Synthetic genomes and the myth of perfection

The genome (genetic material) of an organism constitutes a major element of the transmissible information enabling the

and of its individuals. Since the synthesis in 2008 of the first complete synthetic genome, that of

,

. However, de novo synthetizing a genome is only a first step towards the creation of synthetic living organisms, in the sense that it is still impossible to reconstruct a living being without having, in addition to the genetic information, a natural cellular host structure able to accept it and provide a suitable expression environment. It is nevertheless a

which, even if there is still a long way to go, could be extended to a very wide range of species including not only microorganisms, but also plants, animals, and ultimately man. Concerning the latter, it is no longer altogether science-fiction, as evidenced by the emergence, recently mediatized at Harvard in the USA, of a consortium of scientists seriously considering the possibility of the complete synthesis of a human genome.

In what way is it more than a simple extrapolation, to different scales, of natural genome engineering as practiced for years by biotechnologies? Beyond the technical approaches implemented, some of which can be innovative, the major difference lies in the purposes.

in an organism of industrial interest or with a therapeutic objective, for example in the case of gene therapy. In contrast, and beyond the challenge and what it can bring in terms of knowledge of life’s “logic”,

is more often governed by an “idealization” rationale aiming at recreating an organism if possible

. It should then serve as an

. In other terms, creating an organism in the image of our current or future needs and not of those having ruled over natural evolution.

Credits: image of the film Splice produced by Vincenzo Natali – source Internet

At this stage, it should be recalled that the size of a genome is very variable (factor from 1 to 10 000) and is not only related to the physical or functional complexity of the organism. The genes that encode proteins and which are the easiest functional blocks to define represent only a small fraction of the information present. Their number varies relatively little from one organism to another (factor of 5 between E. coli and man). The large genomes contain therefore a majority of so-called non-coding DNA whose long-neglected role is in fact multiple: it intervenes in particular through micro-RNAs in many regulation mechanisms, often still poorly characterized, but critical for the organism. More generally,

The notion of

is often associated with that of synthetic genome. The rationale seems simple: to keep only the essential, since genome size is extremely variable even for organisms with similar functions. In fact, the definition of this minimum is complex. Whereas defining the genes performing the basic

of an organism is relatively easy, the myriad of other information encoding the

and the auxiliary genes or duplications is another matter. These mechanisms are critical for an organism’s

and compose critical elements for applications in industrial biotechnology. Neglecting them is in particular one of the main causes of failure during process upscaling. This interaction network defines the function of a genome as a whole and makes it

. Defining the optimal structure of these networks is now a major objective of synthetic genome design, in particular through the setting up of artificial recombination mechanisms catalyzing the random rearrangement of the functional elements. The associations so created are then compared to the characteristics of the corresponding organism to identify the critical couplings. Nevertheless, the

, that of genomes drawn by the hand of man for man, that would surpass in every respect the creations of nature, may seem to be a pipe dream.

, themselves constrained by the DNA coding capacity. The latter may seem mathematically almost infinite but it is in fact strongly limited by the very nature of biological mechanisms. The natural solutions probably owe in part their complexity to adaptation and evolution constraints that are generally not necessary or desirable in the context of an industrial process. There is scope for simplification but defining its rules and parameters still remains a challenge. The choice between a

design which claims to be “humanly” rational and the editing, even complex, respecting the solutions retained by nature, remains a difficult choice, especially since the recent development of natural genome editing technologies such as CRISPR-CAS9 greatly facilitates the second approach.

More information:

• Rewriting the blueprint of life by synthetic genomics and genome engineering. Genome Biol. (2015) Jun 16;16:125. doi: 10.1186/s13059-015-0689-y.
• Blogs on synthetic genomes: http://blogs.plos.org/dnascience/2016/03/24/craig-venters-synthetic-genome-3-0-evokes-classic-experiments/
• Minimal genome: https://www.aaas.org/news/scientists-reduce-genome-synthetic-cell-down-genes-essential-life http://science.sciencemag.org.gate1.inist.fr/content/sci/351/6280/aad6253.full.pdf
• Ethical aspects: Freedom and Responsibility in Synthetic Genomics: The Synthetic Yeast Project. Genetics (2015), Vol. 200, 1021–1028.
• Synthetic human genome project: http://www.nytimes.com/2016/05/14/science/synthetic-human-genome.html?_r=1