James (Jim) Michael Cregg

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James Michael Cregg
BornJuly 2, 1950
Syracuse, New York, United States
DiedSeptember 16, 2025
NationalityAmerican
Alma mater
  • Western Maryland College
  • Rice University
Known forPioneering the development and use of the Pichia pastoris protein expression system
Scientific career
FieldsBiotechnology

James (Jim) Michael Cregg (July 2, 1950 - September 16, 2025) was an American biotechnologist best known for advancements in biotechnology, specifically pioneering the development and popularization of the Pichia pastoris protein expression system.[1][2][3] His work established the yeast Pichia pastoris, later reclassified as Komagataella phaffii,[4][5] as a powerful and commercially viable platform for recomiant protein production,[6][7][8] particularly for proteins requiring ekaryotic post-translational modifications.

Early Life and Education

Cregg was born in Syracuse, New York, to James Malachi Cregg and Beatrice Lorraine (Paine) Cregg. He graduated from Western Maryland College (renamed McDaniel College in 2002) in Westminster, Maryland, in 1972. He earned his Ph. D. in biology from Rice University in Houston, Texas, in 1978.

Career

Development of the Pichia pastoris expression system

Between 1983 and 1989, Cregg undertook postdoctoral research at the Salk Institute of Biotechnology Industial Associates (SIBIA), now known as the Salk Institute for Biological Studies), located in La Jolla, California. Under a contract with Phillips Petroleum, he and his colleagues developed the Pichia pastoris expression platform.[9][10][11][12]

This innovation became a cornerstone of biotechnology on a global scale. Cregg's research illustrated that Pichia pastoris could function as a versatile and scalable system for the production of recombinant protein through straightforward microbial fermentation, while also providing benefits over bacterial hosts by facilitating proper protein folding and enabling eukaryotic post-translational modifications.[13][14][15][16]

Industry and Academic Contributions

In 1993, Research Corporation Technologies (RCT)[17] based in Tucson, Arizona, acquired the rights to the Pichia expression system (www.pichia.com from Phillips Petroleum. With the assistance of Cregg, this innovative recombinant protein production platform was transformed from a niche yeast into a widely adopted protein production biotechnology on a global scale. It supports the manufacturing of tehrapeutic proteins, as well as protein for food and feed at a scale of 100,000 liters, along with hundreds of commercial enzymes. Since acquiring the technology in 1993, RCT has licensed the Pichia expression system to numerous companies. This technology has facilitated the production of a variety of medical and industrial products, such as phytase for animal feed, Kalbitor (ecallantide) for the treatment of hereditary angioedema (HAE), and CORBEVAX®, an affordable COVID-19 vaccine. This technology is widely used today for the manufacturing of medical industrial and nutrient products.

Cregg played a pivotal role in organizing the inaugural international Pichia pastoris conference, which subsequently occurred biennially in both the United States and Europe throughout his lifetime. These gatherings promoted collaboration among scientists globally and established an informal network referred to as the "Pichia peopel."

Cregg frequently served as a keynote speaker at various international conferences and held positions as a reviewer and executive editor for numerous scientific journals. His career encompassed both industry and academia. At Keck Graduate Institute (KGI), Cregg's laboratory developed several Pichia pastoris strains aimed at industrial and pharmaceutical protein production. Additionally, his team pioneered the yeast-based technology for the production of monoclonal antibodies, which was used by Alder Biopharmaceuticals (Lundbeck Seattle Biopharmaceuticals) to manufacture the "first in class" Pichia pastoris produced human CGRP inhibiting monocolonal antibody eptinezumab-jjmr (Viepty®), a medication designed for the intravenous therapy (IV) in the preventative treatment of migraines in adults.

Along with his expertise in recombinant expression, Cregg was a respected authority in the field of peroxisome biogenesis and autophagy, pubilshing over 15 papers in this field.[18][19][20]

In 2008, Cregg, along with his long-time colleagues and collaborators, founded a start-up company named BioGrammatics, Inc.[21] (Carlsbad, CA). This contract research organization (CRO) specializes in providing Pichia pastoris host strains, vectors, as well as services and consulting for the development of Pichia pastoris protein production technologies aimed at academic laboratories, small enterprises, and the pharmaceutical sector. A notable commercial achievement for BioGrammatics was its collaboration with Marxi/Impossible Foods, which is currently using an engineered Pichia strain for the large-scale production of soy leghemoglobin (Heme)--a molecule that transports iron, imparting flavor and "bloody" appearance to food. This signature ingredient is essential for making the Impossible Burger and other plant-based foods taste like beef.

Academic Appointments

  • Oregon Graduate Institute (1989-1999): Professor of Molecular Biology in Portland, Oregon.
  • Keck Graduate Institute (1999-2025): Founding professor of KGI, member of the Claremont Colleges, Claremont, CA, later serving as Professor Emeritus.

Legacy

Cregg dedicated over forty years to the development, enhancement, and promotion of the Pichia pastoris expression system. His work connected the realms of industry and academia, adn his initiatives played a significant role in establishing yeast expression as a fundamental aspect of contemporary biotechnology. His overall citation metrics show an H-index of 65 with over 31,000 citations across biology, and biochemistry.

He passed away on September 16, 2025, in Heidelberg, Germany during a visit.

James Cregg was instrumental in the publication and served as an editor for the first edition of "Pichia Protocols,"[22] which became the primary collection of laboratory protocols for experimental work involving Pichia pastoris and facilitated the publication of two subsequent editions.[23][24] The latest edition,[25] released by Humana Press in 2026, titled "Pichia pastoris, Methods and Protocols" was dedicated to the meory of James M. (Jim) Cregg, PhD, whose groundbreaking contributions established Pichia Pastoris as a powerful system for recombinant protein expression.

Selected Publications

  • Cregg J, Latham J, Litton M, Schatzman R, Tolstorukov I. Methods of synthesizing heteromultimeric polypeptides in yeast using a haploid mating strategy. 2001; US Patent 7,927,863.
  • Cregg J, Tolstorukov I. Novel P. pastoris promoters, and the use thereof to direct expression of proteins in yeast, preferably using a haploid mating strategy. 2014; US Patent 8,785,613.
  • Cregg JM, Barringer KJ, Hessler AY, Madden KR. Pichia pastoris as a host system for transformations. Mol Cell Biol. 1985;5(12):3376–85.
  • Cregg JM, Cereghino JL, Shi J, Higgins DR. Recombinant protein expression in Pichia pastoris. Mol Biotechnol. 2000;16(1):23–52.
  • Cregg JM, Chappel TG, Gehlsen KR, Kirkpatrick SA, Madden K. A Brief History of the Pichia pastoris Expression System. Methods Mol Biol. 2026;2697:3–21.
  • Cregg JM, Tolstorukov I, Kusari A, Sunga J, Madden K, Chappell T. Expression in the yeast Pichia pastoris. Methods Enzymol. 2009;463:169–89.
  • Cregg JM, Vedvick TS, Raschke WC. Recent advances in the expression of foreign genes in Pichia pastoris. Biotechnology (N Y). 1993;11(8):905–10.
  • Higgins DR, Cregg JM (editors). Pichia protocols. Methods in Molecular Biology. Springer Science. 1998; 270 p.
  • Lin Cereghino GP, Sunga AJ, Lin Cereghino J, Cregg JM. Expression of foreign genes in the yeast Pichia pastoris. Genet Eng (N Y). 2001;23:157–69.
  • Tolstorukov I, Cregg J, Chappell T, Madden K.). Yeast promoters for protein expression. 2023; US Patent 11,555,194.
  • Tschopp JF, Brust PF, Cregg JM, Stillman CA, Gingeras TR. Expression of the lacZ gene from two methanol‑regulated promoters in Pichia pastoris. Nucleic Acids Res. 1987;15(9):3859–76.

References

  1. ↑ Cregg, James M.; Chappel, Thomas G.; Gehlsen, Kurt R.; Kirkpatrick, Shaun A.; Madden, Knut (2026), "A Brief History of the Pichia pastoris Expression System", in García-Ortega, Xavier; Glieder, Anton; Kovar, Karin; Rieder, Lukas (eds.), Pichia pastoris, vol. 2697, New York, NY: Springer US, pp. 3–21, doi:10.1007/978-1-0716-4779-0_1, ISBN 978-1-0716-4778-3, retrieved 2026-01-30
  2. ↑ Cregg, James M.; Tolstorukov, Ilya; Kusari, Anasua; Sunga, Jay; Madden, Knut; Chappell, Thomas (2009), Chapter 13 Expression in the Yeast Pichia pastoris, Methods in Enzymology, vol. 463, Elsevier, pp. 169–189, doi:10.1016/s0076-6879(09)63013-5, ISBN 978-0-12-374536-1, retrieved 2026-01-30
  3. ↑ Cereghino, Geoffrey P. Lin; Sunga, Anthony J.; Cereghino, Joan Lin; Cregg, James M. (2002), "Expression of Foreign Genes in the yeast Pichia pastoris", in Setlow, Jane K. (ed.), Genetic Engineering: Principles and Methods, vol. 23, Boston: Kluwer Academic Publishers, pp. 157–169, doi:10.1007/0-306-47572-3_9, ISBN 978-0-306-46645-8, PMID 11570102, retrieved 2026-01-30
  4. ↑ Yamada, Yuzo; Matsuda, Minako; Maeda, Kojiro; Mikata, Kozaburo (January 1995). "The Phylogenetic Relationships of Methanol-assimilating Yeasts Based on the Partial Sequences of 18S and 26S Ribosomal RNAs: The Proposal of Komagataella Gen. Nov. (Saccharomycetaceae)". Bioscience, Biotechnology, and Biochemistry. 59 (3): 439–444. doi:10.1271/bbb.59.439. ISSN 0916-8451.
  5. ↑ Kurtzman, Cletus Paul (November 2009). "Biotechnological strains of Komagataella (Pichia) pastoris are Komagataella phaffii as determined from multigene sequence analysis". Journal of Industrial Microbiology & Biotechnology. 36 (11): 1435–1438. doi:10.1007/s10295-009-0638-4. ISSN 1367-5435.
  6. ↑ Cregg, James M.; Barringer, Kevin J.; Hessler, Anita Y.; Madden, Knut R. (1985-12-01). "Pichia pastoris as a Host System for Transformations". Molecular and Cellular Biology. 5 (12): 3376–3385. doi:10.1128/mcb.5.12.3376-3385.1985. ISSN 1098-5549. PMC 369166.
  7. ↑ Tschopp, Juerg F.; Brust, Paul F.; Cregg, James M.; Stillman, Cathy A.; Gingeras, Thomas R. (1987). "Expression of the lacZ gene from two methanol-regulated promoters in Pichia pastoris". Nucleic Acids Research. 15 (9): 3859–3876. doi:10.1093/nar/15.9.3859. ISSN 0305-1048. PMC 340787.
  8. ↑ Cregg, James M.; Vedvick, Thomas S.; Raschke, William C. (August 1993). "Recent Advances in the Expression of Foreign Genes in Pichia pastoris". Nature Biotechnology. 11 (8): 905–910. Bibcode:1993NatBi..11..905C. doi:10.1038/nbt0893-905. ISSN 1087-0156.
  9. ↑ Cregg, James M.; Chappel, Thomas G.; Gehlsen, Kurt R.; Kirkpatrick, Shaun A.; Madden, Knut (2026), "A Brief History of the Pichia pastoris Expression System", in García-Ortega, Xavier; Glieder, Anton; Kovar, Karin; Rieder, Lukas (eds.), Pichia pastoris, vol. 2697, New York, NY: Springer US, pp. 3–21, doi:10.1007/978-1-0716-4779-0_1, ISBN 978-1-0716-4778-3, retrieved 2026-01-30
  10. ↑ Cregg, James M.; Barringer, Kevin J.; Hessler, Anita Y.; Madden, Knut R. (1985-12-01). "Pichia pastoris as a Host System for Transformations". Molecular and Cellular Biology. 5 (12): 3376–3385. doi:10.1128/mcb.5.12.3376-3385.1985. ISSN 1098-5549. PMC 369166.
  11. ↑ Tschopp, Juerg F.; Brust, Paul F.; Cregg, James M.; Stillman, Cathy A.; Gingeras, Thomas R. (1987). "Expression of the lacZ gene from two methanol-regulated promoters in Pichia pastoris". Nucleic Acids Research. 15 (9): 3859–3876. doi:10.1093/nar/15.9.3859. ISSN 0305-1048. PMC 340787.
  12. ↑ Cregg, James M.; Vedvick, Thomas S.; Raschke, William C. (August 1993). "Recent Advances in the Expression of Foreign Genes in Pichia pastoris". Nature Biotechnology. 11 (8): 905–910. Bibcode:1993NatBi..11..905C. doi:10.1038/nbt0893-905. ISSN 1087-0156.
  13. ↑ Cregg, James M.; Chappel, Thomas G.; Gehlsen, Kurt R.; Kirkpatrick, Shaun A.; Madden, Knut (2026), "A Brief History of the Pichia pastoris Expression System", in García-Ortega, Xavier; Glieder, Anton; Kovar, Karin; Rieder, Lukas (eds.), Pichia pastoris, vol. 2697, New York, NY: Springer US, pp. 3–21, doi:10.1007/978-1-0716-4779-0_1, ISBN 978-1-0716-4778-3, retrieved 2026-01-30
  14. ↑ Cregg, James M.; Tolstorukov, Ilya; Kusari, Anasua; Sunga, Jay; Madden, Knut; Chappell, Thomas (2009), Chapter 13 Expression in the Yeast Pichia pastoris, Methods in Enzymology, vol. 463, Elsevier, pp. 169–189, doi:10.1016/s0076-6879(09)63013-5, ISBN 978-0-12-374536-1, retrieved 2026-01-30
  15. ↑ Cereghino, Geoffrey P. Lin; Sunga, Anthony J.; Cereghino, Joan Lin; Cregg, James M. (2002), "Expression of Foreign Genes in the yeast Pichia pastoris", in Setlow, Jane K. (ed.), Genetic Engineering: Principles and Methods, vol. 23, Boston: Kluwer Academic Publishers, pp. 157–169, doi:10.1007/0-306-47572-3_9, ISBN 978-0-306-46645-8, retrieved 2026-01-30
  16. ↑ Cregg, James M.; Cereghino, Joan Lin; Shi, Jianying; Higgins, David R. (September 2000). "Recombinant protein expression in Pichia pastoris". Molecular Biotechnology. 16 (1): 23–52. doi:10.1385/MB:16:1:23. ISSN 1073-6085.
  17. ↑ "Home". Research Corporation Technologies. Retrieved 2026-01-30.
  18. ↑ Stasyk, Oleh V.; van der Klei, Ida J.; Bellu, Anna Rita; Shen, Shigang; Kiel, Jan A. K. W.; Cregg, James M.; Veenhuis, Marten (November 1999). "A Pichia pastoris VPS15 homologue is required in selective peroxisome autophagy". Current Genetics. 36 (5): 262–269. doi:10.1007/s002940050499. ISSN 0172-8083.
  19. ↑ Dunn, Jr., William A.; Cregg, James M.; Kiel, Jan A.K.W.; Klei, Ida J. van der; Oku, Masahide; Sakai, Yasuyoshi; Sibirny, Andrei A.; Stasyk, Oleh V.; Veenhuis, Marten (2005-07-05). "Pexophagy: The Selective Autophagy of Peroxisomes". Autophagy. 1 (2): 75–83. doi:10.4161/auto.1.2.1737. ISSN 1554-8627.
  20. ↑ Farré, Jean-Claude; Carolino, Krypton; Stasyk, Oleh V.; Stasyk, Olena G.; Hodzic, Zlatan; Agrawal, Gaurav; Till, Andreas; Proietto, Marco; Cregg, James; Sibirny, Andriy A.; Subramani, Suresh (November 2017). "A New Yeast Peroxin, Pex36, a Functional Homolog of Mammalian PEX16, Functions in the ER-to-Peroxisome Traffic of Peroxisomal Membrane Proteins". Journal of Molecular Biology. 429 (23): 3743–3762. doi:10.1016/j.jmb.2017.10.009. PMC 5693695.
  21. ↑ "BioGrammatics, Inc. | Pichia protein expression". BioGrammatics, Inc. Retrieved 2026-01-30.
  22. ↑ Higgins, David R.; Cregg, James M., eds. (1998). Pichia Protocols. Methods in Molecular Biology. Vol. 103. doi:10.1385/0896034216. ISBN 978-0-89603-421-1. ISSN 1064-3745.
  23. ↑ Cregg, James M., ed. (2007). Pichia Protocols. Methods in Molecular Biology. Vol. 389. doi:10.1007/978-1-59745-456-8. ISBN 978-1-58829-429-6. ISSN 1064-3745.
  24. ↑ García-Ortega, Xavier; Glieder, Anton; Kovar, Karin; Rieder, Lukas, eds. (2026). Pichia pastoris. Methods in Molecular Biology. Vol. 2697. doi:10.1007/978-1-0716-4779-0. ISBN 978-1-0716-4778-3. ISSN 1064-3745.
  25. ↑ García-Ortega, Xavier; Glieder, Anton; Kovar, Karin; Rieder, Lukas, eds. (2026). Pichia pastoris. Methods in Molecular Biology. Vol. 2697. doi:10.1007/978-1-0716-4779-0. ISBN 978-1-0716-4778-3. ISSN 1064-3745.

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