In 1983, J. William Efcavitch, PhD,—working at a newly formed company based on technology developed by Leroy Hood and Marvin H. Caruthers—was integral to introducing the first chemical DNA synthesizers. As employee number nine of Applied Biosystems, Efcavitch brought DNA “printing” to the world stage.
Nearly thirty years later, Efcavitch and fellow Applied Biosystems founding member Curt Becker noted that the demand for long, high-fidelity, sequence-specific DNA in many industries (industrial synthetic biology and precision medicine) as well as emerging applications (data information storage, nanomachines, and bio-based electronics) was growing faster than the rate of DNA printing. Because the traditional chemical DNA synthesis is highly error prone, time consuming, and unscalable, with unacceptable levels of impurities and numerous post-synthesis steps, the assembly of synthetic DNA is a piecemealed process using stretches of 50 and 100 bases.
So, in 2013, Efcavitch and Becker embarked on a mission to develop DNA synthesis technology that produces highly pure, sequence-specific DNA on demand. Molecular Assemblies aims to produce longer, purer pieces of synthetic DNA to streamline synthetic biology applications and meet significant customer demand for faster turnaround times and reduced error rates.
Molecular Assemblies’ enzymatic approach is based on the way that nature makes DNA—in water—to overcome the length, purity, and accuracy limitations of the chemical DNA synthesis method. The Fully Enzymatic Synthesis™ (or FES™) technology by Molecular Assemblies employs a template-independent DNA polymerase, called terminal deoxynucleotidyl transferase (TdT), which has the ability to synthesize much longer DNA sequences with fewer errors. This two-step proprietary process uses aqueous non-toxic reagents, requires minimal post-synthesis processing, and can scale to longer DNA sequences.
In April 2021, Molecular Assemblies, Inc., announced the closing of an oversubscribed $24 million Series A financing with significant investment from Agilent Technologies, iSelect Fund, Codexis, Alexandria Venture Investments, Argonautic Ventures, and LYFE Capital. In March 2022, the company announced that it had a $25.8 million Series B financing with participation from a new investor, Casdin Capital, and all major Series A investors.
GEN Edge sat down with Efcavitch, now the company’s CSO, and Michael J. Kamdar, President and CEO, to get caught up on how Molecular Assemblies’ fully enzymatic DNA synthesis is shaping the future of established and emerging industries, such as DNA-based data storage. The duo also fills us in on some details regarding their collaboration with the Defense Advanced Research Projects Agency (DARPA) and General Electric (GE) for the production of DNA- or RNA-based vaccines and therapeutics anywhere in the world in just days.
GEN Edge: What is the foundation for Molecular Assemblies?
J. William Efcavitch: I have a deep history in the synthesis of DNA. I was around at the beginning of the invention of DNA synthesis, commercializing the phosphoramidite method in 1983. Since 1983, that’s grown to become a several billion-dollar a year market that supplies oligos to all walks and shapes of life. Around 2012, my co-founder Curt Becker said that the technical performance of phosphoramidite chemistry had plateaued. It had become automated, faster, and cheaper. In terms of raw technical performance, that kind of DNA synthesis was limited by the chemistry invented in 1981 and commercialized in 1983. But that application space has moved on. Gene synthesis has become routine, and the need for long single-stranded oligonucleotides for different applications has grown.
My co-founder knew I had always been interested in an enzymatic way of synthesizing DNA. The idea is that enzymes work in water and at neutral pHs. You have none of the toxic reagents. It’s very green chemistry since everything is aqueous and biological. More importantly, enzymatic DNA synthesis can overcome the length and purity barriers that exist with chemically synthesized DNA. When we opened the doors to Molecular Assemblies in 2014, enzymatic synthesis was a novelty. Today, everyone is very interested in the space, and we are excited to be pioneers and thought leaders in this area.
Michael J. Kamdar: I joined Bill in 2016 as the president and CEO. Over the last six years, we’ve understood deeply that the need for long, pure DNA opens doors to different opportunities. Enzymatically making DNA that is 150 nucleotides is longer than what can be created by the original chemical method. This opens new doors to accelerating innovation in gene synthesis, gene editing, and CRISPR technologies. Another example is our partnership with GE Global Research and DARPA focused on making vaccines in a portable box that can be air-dropped anywhere in the world. There’s many more applications, from agriculture to data storage. All the TikTok and Instagram content is eating up server spaces, so the idea is to store data, especially historical data, on DNA. You can’t accelerate innovation or enable new spaces with 30-year-old technology—chemical DNA synthesis has hit its limit. That’s why we are so excited about enzymatic DNA synthesis.
GEN Edge: What are the revenue streams?
Efcavitch: We do not intend to focus on 20- and 30-mers. That’s a commodity market. The chemical synthesis industry handles that well. We are going to focus on long oligonucleotides and genes. Our DNA molecules are longer than 150 nucleotides. That will be our commercial focus, not primers and probes.
Kamdar: We are building Molecular Assemblies to be a service company. We don’t think customers need to reinvent the wheel, do it yourself, and spend hundreds of thousand dollars on a benchtop synthesizer. We think people are used to ordering DNA from a service. We want to keep that comfort level. The initial offering is going to be much longer DNA, which is a huge unmet need.
We can be the ink in all the printers. If a CRISPR company wants 200 to 300 nucleotides, we can provide that. For vaccines, we’re working to a much longer length, more than 1 Kb, as part of the DARPA initiative. There are many burgeoning uses, applications, and verticals for DNA—it’s our oyster. We will make money from direct sales into the oligo and gene synthesis marketplace and from partnerships.
Bill’s brainchild has proven that we can make a useful technology across many different industries, but it’s also portable. There are abilities to add to varying suites in pharma, biotech, and agriculture. Many opportunities reside in front of us. The challenge for a growing company is that we need to focus on what we can and want to do through partnerships, and that’s where we are. It’s an exciting time. We will start our Key Customer Program later this year, where we have identified several key customers that want to use what we’re making and get it in their hands. Then we’re off to a full commercial launch next year.
Five to six years ago, enzymatic synthesis was down the hall, around the corner, and behind the coffee machine. Now, it’s front and center stage. There’s just so much interest in what we’re doing. It’s up to us to determine the best ways to monetize that, and we’re on the verge.
GEN Edge: How are Molecular Assemblies researching and developing new revenue streams?
Efcavitch: We are finishing the discovery phase of enzymatically synthesizing DNA and developing the technology to do that in a high throughput fashion. Our engineering group is building high throughput synthesizers at two different scales that will go into a factory to feed the customer base. The other part of the R&D group will turn its attention to the subsequent product development like RNA or some embodiment of the synthetic DNA we’ve just commercialized.
Kamdar: We have an R&D organization from the early stage to the manufacturing stage. We do all our organic chemistry and biochemistry in-house. We do some protein engineering, but the majority is now done under our collaboration with Codexis. While we’ve raised quite a bit of money with Agilent Technologies, Codexis, Life Capital, Casdin Capital, and Alexandria Venture Investments, we still have to focus our resources. We spent most of our effort to get to commercialization and are excited to be opening our Key Customer Program later this year.
We also believe this technology will be useful for RNA. We have burgeoning efforts in other dimensions, such as DNA data storage, and we’ve accessed interesting proprietary technology in RNA. So, we can build a much bigger business than just being a DNA manufacturer.
GEN Edge: Will Molecular Assemblies develop therapeutics?
Kamdar: We do not want to be a therapeutic company or to be anything that has to go further downstream than making the “API”—the starting materials. We also have a proprietary enzyme we’ve licensed that would be excellent for RNA. We think we can take the same process and make RNA that would strongly benefit mRNA therapeutics.
Efcavitch: We are exploring new ways to therapeutically utilize this biologically synthesized DNA or RNA. For instance, we already know that we can heavily modify the nucleobases, and we could create heavily modified RNAs to go into a therapeutic product. As we learn more about the capabilities of the enzymes we’re using, we certainly will keep our eye open to unmet needs, like special modifications that benefit a downstream therapeutic market.
GEN Edge: International market?
Kamdar: It’s a global market. No matter where you go, people need DNA. How we address that is TBD. The reality is we’re set up so we could build sites worldwide. We have partners based around the world, so we might not have to do it independently ourselves. It might be through partnership. Those are all exploratory for us because we know the opportunity, what people want, and how to execute it cost-effectively. Market conditions, fundraising, and setting up satellite sites cost money. But the key takeaway is that our technology is based here in San Diego. We could do that if we put it in Portugal, Tokyo, or Korea.
Efcavitch: This chemistry is aqueous and brings less hazardous material regulatory elements. It is portable in that you’re not working with hazardous reagents, flammables, et cetera. We have made sure that we’ve put our IP worldwide. We’ve made sure that we have issued patents both in Europe and Asia so that we can protect our businesses at overseas sites.
Kamdar: We’ve got 30 patents worldwide, including China, Japan, the EU, and the US. The other thing is this portability idea with DARPA and GE to build a 6x6x6 foot box containing our enzymatic approach coupled with GEs vector technology. You couldn’t put anything flammable in the box because the idea is to fly it somewhere and drop it into a hot zone, where it could make 5,000-unit doses overnight. You put in a sequence, and there you go. It’s more relevant now with everything we’ve dealt with in the last couple of years. But it’s closer to reality than most realize.
GEN Edge: What doors do Molecular Assemblies technology open?
Kamdar: We are a founding member of the DNA Data Storage Alliance, which was formed by Illumina, Microsoft, Twist Bioscience, and Western Digital. The initial aim is to create a roadmap for an interoperable storage ecosystem based on manufactured DNA as a data storage medium. Frankly, if we talked to you two to three years ago, we might not even mention it, but it wasn’t just tongue in cheek earlier regarding all the TikTok and Instagram content. We’re running out of server space. There’s no more cloud space. The government’s worry has been about being able to preserve historical data. The DNA Data Storage Alliance is upwards of 30 companies now, all working on a roadmap because it’s an undefined marketplace for how to best store data with DNA. There are a lot of bright minds involved in it.
Efcavitch: Early on, we had identified that enzymatic synthesis of DNA probably would be enabling in the data storage market. We have several issued patents in that area, and we’ve taken our chemistry and adapted it to the specifics of DNA data storage that we think make it more readily automatable than any other way of synthesizing DNA. That is one application that has our attention. We’ve also made many heavily modified DNAs that may have interesting applications in the future. Lastly, our chemistry is scalable. People have been asking if we can make milligram to gram quantities of these long, highly accurate DNAs for therapeutic use. We are excited to extend our technology into those different kinds of spaces.
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