Science NONfiction: The story of synthetic bacterial genomes

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The story of synthetic bacterial genomes began with the question ,“What are the minimum genes required for life?” The ‘Minimum Genome Project’ began with the sequencing of the genome of Mycoplasma genitalium, one of the smallest self-replicating cells. After it had been determined that 100 of its genes were individually dispensable, scientists hoped constructing synthetic genomes could help to determine which of the genes were dispensable together.
In 2008, Daniel Gibson’s team assembled a synthetic M. genitalium genome - the first bacterial genome to be chemically synthesised. The team started with 101 DNA cassettes, each containing terminal sequences that overlapped with the adjacent fragments in the genome. Some cassettes also had identification sequences and another insertion was added to inhibit pathogenicity. A 5-stage assembly was designed to join the fragments together until the complete genome was formed. This was a great innovation that led to not only the first synthetic cell and minimal M. mycoides, but also many other synthetic cells.
The synthetic genome C. ethensis-2.0 was created by rewriting the genome of C. crescentu with synonymous substitutions within coding genes, and non-synonymous substitutions in other regions. Testing segments of the genome in other cells revealed new gene elements as well as errors in the annotations of the native C. crescentu genome. Syn61, a synthetic bacteria derived from E. coli, was engineered to only use 61 codons, with two serine and one stop codon completely removed. Despite this, Syn61 cells retained functionality, showcasing the redundancy of the natural 64 codon set.
However, the expansion of synthetic genomics has been limited by the expensive, time consuming initial genome assembly process. Bacteria have been engineered for decades to create vital compounds like insulin, and synthetic genomes could expand this to the production of new medicines or biofuels. One day, synthetic bacteria could even help to detect or treat a range of conditions like other bacterial infections, diabetes, or cancer.
Creator: Taylor Zwisler
References:
The minimal gene complement of Mycoplasma genitalium. Fraser CM, Gocayne JD, White O, Adams MD, Clayton RA, Fleischmann RD, Bult CJ, Kerlavage AR, Sutton G, Kelley JM, Fritchman RD, Weidman JF, Small KV, Sandusky M, Fuhrmann J, Nguyen D, Utterback TR, Saudek DM, Phillips CA, Merrick JM, Tomb JF, Dougherty BA, Bott KF, Hu PC, Lucier TS, Peterson SN, Smith HO, Hutchison CA, Venter JC. Science. 1995 Oct 20;270(5235):397-403. doi: 10.1126/science.270.5235.397.
Essential genes of a minimal bacterium. Glass JI, Assad-Garcia N, Alperovich N, Yooseph S, Lewis MR, Maruf M, Hutchison CA, Smith HO, Venter JC. Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):425-30. doi: 10.1073/pnas.0510013103.
Generating a synthetic genome by whole genome assembly: phiX174 bacteriophage from synthetic oligonucleotides. Smith HO, Hutchison CA, Pfannkoch C, Venter JC. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15440-5. doi: 10.1073/pnas.2237126100.
Complete chemical synthesis, assembly, and cloning of a Mycoplasma genitalium genome. Gibson DG, Benders GA, Andrews-Pfannkoch C, Denisova EA, Baden-Tillson H, Zaveri J, Stockwell TB, Brownley A, Thomas DW, Algire MA, Merryman C, Young L, Noskov VN, Glass JI, Venter JC, Hutchison CA, Smith HO. Science. 2008 Feb 29;319(5867):1215-20. doi: 10.1126/science.1151721.
Creation of a bacterial cell controlled by a chemically synthesized genome. Gibson DG, Glass JI, Lartigue C, Noskov VN, Chuang RY, Algire MA, Benders GA, Montague MG, Ma L, Moodie MM, Merryman C, Vashee S, Krishnakumar R, Assad-Garcia N, Andrews-Pfannkoch C, Denisova EA, Young L, Qi ZQ, Segall-Shapiro TH, Calvey CH, Parmar PP, Hutchison CA, Smith HO, Venter JC. Science. 2010 Jul 2;329(5987):52-6. doi: 10.1126/science.1190719.
Design and synthesis of a minimal bacterial genome. Hutchison CA, Chuang RY, Noskov VN, Assad-Garcia N, Deerinck TJ, Ellisman MH, Gill J, Kannan K, Karas BJ, Ma L, Pelletier JF, Qi ZQ, Richter RA, Strychalski EA, Sun L, Suzuki Y, Tsvetanova B, Wise KS, Smith HO, Glass JI, Merryman C, Gibson DG, Venter JC. Science. 2016 Mar 25;351(6280):aad6253. doi: 10.1126/science.aad6253.