After constructing a synthetic genome, the challenge is to prove its functionality.
A major long-term goal of synthetic biology is to design a living organism with a minimal, redundancy-free genome, custom made for certain functions. The short-term challenge lies in assembling a whole genome, nonessential genes and all, from raw chemicals.
In 2008, technical breakthroughs were achieved for genome assembly. J. Craig Venter and colleagues used an in vitro recombination strategy to recombine oligonucleotide cassettes of 24 kb into larger modules and then moved to yeast for the final recombination steps to obtain the 582.9 kb genome of Mycoplasma genitalium (Science 319, 1215–1220; 2008). Similarly, the group led by Mitsuhiro Itaya assembled the 134.5 kb genome of rice chloroplasts with an in vivo recombination strategy in which domino clones of 4–6 kb are assembled in Bacillus subtilis (Nat. Methods 5, 41–43; 2008).
Testing these synthetic genomes for functionality will be the next step on the path to synthetic life. The Venter group had shown previously that they can swap the entire natural genome of M. mycoides for that of M. capricolum, and they are now looking to transplant the synthetic M. genitalium genome into M. capriolum—an endeavor not without technical challenges. It remains to be seen whether the synthetic genome assembled in yeast, and consequently not protected against bacterial restriction nucleases, will replicate and indeed encode a living bacterium. Another aspect that will need optimizing is codon usage. The genomic fragments should be nontoxic for the host within which they assemble. The completed genome, however, has to be transplanted into a final recipient that will translate the genetic code into functional proteins.
Understandably, this prospect of custom-building life raises concerns and, like any technology, it can evoke horror scenarios, but it also holds tremendous promise for both understanding biology and harnessing its power for technology and medicine.
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Rusk, N. Synthetic life. Nat Methods 6, 33 (2009). https://doi.org/10.1038/nmeth.f.237