Nediljko Budisa


Nediljko "'Ned" Budisa' is a Croatian biochemist, professor and holder of the Tier 1 Canada Research Chair for chemical synthetic biology at the University of Manitoba. As pioneer in the areas of genetic code engineering and chemical synthetic biology and 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. His research has produced numerous innovations in bioorganic chemistry, biotechnology, and engineering biology, shaping the way new proteins and synthetic cells are designed and developed. 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".

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 at the Max Planck Institute for Biochemistry in Munich. Between 2007 and 2010 he was a member of CIPSM in Munich. He was appointed as full professor of biocatalysis at the TU Berlin in 2010 until the end of 2018, when he accepted the Tier 1 CRC position in Chemical Synthetic Biology and Xenobiology at the University of Manitoba. He remained affiliated with TU Berlin through an adjunct professorship and was also a member of the Excellence Cluster 'Unifying Systems in Catalysis'. In 2014, he founded the first Berlin iGEM team. In 2022, he founded the first iGEM team at the University of Manitoba.

Research

Ned Budisa works in genetic code engineering and chemical synthetic biology, developing in vivo techniques to introduce genetically encoded modifications into proteins and entire proteomes. He applies the Selective Pressure Incorporation (SPI) method that enables single and multiple in vivo incorporations of synthetic amino acid analogs in proteins, preferably by sense codon reassignment. 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.
Ned's research goal is the transfer of various physicochemical properties and bioorthogonal chemistry reactions as well as special spectroscopic features into the proteins of living cells. In addition, his method allows the delivery of element-specific properties into the biochemistry of life. He also pioneered computer-aided design libraries for directed evolution, creating novel enzymes that rival their natural counterparts and enabling the efficient engineering of synthetic proteins. By merging genetic code expansion and metabolic engineering with genome editing, he created artificial microbes based on the intestinal bacterium Escherichia coli with an intrinsic 'genetic firewall' that, unlike genetically modified organisms, enables the safe production of proteins and other metabolites in genetic isolation within a single fermentation process that does not require the use of expensive and often harmful antibiotics.
Ned Budisa is well known for the establishment of the use of selenium-containing non-canonical amino acids for protein X-ray crystallography and fluorine-containing analogs for 19F NMR-spectroscopy and protein folding studies. He was the first to demonstrate the use of genetic code engineering as a tool for the creation of therapeutic proteins and ribosomally synthesized peptide-drugs. He has succeeded with innovative engineering of biomaterials, in particular photoactivatable mussel-based underwater adhesives. Ned Budisa made seminal contributions to our understanding of the role of methionine oxidation in prion protein aggregation and has discovered the roles of proline side chain conformations in translation, folding and stability of proteins.
Together with his co-worker Vladimir Kubyshkin, the new-to-nature hydrophobic 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. It explains why nature chose the genetic code with "only" 20 canonical amino acids for ribosomal protein synthesis.
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. This is a solid basis for the evolution of life with alternative building blocks, foldamers or biochemistries. At the same time, this approach might be an interesting biosafety technology to evolve biocontained synthetic cells equipped with a "genetic firewall" which prevents their survival outside of man-made unnatural environments. Similar experiments with fluorinated tryptophan analogs as xenobiotic compounds 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.

Awards and honors (selection)