The minimal genome of Craig Venter’s Syn3.0

The J Craig Venter Institute has published a paper detailing the genome of their new Syn3.0 synthetic organism. The major accomplishment was to construct a viable cell with a synthetic, extremely small genome: only 473 genes and about 500 kbp.

Even though it is considered to be fully “synthetic”, this genome is not built from scratch. Instead, the starting point is the Mycoplasma genitalium bacterium, from which genes and regions are deleted to produce something that is much smaller, but still viable. This means that even this fully synthetic genome still contains regions and functionalities that are not fully understood. M. genitalium was also the basis for JCVI’s Syn1.0, which was produced in 2008, but the genome of Syn3.0 is the smallest so far – “smaller than that of any autonomously replicating cell found in nature”. Syn3.0 should be a very valuable starting point for developing an explicit understanding of the basic gene frameworks needed by any cell for its survival – the “operating system of the cell” in the words of the authors.

Since so many genes are still basically not understood, the authors could not rely entirely on logic and common sense when choosing what genes to remove. They used an approach that introduced random mutations into the starting organism, and then checked which mutations where viable and which were not. This allowed them to classify genes as essential, inessential or quasi-essential (!). The deletion of essential genes would cause the cell to simply die. The deletion of quasi-essential genes would not kill it, but would dramatically slow its replication rate, severely crippling it. The final Syn3.0 organism has a doubling time of about 3 hours.

Some of the points I took away from this readable and interesting paper were:

Synthetic biology methods are starting to resemble software development methods. The authors describe a design-build-test (DBT) cycle that involve several nontrivial methods, such as in silico design, oligonucleotide synthesis, yeast cloning, insertion into the bacteria, testing, and then (perhaps) sequencing to go back to computers and figure out what went wrong or what went well. Thus, a feedback loop between the cells and the in silico design space is set up.

A very small genome needs a very tightly controlled environment to survive. The medium (nutrient solution) that Syn3.0 lives in apparently contains almost all the nutrients and raw materials it could possibly need from its environment. This means that many genes that would normally be useful for overcoming adverse conditions, perhaps for synthesising nutrients that are not available from the environment, are now redundant and can be removed. So when thinking about genome design, it seems we really have to think about how everything relates to a specific environment.

The mechanics of getting a synthetic genome into a living cell are still complex. A huge amount of wet-lab (and, presumably, dry-lab) processes are still needed to get the genome from the computer into something viable in a cell culture. However, things are going much faster than in 2008, and it’s interesting to think about where this field might be in 2021.

 

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