An Ongoing Revolution in DNA Synthesis Could Help Build Genomes from Scratch

DNA Script, a French company, has announced a breakthrough in enzymatic DNA synthesis, a technique that may one day help scientists build genomes from scratch — though further research is required.

DNA is the blueprint that ensures life’s brilliant complexity and continuity. This chemical polymer is present in every one of our trillions of cells and, in some cases, a single change to a letter of DNA (A, T, C and G), can cause serious genetic illnesses, including cystic fibrosis and sickle cell anemia.

Dr. Alexander Todd, a British biochemist, was one of the first scientists to develop methods to chemically synthesize DNA polymers. Todd received the 1957 Nobel Prize in Chemistry for his work on nucleotide chemistry and DNA synthesis, most of which happened on the heels of Watson and Crick’s 1953 structure of DNA. Todd developed a method to synthesize DNA called H-phosphonate synthesis, which was quickly supplanted by more efficient chemical approaches.

By the 1970s, Dr. Marvin H. Caruthers, an American biochemist, had developed a far better way to synthesize DNA that still relied on chemical means, but was more efficient and stable than previous approaches. To this day, most companies that offer synthetic DNA use the Caruthers approach, which is called the phosphoramidite method.

There are some serious drawbacks to modern DNA synthesis methods, the most vexing of which is that the technology cannot be used to synthesize DNA strands with repetitive nucleotide sequences because they bunch up and halt the build process. This is a serious problem because the genomes of living organisms often contain long, repetitive DNA sequences. As scientists look to create entire genomes from scratch, which require millions or even billions of bases of DNA, drastically improved methods for DNA synthesis are required.

Last week, DNA Script, a company based in Paris, France, reported that they had successfully synthesized a DNA strand 50 nucleotides long using exclusively enzymatic approaches. This means that rather than employing the conventional phosphoramidite chemistry, they used proteins to synthesize the DNA for them without the need for expensive reagents and unstable intermediate sequences. While 50 nucleotides may not sound like a lot, and the technology is still nowhere close to the capabilities of phosphoramidite synthesis, the company was only able to synthesize a 3 nucleotide strand of DNA using this approach in 2015.

One important advantage that enzymatic DNA synthesis holds over phosphoramidite chemistry is that the technology, once scaled, will likely be much less expensive than phosphoramidite chemistry because it does not use costly (and environmentally-damaging) chemical reagents.

DNA Script are not alone in their endeavors to unlock a new, more efficient approach to DNA synthesis, either. Nuclera Nucleics, a company based in the UK that boasts Dr. George Church as a scientific advisor, is also competing for future market share.

The pace of enzymatic DNA synthesis research is progressing at a breakneck pace in academia, also — on Monday, Jay Keasling’s laboratory at UC-Berkeley reported an enzymatic DNA synthesis system that uses nucleotides tethered to polymerase proteins to extend DNA strands. This work, led by graduate students Daniel Arlow and Sebastian Palluk, demonstrates that the new enzymatic synthesis system can add a new base pair of DNA to a growing strand in 10–20s, and can do so without using toxic reagents from the phosphoramidite approach.

Though this enzymatic DNA synthesis method is still nowhere near as efficient or accurate enough for whole genome synthesis, it is only a matter of time before the genomes of organisms can be designed and built from scratch in a rapid, efficient manner — either using enzymes or conventional phosphoramidite chemistry.

The Yeast 2.0 consortium is an ongoing, international effort led by Dr. Jef Boeke, a geneticist at NYU Langone Medical Center, to build the genome of Saccharomyces cerevisiae, or baker’s yeast, completely from scratch using chemical methods. This project is particularly ambitious because yeast have over 12 million bases of DNA organized across 16 different chromosomes. Teams in Australia, China, the US, the UK and Singapore are each responsible for building part of the genome. The first synthetic chromosome for the Yeast 2.0 consortium was completed in March 2014. Since then, five additional chromosomes have been finished.

Baker’s yeast, which is used to brew beer and make bread, is the focal point of the Yeast 2.0 project, which aims to synthesize its entire genome using chemical DNA synthesis.

Never content to rest, scientists will continue to push the envelope of genome synthesis. One initiative, which is still in its infancy, is called GP-Write. Led in part by Drs. George Church and Jef Boeke, GP-Write aims to uncover guiding biological principles that will enable the rapid, cost-effective synthesis of large-scale genomes from scratch. As this consortium grows and continues to recruit leading scientists from around the world, it is only a matter of time before a human genome can be built completely de novo, possibly with the enzymatic DNA synthesis approaches that are being pioneered today.

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Science journalism at NYU. Previously Caltech, Imperial College. #SynBio newsletter: https://synbio.substack.com Web: https://nikomccarty.com

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