Sensible Biotechnologies And Ginkgo Bioworks Announce Partnership To Make In Vivo RNA To Unlock The Promise Of RNA Therapeutics

Fermentation tanks filled with thousands of liters of growth media and cells have been the picture of therapeutics production for decades. But you won’t find mRNA-based therapeutics being produced en masse by microorganisms. The E. coli cells used to make other therapeutic molecules like insulin can’t perform the modifications required to produce functional mRNA. So the major component of the life-saving COVID-19 vaccines produced by Moderna, Pfizer, and BioNTech is produced instead via a series of cell-free, in vitro reactions facilitated by purified enzymes.

For now, that is. Sensible Biotechnologies, a startup based in Bratislava, Slovakia and Oxford in the U.K. has just announced a partnership with Ginkgo Bioworks that might just turn mRNA-based therapeutics production on its head.

Moving mRNA from in vitro to in vivoroducing therapeutic mRNA in vitro is costly and cumbersome. It requires extensive purification processes — not just of the enzymes used in the various steps used to create the final mRNA, but also of the final mRNA itself, which is often contaminated with immune reaction-inducing double stranded RNA and other impurities. But perhaps most importantly, in vitro production of certain types of mRNA (such as long RNA) is difficult and just isn’t scalable, limiting the incredible therapeutic potential of this amazing molecule.

So why not make RNA using nature’s own RNA factory—cells?

This is the natural question that struck Miroslav Gasparek and Marian Kupculak as they began exploring some of the biotechnology industry’s biggest challenges. I sat down and talked with Gasparek ahead of this year’s SynBioBeta Conference in Oakland, where he’ll be speaking, and he told me a truly interesting story.

“We talked to a lot of startups, mentors, advisors, and biotech executives, and one thing that we kept hearing was, ‘mRNA is expensive, it’s cumbersome to develop and to make ourselves, and it’s not working as well as it could,’” Gasparek explained to me as he told me the story of how Sensible Biotechnologies was born. “There were some attempts to make mRNA in bacteria before, but bacteria will not work for making mRNA that is functional in human cells. So, we started wondering whether anyone had tried to do mRNA in eukaryotic cells. Even the world’s leading mRNA manufacturing experts hadn’t heard about anyone who would be successful in that. And I was like, ‘wow, that’s something.’”

And so began the quest to do something no one else has done successfully—produce mRNA in cells. While accomplishing this will be a challenge, a challenge is something that Gasparek was looking for, to address through his expertise with and passion for synthetic biology.

Why synthetic biology is the tool for the job

Synthetic biology, according to Karl Handelsman, Founder and General Partner of Codon Capital, a VC firm that invests in visionary, early-stage biotechnology teams, is indeed the perfect tool to make cell-based production of mRNA possible.

“We’ve always been studying mRNA, so asking ourselves whether we can tweak it, bend it, and modify it so it does something totally different is synthetic biology at its core,” he says. “The tricks you’ll have to invent to engineer cells to actually spit out mRNA will be very clever and unique things that only the people trying to do it will figure out. It’s what Lindy Fishburne at Breakout Labs calls ‘creative biology.’ It’s going to work, we just don’t know yet if it’s going to work in a way better than other approaches.”

If it does work better, then the future of mRNA therapeutics is going to be incredibly exciting.

“When we think about mRNA therapeutics, what we would really like to do is go to the essence of mRNA and express a protein that will, for example, kill tumor cells or replace malfunctioning proteins in the human body,” explains Gasparek. “One of the most striking applications of mRNA technology is self-amplifying RNA, where we can deliver RNA together with a small piece of its own replication machinery and thus achieve prolonged expression of the mRNA, in effect getting a bigger therapeutic effect with a smaller dose of RNA delivered initially.”

Gasparek is convinced that to fully realize the therapeutic potential of mRNA, including self-amplifying RNA, it has to be made in cells.

“Using self-amplifying RNA to elicit a given response in the body is really exciting, but there is a big but,” he says. “It’s more complex, there is a much bigger and unexplored design space, you have to think about whether you want cis or trans configurations — to leverage all of this requires long RNA, and long RNA is one of the biggest challenges that the mRNA manufacturing field is facing. That’s precisely what we’re trying to address with our platform.”

And from a more practical standpoint, there are several additional advantages to producing mRNA in cells instead of in vitro. It has the potential to be much cheaper and more scalable, which has implications for biosecurity, as it helps to make the critical supply chain leaner and more robust. It also can minimize some of the immunogenicity risks, because the mRNA is in a more natural state. The impact of the COVID-19 mRNA vaccines was incredible, but that’s really only scratching the surface of what we can achieve with mRNA. It’s easy to imagine a future where mRNA-based therapeutics are a critical component of personalized medicine for a variety of diseases.

Joining forces to bring cell-based mRNA production to the market

To make this exciting future a reality, however, Gasparek and his team are going to need to optimize and scale their technology. They are well on their way to achieving this goal through their partnership with Ginkgo Bioworks, announced earlier today in a press release. This partnership comes on the heels of a $4.2 million pre-seed financing round led by BlueYard Capital with participation from Civilization Ventures, Amino Collective, Y Combinator and several other VCs and life science executives investing as angels.

“Sensible is a product of tech and bio convergence. They are combining the best tools from both to overcome challenges in producing high quality mRNA on demand without which much of the future potential of mRNA therapeutics may never be realized,” said Vishal Gulati, Managing Partner at Recode Health Ventures, who also invested in Sensible Biotechnologies.

Gasparek says the partnership with Ginkgo — whose expertise in microbial cell programming platforms is unmatched — will accelerate the development of Sensible Biotechnologies’ cell-based mRNA production platform to market-relevant scale and enable the development of a new generation of mRNA therapeutics. The partnership will also help Ginkgo, which is a sponsor at this year’s SynBioBeta Conference, deepen its growing commitment to the emerging field of nucleic acid therapeutics.

“Our living cells make high quality, non-immunogenic, long mRNA all the time,” says Gasparek. “Drew Endy taught me about this concept of beauty — it’s just really elegant and beautiful to exploit the biology of existing cells to make something useful. The whole field of biotechnology is pioneering this trend, and we are thrilled to be at the forefront of pioneering mRNA innovation.”

Thank you to Embriette Hyde for additional research and reporting on this article. I’m the founder of SynBioBeta and some of the companies I write about, such as Ginkgo Bioworks, are sponsors of the SynBioBeta conference and weekly digest.