DNA synthesis is one of the biggest bottlenecks in the bioeconomy so a company that is able to materially decrease cost will be an incredible company to back. As it stands, DNA synthesis is an engineering and not a biological problem.
DNA synthesis is a primary bottleneck in the bioeconomy. Without rapid and high fidelity DNA writing technology, the promise of DNA storage, de novo organisms, and gene therapy cannot be realized. Where DNA sequencing has decreased by six orders of magnitude (in light of the $100 Ultima genome), DNA synthesis has lagged behind, only decreasing in cost by three orders of magnitude. This is due to the comparative difficulty in having a template (sequencing) or not (synthesis). De novo DNA synthesis first requires the synthesis of a single strand of DNA which can be conducted through phosphoramidite chemistry or template-free DNA synthesis enzymes. Both techniques require the sequential addition of nucleotides. The DNA synthesis market first took off when Twist was able to miniaturize the phosphoramidite chemistry on a silicon wafer (chemical polymerization of nucleotides chronicled here). This is their current standard with 9,500+ oligos able to be synthesized in parallel. However, phosphoramidite chemistry is still limited by the length of sequences its able to produce (200 mers) and the hazardous waste byproduct.
https://www.twistbioscience.com/blog/science/simple-guide-phosphoramidite-chemistry-and-how-it-fits-twist-biosciences-commercial
Enzymatic methods of DNA synthesis have been proposed as alternatives, the most common of which being terminal deoxynucleotidyl transferase (TdT), used in nature to add bases to B and T-cell receptor sequences. Like phosphoramidite chemistry, TdT requires sequential and controlled addition of nucleotide bases but has not reached the n-mer length of phosphoramadite synthesis, but is faster and non-hazardous. DNA Script, Nuclera, Kern Systems, Ansa and Molecular Assemblies all use TdT technology. Other companies, such as SynHelix/Quantoom use DNA primase enzymes and others employ proprietary enzymes geometric enzymatic synthesis instead. Subsequent rounds of PCR and/or ligation can increase the size of genome fragments synthesized in a larger way. For example, Gigabases (from ETH Zurich) became the first entity to build a bacterial genome entirely designed by a computer algorithm. They did this through evolution guided multiplex DNA assembly (patent here). However, the cost of synthesis from Gigabases ranged from $30,000 for 100 kb to $400,000+ for genome level synthesis, a price far too high for many companies and labs. Technical hurdles for first strand DNA synthesis remain a serious impediment (and cost driver) no matter the DNA synthesis method. The template is such a bottleneck where, I doubt whether DNA synthesis will ever be the same price as DNA sequencing. That said, the current companies are adding undoubtable value and larger players are noticing.
Gingko led the way in DNA synthesis deals by acquiring Gen9, which could synthesize 50 gene constructs in the same reaction. In the past few years, partnerships or acquisitions of DNA synthesis companies by vaccine and gene therapy companies reached an all-time high. Touchlight signed a deal with Pfizer for exclusive rights to DNA synthesis in July 2022. Synhelix was acquired by mRNA producer and CMO, Quantoom Biosciences, as DNA synthesis is essential in the RNA production processes at Quantoom. A Swedish drug discovery company, Biotage, acquired DNA synthesis company ADTbio for ~$55m in 2021. Gigabases’s computer-augmented, multiplexing technology enables Swiss Rockets COVID vaccine company, RocketVax, to quickly make viral particles to fight disease. Although each of the deals individually are beneficial, collectively, they freeze the use of important and useful technologies. Decentralized DNA synthesis companies such as DNA Script and Evonetix think the maximal value will be returned via democratization of synthesis. However, it does raise questions regarding maximal market size and use-cases as quality control would not be as robust in these settings. Until a superior technology emerges (and even then!) acquisitions in DNA synthesis are bad for everyone because the competition and access to the technology is removed from the community, and innovative technology becomes locked behind a paywall (e.g. DNA primase technology by SynHelix). Moreover, these companies show us that DNA synthesis is an engineering (and potentially computational challenge), not a biological one. Both phosphoramidite and enzymatic DNA synthesis require sequential nucleotide additions, protection/deprotection of vulnerable functional groups, washing steps, etc. Indeed, Twist has issued two patents which has the synthesis capacity of up to 1,000,000 nucleotides concurrently (https://patents.google.com/patent/US10894242B2/en?q=B01J19%2F0046&assignee=Twist+Bioscience+Corporation https://patents.google.com/patent/US10744477B2/en?q=twist+bioscience), two orders of magnitude higher than their current capacity, suggesting their aspirational technical goal. Other advancements include computationally predicting fragment parsing for the de novo synthesis of genome-scale DNA via pooled assemblies (https://patents.google.com/patent/US10744477B2/en?q=twist+bioscience).
DNA synthesis itself is a commodity which is a reliably increasing market. Thus, a company which would directly compete with incumbents would be imminently interesting. DNA storage is a very abstract market so not bullish on these companies but it is interesting Twist is trying this as a way of capturing more revenue. However, to achieve higher margins and greater market capture, a company would ideally develop things on top of the DNA synthesis, like using oligo pools for in-house assays and/or other high throughput experiments.
https://www.notion.so/compoundvc/DNA-synthesis-post-bf531ff5ca4f41dd845f18d7c292e1c4#d8c94de5c9d041fa8f017c59bc7d7fd3