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Camena Bioscience Eyes DNA Synthesis Market With 'TdT-Free' Enzymatic Technology


NEW YORK – Having closed a $10 million Series A financing round last month, synthetic biology company Camena Bioscience is poised to scale up what it calls a "unique and highly accurate enzyme-based DNA synthesis technology" to meet increasing market demand.

While the Cambridge, UK-based firm claims that its approach, termed gSynth, improves the quality and speed of DNA synthesis over existing methods, it is revealing little technical detail.

"We are quite secretive about these things, unfortunately," said Camena CEO and Cofounder Steve Harvey. "The way I describe it is that we use a cocktail of enzymes that are essentially TdT-free."

Short for terminal deoxynucleotidyl transferase, TdT is a vertebrate polymerase that, with some optimization, can add single nucleotides to the 3'-end of single-stranded DNA without a template.

Taking advantage of this characteristic, in recent years, a revolving door of companies — including DNA Script, Ansa Biotechnologies, Molecular Assemblies, and Twist Bioscience — have been engineering their versions of TdT to achieve de novo enzymatic DNA synthesis as an alternative to the traditional phosphoramidite-based approach, which typically involves harsh chemicals.

Harvey said Camena also started out by using TdT, but later the company realized that the enzyme "didn't work particularly well."

"In our hands, we actually found that [TdT] incorporated too many nucleotides, or it didn't incorporate any at all," he said. In addition, Harvey noted that the enzyme exhibited "a strong preference" for incorporating natural nucleotides rather than the modified nucleotide libraries, resulting in "more errors" compared with the traditional chemical synthesis.

After abandoning the TdT approach, Harvey said the company came up with a new technology named gSynth. He declined to further disclose the details of gSynth, however, other than referring to it as "a fermentation, aqueous, and enzymatic approach of making DNA."

With gSynth, Harvey claimed the company can produce a wide range of synthetic genes up to 6.5 kb long and is especially well-suited to tackle complex gene sequences that are hard to attain using existing methods. 

Camena asserted that its technology "offers increased accuracy" over existing phosphoramidite synthesis approaches, though Harvey said he does not know the latest metrics. The firm's website notes that gSynth can produce DNA molecules over 300 bp in length with 90 percent accuracy, compared to that of the existing phosphoramidite-based approach, which is just about 30 percent.

Harvey also did not disclose gSynth's cycle efficiency, though he said the company's ambition is to cut gene synthesis time down to a third of the usual turnaround time of existing providers, achieving multi-kb DNA constructs in 10 days, for instance.

As for production cost, Harvey declined to give out a specific number, as well, but said the company "[has] not been as pressured by price per base of DNA. The proposition that we have to customers is the ability to make genes that they can't get from other places."

To that end, Harvey said the company's target clients are large consumers of genes, such as the pharmaceutical and synthetic biology firms, as well as those "who are frustrated by not being able to buy [hard-to-produce] genes from existing companies."

While Camena stays reticent about its manufacturing process, one patent from the company, titled "Compositions and methods for template-free geometric enzymatic nucleic acid synthesis," appears to suggest that the firm's technology employs DNA building blocks to construct longer DNA molecules enzymatically.

This strategy is principally similar to the frameworks developed by some other DNA synthesis companies, such as the short oligonucleotide ligation assembly (SOLA) method from Telesis Bio (formerly known as Codex DNA) and the Enfinia DNA technology by San Carlos, California-based startup Elegen.

Harvey, however, declined to comment on the relevance of this patent to the company's underlying technology and the difference between gSynth and other offerings in the market.

"To the best of my knowledge, Camena is doing an assembly-based technology for gene synthesis," said Thomas Ybert, CEO and cofounder of DNA Script, which has already launched a commercial benchtop enzymatic synthesis platform using the TdT chemistry.

Ybert contended that assembling DNA building blocks together using enzymes has "quite a difference" from the TdT-based enzymatic approach, which only uses four bases to write DNA. As such, the former technology is not solving the issues associated with the initial supply of the DNA fragments, which can still be synthesized using the traditional chemical methods, he said.

Ybert acknowledged that wild-type TdT can be inefficient in incorporating modified nucleotides and tends to have sequence bias; however, he said companies need to "fight against" these obstacles with protein engineering.

"If you start using TDT and you don't manage to engineer it correctly," he said. "You will end up with a TDT that, yes, will not work."

In that regard, Ybert said DNA Script has incorporated more than 40 different mutations into its TdT. As a result, the company's TdT method can produce DNA with an error rate of about 0.3 percent, on par with the "gold standard" chemically synthesized DNA produced by Integrated DNA Technologies.

With the money raised from the Series A round, Harvey said the company plans to scale up the production capabilities for gSynth. He noted that since the technology's launch last year, gSynth has already generated a multimillion-dollar revenue stream, with customers in Europe as well as the US. Harvey did not disclose specific customers, however.

Additionally, he said the firm plans to continue expanding its workforce, which has already grown from five full-time employees last year to roughly 25 people this year.