Peter G Schultz

The Scripps Research Institute, لا هویا, California, United States

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Publications (617)6039.65 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The bovine antibody (BLV1H12) which has an ultralong CDR3H provides a novel scaffold for engineering new func-tions into the antibody variable region. By modifying the β-strand "stalk" of BLV1H12 with sequences derived from natu-ral or synthetic protease inhibitors, we have generated anti-bodies that inhibit bovine trypsin and human neutrophil elastase (HNE) with low nanomolar affinities. We were also able to generate a humanized variant using a human immu-noglobulin scaffold that shares a high degree of homology with BLV1H12. Further optimization yielded a highly selec-tive humanized anti-HNE antibody with sub-nanomolar affinity. This work demonstrates a novel strategy for gener-ating antibodies with potent and selective inhibitory activi-ties against extracellular proteases involved in human dis-ease.
    Journal of the American Chemical Society 03/2015; 137(12). DOI:10.1021/ja5130786 · 11.44 Impact Factor
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    ABSTRACT: The fleeting lifetimes of the transition states (TSs) of chemical reactions make determination of their three-dimensional structures by diffraction methods a challenge. Here, we used packing interactions within the core of a protein to stabilize the planar TS conformation for rotation around the central carbon-carbon bond of biphenyl so that it could be directly observed by x-ray crystallography. The computational protein design software Rosetta was used to design a pocket within threonyl-transfer RNA synthetase from the thermophile Pyrococcus abyssi that forms complementary van der Waals interactions with a planar biphenyl. This latter moiety was introduced biosynthetically as the side chain of the noncanonical amino acid p-biphenylalanine. Through iterative rounds of computational design and structural analysis, we identified a protein in which the side chain of p-biphenylalanine is trapped in the energetically disfavored, coplanar conformation of the TS of the bond rotation reaction. Copyright © 2015, American Association for the Advancement of Science.
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    ABSTRACT: We have developed a novel antibody drug-conjugate (ADC) which can selectively deliver the Lck inhibitor dasatinib to human T lym-phocytes. This ADC is based on a humanized antibody which se-lectively binds with high affinity to CXCR4, an antigen that is se-lectively expressed on hematopoietic cells. The resulting dasatinib-antibody conjugate suppresses T-cell-receptor (TCR)-mediated T cell activation and cytokine expression with low nM EC50 and has minimal effects on cell viability. This ADC may lead to a new class of selective immunosuppressive drugs with improved safety, and extends the antibody-drug conjugate strategy to the targeted deliv-ery of kinase inhibitors for indications beyond oncology.
    Journal of the American Chemical Society 02/2015; DOI:10.1021/jacs.5b00620 · 11.44 Impact Factor
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    ABSTRACT: Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) provide a potent anti-tumor response and have become a promising treatment option for cancer. However, despite their efficacy, CAR-T cells are associated with significant safety challenges related to the inability to control their activation and expansion, and terminate their response. Herein, we demonstrate that a bifunctional small molecule "switch" consisting of folate conjugated to fluorescein isothiocyanate (folate-FITC) can redirect and regulate FITC-specific CAR-T cell activity towards folate receptor (FR)-overexpressing tumor cells. This system was shown to be highly cytotoxic to FR-positive cells with no activity against FR-negative cells, demonstrating the specificity of redirec-tion by folate-FITC. FITC-CAR-T cell activation and prolifer-ation was strictly dependent on the presence of both folate-FITC and FR-positive cells and was dose titratable with folate-FITC switch. This novel treatment paradigm may ul-timately lead to increased safety for CAR-T cell immunotherpy.
    Journal of the American Chemical Society 02/2015; DOI:10.1021/jacs.5b00106 · 11.44 Impact Factor
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    ABSTRACT: On the basis of the 3D structure of a bovine antibody with a well-folded, ultralong complementarity-determining region (CDR), we have developed a versatile approach for generating human or humanized antibody agonists with excellent pharmacological properties. Using human growth hormone (hGH) and human leptin (hLeptin) as model proteins, we have demonstrated that functional human antibody CDR fusions can be efficiently engineered by grafting the native hormones into different CDRs of the humanized antibody Herceptin. The resulting Herceptin CDR fusion proteins were expressed in good yields in mammalian cells and retain comparable in vitro biological activity to the native hormones. Pharmacological studies in rodents indicated a 20- to 100-fold increase in plasma circulating half-life for these antibody agonists and significantly extended in vivo activities in the GH-deficient rat model and leptin-deficient obese mouse model for the hGH and hLeptin antibody fusions, respectively. These results illustrate the utility of antibody CDR fusions as a general and versatile strategy for generating long-acting protein therapeutics.
    Proceedings of the National Academy of Sciences 02/2015; 112(5):1356-1361. DOI:10.1073/pnas.1423668112 · 9.81 Impact Factor
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    ABSTRACT: Bovine antibody BLV1H12 possesses a unique “stalk–knob” architecture in its ultralong heavy chain CDR3, allowing substitutions of the “knob” domain with protein agonists to generate functional antibody chimeras. We have generated a humanized glucagon-like peptide-1 (GLP-1) receptor agonist antibody by first introducing a coiled-coil “stalk” into CDR3H of the antibody herceptin. Exendin-4 (Ex-4), a GLP-1 receptor agonist, was then fused to the engineered stalk with flexible linkers, and a Factor Xa cleavage site was inserted immediately in front of Ex-4 to allow release of the N-terminus of the fused peptide. The resulting clipped herceptin–Ex-4 fusion protein is more potent in vitro in activating GLP-1 receptors than the Ex-4 peptide. The clipped herceptin–Ex-4 has an extended plasma half-life of approximately four days and sustained control of blood glucose levels for more than a week in mice. This work provides a novel approach to the development of human or humanized agonist antibodies as therapeutics.
    Angewandte Chemie International Edition 12/2014; 54(7). DOI:10.1002/anie.201410049 · 11.34 Impact Factor
  • Yong Zhang, Yan Liu, Ying Wang, Peter G Schultz, Feng Wang
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    ABSTRACT: The ultralong heavy chain complementarity determining region 3 (CDR3H) of bovine antibody BLV1H12 folds into a novel "stalk-knob" structural motif and has been exploited to generate novel agonist antibodies through replacement of the "knob" domain with cytokines and growth factors. By translating this unique "stalk-knob" architecture to the humanized antibody Herceptin, we have developed a versatile approach to the generation of human antibody agonists. Human erythropoietin (hEPO) or granulocyte colony-stimulating factor (hGCSF) was independently fused into CDR3H, CDR2H, or CDR3L of Herceptin using an engineered "stalk" mo-tif. The fusion proteins express in mammalian cells in good yields and have similar in vitro biological activities compared to hEPO and hGCSF. On the basis of these results we then generated a bi-functional Herceptin-CDR fusion protein in which both hEPO and hGCSF were grafted into the heavy and light chain CDR3 loops, respectively. This bi-functional antibody fusion exhibited potent EPO and GCSF agonist activities. This work demonstrates the versatility of the CDR-fusion strategy for generating functional human antibody chimeras and provides a novel approach to the development of multi-functional antibody-based therapeutics.
    Journal of the American Chemical Society 12/2014; 137(1). DOI:10.1021/ja510519u · 11.44 Impact Factor
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    ABSTRACT: Limb development requires the coordinated growth of several tissues and structures including long bones, joints and tendons, but the underlying mechanisms are not wholly clear. Recently, we identified a small drug-like molecule -we named Kartogenin (KGN)- that greatly stimulates chondrogenesis in marrow-derived mesenchymal stem cells (MSCs) and enhances cartilage repair in mouse osteoarthritis (OA) models. To determine whether limb developmental processes are regulated by KGN, we tested its activity on committed preskeletal mesenchymal cells from mouse embryo limb buds and whole limb explants. KGN did stimulate cartilage nodule formation and more strikingly, boosted digit cartilaginous anlaga elongation, synovial joint formation and interzone compaction, tendon maturation as monitored by ScxGFP, and interdigit invagination. To identify mechanisms, we carried out gene expression analyses and found that several genes, including those encoding key signaling proteins, were up-regulated by KGN. Amongst highly up-regulated genes were those encoding hedgehog and TGFβ superfamily members, particularly TFGβ1. The former response was verified by increases in Gli1-LacZ activity and Gli1 mRNA expression. Exogenous TGFβ1 stimulated cartilage nodule formation to levels similar to KGN, and KGN and TGFβ1 both greatly enhanced expression of lubricin/Prg4 in articular superficial zone cells. KGN also strongly increased the cellular levels of phospho-Smads that mediate canonical TGFβ and BMP signaling. Thus, limb development is potently and harmoniously stimulated by KGN. The growth effects of KGN appear to result from its ability to boost several key signaling pathways and in particular TGFβ signaling, working in addition to and/or in concert with the filamin A/CBFβ/RUNX1 pathway we identified previously to orchestrate overall limb development. KGN may thus represent a very powerful tool not only for OA therapy, but also limb regeneration and tissue repair strategies.
    Developmental Biology 09/2014; DOI:10.1016/j.ydbio.2014.09.011 · 3.64 Impact Factor
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    ABSTRACT: A chemically defined anti-CXCR4–auristatin antibody–drug conjugate (ADC) was synthesized that selectively eliminates tumor cells overexpressing the CXCR4 receptor. The unnatural amino acid p-acetylphenylalanine (pAcF) was site-specifically incorporated into an anti-CXCR4 immunoglobulin G (IgG) and conjugated to an auristatin through a stable, non-cleavable oxime linkage to afford a chemically homogeneous ADC. The full-length anti-CXCR4 ADC was selectively cytotoxic to CXCR4+ cancer cells in vitro (half maximal effective concentration (EC50)≈80–100 pM). Moreover, the anti-CXCR4 ADC eliminated pulmonary lesions from human osteosarcoma cells in a lung-seeding tumor model in mice. No significant overt toxicity was observed but there was a modest decrease in the bone-marrow-derived CXCR4+ cell population. Because CXCR4 is highly expressed in a majority of metastatic cancers, a CXCR4–auristatin ADC may be useful for the treatment of a variety of metastatic malignancies.
    Angewandte Chemie 09/2014; 53(44). DOI:10.1002/ange.201408103
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    ABSTRACT: Acute myeloid leukemia (AML), which is the most common acute adult leukemia and the second most common pediatric leukemia, still has a poor prognosis. Human C-type lectin-like molecule-1 (CLL1) is a recently identified myeloid lineage restricted cell surface marker, which is overexpressed in over 90 % of AML patient myeloid blasts and in leukemic stem cells. Here, we describe the synthesis of a novel bispecific antibody, αCLL1-αCD3, using the genetically encoded unnatural amino acid, p-acetylphenylalanine. The resulting αCLL1-αCD3 recruits cytotoxic T cells to CLL1 positive cells, and demonstrates potent and selective cytotoxicity against several human AML cell lines and primary AML patient derived cells in vitro. Moreover, αCLL1-αCD3 treatment completely eliminates established tumors in an U937 AML cell line xenograft model. These results validate the clinical potential of CLL1 as an AML-specific antigen for the generation of a novel immunotherapeutic for AML.
    Angewandte Chemie 09/2014; 126(37). DOI:10.1002/ange.201405353
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    ABSTRACT: Acute myeloid leukemia (AML), which is the most common acute adult leukemia and the second most common pediatric leukemia, still has a poor prognosis. Human C-type lectin-like molecule-1 (CLL1) is a recently identified myeloid lineage restricted cell surface marker, which is overexpressed in over 90 % of AML patient myeloid blasts and in leukemic stem cells. Here, we describe the synthesis of a novel bispecific antibody, αCLL1-αCD3, using the genetically encoded unnatural amino acid, p-acetylphenylalanine. The resulting αCLL1-αCD3 recruits cytotoxic T cells to CLL1 positive cells, and demonstrates potent and selective cytotoxicity against several human AML cell lines and primary AML patient derived cells in vitro. Moreover, αCLL1-αCD3 treatment completely eliminates established tumors in an U937 AML cell line xenograft model. These results validate the clinical potential of CLL1 as an AML-specific antigen for the generation of a novel immunotherapeutic for AML.
    Angewandte Chemie International Edition 09/2014; 53(37). DOI:10.1002/anie.201405353 · 11.34 Impact Factor
  • Sophie B. Sun, Peter G. Schultz, Chan Hyuk Kim
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    ABSTRACT: To date, over 100 noncanonical amino acids (ncAAs) have been genetically encoded in living cells in order to expand the functional repertoire of the canonical 20 amino acids. More recently, this technology has been expanded to the field of protein therapeutics, where traditional chemical methods typically result in heterogeneous mixtures of proteins. The site-specific incorporation of ncAAs with orthogonal chemical groups allows unprecedented control over the site of conjugation and the stoichiometry, thus facilitating the rational optimization of the biological functions and/or pharmacokinetics of biologics. Herein, we discuss the recent contribution of ncAA technology in enhancing the pharmacological properties of current protein therapeutics as well as developing novel therapeutic modalities.
    ChemBioChem 08/2014; 15(12). DOI:10.1002/cbic.201402154 · 3.06 Impact Factor
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    ABSTRACT: The addition of noncanonical amino acids to the genetic code requires unique codons not assigned to the 20 canonical amino acids. Among the 64 triplet codons, only the three nonsense “stop” codons have been used to encode non-native amino acids. Use of quadruplet “frame-shift” suppressor codons provides an abundant alternative but suffers from low suppression efficiency as a result of competing recognition of their first three bases by endogenous host tRNAs or release factors. Deletion of release factor 1 in a genomically recoded strain of E. coli (E. coli C321), in which all endogenous amber stop codons (UAG) are replaced with UAA, abolished UAG mediated translation termination. Here we show that a Methanocaldococcus jannaschii-derived frame-shift suppressor tRNA/aminoacyl-tRNA synthetase pair enhanced UAGN suppression efficiency in this recoded bacterial strain. These results demonstrate that efficient quadruplet codons for encoding non-native amino acids can be generated by eliminating competing triplet codon recognition at the ribosome.
    ChemBioChem 08/2014; 15(12). DOI:10.1002/cbic.201402104 · 3.06 Impact Factor
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    ABSTRACT: A sensitive and highly multiplex method to directly measure RNA sequence abundance without requiring reverse transcription would be of value for a number of biomedical applications, including high throughput small molecule screening, pathogen transcript detection and quantification of short/degraded RNAs. RNA Annealing, Selection and Ligation (RASL) assays, which are based on RNA template-dependent oligonucleotide probe ligation, have been developed to meet this need, but technical limitations have impeded their adoption. Whereas DNA ligase-based RASL assays suffer from extremely low and sequence-dependent ligation efficiencies that compromise assay robustness, Rnl2 can join a fully DNA donor probe to a 3'-diribonucleotide-terminated acceptor probe with high efficiency on an RNA template strand. Rnl2-based RASL exhibits sub-femtomolar transcript detection sensitivity, and permits the rational tuning of probe signals for optimal analysis by massively parallel DNA sequencing (RASL-seq). A streamlined Rnl2-based RASL-seq protocol was assessed in a small molecule screen using 77 probe sets designed to monitor complex human B cell phenotypes during antibody class switch recombination. Our data demonstrate the robustness, cost-efficiency and broad applicability of Rnl2-based RASL assays.
    Nucleic Acids Research 07/2014; 42(14). DOI:10.1093/nar/gku636 · 8.81 Impact Factor
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    ABSTRACT: The bovine antibody (BLV1H12) which has an ultralong heavy chain complementarity determining region 3 (CDRH3) provides a novel scaffold for antibody engineering. By substituting the extended CDRH3 of BLV1H12 with modified CXCR4 binding peptides that adopt a β-hairpin conformation, we generated antibodies specifically targeting the ligand binding pocket of CXCR4 receptor. These engineered antibodies selectively bind to CXCR4 expressing cells with binding affinities in the low nanomolar range. In addition, they inhibit SDF-1-dependent signal transduction and cell migration in a transwell assay. Finally, we also demonstrate that a similar strategy can be applied to other CDRs and show that a CDRH2-peptide fusion binds CXCR4 with a Kd of 0.9 nM. This work illustrates the versatility of scaffold-based antibody engineering and could greatly expand the antibody functional repertoire in the future.
    Journal of the American Chemical Society 07/2014; 136(30). DOI:10.1021/ja5042447 · 11.44 Impact Factor
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    ABSTRACT: Selective covalent bond formation at a protein-protein interface potentially can be achieved by genetically introducing into a protein an appropriately "tuned" electrophilic unnatural amino acid that reacts with a native nucleophilic residue in its cognate receptor upon complex formation. We have evolved orthogonal aminoacyl-tRNA synthetase/tRNACUA pairs that genetically encode three aza-Michael acceptor amino acids, Nε-acryloyl-(S)-lysine (AcrK, 1), p-acrylamido-(S)-phenylalanine (AcrF, 2), and p-vinylsulfonamido-(S)-phenylalanine (VSF, 3), in response to the amber stop codon in Escherichia coli. Using an αErbB2 Fab-ErbB2 antibody-receptor pair as an example, we demonstrate covalent bond formation between an αErbB2-VSF mutant and a specific surface lysine ε-amino group of ErbB2, leading to near quantitative crosslinking to either purified ErbB2 in vitro or to native cellular ErbB2 at physiological pH. This efficient biocompatible reaction may be useful for creating novel cell biological probes, diagnostics, or therapeutics that selectively and irreversibly bind a target protein in vitro or in living cells.
    Journal of the American Chemical Society 05/2014; 136(23). DOI:10.1021/ja502851h · 11.44 Impact Factor
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    ABSTRACT: We report the engineering of zinc-finger-like motifs containing the unnatural amino acid (2,2'-bipyridin-5-yl)alanine (Bpy-Ala). A phage-display library was constructed in which five residues in the N-terminal finger of zif268 were randomized to include both canonical amino acids and Bpy-Ala. Panning of this library against a nine-base-pair DNA binding site identified several Bpy-Ala-containing functional Zif268 mutants. These mutants bind the Zif268 recognition site with affinities comparable to that of the wild-type protein. Further characterization indicated that the mutant fingers bind low-spin Fe(II) rather than Zn(II) . This work demonstrates that an expanded genetic code can lead to new metal ion binding motifs that can serve as structural, catalytic, or regulatory elements in proteins.
    ChemBioChem 04/2014; 15(6). DOI:10.1002/cbic.201300727 · 3.06 Impact Factor
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    ABSTRACT: A deficiency in C5 protects against arthritis development. However, there is currently no approach successfully translating these findings into arthritis therapy, as by targeting the key component, C5a. The aim of this study was to develop a vaccination strategy targeting C5a as therapy for patients with rheumatoid arthritis. An anti-C5a vaccine was generated by incorporating the unnatural amino acid p-nitrophenylalanine (4NPA) into selected sites in the murine C5a molecule. C5a-4NPA variants were screened for their immunogenicity in mice on different arthritis-susceptible class II major histocompatibility complex (MHC) backgrounds. A candidate vaccine was tested for its impact on disease in a murine model of collagen-induced arthritis (CIA). Immunity toward endogenous C5a as well as type II collagen was monitored and characterized. Replacing a single tyrosine residue in position 35 (Y(35) ) with 4NPA allowed the generation of an anti-C5a vaccine, which partly protected mice against the development of CIA while strongly ameliorating the severity of clinical disease. Although differing in just 3 atoms from wild-type C5a (wtC5a), C5aY(35) 4NPA induced loss of T cell and B cell tolerance toward the endogenous protein in mice expressing class II MHC H-2(q) molecules. Despite differential B cell epitope recognition, antibodies induced by both wtC5a and C5aY(35) 4NPA neutralized C5a. Thus, anti-wtC5a IgG titers during arthritis priming were potentially of critical importance for disease protection, because high titers of C5a-neutralizing antibodies after disease onset were unable to reverse the course of arthritis. The results of this study suggest that the most effective anti-C5a treatment in arthritis can be accomplished using a preventive vaccination strategy, and that treatment using conventional biologic or small molecule strategies targeting the C5a/C5aR axis may miss the optimal window for therapeutic intervention during the subclinical priming phase of the disease.
    Arthritis & Rheumatology 03/2014; 66(3):610-21. DOI:10.1002/art.38237 · 7.87 Impact Factor
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    ABSTRACT: A polyspecific amber suppressor aminoacyl-tRNA synthetase/tRNA pair was evolved that genetically encodes a series of histidine analogs in both E. coli and mammalian cells. In combination with tRNACUAPyl, a pyrrolysyl-tRNA synthetase mutant was able to site-specifically incorporate 3-methyl-histidine, 3-pyridyl-alanine, 2-furyl-alanine, and 3-(2-thienyl)-alanine into proteins in response to an amber codon. Substitution of His66 in the blue fluorescent protein (BFP) with these histidine analogs created mutant proteins with distinct spectral properties. This work further expands the structural and chemical diversity of UAAs that can be genetically encoded in prokaryotic and eukaryotic organisms, and affords new probes of protein structure and function.
    ACS Chemical Biology 02/2014; 9(5). DOI:10.1021/cb500032c · 5.36 Impact Factor
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    ABSTRACT: We found that Methanocaldococcus jannaschii DSM2661 tyrosyl-tRNA synthetase (Mj E9RS), specifically evolved to charge its cognate tRNA with the unnatural amino acid p-acetylphenylalanine (pAcF) in E coli, misaminoacylates the endogenous E. coli prolyl-tRNAs with pAcF at a low level (0.5% per proline frequency) in both the absence or presence of its coevolved amber suppressor tRNA (M. jannaschii tyrosyl-tRNA, ). In contrast to other E. coli tRNAs, the identity elements for recognition of the proly-tRNAs by the E. coli prolyl-tRNA synthetase (C1, G72, and A73) are similar to those in . Although the unique acceptor stem identity elements of the prolyl-tRNAs likely lower their recognition by the other endogenous aaRSs in E. coli, resulting in enhanced fidelity in the wild type strain, they lead to misaminoacylation by the archae-derived E9RS. Misincorporation of pAcF for proline was resolved to below detectable levels by overexpression of the endogenous E. coli prolyl-tRNA synthetase (proS) gene in combination with additional genomic manipulations to further increase the intracellular ratio of the ProS over its cognate proline tRNA's. These experiments suggest another mechanism by which the cell maintains the high fidelity of protein biosynthesis.
    ACS Chemical Biology 01/2014; 9(4). DOI:10.1021/cb4005172 · 5.36 Impact Factor

Publication Stats

38k Citations
6,039.65 Total Impact Points

Institutions

  • 1996–2015
    • The Scripps Research Institute
      • • Department of Chemistry
      • • Skaggs Institute for Chemical Biology
      لا هویا, California, United States
    • Stanford University
      • Department of Microbiology and Immunology
      Palo Alto, California, United States
  • 2013–2014
    • The California Institute for Biomedical Research
      San Diego, California, United States
  • 2000–2013
    • Genomics Institute of the Novartis Research Foundation
      San Diego, California, United States
    • University of Minnesota Duluth
      • Department of Chemistry and Biochemistry
      Duluth, Minnesota, United States
  • 2010
    • University of California, San Diego
      • Division of Biological Sciences
      San Diego, CA, United States
  • 1987–2010
    • University of California, Berkeley
      • • Department of Chemistry
      • • Department of Physics
      Berkeley, California, United States
  • 2007
    • Wayne State University
      • Department of Chemistry
      Detroit, Michigan, United States
  • 2002
    • Pasadena City College
      Pasadena, Texas, United States
  • 1995–2002
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • CSU Mentor
      • Department of Chemistry
      Long Beach, California, United States
  • 1999
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 1996–1999
    • Lawrence Berkeley National Laboratory
      • • Materials Sciences Division
      • • Geochemistry Department
      Berkeley, CA, United States
  • 1998
    • Yonsei University
      • Department of Chemistry
      Sŏul, Seoul, South Korea
  • 1997
    • Uppsala University
      Uppsala, Uppsala, Sweden
  • 1994
    • University of Pécs
      Fuenfkirchen, Baranya, Hungary
    • Lawrence University
      • Chemistry
      Berkeley, California, United States
  • 1991
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany