Enzymatic DNA synthesis gets a significant new player

The synthetic DNA maker Twist Bioscience announced at the J.P. Morgan Health Care Conference earlier this month that it is developing enzymatic DNA synthesis technology. The revelation—by a major player in chemical DNA synthesis—offers validation that the new technology is here to stay.

“It doesn’t matter if chemical synthesis is better or enzymatic synthesis is better,” Twist CEO Emily Leproust said at the conference. “We have it, and we can continue to dominate the DNA synthesis market.”

Twist shook up DNA synthesis about 7 years ago, when it introduced a method of conducting phosphoramidite chemistry on silicon chips rather than in traditional well plates. More recently, a group of start-ups has been trying to improve on the decades-old chemical process by using enzymes to make DNA. Those technologies are still in the earliest stages of commercialization.

Companies working on synthetic biology, gene sequencing, pharmaceuticals, and next-generation data storage all need synthetic DNA, and demand is increasing as those industries mature.

Twist’s move follows a $200 million investment earlier this month in the benchtop DNA printing company DNA Script, which uses enzymes. In addition, Codex DNA recently announced it is working with Pfizer to use enzymatic synthesis for vaccine research.

DNA Script CEO Thomas Ybert, whose company received an investment from the chemical DNA maker Agilent Technologies in 2020, says it’s only a matter of time before enzymatic synthesis wins out. “It’s going to be better in every aspect,” he says.

Leproust argues that, for the moment, chemical synthesis is cheaper and more accurate, and can produce longer strands of DNA. “The real fatal flaw of enzymatic synthesis is around the cost,” she said at the conference.

Twist hopes to lower the cost of enzymatic synthesis by reducing the amount of expensive nucleoside triphosphate (NTP) needed during the process. Incorporating NTP into a strand of DNA also normally leaves a scar, but Twist claims that its process doesn’t scar the DNA.

The company has yet to use enzymatic synthesis for any commercial products. Leproust tells C&EN that the process isn’t producing DNA strands that are as accurate or as long as the company wants.

Despite its limitations, Leproust says, enzymatic synthesis will be required for some products. “There will be settings where chemistry is going to be better. There will be settings where enzymes are absolutely needed,” she says.

One such setting is using DNA for digital information storage. Right now, companies have to send their data to Twist, which then manufactures a DNA-based storage chip at its own facilities.

Leproust says some companies don’t want to share their data, but phosphoramidite chemistry requires the use of harsh chemicals, making it difficult to set up the chip production process outside a specialized facility. The reagents used for enzymatic synthesis are more benign and could be used inside a data storage center.

Michael Kamdar, CEO of the enzymatic DNA synthesis company Molecular Assemblies, which received a $10 million investment from the enzyme engineering firm Codexis in November, says Leproust’s evaluation of enzymatic synthesis is unnecessarily gloomy. He maintains that enzymatic synthesis is better at building long strands of DNA, even though the technology is still young.

“There’s a limitation to the chemical synthesis,” Kamdar says. “We think that our technology has the ability to generate 150 nucleotides on up, which we think is a game changer.”

Bill Efcavitch, chief scientific officer at Molecular Assemblies, adds that Twist wouldn’t have invested in enzymatic synthesis if the firm believed it didn’t have much of a future.

Barry Canton, chief technology officer at Ginkgo Bioworks, a synthetic biology firm that is a major Twist customer, says he’s excited about the activity on enzymatic synthesis. The chemical process has been around for decades and is probably mature, Canton says. A major advance through enzymatic synthesis is likely years away, but he says Twist may be well positioned to make that happen.

“Twist’s entry into this space is significant,” Canton says. “Given everything they’ve been able to do successfully with phosphoramidite chemistry, that ups the odds that enzymatic synthesis can get to a new level.”