Thursday, 1 April 2021

Making Artificial Life. A Cell With A Minimal Synthetic Genome That Lives and Replicates Normally

Some of the first synthetic Mycoplasma bacteria produced by Craig Venter and his colleagues
Credit: Thomas Deerick, NCMIR/Science Photo Library
Genes necessary for cell division in modern bacterial cells identified | J. Craig Venter Institute

Scientists at the J. Craig Venter Institute at the Massachusetts Institute of Technology (MIT) have now produced an artificial cell that reproduces like any other single-celled organism.

In 2010 Venter produced the first cell with a synthetic genome when he constructed a genome that was almost identical to that of Mycoplasma mycoides, a bacterial parasite commonly found in goats.

In 2016, this genome was, stripped it down to its bare essentials to contain just 237 genes, to become the smallest known viable genome capable of independent living. However, there was something not quite right about the way this cell (termed Mycoplasma mycoides JCVI-syn3.0) because when it replicated, the daughter cells were not equal in size, as they are in the wild type and in Venter's 2010 version (JVCI-syn1.0). It became apparent that some genes needed for normal replication had been removed along with about half the genome to reduce it down to 237 genes.

Now, after a painstaking trial and error process, Venter's team have identified the seven missing genes to produce the latest version.

In fact, the clue which helped narrow the research down to just those seven was in a mutant version of JVCI-syn3.0, JVCI-syn3A which reproduced normally. This mutant was found to contain 19 additional genes. The missing seven essential ones were found in these 19. However there was a surprise: of the seven genes now know to be needed for normal replication, only two have a known function - ftsZ and sepF - the other five have an as yet unidentified role in cell reproduction.

As Dr. Elizabeth Strychalski, (lead author) of National Institute of Standards and Technology, Gaithersburg, MD, USA, stated
Designing whole genomes to achieve desired phenotypes stands as a grand challenge in synthetic biology. But our capacity to synthesize and modify genomes has rapidly outpaced our ability to predict phenotype from genotype for large-scale genome design. Our work uses reverse genetics to understand the function of genes of unknown function involved in the basic cell processes of controlling cell size and shape, and cell division. Every gene we are able to pair with its function gets us closer to realizing the goal of designing genomes for engineering cells.
The team's research findings were published a few days ago in Cell, regrettably, behind an expensive paywall. However, the abstract can be read here.

In case you're wondering what the point of synthetic genomes like this is, the JCVI's news release has the following:
JCVI-syn3.0 and JCVI-syn3A now provide a robust platform for investigating how modern cell division and cell size evolved. The synthetic cell and minimal cell are being used by over 40 labs worldwide. Among those research studies there are adapted laboratory evolution experiments being done by Bernhard Palsson’s lab at University of California, San Diego and Jay Lennon’s lab at the University of Indiana, research into membrane composition work being done in James Saenz’s lab at the Technische Universität Dresden, and whole cell computational modeling being done by Zan Luthey-Schulten’s group at the University of Illinois Urbana-Champaign. The cells are even being explored for commercial application.

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