The progress bar for the creation of the first fully synthetic complex organism jumped forward today, as indicated by a suite of articles appearing in Science.
Since 2014, the progress bar was stuck at the 6% mark, reflecting the completion of the first synthetic yeast chromosome (synthetic chromosome 3, or synIII). According to Science, five additional synthetic yeast chromosomes have been built, so now the progress bar stands at about 30%.
The Science articles emphasize that the design phase for a completely artificial yeast genome is largely complete. This genome, however, remains malleable, amenable to patches and updates, and the new chromosomes have already proven to admirably plastic. To preserve and consistency of gene expression, the genome’s designers removed large swaths of DNA from some chromosomes, and added them to others. Also, certain portions of noncoding “junk” DNA have been removed altogether.
Despite incorporating all these changes, and being integrated into living yeast cells in “chunks,” the newly synthesized chromosomes remained functional, and the cells into which they were incorporated grew normally. Even more drastic changes are planned by the synthetic genome’s designers, the participants in the Synthetic Yeast Genome Project (Sc2.0). For example, they expect to expand the yeast genome to 17 chromosomes, up from the 16 seen in natural yeast.
The papers detailing the new work consist of an overview paper and five papers describing the first assembly of synthetic yeast chromosomes synII, synV, synVI, synX, and synXII. A seventh paper provides a first look at the 3D structures of synthetic chromosomes in the cell nucleus.
The overview—“Design of a synthetic yeast genome”—has two corresponding authors, Jef D. Boeke, Ph.D., a geneticist at NYU Langone Medical Center, and Joel S. Bader, Ph.D., a biomedical engineer at Johns Hopkins University School of Medicine. This paper describes the plans for Sc2.0, a Saccharomyces cerevisiae genome that has features significant modifications. For example, it was reduced in size by nearly 8% with respect to its natural counterpart, and it was altered with 1.1 megabases of deleted, inserted, or altered genetic material.
“Sc2.0 chromosome design was implemented with BioStudio, an open-source framework developed for eukaryotic genome design, which coordinates design modifications from nucleotide to genome scales and enforces version control to systematically track edits,” wrote the article’s authors. “To achieve complete Sc2.0 genome synthesis, individual synthetic chromosomes built by Sc2.0 Consortium teams around the world will be consolidated into a single strain by ‘endoreduplication intercross.’ Chemically synthesized genomes like Sc2.0 are fully customizable and allow experimentalists to ask otherwise intractable questions about chromosome structure, function, and evolution with a bottom-up design strategy.”
The synthetic genome is designed for customization, so scientists can study questions related to the structure, function, and evolution of chromosomes that are otherwise too difficult to answer. For example, Dr. Bader noted, the Sc2.0 genome is equipped with a biochemical system, SCRaMbLE, that allows researchers to simultaneously explore the outcomes of numerous variations in the copy number of genes so that the yeast strains will make more or less of particular proteins of interest.
Another exciting feature of Sc2.0 involves the three-letter codes, known as codons, used to make proteins from DNA. Natural yeast has three stop codons that signal to protein-making machinery that a protein is finished, but Sc2.0 has been designed with just one. “This gives us the freedom to use the unused codons to essentially extend the genetic code for a particular purpose,” Dr. Bader explains.
Also, if the synthetic version looks compromised at any point in the integration process, investigators can look over the synthetic sequence to find and replace a faulty piece of the genome, much as programmers “debug” computer code that contains errors.
The overview paper concluded by noting that the next design frontier could involve living systems that will be less and less similar to native genomes and more like de novo designs.
“This work sets the stage for completion of designer, synthetic genomes to address unmet needs in medicine and industry,” said Dr. Boeke. “Beyond any one application, the papers confirm that newly created systems and software can answer basic questions about the nature of genetic machinery by reprogramming chromosomes in living cells.”
Many technologies developed in Sc2.0 serve as the foundation for GP-write, a related initiative aiming to synthesize complete sets of human and plant chromosomes (genomes) in the next 10 years. The largest synthetic chromosome constructed to date is still 1/3,000th of what would be needed to build a human genome molecule, so new techniques will be needed.
Cue the next synthetic genome progress bar.