This Desktop Machine Is About To Transform The Decades-Old DNA Synthesis Industry

There is so much happening in the field of DNA synthesis these days that it can be hard to keep up. Just a few weeks ago, synthetic biology startup Molecular Assemblies announced that they are shipping DNA orders made with fully-enzymatic synthesis technology and Ansa Bio synthesized the longest continuous DNA piece. These and other companies are racing to provide cheaper, longer, and cleaner DNA – the lifeblood of the bioeconomy. But despite all the progress, there is still one major problem that is impossible to circumvent: the centralized DNA synthesis model creates an inherent bottleneck when it comes to speed and ease of access.

As a seasoned player in the synthetic biology industry and a former heavy DNA user, Thomas Ybert, CEO and co-founder of DNA Script, knows all too well about the frustrations of having to wait for DNA to be shipped to you. I caught up with Thomas ahead of the SynBioBeta conference in May where DNA Script will be showcasing its latest instrument. His advice to newcomers in this field is not to let someone else control your access to DNA: “There are things you can control and others you cannot. But the most critical part of your business is what should be under your control,” Ybert is convinced.

And what better way to empower the end-user than to enable them to make their own DNA on demand? The idea of a desktop DNA printer that you can have right in your lab has fascinated researchers for a while. Now, their dreams are finally coming true, as companies like DNA Script, Kilobaser, and Telesis Bio have come out with their versions of portable DNA, RNA, and gene synthesizers. Looking ahead, Ybert thinks that DNA printers will become as ubiquitous as PCR machines or sequencers are today:

“Nobody would think about outsourcing PCR which is basically the photocopier of biology. Similarly, nobody should think about outsourcing the printing of DNA.”

From Champs-Élysées to Silicon Valley and Every Lab

Founded in 2014 in Paris, DNA Script has since then amassed close to half a billion dollars in funding and expanded its operations to South San Francisco to take on the hot U.S.-based synthetic biology markets.

DNA Script is disrupting DNA synthesis in more than one way. The company is the maker
maker
of the world’s first benchtop DNA printer, SYNTAX, which was released in June 2021. This machine can print DNA oligos up to 60 nucleotides long overnight, with no hands-on intervention. What is more, the platform is powered by enzymes that can put together DNA molecules from genetic “inks”— A, T, C, and G letters – in a water-based solution, avoiding the need for potentially hazardous solvents.

The enzymatic DNA synthesis technology is a game-changing and integral part of the SYNTAX platform. Its key player is an enigmatic enzyme called terminal deoxynucleotidyl transferase, or TdT for short. For years, scientists have been after it for its potential to revolutionize the way we make DNA and the folks at DNA Script were one of the first to finally unlock this capability:

“We worked closely with the team led by Marc Delarue at CNRS in Paris that discovered the 3-D structure of the TdT enzyme,” recalls Ybert. The enzymatic synthesis technology, developed in collaboration with the scientists at the French National Centre for Scientific Research (CNRS), turned out to be a crucial component of the company’s desktop platform, as it makes DNA synthesis much more predictable:

“The [chemical] DNA synthesis technology is powerful but it’s super difficult to obtain good results unless you are a fully skilled and experienced organic chemist,” says Ybert. DNA Script’s goal is to take the guesswork out of the equation and make DNA synthesis as easy and accessible as PCR is today: “If you are a biologist working, for example, at Moderna developing an mRNA vaccine, you don’t care about how to react phosphoramidite molecule with a growing chain of DNA – all you care about just doing your research, and testing as many mRNA candidates as possible.”

This is why the SYNTAX platform does not require any additional training and takes less than 15 minutes to set up. Once customers have the printer and the DNA kits from DNA Script, they choose the DNA sequences they want, upload those into the system, and then press run. A few hours later, depending on the length of the sequence, the DNA is ready to use.

Printing vaccines to stop emerging diseases – or man-made biological threats

Having access to DNA when you need it is not just critical for business – it is also essential for a successful and rapid response to emerging threats. In 2021, at the height of the pandemic, DNA Script partnered with Moderna to develop on-demand vaccines and therapeutics. With $5 million from DARPA, the companies worked to develop a mobile vaccine manufacturing platform, like a small factory that can be deployed anywhere and programmed on the spot to quickly produce vaccines and treatments to fight emerging viruses.

However, such a powerful technology could also present a threat in itself, with the possibility of misuse. Luckily, the SYNTAX System has built-in mechanisms to prevent potential bad actors from printing something that could be harmful: “What we are doing is super impactful and super powerful. And so clearly, it should be regulated,” Ybert thinks. DNA Script is prioritizing biosecurity, with dedicated personnel working to put in place mechanisms that would prevent its misuse. “For us, the three main pillars are: screen the customer, screen sequences, and, of course, our closed systems.”

With a closed system like SYNTAX, it is a lot easier to control how the platform is being used and what is synthesized on it than the current systems that use phosphoramidite chemistry: “This is a much-needed upgrade compared to what exists today. Nobody is really looking at who is using the [phosphoramidite] oligo synthesizers.”

Making writing DNA as simple as writing code

For this, and many other reasons, Ybert thinks the traditional phosphoramidite chemistry is poised to disappear soon: “This type of chemistry is super difficult to put in practice, whereas enzymatic DNA synthesis offers some best performances and is super accessible. This is the very reason why we have created this company: we think that access to DNA should be like writing code on a computer – super fast – to allow rapid iteration and foster innovation.”

The speed and accessibility have massive implications for applications like DNA data storage and many others. But as DNA becomes more and more like a commodity, we have to think about the environmental footprint of its production as well. And enzymatic technology is far superior in this respect:

“Ultimately when you order DNA through a website, you don’t care if it’s made enzymatically. The only thing you care about is turnaround time, price, and the quality of the product. And so we wanted to change that by providing full control, super-fast turnaround time, and a clean way to make DNA”, says Ybert. “With SYNTAX, you don’t need to have any skills or experience to get to the best DNA synthesis performances, which is a big, big differentiator.”

With speed, accessibility, and sustainability issues taken care of, scientists can focus on finding the perfect drug candidate for diseases or the next breakthrough biology innovation.

Thank you to Katia Tarasava for additional research and reporting on this article. I’m the founder of SynBioBeta and some of the companies I write about, such as DNA Script, Molecular Assemblies, Ansa Biotechnologies and Telesis Bio, are sponsors of the SynBioBeta conference and weekly digest.