Synthetic Biology by the Letters

Synthetic biology has been in the news a lot lately—or maybe it only seems like it because I’m spending a lot of my time thinking about our partnership with the iGEM Foundation, which is dedicated to the advancement of synthetic biology. As the 2019 iGEM teams are forming, figuring out what their projects will be and how to fund them, it seemed fitting to share some of these stories.

A, C, T, G…S, P, Z, B?

Researchers recently developed four synthetic nucleotides that, when combined with the four natural nucleotides (A, C, T and G), make up a new eight-letter synthetic system called “hachimoji” DNA. The synthetic nucleotides—S, P, Z and B— function like natural DNA by pairing predictably and evolving.

While this development may seem superfluous, there are a handful of useful applications for extra letters in the DNA alphabet, such as DNA data storage. These applications hinge on the fact that doubling the number of nucleotides increases the number of possible codons from just 64 to 4,096.

The next step for scientists is developing the other molecular components necessary to read hachimoji and create synthetic proteins with novel properties and functions. Currently, humans make 20 amino acids; additional codons could mean the possibility of new amino acids and proteins with valuable characteristics.

ABEs and CBEs

While CRISPR-Cas9 always seems to be in the news, it has received a lot of recent criticism for its potential lack of specificity. Base editing is a technique that uses components of the CRISPR-Cas9 system to target specific nucleotides within a genome for point mutations, offering more precise and efficient gene editing.

Traditional CRISPR-Cas9 uses a guide RNA to target a specific gene sequence and recruit Cas9 nuclease to cut the DNA. This can be used to knock out a gene via indels created during repair or a desired sequence change can be introduced using a DNA template and homology-driven repair. Although indels usually result in conversion of greater than 50% of alleles, homology-driven repair has an efficiency of less than 1%.

Base editing uses Cas9 proteins modified to lack nuclease activity. These proteins are fused to enzyme domains that facilitate conversion of cytosines to thymines or adenines to guanines. Cytosine base editors (CBEs) convert C-G base pairs to T-A and adenine base editors (ABEs) convert A-T base pairs to G-C. (Check out this infographic of ABEs and CBEs.)

Guide RNAs then direct the CBE or ABE to a site of interest within the genome, which results in more precise editing by swapping out C-G base pairs for A-T or vice versa. Although it has comparable efficiency (ranging from 5-50%) to traditional CRISPR-Cas9, the real benefit to base editing is that it reduces the likelihood of off-target mutations since it doesn’t cut DNA.

This technique was originally developed for us in mammalian cells, but it was recently adapted for plants. This lab applied the technique by converting Arabidopsis thaliana to a late-flowering variety by base editing the gene for a single amino acid. Another lab created albino plants by altering a single splice site. This is an important development that expands the available toolkit for editing plant genomes.


Speaking of plants, Cannabis has also been in the news a lot lately—particularly one of its constituent compounds, CBD, which is being added to everything from beer to lip balm. Purifying cannabinoids like CBD or THC from all of the other plant products present can be challenging. By using microbes to produce these compounds through fermentation, the problem of contamination is eliminated.

A recent paper in Nature explains how one lab did just that. The lab modified yeast by introducing several genes for enzymes that convert galactose into CBGA, a cannabinoid. The yeast had also been transformed to contain genes that could make inactivated forms of either THC or CBD. Once the yeast had made their respective cannabinoid, they could be activated by heating the yeast.

This work is a proof-of-concept that the introduced genes can accomplish cannabinoid synthesis in a single yeast cell. To compete with plant-based production of cannabinoids, the yeast output would need to be scaled up significantly. In addition, this technique could be used to synthesize novel cannabinoids, which could be studied further and might lead to new medicines.


Biohackers have created a way to spy on synthetic DNA machines. They were able to carry out what they call an “acoustic side-channel attack” on common DNA synthesis instrument. By using an audio recorder, the researchers listened to the noise made by the machine while it went through the process of directing chemical reactions to assemble DNA sequences.

The unique sounds of the moving parts of the process—tubes, valves, liquids—moving in the machine were analyzed using machine learning models to identify what it “sounds” like when each nucleotide (A, G, T or C) is add to the sequence. While this approach isn’t something you would expect to occur outside of a research lab right now, it could be on the horizon.

Devices like voice assistants in labs with automated processes could be hacked to listen in and steal information. This could pave the way for stealing proprietary sequences related to novel synthetic biology. Looking to the future, this could also complicate the efforts to use DNA for data storage since the possibility of this kind of attack would raise security concerns.

Perhaps these feats of synthetic biology (or so many others I didn’t include) will inspire iGEM teams and other young scientists, setting them on a path to discovering other breakthroughs in the field.

We’re curious about what other synthetic biology discoveries are inspiring you—please let us know!

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Darcia Schweitzer
Darcia is a Content Lead at Promega. She earned her BS in Secondary Education at the University of Wisconsin Oshkosh, with minors in Biology and Spanish, and her MS in Biotechnology at the University of Wisconsin Madison. She is passionate about sharing scientific knowledge with all audiences, including her family and friends—whether they have solicited the lesson or not! In her free time, Darcia enjoys reading, playing volleyball, eating delicious food and cheering for the Chicago Cubs.

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