Life has been evolving on earth for about 3.7 billion years. And in spite of its diversity, all living things have one thing in common – DNA, a fundamental code containing just four chemical letters; adenine, thymine, guanine, and cytosine. A fifth base–uracil–replaces thymine under certain conditions, but the core genetic alphabet of every organism throughout time, from bacteria to brontosauruses has been four nucleic acid bases. That is, until now. Synthetic biologists from the Scripps Research Institute in California have, for the first time, created semi-synthetic E. coli bacteria, with a 6-letter genetic code. That might sound like something out of Jurassic Park, but even in Jurassic Park the cloned dinosaurs were coded using A, T, G and C. These new semi-synthetic organisms are an entirely new variation on life. The two synthetic bases that have been added are dNaM and dTPT3, but for short they’re called X and Y. The team have been hunting for the right chemical candidates to add to DNA since the 1990s. Any successful addition to the base pair family would need to match their ability to stick and unstick as the double strand of DNA zips and unzips, while fooling the cell’s own repair machinery into thinking it belongs there. The team had come up with base pair candidates by 2008, but the next challenge was getting them in a living organism. In 2014, the geneticists managed to slip versions of X and Y into the circular plasmid ring of DNA in an E. coli bacterium. While the E. coli managed to hold onto the new bases for a short period and even reproduce, it eventually rejected them. Now the E. coli they’ve created aren’t just stable, they’re healthy and capable of growing. Right now, these new types of E. coli can’t do much more than copy their unique string of genetic code. So what’s the point of adding more letters? Well, it changes a lot. And to understand that, we need to go back to the earliest days of DNA discovery.

While history has made names such as James Watson, Francis Crick, and Rosalind Franklin synonymous with the discovery of the physical structure of DNA, the global search for such a chemical coding system was inspired by a name better known for his account of a dead-but-not-dead cat. That’s right, in 1944 the physicist Erwin Schrodinger, delivered a lecture series on how ordinary matter can create complex living organisms, and one question he asked, is how could genetic information be stored? His solution was something called an aperiodic crystal– –a chemical with a repetitive structure, but with variations for encoding genetic information. He felt such a material could easily fit inside a cell, and hold enough information to describe incredibly complex chemical machines. So the search was on on to identify this aperiodic crystal, and its variable pattern of interlocking chemicals. And wrapped up in the dark insides of the cell’s nucleus, Deoxyribonucleic acid was the perfect candidate. But it took Watson and Crick using Franklin’s X-ray diffraction images, to show how ideal its structure was for containing such a code. So for the past half-century, we’ve understood how vast complexity can arise in living organisms using a remarkably simple code. When the four letters of DNA are put together in short combinations of just three letters, those four chemicals can create 64 unique chemical words, or codons. These link together in extensive sentences to produce a seemingly endless variety of genetic sequences, coding for a multitude of proteins and genetic programs. So adding new bases seems like overkill when we can already do so much. Yet the important thing about these new letters is their uniqueness. Found nowhere else in nature, organisms coded with them offer scientists an unprecedented level of control.

The next step is getting these new bases to make changes to the organisms themselves. New amino acids could be designed to be activated by the new genetic codes, amino acids which could be used to make new therapeutic drugs. But should we be concerned about this new form of life? Given the artificial nature of these new X and Y bases, even the hardiest synthetic specimens can’t survive outside the lab. That’s because the organisms can’t produce X or Y on their own and there’s no supply of X and Y in nature. In fact, te team has shown in multiple experiments that if X and Y aren’t provided, the semi-synthetic E. coli die every time, so there is no risk of them getting out and spreading these new bases into the gene pool. In many ways, this research is about enhancing the safety of biotechnology, by providing more ways to control new organisms. It’s not yet clear how far this work will or should be allowed to progress, it’s still very early days, but, one day in our future, people might look back and think it was quaint there was a time the only genetic letters scientists could work with, were the ones nature provided for us.

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