P. L., et al. (1994) Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 266, 1024−1027. (3) Segal, D. J., Dreier, B., Beerli, R. R., and Barbas, C. F., 3rd (1999) Toward controlling gene expression at will: Selection and design of zinc finger domains recognizing each of the 5′-GNN-3′ DNA target sequences. Proc. Natl. Acad. Sci. U.S.A. 96, 2758−2763. (4) Beerli, R. R., Dreier, B., and Barbas, C. F., 3rd (2000) Positive and negative regulation of endogenous genes by designed transcription factors. Proc. Natl. Acad. Sci. U. S. A. 97, 1495−1500. (5) Gersbach, C. A., Gaj, T., and Barbas, C. F. (2014) Synthetic zinc finger proteins: The advent of targeted gene regulation and genome modification technologies. Acc. Chem. Res., DOI: 10.1021/ar500039w. (6) Barbas, C. F., 3rd, Wang, Y.-F., and Wong, C.-H. (1990) Deoxyribose-5-phosphate aldolase as a synthetic catalyst. J. Am. Chem. Soc. 112, 2013−2014. (7) (a) Wagner, J., Lerner, R. A., and Barbas, C. F., 3rd (1995) Efficient aldolase catalytic antibodies that use the enamine mechanism of natural enzymes. Science 270, 1797−1800. (b) Barbas, C. F., 3rd, Heine, A., Zhong, G., Hoffmann, T., Gramatikova, S., Bjornestedt, R., List, B., Anderson, J., Stura, E. A., Wilson, I. A., and Lerner, R. A. (1997) Immune versus natural selection: antibody aldolases with enzymic rates but broader scope. Science 278, 2085−2092. (8) Shabat, D., Rader, C., List, B., Lerner, R. A., and Barbas, C. F., 3rd (1999) Multiple event activation of a generic prodrug trigger by antibody catalysis. Proc. Natl. Acad. Sci. U.S.A. 96, 6925−6930. (9) Rader, C., Sinha, S. C., Popkov, M., Lerner, R. A., and Barbas, C. F., 3rd (2003) Chemically programmed monoclonal antibodies for cancer therapy: adaptor immunotherapy based on a covalent antibody catalyst. Proc. Natl. Acad. Sci. U.S.A. 100, 5396−5400. (10) (a) Ban, H., Gavrilyuk, J., and Barbas, C. F., 3rd (2010) Tyrosine bioconjugation through aqueous ene-type reactions: a clicklike reaction for tyrosine. J. Am. Chem. Soc. 132, 1523−1525. (b) Gavrilyuk, J., Ban, H., Nagano, M., Hakamata, W., and Barbas, C. F., 3rd (2012) Formylbenzene diazonium hexafluorophosphate reagent for tyrosine-selective modification of proteins and the introduction of a bioorthogonal aldehyde. Bioconjugate Chem. 23, 2321−2328. (c) Toda, N., Asano, S., and Barbas, C. F., 3rd (2013) Rapid, stable, chemoselective labeling of thiols with Julia-Kocienski1646
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