Peter G Schultz

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

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Publications (638)6523.17 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in children. We have generated an epitope-specific RSV vaccine by grafting a neutralizing epitope (F-epitope) in its native conformation into an immunoglobulin scaffold. The resulting antibody fusion exhibited strong binding affinity to Motavizumab, an RSV neutralizing antibody, and effectively induced potent neutralizing antibodies in mice. This work illustrates the potential of the immunoglobulin molecule as a scaffold to present conformationally constrained B-cell epitopes.
    Angewandte Chemie International Edition 10/2015; DOI:10.1002/anie.201507928 · 11.26 Impact Factor
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    ABSTRACT: NRF2 serves as the master regulator of oxidative stress resistance in mammalian cells. Although NRF2 activation decreases tumorigenic events in normal cells, accumulating evidence suggests that cancers have broadly selected for NRF2-activating mutations to promote anabolic growth and chemoresistance. Small molecules which inhibit NRF2 activity may therefore offer promise as an alternative anticancer treatment in NRF2 dependent cancers. We have used a high throughput screen to identify small molecules which decrease NRF2 transcriptional activity at antioxidant response element sites. One such molecule, termed AEM1, is capable of broadly decreasing the expression of NRF2 controlled genes, sensitizing A549 cells to various chemotherapeutic agents, and inhibiting the growth of A549 cells in vitro and in vivo. Profiling of multiple cell lines for their responsiveness to AEM1 revealed that AEM1's activities are restricted to cell lines harboring mutations which render NRF2 constitutively active.
    ACS Chemical Biology 08/2015; DOI:10.1021/acschembio.5b00448 · 5.33 Impact Factor
  • Tao Liu · Juanjuan Du · Xiaozhou Luo · Peter G Schultz · Feng Wang ·
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    ABSTRACT: The field of therapeutic antibodies has been revolutionized over the past decade, led by the development of novel antibody-modification technologies. Besides the huge success achieved by therapeutic monoclonal antibodies, a diversity of antibody derivatives have emerged with hope to outperform their parental antibodies. Here we review the recent development of methodologies to modify immunoglobulin domains and their therapeutic applications. The innovative genetic and chemical approaches enable novel and controllable modifications on immunoglobulin domains, producing homogeneous therapeutics with new functionalities or enhanced therapeutic profiles. Such therapeutics, including antibody-drug conjugates, bispecific antibodies, and antibody/Fc fusion proteins, have demonstrated great prospects in the treatment of cancer, auto-immune diseases, infectious diseases, and many other disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Current opinion in chemical biology 06/2015; 28:66-74. DOI:10.1016/j.cbpa.2015.06.007 · 6.81 Impact Factor
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    ABSTRACT: With few exceptions, all living organisms encode the same 20 canonical amino acids; however, it remains an open question whether organisms with additional amino acids beyond the common 20 might have an evolutionary advantage. Here, we begin to test that notion by making a large library of mutant enzymes in which 10 structurally distinct noncanonical amino acids were substituted at single sites randomly throughout TEM-1 β-lactamase. A screen for growth on the β-lactam antibiotic cephalexin afforded a unique p-acrylamido-phenylalanine (AcrF) mutation at Val-216 that leads to an increase in catalytic efficiency by increasing kcat, but not significantly affecting KM. To understand the structural basis for this enhanced activity, we solved the X-ray crystal structures of the ligand-free mutant enzyme and of the deacylation-defective wild-type and mutant cephalexin acyl-enzyme intermediates. These structures show that the Val-216-AcrF mutation leads to conformational changes in key active site residues-both in the free enzyme and upon formation of the acyl-enzyme intermediate-that lower the free energy of activation of the substrate transacylation reaction. The functional changes induced by this mutation could not be reproduced by substitution of any of the 20 canonical amino acids for Val-216, indicating that an expanded genetic code may offer novel solutions to proteins as they evolve new activities.
    Proceedings of the National Academy of Sciences 06/2015; 112(22):201507741. DOI:10.1073/pnas.1507741112 · 9.67 Impact Factor
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    ABSTRACT: Liver X receptor (LXR) agonists have been explored as potential treatments for atherosclerosis and other diseases based on their ability to induce reverse cholesterol transport and suppress inflammation. However, this therapeutic potential has been hindered by on-target adverse effects in the liver mediated by excessive lipogenesis. Herein, we report a novel site-specific antibody-drug conjugate (ADC) that selectively delivers a LXR agonist to monocytes/macrophages while sparing hepatocytes. The unnatural amino acid para-acetylphenylalanine (pAcF) was site-specifically incorporated into anti-CD11a IgG, which binds the α-chain component of the lymphocyte function-associated antigen 1 (LFA-1) expressed on nearly all monocytes and macrophages. An aminooxy-modified LXR agonist was conjugated to anti-CD11a IgG through a stable, cathepsin B cleavable oxime linkage to afford a chemically-defined ADC. The anti-CD11a IgG-LXR agonist ADC induced LXR activation specifically in human THP-1 monocyte/macrophage cells in vitro (EC50 ~ 27 nM), but had no effect in hepatocytes, indicating that payload delivery is CD11a-mediated. Moreover, the ADC exhibited higher fold activation compared to a conventional synthetic LXR agonist T0901317 (Tularik) (3 fold). This novel ADC represents a fundamentally different strategy that uses tissue targeting to overcome the limitations of LXR agonists for potential use in treating atherosclerosis.
    Bioconjugate Chemistry 05/2015; 26(11). DOI:10.1021/acs.bioconjchem.5b00203 · 4.51 Impact Factor
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    ABSTRACT: Four different formats of bispecific antibodies (bsAbs) were generated that consist of anti-Her2 IgG or Fab site-specifically conjugated to anti-CD3 Fab using the genetically encoded noncanonical amino acid. These bsAbs varied in valency or in the presence or absence of an Fc domain. Different valencies did not significantly affect antitumor efficacy, whereas the presence of an Fc domain enhanced cytotoxic activity, but triggered antigen-independent T-cell activation. We show that the bsAbs can efficiently redirect T cells to kill all Her2 expressing cancer cells, including Her2 1+ cancers, both in vitro and in rodent xenograft models. This work increases our understanding of the structural features that affect bsAb activity, and underscores the potential of bsAbs as a promising therapeutic option for breast cancer patients with low or heterogeneous Her2 expression. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie International Edition 04/2015; 127(24). DOI:10.1002/anie.201500799 · 11.26 Impact Factor
  • Han Xiao · Weimin Xuan · Sida Shao · Tao Liu · Peter G Schultz ·
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    ABSTRACT: Here we report the evolution of an orthogonal amber suppressor pyrrolysyl-tRNA synthetase (PylRS)/tRNACUAPyl pair that genetically encodes the post-translationally modified amino acid, ε-N-2-hydroxyisobutyryl-lysine (HibK), in bacteria and mammalian cells. HibK is a new type of histone mark that is widely distributed in histone proteins. The ability to site-specifically incorporate HibK into proteins provides a useful tool to probe the biological function of this newly identified post-translational modification.
    ACS Chemical Biology 04/2015; 10(7). DOI:10.1021/cb501055h · 5.33 Impact Factor
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    ABSTRACT: Infections caused by antibiotic-resistant bacteria are a rising public health threat and make the identification of new antibiotics a priority. From a cell-based screen for bactericidal compounds against Mycobacterium tuberculosis under nutrient-deprivation conditions we identified auranofin, an orally bioavailable FDA-approved antirheumatic drug, as having potent bactericidal activities against both replicating and nonreplicating M. tuberculosis. We also found that auranofin is active against other Gram-positive bacteria, including Bacillus subtilis and Enterococcus faecalis, and drug-sensitive and drug-resistant strains of Enterococcus faecium and Staphylococcus aureus. Our biochemical studies showed that auranofin inhibits the bacterial thioredoxin reductase, a protein essential in many Gram-positive bacteria for maintaining the thiol-redox balance and protecting against reactive oxidative species. Auranofin decreases the reducing capacity of target bacteria, thereby sensitizing them to oxidative stress. Finally, auranofin was efficacious in a murine model of methicillin-resistant S. aureus infection. These results suggest that the thioredoxin-mediated redox cascade of Gram-positive pathogens is a valid target for the development of antibacterial drugs, and that the existing clinical agent auranofin may be repurposed to aid in the treatment of several important antibiotic-resistant pathogens.
    Proceedings of the National Academy of Sciences 04/2015; 112(14):4453-4458. DOI:10.1073/pnas.1504022112 · 9.67 Impact Factor
  • Tao Liu · Guangsen Fu · Xiaozhou Luo · Yan Liu · Ying Wang · Rongsheng E Wang · Peter G Schultz · Feng Wang ·
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    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 · 12.11 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.
    Science 02/2015; 347(6224):863-867. DOI:10.1126/science.aaa2424 · 33.61 Impact Factor
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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; 137(9). DOI:10.1021/jacs.5b00620 · 12.11 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; 137(8). DOI:10.1021/jacs.5b00106 · 12.11 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 · 9.67 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 · 11.26 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 · 12.11 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 · 3.55 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 · 11.26 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 · 3.09 Impact Factor

Publication Stats

46k Citations
6,523.17 Total Impact Points


  • 1991-2015
    • The Scripps Research Institute
      • • Department of Chemistry
      • • Skaggs Institute for Chemical Biology
      لا هویا, California, United States
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 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
    • Princeton University
      • Department of Molecular Biology
      Princeton, New Jersey, United States
  • 1987-2010
    • University of California, Berkeley
      • Department of Chemistry
      Berkeley, California, United States
  • 2002
    • Station Biologique de Roscoff
      Rosko, Brittany, France
  • 1999
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 1996-1999
    • Lawrence Berkeley National Laboratory
      • • Materials Sciences Division
      • • Geochemistry Department
      Berkeley, CA, United States
  • 1995-1999
    • Howard Hughes Medical Institute
      Ashburn, Virginia, 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