Making it as easy to write DNA as it is to read it

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September 2020 – Synthetic DNA is used for all kinds of things today. In research, it has helped elucidate how DNA works in biological systems and enabled metabolic and protein engineering processes. Oligos — short strands of synthetic DNA or RNA — are the starting point for many molecular biology applications, including PCR testing for diseases and next-generation sequencing. And the emerging field of synthetic biology is built upon our ability to write (or “print” or “synthesize”) made-to-order DNA to make bio-based materials, fuels and medicines.

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A Key Bottleneck in Biology

The traditional way of synthesizing DNA is using a method called phosphoramidite chemistry, developed in the 1980s. Each nucleotide base is added one at a time, and a protecting cap is added to keep the base from reacting until a new base is added. Companies such as Twist Bioscience, an Illumina Ventures portfolio company, have made vast improvements to the scale and cost of oligo manufacturing through miniaturization and automation but still rely on a capital-intensive and centralized model using traditional phosphoramidite chemistry.

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The longer the oligo, the more likely errors will be introduced, meaning that 300 bases is about the longest that can be reliably synthesized in a single run. Longer fragments need to be stitched together in a tedious process called DNA assembly. For applications that require DNA, this translates into very practical limitations: DNA is expensive, turnaround time can be long and some sequences are very difficult to make.

Pioneering a New Approach

DNA Script is pioneering a new approach to solve these challenges: enzymatic DNA synthesis (EDS). The basic idea comes from a simple observation: nature is exceptionally efficient at synthesizing DNA. When bacteria replicate their genomes, they couple millions of nucleotides together in less than 20 minutes (the average time of cell division) and make very few mistakes. They do so by using very efficient enzymes called polymerases. Polymerases are small "robot-like" molecules that are present in every living cell, dedicated to one task: synthesizing DNA. They have been optimized through billions of years of evolution to be extremely efficient in catalyzing the addition of nucleotides to a strand of DNA. This process can be very fast, as much as one nucleotide addition every millisecond. And the process doesn’t require chemical solvents, so there is no chemical waste.

Enzymatic DNA synthesis will enable the fast, accurate and decentralized writing of DNA that will lead to a wave of innovation in biomedical research and industrial and agricultural biotech. In drug discovery, the writing of high-quality fragments of DNA that are 400 bases in length or longer will enable antibody engineering in days rather than months. The cellular engineering needed to produce new kinds of fibers for clothing or food products that provide greater nutrition with fewer resources will be much more efficient. The ability of clinical labs to rapidly synthesize patient-specific tests will streamline confirmatory diagnosis of genetic diseases following whole exome or whole genome sequencing, enabling potentially life-saving treatments to start sooner. Eventually, it may be possible to make patient-specific gene and cell therapies on demand for the ultimate personalized medicines.

A Transformational Product

DNA Script is applying its EDS technology to a transformational instrument that enables faster, cleaner, more accurate DNA writing and puts it right in the hands of researchers. The SYNTAX™ EDS system was inspired by the wide availability of in-lab and benchtop next-generation sequencing systems and the impact they have had on genomics research and personalized medicine.

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“This first-of-its-kind DNA printer makes writing DNA as simple and straightforward as reading DNA.  Research and clinical labs will be able to do same-day synthesis of oligonucleotides, saving precious time when it comes to iterating experiments or developing diagnostic or confirmatory tools. In light of the COVID-19 pandemic, laboratories all around the world have experienced the importance of controlling their supply of synthetic DNA as a critical reagent, in several cases turning to DNA Script to support their efforts to develop diagnostic tests. The current global pandemic has made clear the value of in-lab tools like the SYNTAX system to enable quick research iteration without relying on centralized distributors that can be hampered by capacity and shipping bottlenecks.

“DNA Script’s enzymatic synthesis technology will be a foundational technology for a 21st-century biological revolution,” said Nick Naclerio, founding partner at Illumina Ventures. “In the near term, DNA Script’s SYNTAX system will enable clinical and research labs to print DNA using the company’s enzymatic synthesis technology as the ink. In an era of severe disruption to centralized systems and the supply chain, I can’t imagine a more vital tool for moving biological research and development forward.”

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DNA Script is about to start testing the SYNTAX system with a select group of partners, with plans to launch a beta testing program later this year.

DNA Data Storage – The next frontier

One of the most significant opportunities for DNA Script is its work on a technology even further out on the leading edge of science: DNA data storage.

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Massive amounts of digital data are being generated every day, and emerging technologies such as autonomous cars and artificial intelligence will further increase the need for data storage at unprecedented scales. DNA is extremely durable and has a much greater information density than magnetic storage technologies: DNA can hold a billion terabytes of information per cubic centimeter – about the size of a sugar cube. Furthermore, because of the role DNA plays in sustaining life, it is a technology that will never be obsolete.  Along with partners at the Broad Institute and Harvard, DNA Script has been awarded a grant from the Intelligence Advanced Research Projects Activity (IARPA) to develop a prototype instrument able to store and retrieve 1TB of information in 24 hours.

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“The results DNA Script has already obtained in making functional DNA today is impressive, but even more inspiring is the company’s vision of a tomorrow with manufacturing platforms focused upon massively parallel synthesis of longer, high-fidelity nucleic acids — a vision that holds great promise for completely transforming the molecular and synthetic biology solutions market while enabling the data-intensive technology of tomorrow,” added Nick.