Research | Nyerges Lab

Multi-omics-guided genome synthesis and design

Rational genome design and genetic code engineering enable three key innovations: (i) broad resistance to natural viruses, (ii) prevention of genetic information flow between engineered organisms and natural species, and (iii) the capability to biosynthesize entirely new classes of genetically encoded polymers.

Multi-omics-guided synthesis and rescue of radically recoded E. coli genomes.

We have developed a multi-omics-guided directed evolution and genome-design strategy that rapidly debugs synthetic chromosomal regions and restores fitness, paving the way for the synthesis of functional, high-fitness genomes with radical changes. This technology serves as foundation for our current research projects.

Relevant publication Akos Nyerges^#, Chiappino-Pepe A, Budnik B, Baas-Thomas M, Flynn R, Yan S, Ostrov N, Liu M, Wang M, Zheng Q, Hu F, Chen K, Rudolph A, Chen D, Ahn J, Spencer O, Ayalavarapu V, Tarver A, Harmon-Smith M, Hamilton M, Blaby I, Yoshikuni Y, Hajian B, Jin A, Kintses B, Szamel M, Seregi V, Shen Y, Li Z, Church GM^# (2024). Synthetic genomes unveil the effects of synonymous recoding. bioRxiv. 10.1101/2024.06.16.599206

Highlighted in Nature and The New York Times Why is it so hard to rewrite a genome? — Michael Eisenstein, Nature 638, 848-850 (2025) Interview with Carl Zimmer for The New York Times, on engineering the genetic code and the creation of radically engineered synthetic genomes (August 2025)

Amino-acid-swapped genetic code providing virus-resistance and biocontainment.
Illustration by Behnoush Hajian; celline.design

Genetic firewall for virus-resistance and biocontainment

The universal nature of the genetic code allows organisms to exchange functions through horizontal gene transfer (HGT) and enables recombinant gene expression in heterologous hosts. However, the shared language of the same code permits the undesired spread of antibiotic-, herbicide-, and pesticide-resistance genes and allows viruses to cause diseases.

We have developed a technology that renders cells resistant to natural viruses and biocontains cells and their genetic information by establishing a genetic-code-based firewall.

This genetic-code-based firewall renders Escherichia coli cells resistant to viruses (including bacteriophages in environmental samples) by mistranslating viral proteomes and prevents the escape of synthetic genetic information. Simultaneously, we biocontain this virus-resistant host through dependence on an amino acid not found in nature. This work establishes a strategy to make organisms safely resistant to natural viruses and prevent genetic information flow into and out of Genetically Modified Organisms (GMOs).

Selected as one of the most important discoveries at Harvard Medical School in 2023, by Harvard Medicine News.

Relevant publication & patent applications Akos Nyerges^#, Vinke S, Flynn R, Owen SV, Rand EA, Budnik B, Keen E, Narasimhan K, Marchand JA, Baas-Thomas M, Liu M, Chen K, Chiappino-Pepe A, Hu F, Baym M, Church GM^# (2023). A swapped genetic code prevents viral infections and gene transfer. Nature 2023:1-8. 10.1038/s41586-023-05824-z (Preprint: bioRxiv, Jul. 8, 2022.) Nyerges AJ, Church GM (2022). Methods and compositions for conferring cellular resistance to viral infection. PCT/US2023/069468 Nyerges AJ, Church GM (2021). Methods for making and using genomically recoded cells. PCT/US2021/062177 (WO2022/125531)

Highlights & press coverage

Highlighted in Nature Biotechnology; New Scientist; Synthetic Biology; Science; U.S. Department of Energy; Nature News & Views.

Interviews in Nature Podcast, Drug Discovery News, The Scientist, and Harvard Medical School News.

Accelerated directed evolution in diverse bacteria

We developed a method that enables the precise mutagenesis of multiple, long genomic segments in multiple species without off-target modifications. This technology (DIvERGE) enables the exploration of vast numbers of combinatorial genetic alterations in their native genomic context and allows accelerated directed evolution.

We demonstrated that our broad-host-range genome engineering (pORTMAGE; Nyerges, A. et al., PNAS, 2016, PMID: 26884157) enables the translation of chemical DNA-synthesis-based mutagenesis into focused genome-diversification with up to >1,000,000x the wild-type mutation rate.

DIvERGE and pORTMAGE: accelerated directed evolution across bacterial species.

DIvERGE + pORTMAGE enable precise, portable, multi-species directed evolution.

Using the combinatorial mutagenes of drug targets with DIvERGE, we identified previously undetected resistance processes for multiple antibiotics, including a clinical-stage antibiotic, gepotidacin (blujepa). Strikingly, gepotidacin's clinical trial later revealed the same resistance process in patients.

This technology was later outlicensed for drug development.

Relevant publications & patent Akos Nyerges^#, Csorgo B, Draskovits G, Kintses B, Szili P, Ferenc G, Revesz T, Ari E, Nagy I, Balint B, Vasarhelyi BM, Bihari P, Szamel M, Balogh D, Papp H, Kalapis D, Papp B, Pal C^# (2018). Directed evolution of multiple genomic loci allows the prediction of antibiotic resistance. PNAS 115, E5726-E5735. 10.1073/pnas.1801646115 US10669537B2: Mutagenizing intracellular nucleic acids (granted U.S. Patent; PCT/EP2017/082574; outlicensed) Akos Nyerges^*, Csorgo B^*, Nagy I, Balint B, Bihari P, Lazar V, Apjok G, Umenhoffer K, Bogos B, Posfai G, Pal C (2016). A highly precise and portable genome engineering method allows comparison of mutational effects across bacterial species. PNAS 201520040. 10.1073/pnas.1520040113

Rational design of balanced dual-targeting antibiotics.

Rational design of dual-targeting DNA gyrase and topoisomerase IV inhibitors with suppressed resistance evolution.

Rational design of antibiotic drugs with limited resistance

In collaboration with Lucija Peterlin Masic's team — using structure-guided rational drug design, we developed a series of novel DNA gyrase and topoisomerase IV dual-targeting antibiotics.

We combined rational, target-based drug development with evolutionary analysis and the high-throughput prediction of resistance processes to identify key residues in drug-target interaction and suppress the evolution of drug resistance by rationally modifying our drug candidate.

This novel antibiotic displays broad activity against both drug-susceptible and multidrug-resistant Gram-positive bacterial pathogens, lacks toxicity in preclinical tests, was well-tolerated in mice, and demonstrated exceptional potency in mouse infection models.

Relevant publications & patent application Szili P, Draskovits G, Revesz T, Bogar F, Balogh D, Martinek T, Daruka L, Spohn R, Vasarhelyi BM, Czikkely M, Kintses B, Grezal G, Ferenc G, Pal C^#, Akos Nyerges^# (2019). Rapid evolution of reduced susceptibility against a balanced dual-targeting antibiotic through stepping-stone mutations. Antimicrobial Agents and Chemotherapy 63. 10.1128/aac.00207-19 US12258342B2 (PCT/EP2019/073412): New Class of DNA Gyrase and/or Topoisomerase IV Inhibitors with Activity Against Gram-Positive and Gram-Negative Bacteria (granted U.S. Patent) Akos Nyerges^*, Tomasic T^*, Durcik M^*, Revesz T, Szili P, Draskovits G, Bogar F, Skok Z, Zidar N, Ilas J, Zega A, Kikelj D, Daruka L, Kintses B, Vasarhelyi B, Foldesi I, Kata D, Welin M, Kimbung R, Focht D, Masic LP^#, Pal C^# (2020). Rational design of balanced dual-targeting antibiotics with limited resistance. PLOS Biology 18, e3000819. 10.1371/journal.pbio.3000819

PDB structures deposited RCSB 6TCK RCSB 6TTG

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Funding

Our research is supported by the U.S. National Institutes of Health and the U.S. Department of Energy.

NIH/NIBIB — Pathway to Independence (K99/R00)
Development of a Gene-Transfer-Resistant and Biocontained Next-Generation Bacterial Host for Controlled Drug Delivery

U.S. Department of Energy — Macromolecular Crystallography
Structure-guided genetic code engineering for tight microbial biocontainment