Evolution of artificial cells shows that life finds a way

In the 1993 science-fiction film Jurassic Park, the titular theme park is home to living dinosaurs that gain the ability to breed — despite having been genetically engineered to be all female — thus fulfilling the prediction of chaos theorist Ian Malcolm that “life finds a way”. US researchers have now experienced a similar phenomenon with a synthetically constructed cell, which was found to evolve just as fast as a normal cell despite having a significant handicap.

The researchers were studying the synthetic organism Mycoplasma mycoides JCVI-syn3B — a minimised version of the bacterium M. mycoides, commonly found in the guts of goats and similar animals. Over millennia, the parasitic bacterium has naturally lost many of its genes as it evolved to depend on its host for nutrition — and in 2016, researchers at the J. Craig Venter Institute (JCVI) in California took this one step further.

The researchers eliminated 45% of the 901 genes from the natural M. mycoides genome, reducing it to the smallest set of genes required for autonomous cellular life. At 493 genes, the minimal genome of M. mycoides JCVI-syn3B is said to be the smallest of any known free-living organism; in comparison, many animal and plant genomes contain more than 20,000 genes.

In principle, the simplest organism would have no functional redundancies and possess only the minimum number of genes essential for life. Any mutation in such an organism could lethally disrupt one or more cellular functions, placing constraints on evolution. Organisms with streamlined genomes have fewer targets upon which positive selection can act, thus limiting opportunities for adaptation.

Although M. mycoides JCVI-syn3B could grow and divide in laboratory conditions, evolutionary biologist Jay T Lennon and his team at Indiana University Bloomington wanted to know how a minimal cell would respond to the forces of evolution over time, particularly given the limited raw materials upon which natural selection could operate as well as the uncharacterised input of new mutations. Speaking in reference to M. mycoides JCVI-syn3B, Lennon said, “Every single gene in its genome is essential. One could hypothesise that there is no wiggle room for mutations, which could constrain its potential to evolve.”

The researchers established that M. mycoides JCVI-syn3B in fact does have an exceptionally high mutation rate, and that it could evolve just as fast as a normal cell — even with an unnatural genome that would seemingly provide little flexibility. They then grew it in the lab, where it was allowed to evolve freely for 300 days — equivalent to 2000 bacterial generations or about 40,000 years of human evolution.

“It appears there’s something about life that’s really robust,” Lennon said. “We can simplify it down to just the bare essentials, but that doesn’t stop evolution from going to work.”

The next step was to set up experiments to determine how the minimal cells that had evolved for 300 days performed in comparison to the original, non-minimal M. mycoides as well as to a strain of minimal cells that hadn’t evolved for 300 days. In the comparison tests, the researchers put equal amounts of the strains being assessed together in a test tube. The strain better suited to its environment became the more common strain.

The team found that the non-minimal version of the bacterium easily outcompeted the unevolved minimal version. The minimal bacterium that had evolved for 300 days, however, did much better, effectively recovering all of the fitness that it had lost due to genome streamlining. Identifying the genes that changed the most during evolution, the researchers found that some of these genes were involved in constructing the surface of the cell, while the functions of several others remained unknown.

Understanding how organisms with simplified genomes overcome evolutionary challenges has important implications for longstanding problems in biology, including the treatment of clinical pathogens, the persistence of host-associated endosymbionts, the refinement of engineered microorganisms and the origin of life itself. The work done by Lennon and his team, which has been published in the journal Nature, demonstrates the power of natural selection to rapidly optimise fitness in the simplest autonomous organism, with implications for the evolution of cellular complexity. In other words, it shows that life finds a way.

Image caption: Electron micrograph of clusters of JCVI-syn3.0 cells magnified about 15,000 times. Image courtesy Tom Deerinck and Mark Ellisman of the National Center for Imaging and Microscopy Research at the University of California at San Diego.