CONEXER: a new era in genome writing

We are delighted to share the latest advances from the Chin lab in the field of genome synthesis describing CONEXER, a next generation genome synthesis technology exclusively licensed to Constructive Bio, which enables large scale assembly of synthetic DNA. 

At Constructive Bio, we leverage these advances to build synthetic genomes from scratch, creating novel organisms with useful properties across industries, and we are very excited about it.

Published in Nature (check it out here), the latest publication from Jason Chin’s lab, and led by Jérôme Zürcher, Askar Kleefeldt, Louise F. H. Funke, PhD, Julius Fredens and Jakob Birnbaum, addresses this challenge through the development of CONEXER, the next generation in genome synthesis technology. CONEXER combines conceptual and genetic advances to turn genome synthesis into a continuous process, massively accelerating the iteration between synthetic replacement steps. This means the implementation of 500 kbp of synthetic DNA can be achieved in only 10 days! 

Genomes provide a formula for the life of an organism – being able to write them from the bottom up constitutes a powerful approach for testing fundamental biological hypotheses, and for endowing organisms with new properties that may not be found in nature. We previously demonstrated the creation of an E. coli cell with a synthetic genome, Syn61, which uses a reduced set of codons (61 as opposed to 64) to make the proteins it needs to survive. By reprogramming its genetic code, we showed that Syn61 is resistant to viral infection and has the ability to produce entirely unnatural biopolymers.

Synthesizing a heavily modified genome and implementing it into a living cell is no easy task – it is a stepwise process, where the product of each step serves as a template for the next. Our proprietary technologies for genome synthesis, REXER, GENESIS and most recently CONEXER, enable the assembly of synthetic DNA in the scale of hundreds of kbp, and the replacement of ‘natural’ DNA with its synthetic counterpart. Each step of replacement can provide valuable information about the biological functionality of a synthetic DNA sequence, but performing many steps comes at the cost of speed. Accelerating the transition between steps is paramount for achieving throughput and scalability in the genome synthesis process.

Moreover, the paper describes a complementary technology, termed BASIS, which enables the construction of heterologous megabase-scale DNA constructs as extrachromosomal episomes in E. coli. The researchers use BASIS to build a 1 Mb fragment of human DNA in E. coli, encoding the CFTR gene, and demonstrate that the construct can be successfully delivered intact into human cells. This technology sets a foundation for extending the genome building toolkit developed in E. coli for the assembly of large, synthetic DNA pieces for organisms across all walks of life.

Congratulations to the authors for this amazing work!