Changing the Paradigm for Writing DNA

In the first of four features on Molecular Assemblies, Big4Bio spoke with CEO and President Mike Kamdar and Co-founder and Chief Scientific Officer Bill Efcavitch about how the company got started, their technology for synthesizing DNA and why it is better than current methods, and their plans moving forward. The second feature will provide an in-depth focus on the technology, why it is needed, and the markets it serves.

Companies to Watch – Molecular Assemblies

by Marie Daghlian

DNA is at the heart of biological processes and Molecular Assemblies has developed a new way to write DNA that could revolutionize industries, ranging from food, agriculture, and pharmaceuticals to DNA storage and microelectronics that are incorporating biological systems into their mainstream processes.

Molecular Assemblies Co-founder and CSO William Efcavitch

The company is banking on its enzymatic DNA synthesis technology as a major improvement to the decades’ old chemical method currently in use because it can synthesize longer strands of DNA quickly, accurately, and cost-efficiently compared to conventional chemical DNA synthesis, according to Molecular Assemblies co-founder and CSO William Efcavitch.

In 1983, while working at Applied Biosystems, Efcavitch introduced the use of the first chemical DNA synthesizers, a phosphoramidite method that entails many rounds of stepwise assembly of chemically modified nucleotides, which limits synthesized DNA lengths to 70 to 100 nucleotides. He also also led the teams that commercialized three generations of Sanger sequencing machines that were used by the Human Genome Project.

By 2013, as demand for synthetic DNA was skyrocketing, the chemical technology for synthesizing it remained virtually unchanged. Efcavitch and his colleague Curt Becker noted that the chemical method had reached a technological plateau while the applications continued to grow to the point where longer and longer synthetic DNAs were required. Efcavitch had been aware of an enzymatic polymerase that could do template independent synthesis and had been shown to be capable of making very long stretches of DNA. So, the two of them got together and formed Molecular Assemblies to develop the platform.

“We opened our doors in 2014 with the idea of not competing in the small probe and primer market, 20 30, 40 nucleotides, but synthesizing the oligonucleotides that are 150 nucleotides and larger for all of the new applications that have evolved, like gene editing, like gene synthesis, and other applications like DNA data storage, or even material sciences,” says Efcavitch.

President and CEO Mike Kamdar, who has a long track record of building companies in different ways, joined in 2016. He was impressed by all the possibilities that enzymatic DNA synthesis could provide in terms of its applications in therapeutics such as CRISPR Cas gene editing and vaccines, in agriculture, in DNA storage.

Molecular Assemblies CEO Michael J. Kamdar

“There’s just so many possibilities that long DNA could provide,” he says. “It was certainly appealing to me and really one of the driving forces to join Molecular Assemblies and join Bill’s vision for starting the company.”

Molecular Assemblies hasn’t sold any of its synthesized DNA—yet. But it plans to go commercial in 2022. The San Diego, California-based company used some of the $24 million it received in an oversubscribed series A funding round in April to continue building out the executive team, hiring a vice president of sales and marketing and a vice president of platform development to build out the various platforms.

“We’ve moved the company from the idea or research phase and the proof-of-concept phase into development and optimization on our way to commercialization,” says Kamdar. “We expect to commercialize sometime early next year with the start of a key customer program.”

As part of that next step, the company has spent a lot of time talking to customers and understanding what their pain points are and what their issues are relative to DNA. Kamdar says their issues relate to security, turnaround time, costs, and the need for DNA sequences longer than 70 to 100 nucleotides.

This is the sweet spot that can be filled using enzymatic synthesis. “The industry is limited to making 70 to 100 nucleotides for people because it’s just not cost-effective to go beyond that,” says Efcavitch.

He explains that DNA synthesis is a step-by-step procedure of attaching one nucleotide at a time to build the DNA strand. With any stepwise synthesis, the length of the molecule decreases exponentially at each step. If a yield of 99.5 percent is assumed, which is the chemical industry standard today, by the time 70 nucleotides are attached, yield drops to about 50 percent of the full-length product, with the other 50 percent a mixture of smaller, shorter sequences.

“So, it becomes a diminishing return,” says Efcavitch. “I showed the chemical synthesis of a 150-mer in 1987.”

More critical is that purifying molecules much above 70 nucleotides is very expensive and time consuming and not cost-effective. In contrast, the enzymatic process is aqueous, a green methodology, and the company can produce much longer strands of DNA.

Through a strategic collaboration with protein engineering company Codexis, struck in June 2020, the company is optimizing the enzyme, a polymerase, it uses to drive its yield to the highest possible point beyond 99.5 percent. And because its process is aqueous based, it can use an enzymatic cleanup step, which means that even though it is faced with diminishing yield of the full-length product, it will be able to enrich it, clean it up, and produce a pure fraction of a longer molecule.

Today, despite advancements in chemical synthesis of DNA in terms of miniaturization and throughput, companies looking for longer stretches of nucleotides, all the way to genes, go through a process of stitching shorter strands together, which comes with errors, loss of yield, and post-processing costs.

“We’ve heard consistently from industry leaders that 150 nucleotides is really a game changer,” says Kamdar. “Now it’s not to say that people, along the way, won’t use our DNA in that 70 to 100 nucleotide space. We’re not ruling that out, but that’s not our primary focus. Our focus is what we call long-mers, being able to provide 150 nucleotides, 200 nucleotides all the way up to gene length, because I think that’s where the difference can be really impactful because some of these areas like CRISPR, like some of the work we’re looking at an agriculture, like what we’re doing in vaccines, none of that has been able to be opened up by the chemical method, and we’re already starting to open it up using our enzymatic approach.”


NEXT: A closer look at the innovation behind Molecular Assemblies

This is part of the Big4Bio Company to Watch program for September 2021: Molecular Assemblies.
For more information on the series, click here.