Four DNA bases good, six better

The biological world thrives on variation. Organisms vary widely within a single species, and evolution uses this to produce yet more variation through speciation. 

It’s hard to make sense of.

There is one constant, however: all living things use the genetic alphabet of guanine, cytosine, adenine and thymine, better known as G, C, A and T. These four nucleobases come together via hydrogen bonding to form distinctive base pairs, and together they comprise the language of genes and the building blocks of DNA.

New research, however, might be about to change all this.

While it’s fair to say that the last common ancestor of all life must have used this language, other genomic systems may have arisen, written in different tongues, but fell by the wayside over evolutionary history. 

Now the emerging field of synthetic biology is seeking to explore such exotic genetic languages. A team from the Scripps Research Institute in California and the private company Synthorx, led by Yorke Zhang and Floyd Romesberg, has announced in the journal Nature the creation of the first stable and fully functioning bacteria that comprises not four base pairs, but six. 

Synthetic biology is an interdisciplinary field that takes in biological and engineering disciplines. While there is no consensus definition, a 2012 paper argues it is “best understood as the rational design of biological systems and living organisms using engineering principles”. 

There is an array of applications: biomedical therapies, biological computers, nanotechnology, synthetic life (like Craig Venter’s Mycoplasma laboratorium) and novel materials and industrial processes, among them.

According to Zhang and Romesberg, synthetic biology’s central goal “is to create new life forms and functions, and the most general route to this goal is the creation of semi-synthetic organisms whose DNA harbours two additional letters that form a third, unnatural base pair”.

And that’s exactly what they’ve done. 

In 2014, the researchers reported the construction of such a semi-synthetic strain of E. coli with six base pairs. The additional artificial letters are designated dNaM and dTPT3, and, importantly, do not bond via hydrogen. Due in part to this unique chemistry, it was unclear whether these synthetic base pairs could be used to encode proteins as well as natural pairs.

Their current research demonstrates, however, that it can do just that. Despite hydrogen bonding being replaced with other mechanisms, such as packing and hydrophobic forces, “the unnatural codons can be decoded as efficiently as their fully natural counterparts.” In fact, the authors have shown that this novel system can store and retrieve an increased amount of genetic information.

And they don’t plan to stop there.

Given their experimental success, the team speculate that, with the aid of CRISPR gene editing technology, a wider range of unnatural base pairs could be incorporated into semi-synthetic bacteria, producing any number of artificial proteins. Their six-letter bacterium “is likely to be just the first of a new form of semi-synthetic life that is able to access a broad range of forms and functions not available to natural organisms.”