Synthetic biology

What I cannot create, I do not understand. – Richard Feynman

[Disclaimer: I am an amateur when it comes to synthetic biology, so if you spot mistakes in terminology or just sloppy expressions then please feel free to correct me.]

Synthetic biology is a topic that is being mentioned more and more frequently in scientific, but also mainstream, news. As with many things in life there is no one single, clean definition of this field of study. Broadly speaking, synthetic biology can either mean using existing building blocks (e.g. components of an organism’s DNA such as regulatory sequences or protein-coding sequences) to create new combinations, or to make up completely new biological building blocks (see, for example, the Editorial in Nature Methods, 2014 and a Q&A-style paper by Church et al., 2014).

Recently, a paper published in Science (Hutchison et al., 2016) made headlines: Craig Venter and his research team (or should I call it an army?) created the first fully synthetic cell. That is, they designed its genome, artificially synthesised its DNA and then transplanted it into existing cells, which subsequently lost their own genetic information, thus creating an entirely new type of cell. The cells were imaginatively called “JCVI-syn3.0” and look like this by scanning electron microscopy:

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JCVI-syn3.0 (scale bar: 0.2 µm) – image copied directly from Hutchison et al., 2016

Ignoring the fact that these cells were created almost entirely from scratch (the DNA did go into existing cells that already had a membrane etc.) in a Herculean effort, one of the interesting features of their genomes is that 17% of their genes have an unknown function. The cells have a minimal genome comprising 473 genes of which 83% can be classified into one of the following four functional groups: expression of genome information, preservation of genome information, cell membrane and cytosolic metabolism. So we do not even fully understand these simplest of all cells. This is in stark contrast to the (earlier) studies on bacteriophages (viruses that infect bacteria): here the so-called lambda phage is a good example of us understanding what each element of its genome does. An accessible account of how it works is given in Mark Ptashne’s 1986 book “A Genetic Switch”, which also, in some ways, paved the way for synthetic biology since it describes how knowledge of gene regulatory networks could be one day exploited to build new networks.

This means that Richard Feynman’s quote above does not hold completely true in the realm of synthetic biology. Funnily enough, when Venter & Co. first built semi-synthetic cells (Gibson et al., 2010) they used the four DNA codons (A, T, C, G) to incorporate small messages, the names of the authors of the paper and some quotes, including Feynman’s. However, according to this article in The Scientist they misquoted him as having written, “What I cannot build, I cannot understand.”

The example of JCVI-syn3.0 falls into the category of building something new from existing building blocks (genetic elements). However, other researchers are trying to expand the way cells work. For example, in a proof-of-principle paper Neumann et al., 2010 showed that they could expand the way ribosomes decode the famous genetic code. Normally, DNA in the form of messenger RNA is decoded in triplets (e.g. AUG represents a common start codon, which is translated into the amino acid methionine). Neumann et al. forced the evolution of a ribosome that can read the nucleotides in quadruplets. At the same time they managed to make these ribosomes translate the new codons into unnatural amino acids. This sort of approach may allow for the production of completely new proteins and molecules, which may, for example, have therapeutic applications. In fact, this has already been partially achieved for the anti-malarial drug artemisinin (see Paddon & Keasling, 2014 for a review).

Lastly, I would just like to add that part of my inspiration to read and write on the topic of synthetic biology came from a fellow PhD student, Aakriti Jain.  Until recently, Aakriti was an editor of the PLoS synthetic biology community, which aims to bring together scientists from different fields and allows them to communicate their research to a wider audience.

References:

Church GM, Elowitz MB, Smolke CD, Voigt CA, Weiss R (2014) Realizing the potential of synthetic biology. Nat Rev Mol Cell Biol 15: 289-294

Editorial (2014) Synthetic biology: back to the basics. Nature Methods 11: 463-463

Gibson DG, Glass JI, Lartigue C, Noskov VN, Chuang R-Y, Algire MA, Benders GA, Montague MG, Ma L, Moodie MM, Merryman C, Vashee S, Krishnakumar R, Assad-Garcia N, Andrews-Pfannkoch C, Denisova EA, Young L, Qi Z-Q, Segall-Shapiro TH, Calvey CH et al. (2010) Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome. Science 329: 52-56

Hutchison CA, III, Chuang R-Y, Noskov VN, Assad-Garcia N, Deerinck TJ, Ellisman MH, Gill J, Kannan K, Karas BJ, Ma L, Pelletier JF, Qi Z-Q, Richter RA, Strychalski EA, Sun L, Suzuki Y, Tsvetanova B, Wise KS, Smith HO, Glass JI et al. (2016) Design and synthesis of a minimal bacterial genome. Science 351: 1414-U73

Neumann H, Wang K, Davis L, Garcia-Alai M, Chin JW (2010) Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome. Nature 464: 441-444

Paddon CJ, Keasling JD (2014) Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development. Nat Rev Micro 12: 355-367

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