Nediljko Budisa

Nediljko "Ned" Budisa (Croatian: Nediljko Budiša; born November 21, 1966 in Šibenik, Croatia) is a Croatian biochemist, professor and holder of the Tier 1 Canada Research Chair (CRC) for chemical synthetic biology at the University of Manitoba. As pioneer in the areas of genetic code engineering and chemical synthetic biology (Xenobiology), his research has a wide range of applications in biotechnology and engineering biology in general. Being highly interdisciplinary, it includes bioorganic and medical chemistry, structural biology, biophysics and molecular biotechnology as well as metabolic and biomaterial engineering. He is the author of the only textbook in his research field: “Engineering the genetic code: expanding the amino acid repertoire for the design of novel proteins”.[1]

Nediljko "Ned" Budisa
Ned in a TUB Laboratory in 2012
Born (1966-11-21) November 21, 1966
Šibenik, Croatia
NationalityCroatian
Alma materFaculty of Science, University of Zagreb
Scientific career
FieldsBiochemistry, bioorganic chemistry, synthetic biology
InstitutionsTechnical University of Berlin, University of Manitoba

Early life, education and career

Ned Budisa earned a High school teacher diploma in Chemistry and Biology in 1990, a B.S. in Molecular Biology and MSc in Biophysics in 1993 from the University of Zagreb. He received a PhD in 1997 from the Technical University of Munich where his thesis advisor was Professor Robert Huber. He also habilitated at the Technical University of Munich in 2005 and worked afterwards as a junior group leader ("Molecular Biotechnology")[2] at the Max Planck Institute for Biochemistry in Munich. Between 2007 and 2010 he was a member of CIPSM in Munich.[3] He was appointed as full professor of biocatalysis at the TU Berlin in 2010[4] until the end of 2018, when he accepted the Tier 1 CRC position in Chemical Synthetic Biology at the University of Manitoba.[5] Ned Budisa is also a member of the Excellence Cluster ‘Unifying Systems in Catalysis’ (UniSysCat)[6] and keeps adjunct professor status at the TU Berlin. In 2014, he founded the first Berlin iGEM team.[7]

Research

Ned Budisa applies the Selective Pressure Incorporation (SPI) method[8] that enables single and multiple[9] in vivo incorporations of synthetic (i.e. non-canonical) amino acid analogs in proteins, preferably by sense codon reassignment.[10] His methodology allows for fine chemical manipulations of the amino acid side chains, mainly of proline, tryptophan and methionine. These experiments are often assisted with simple metabolic engineering.[11][12] Ned's research goal is the transfer of various physicochemical properties and bioorthogonal chemistry reactions (chemoselective ligations such as click chemistry) as well as special spectroscopic features (e.g. blue[13] and golden[14] fluorescence or vibration energy transfer[15]) into the proteins of living cells. In addition, his method allows the delivery of element-specific properties (fluorine, selenium and tellurium) into the biochemistry of life.[16]

Ned Budisa is well known for the establishment of the use of selenium-containing non-canonical amino acids for protein X-ray crystallography[17] and fluorine-containing analogs for 19F NMR-spectroscopy and protein folding studies.[18] He was the first to demonstrate the use of genetic code engineering as a tool for the creation of therapeutic proteins[19] and ribosomally synthetized peptide-drugs.[20] He has succeeded with innovative engineering of biomaterials, in particular photoactivatable mussel-based underwater adhesives.[21] Ned Budisa made seminal contributions to our understanding of the role of methionine oxidation in prion protein aggregation[22] and has discovered the roles of proline side chain conformations (endo-exo isomerism) in translation, folding and stability of proteins.[23][24]

Together with his co-worker Vladimir Kubyshkin, the new-to-nature hydrophobic[25] polyproline-II helix foldamer was designed. Along with Budisa's previous work on bioexpression using proline analogues, the results of this project contributed to the establishment of the Alanine World hypothesis.[26] It explains why nature chose the genetic code [27] with "only" 20 canonical amino acids for ribosomal protein synthesis.[28]

In 2015, the team led by Ned Budisa reported the successful completion of a long-term evolution experiment that resulted in full, proteome-wide substitution of all 20,899 tryptophan residues with thienopyrrole-alanine in the genetic code of the bacterium Escherichia coli.[29] This is a solid basis for the evolution of life with alternative building blocks, foldamers or biochemistries.[30] At the same time, this approach might be an interesting biosafety technology to evolve biocontained synthetic cells[31] equipped with a "genetic firewall" which prevents their survival outside of man-made unnatural environments.[32] Similar experiments with flourinated tryptophan analogs[33] as xenobiotic compounds (in collaboration with Beate Koksch from the Free University of Berlin) has led to the discovery of exceptional physiological plasticity in microbial cultures during adaptive laboratory evolution, making them potential environmentally friendly tools for new bioremediation strategies.

Ned Budisa is also actively involved in the debate of possible societal, ethical and philosophical impacts of radical genetic code engineering in the context of synthetic cells and life as well as technologies derived thereof.[34]

Awards and Honors (Selection)
  • 2004: BioFuture Award[35]
  • 2017: Publication Award Fluorine Chemistry[36]
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See also

References
  1. Budisa, Nediljko (2005). The book at the Wiley Online Library. doi:10.1002/3527607188. ISBN 9783527312436.
  2. "Molecular Biotechnology". Max Planck Institute. Archived from the original on June 10, 2007. Retrieved August 10, 2017.
  3. "List of CIPSM professors". Retrieved August 10, 2017.
  4. "Website of the Biocatalysis group". Retrieved August 10, 2017.
  5. "University of Manitoba welcoming Ned Budisa". October 16, 2018. Retrieved August 17, 2019.
  6. "UniSysCat Cluster of Excellence". Retrieved August 17, 2019.
  7. "iGEM team Berlin". Retrieved August 10, 2017.
  8. Budisa, N. (2004). "Prolegomena to future efforts on genetic code engineering by expanding its amino acid repertoire". Angewandte Chemie International Edition. 43: 3387–3428. doi:10.1002/anie.20030064 (inactive January 22, 2020).
  9. Lepthien, S.; Merkel, L.; Budisa, N. (2010). "In Vivo Double and Triple Labeling of Proteins Using Synthetic Amino Acids". Angewandte Chemie International Edition. 49 (32): 5446–5450. doi:10.1002/anie.201000439. PMID 20575122.
  10. Bohlke, N.; Budisa, N. (2014). "Sense codon emancipation for proteome-wide incorporation of noncanonical amino acids: rare isoleucine codon AUA as a target for genetic code expansion". FEMS Microbiology Letters. 351 (2): 133–44. doi:10.1111/1574-6968.12371. PMC 4237120. PMID 24433543.
  11. Völler, J.-S.; Budisa, N. (2017). "Coupling genetic code expansion and metabolic engineering for synthetic cells". Current Opinion in Biotechnology. 48: 1–7. doi:10.1016/j.copbio.2017.02.002. PMID 28237511.
  12. Exner, M. P.; Kuenzl, S.; Schwagerus, S.; To, T.; Ouyang, Z.; Hoesl, M. G.; Lensen, M. C.; Hackenberger, C. P. R.; Panke, S.; Budisa, N. (2017). "Design of an S-Allylcysteine in situ production and incorporation system based on a novel pyrrolysyl-tRNA synthetase variant". ChemBioChem. 18 (1): 85–90. doi:10.1002/cbic.201600537. PMID 27862817.
  13. Lepthien, S.; Hoesl, M. G.; Merkel, L.; Budisa, N. (2008). "Azatryptophans endow proteins with intrinsic blue fluorescence". Proc. Natl. Acad. Sci. USA. 105 (42): 16095–16100. Bibcode:2008PNAS..10516095L. doi:10.1073/pnas.0802804105. PMC 2571030. PMID 18854410.
  14. Bae, J.; Rubini, M.; Jung, G.; Wiegand, G.; Seifert, M. H. J.; Azim, M. K.; Kim, J. S.; Zumbusch, A.; Holak, T. A.; Moroder, L.; Huber, R.; Budisa, N. (2003). "Expansion of the Genetic Code Enables Design of a Novel "Gold" Class of Green Fluorescent Proteins". Journal of Molecular Biology. 328 (5): 977–1202. doi:10.1016/s0022-2836(03)00364-4. PMID 12729742.
  15. Baumann, T.; Hauf, M.; Schildhauer, F.; Eberl, K.; Durkin, P. M.; Deniz, E.; Löffler, J. G.; Acevedo-Rocha, C. G.; Jaric, J.; Martins, B. M.; Dobbek, H.; Bredenbeck, J.; Budisa, N. (2019). "Site‐Resolved Observation of Vibrational Energy Transfer Using a Genetically Encoded Ultrafast Heater". Angewandte Chemie International Edition. 58 (9): 2527–2903. doi:10.1002/anie.201812995. PMID 30589180.
  16. Agostini, F.; Völler, J-S.; Koksch, B.; Acevedo-Rocha, C. G.; Kubyshkin, V.; Budisa, N. (2017). "Biocatalysis with Unnatural Amino Acids: Enzymology Meets Xenobiology". Angewandte Chemie International Edition. 56 (33): 9680–9703. doi:10.1002/anie.201610129. PMID 28085996.
  17. Budisa, N.; Steipe, B.; Demange, P.; Eckerskorn, C.; Kellermann, J.; Huber, R. (1995). "High level biosynthetic substitution of methionine in proteins by its analogues 2-aminohexanoic acid, selenomethionine, telluromethionine and ethionine in Escherichia coli". Eur. J. Biochem. 230 (2): 788–796. doi:10.1111/j.1432-1033.1995.tb20622.x. PMID 7607253.
  18. Seifert, M. H.; Ksiazek, D.; Smialowski, P.; Azim, M. K.; Budisa, N.; Holak, T. A. (2002). "Slow Conformational Exchange Processes in Green Fluorescent Protein Variants evidenced by NMR Spectroscopy". J. Am. Chem. Soc. 124 (27): 7932–7942. doi:10.1021/ja0257725. PMID 12095337.
  19. Budisa, N.; Minks, C.; Medrano, F. J.; Lutz, J.; Huber, R.; Moroder, L. (1998). "Residue specific bioincorporation of non-natural biologically active amino acids into proteins as possible drug carriers. Structure and stability of per-thiaproline mutant or annexin V". Proc. Natl. Acad. Sci. USA. 95 (2): 455–459. doi:10.1073/pnas.95.2.455. PMC 18441. PMID 9435213.
  20. Budisa, N. (2013). "Expanded genetic code for the engineering of ribosomally synthetized and post-translationally modified peptide natural products (RiPPs)". Current Opinion in Biotechnology. 24 (4): 591–598. doi:10.1016/j.copbio.2013.02.026. PMID 23537814.
  21. Hauf, M.; Richter, F.; Schneider, T.; Faidt, T.; Martins, B. M.; Baumann, T.; Durkin, P.; Dobbek, H.; Jacobs, K.; Moeglich, A.; Budisa, N. (2017). "Photoactivatable mussel-based underwater adhesive proteins by an expanded genetic code". ChemBioChem. 18 (18): 1819–1823. doi:10.1002/cbic.201700327. PMID 28650092.
  22. Wolschner, C.; Giese, A.; Kretzschmar, H.; Huber, R.; Moroder, L.; Budisa, N. (2009). "Design of anti- and pro-aggregation variants to assess the effects of methionine oxidation in human prion protein". Proc. Natl. Acad. Sci. USA. 106 (19): 7756–7761. Bibcode:2009PNAS..106.7756W. doi:10.1073/pnas.0902688106. PMC 2674404. PMID 19416900.
  23. Steiner, T.; Hess, P.; Bae, J. H.; Moroder, L.; Budisa, N. (2008). "Synthetic Biology of Proteins: Tuning GFP´s Folding and Stability with Fluoroproline". PLOS ONE. 3 (2): e1680. Bibcode:2008PLoSO...3.1680S. doi:10.1371/journal.pone.0001680. PMC 2243022. PMID 18301757.
  24. Doerfel, L. K.; Wohlgemuth, I.; Kubyshkin, V.; Starosta, A. L.; Wilson, D. N.; Budisa, N. (2015). "Entropic Contribution of Elongation Factor P to Proline Positioning at the Catalytic Center of the Ribosome". J. Am. Chem. Soc. 137 (40): 12997–13006. doi:10.1021/jacs.5b07427. hdl:11858/00-001M-0000-0028-E3C7-1. PMID 26384033.
  25. Kubyshkin, V.; Grage, S. L.; Bürck, J.; Ulrich, A. S.; Budisa, N. (2018). "Transmembrane Polyproline Helix". J. Phys. Chem. Lett. 9 (9): 2170–2174. doi:10.1021/acs.jpclett.8b00829. PMID 29638132.
  26. Kubyshkin, V.; Budisa, N. (2019). "Anticipating alien cells with alternative genetic codes: away from the alanine world!". Current Opinion in Biotechnology. 60: 242–249. doi:10.1016/j.copbio.2019.05.006. PMID 31279217.
  27. Kubyshkin, V.; Acevedo-Rocha, C. G.; Budisa, N. (2017). "On universal coding events in protein biogenesis". Biosystems. 164: 16–25. doi:10.1016/j.biosystems.2017.10.004. PMID 29030023.
  28. Kubyshkin, V.; Budisa, N. (2019). "The Alanine World Model for the Development of the Amino Acid Repertoire in Protein Biosynthesis". Int. J. Mol. Sci. 20 (21): 5507. doi:10.3390/ijms20215507. PMC 6862034. PMID 31694194.
  29. Hoesl, M. G.; Oehm, S.; Durkin, P.; Darmon, E.; Peil, L.; Aerni, H.-R.; Rappsilber, J.; Rinehart, J.; Leach, D.; Söll, D.; Budisa, N. (2015). "Chemical evolution of a bacterial proteome". Angewandte Chemie International Edition. 54 (34): 10030–10034. doi:10.1002/anie.201502868. PMC 4782924. PMID 26136259. NIHMSID: NIHMS711205
  30. Kubyshkin, V.; Budisa, N. (2017). "Synthetic alienation of microbial organisms by using genetic code engineering: Why and how?". Biotechnology Journal. 12 (8): 1600097. doi:10.1002/biot.201600097. PMID 28671771.
  31. Diwo, C.; Budisa, N. (2019). "Alternative Biochemistries for Alien Life: Basic Concepts and Requirements for the Design of a Robust Biocontainment System in Genetic Isolation". Genes. 10 (1): 17. doi:10.3390/genes10010017. PMC 6356944. PMID 30597824.
  32. Acevedo-Rocha, C. G.; Budisa, N. (2011). "On the Road towards Chemically Modified Organisms Endowed with a Genetic Firewall". Angewandte Chemie International Edition. 50 (31): 6960–6962. doi:10.1002/anie.201103010. PMID 21710510.
  33. Agostini, F.; Sinn, L.; Petras, D.; Schipp, C. J.; Kubyshikin, V,; Berger, A. A.; Dorrestein, P. C,; Rappsilber, J.; Budisa, N.; Koksch, B. (2019). "Laboratory evolution of Escherichia coli enables life based on fluorinated amino acids". bioRxiv 10.1101/665950.CS1 maint: extra punctuation (link)
  34. Schmidt, M.; Pei, L.; Budisa, N. (2018). Xenobiology: State-of-the-art, Ethics and Philosophy of new-to-nature organisms. Advances in Biochemical Engineering/Biotechnology. 162. pp. 301–315. doi:10.1007/10_2016_14. ISBN 978-3-319-55317-7. ISSN 0724-6145. PMID 28567486.
  35. "BioFuture Award profile". Archived from the original on June 30, 2007. Retrieved August 10, 2017.
  36. "UniCat – Publication Award Fluorine Chemistry". Retrieved October 16, 2017.
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