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Oligos are on fire (🧬 🔥 )

Oligonucleotides are the new gold. From the land grab/gold rush atmosphere of JP Morgan 2022 (the superbowl in biopharma and life science tools) to a rush of DNA synthesis announcements last week, it seems like oligos are cool again.

RNA Heydey

RNA has received its rightful share of attention these past 2 years. In fact, every species of the RNA molecule is now popular, we see incredible velocity in licensing of RNA assets in biopharma, and everything in RNA is mega – funding (Resilience), acquisition (Danaher buys Aldevron for $9.6B), and large risk-adjusted market (more from Nature Reviews Drug Discovery).

This is indeed just the beginning for RNA as modality, and we think that the $23B projected 2035 revenue is underestimating the potential for therapeutic vaccines.

In turn, we still have tremendous conviction around infrastructure plays there that can bring the cost per dose of RNA vaccines down substantially, enable lower/test manufacturing scales, and address the supply chain risks of having only a handful of nucleotide synthesis, medium suppliers, and oligo synthesis companies.

What’s the big deal?

The deals highlighted above are big movements in therapeutic oligonucleotide/RNA synthesis, and on the RUO and DNA synthesis side, it has all boiled down to one dominant supplier with two others emerging to compete in the space.

IDT (part of Danaher since March 2018) is still the elephant in the room, leveraging phosphoramidite chemistry (IDT). It's no understatement to say that they made and still make nearly all of the primers for COVID testing. Eurofins has been making gains in the large synthesis market, and also uses phosphoramidite chemistry (Eurofins Genomics FAQ).

Twist Biosciences was the first tremor in what we expect to be a multi-year earthquake for oligonucleotide synthesis, reborn from the market forces behind RNA synthesis, fueled by extensive pools of capital, and enabled by better biological engineering tools.

Twist used a semiconductor-based synthetic DNA manufacturing process which miniaturized the chemistry necessary for DNA synthesis. (Twist Bioscience) They paired this with a nice API and great customer experience. The platform still has some limitations beyond sequence design for large-scale projects, and the door is still wide open for oligos.

At some point, someone or several someones was going to go after beyond-phosphoramidite chemistry and possibly biological synthesis of oligos (your cells are doing this, all the time, so can’t we replicate that?

All In for Enzymatic Synthesis

It comes as no surprise then, that 2022 sees a flurry of action … and has become interesting enough for Forbes to write about (albeit with a cringe-worthy title… “DNA Synthesis Goes Green” Forbes March 25, 2022)

  • that Twist is going after enzymatic synthesis (JP Morgan press release, 2022).

  • So is Molecular Assemblies

  • Several weeks ago enzymatic DNA synthesis Ansa Biotechnologies closes 68M series A

  • And a day later DNA Script Launched Early-Access Program for Enzymatic DNA Synthesis Platform

  • Evonetix, also using semiconductor controlled synthesis, “re-engineered” phosphoramidite chemistry and an effort in enzymatic synthesis

  • Touchlight Genetics has a really interesting in vitro approach using doggybone DNA structure (the oligo literally looks like a dogbone)

All going over the fundamental issues of phosphoramidite chemistry – the length of an oligo that can be synthesized (up to 200 base pairs in length) and the purity of the end product.

The game is afoot

It’s going to be fun to watch this play out – medicine and research are going to substantially benefit from the competition here, and we still see large opportunity here for additional synthetic biology approaches, and second-order providers of medium and consumables to enable synthesis, monitoring and quality assurance.

We would call your attention to Primordial Genetics, who are using their Function Generator™ to enable dramatic productivity improvements to enzymes and really deliver on the promise of synthetic biology. They were just awarded a $1.06M Phase II SBIR Grant From The National Human Genome Research Institute to tackle new DNA and RNA synthesis technologies, and according to their press release -

Primordial Genetics will enable a >99% rate of single nucleotide addition in each synthesis cycle that is needed for a prototype industrial enzymatic strategy of manufacturing DNA.

Fantastic and game-changing work from this team.


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