Mar 28, 2013

Update on Synthetic Biology II




Last year, I wrote about the "mainstream fronts" of development of Synthetic Biology: DNA synthesis and synthetic life, standard biological parts, genetic code expansion, synthetic genetic circuits and metabolic engineering. 

Aside from the noise in the media, I think that, for us to gain perspective and better guide those who get in touch with Synthetic Biology for the first time, it could be of some use to recall recent advances on those "fronts".

DNA synthesis, synthetic life and minimal genomes - nowadays, one can have genes synthesized for around $ 0.30 USD per base pair. This may lead the newcomer to think that we have effectively surpassed the limitations imposed by the "classical" cloning protocols.

Again, we have to be cautious we this kind of exaggerated enthusiasm, but I'll deal with this later in the gene circuit section. What I'd like to expose here are the advances on synthetic life and the quest for the minimal cell.

In 2012, a report was published where the authors claimed they synthesized a molecule different from DNA that was able to transmit genetic information and evolve. Vitor Pinheiro, from the Philipp Holliger group, successfully changed the specificity of some polymerases through directed evolution to make them able to use other chemical structures instead of the regular nucleotides (adenine, thymine, guanine and cytosine). In this way, molecules called "XNA" (xeno-nucleic acids) were polymerized. The implications of this advancement are interesting: from the generation of aptamers that can be used as sensors or actuators, to the possibility of modifying biological systems -even whole organisms- in new ways, without the  eventual release of this new genetic molecules being a risk for natural living organisms.

Some months afterwards, a review by Pinheiro and Holliger was published; they wrote about the work on XNAs and gave us their own insights on the potential applications in the generation of novel ligands, catalysts, biomaterials and alternative genetic systems to those based on DNA and RNA.

In other area of the research on synthetic life ...
is the research being done to define the universal minimal cell, which is of special interest for the construction of synthetic biological systems.


In a review published in 2013, Dr. Pasquale Stano and Dr. Pier Luigi Luisi from the University of Rome give us an excellent overview of the current research on semi-synthetic minimal cells. Dr. Stano and Luisi talk about "the physics of solute encapsulation in liposomes, the attempts to generate a self-reproducing synthetic cells and the focus shift from single compartments to colonies". 


It would be interesting to combine the random polymerization of biomolecules, some environmental pressure -of course, under a directed evolution scheme- and the experiments with vesicle communities and... why not? Maybe also alternative genetic systems, like those made by XNAs and other polymers.

Now, talking about minimal genomes...
already in 2010 we saw the bacteria with the synthetic genome generated by researchers from the JCV Institute; this development was presented as a platform to study essential genes. Nevertheless, the very concepts of "essential genes" and "minimal universal cell" are now questioned.


In another review, this time from 2012, Dr. Carlos Acevedo-Rocha and some of his colleagues make us see why the quest for the "minimal universal cell" may lead nowhere. They do so by pointing out that comparative genomics studies have reported practically no essential gene -in terms of conserved orthologs- when a thousand genomes are compared and that those studies that combine experimental data with in silico analysis report contrasting results.

Because the essentiality of a gene depends on its genomic context -i.e., the interactions with other genes and the effects of such interactions- and its environmental context -like the presence or absence of an essential amino acid- it is likely that a minimal universal genome does not exist.

Dr. Acevedo-Rocha tells us in his review that to define a "minimal genome" maybe it is more useful to talk about "persistent genes" rather than "essential genes".

Persistent genes are those that are shared by a group of organisms and whose function is so fundamental that it is very likely to find at least one gene family with such function in different genomes. They also have characteristics, such as being expressed at a high level and usually being on the leading DNA strand.

Dr. Acevedo-Rocha and his colleagues then define the concepts of "cenome" and "paleome" in the light of the concept of persistent genes -they do so using the example of a bacteria species and its different strains- and how they are related to the concepts of a pan-genome and a metagenome.

The last figure of the review condenses the main ideas exposed on the text: a conceptual framework where the minimal set of genetic information that is able to sustain life is defined by genetic functions -not by genes per se- and where the additions to that minimal set are specializations adapted to a particular environmental context.

It's likely that we start seeing less and less studies focused on finding a minimal universal set of genes and more studies that approach and deepen the concepts of persistent genes and  "degree of essentiality" of a gene considering different environmental and genomic contexts.

MLS