The gene synthesis landscape is continuously evolving in pursuit of perfection, with innovations often aimed at improving the speed, cost, and fidelity of oligonucleotide synthesis. More broadly, there is intense interest in developing RNA and cell therapeutics, as well as an ongoing inflection point in the advent of artificial intelligence (AI). As a result, there is an increasing need for reliable complex gene synthesis.
Emily M. LeProust, PhD
Chief Executive Officer and Co-Founder
Twist Bioscience
Twist Bioscience has developed a reliable, high-throughput complex gene synthesis solution. In this Innovation Spotlight, Emily M. LeProust, chief executive officer and co-founder of Twist Bioscience, discusses the advantages and vast potential of this system for enabling breakthrough research.
What is the current landscape for innovation in gene synthesis and what are the challenges?
Today’s innovation landscape is directed at making complex gene synthesis as routine and hassle free as conventional gene synthesis. That’s what we’ve done with our recently launched complex gene synthesis platform, which broadens the types of genes that can be synthesized and introduces consistency and affordability to the process.
Guanine cytosine (GC)-rich regions, homopolymers, and other complex elements make it difficult to reliably synthesize some DNA sequences. There are ways to do it, but they are inconsistent, can be costly, and may require months to complete. Even then, success isn’t guaranteed. The prospect of ordering promoters (often rich in GC) or genes with complex untranslated regions (UTRs) can be daunting for labs that are on a tight timeline and budget.
Can you describe the need of scientists for a more flexible, reliable DNA synthesis solution, particularly in the age of AI?
AI has changed the research workflow in some significant ways, particularly in the development of biologics. We used to say the process followed a design-build-test-learn cycle, but with AI, it now follows a learn-design-build-test cycle. In that first step, AI learns from available data and guides the design of diverse screening libraries. This encourages researchers to screen a wider array of custom candidates, each of which must be coded in synthetic DNA.
Now more than ever, researchers need synthetic DNA that is precisely synthesized according to AI designs, and they need it on a large, high-throughput scale. Complex gene synthesis becomes more important, too, as the industry takes an interest in RNA therapeutics, which may require the use of GC-rich promoter elements that are traditionally difficult to produce.
Today’s innovation landscape is directed at making complex gene synthesis as routine and hassle free as conventional gene synthesis.
©iStock, Vertigo3d
Will enzymatic synthesis technology be required to make complex gene synthesis routine?
The short answer is no. Many industry observers expected complex gene synthesis to be unlocked by enzymatic technology. It is true that enzymatic methods can synthesize complex genes, but no platform has been able to truly unlock complex genes for the industry because they lack the scale, consistency, and affordability that is prerequisite for widespread adoption.
We have developed a complex gene synthesis platform that is built around solid-phase phosphoramidite chemistry. I think the innovation in this space isn’t dependent on the type of synthesis technology that we use. Researchers don’t care how you make the DNA, they just care that they can get what they want, when they want it, at a price that is affordable.
How is Twist Bioscience’s approach to complex gene synthesis disrupting the market?
At Twist we are disrupting the market by doing more than just enabling complex gene synthesis. We have also built the necessary platform infrastructure to make this service useful for modern needs.
We’ve built efficiency into our platform, so that we can provide affordable pricing, regardless of complexity, and help researchers keep their research on track when DNA gets complex. We’ve innovated synthesis workflows such that we can now accept 99.5% of requested sequences and make them within 15 business days. We’ve also made the ordering process intuitive, automated, and transparent. When researchers need help, they are put in touch with one of our scientific experts, not a chatbot, and will know early if there is a delay.
Lastly, the process is built to provide customization at scale. This means you can order complex genes in whatever “flavor” of DNA you need, whether that’s multiplexed gene fragments, gene pools, custom vectors, IgGs, or other needed formats.
Collectively, this makes us the only US-based one-stop-shop for gene synthesis. Where others specialize in one aspect at the expense of another, Twist is now able to provide it all: reliable, high-throughput synthesis regardless of complexity.
We firmly believe that the market now needs to play catch up. I can’t think of another solution that can not only synthesize complex genes, but also makes ordering them as affordable, transparent, and simple as we do.
What are some of the applications of this technology and what does the future hold?
The potential applications of this technology are endless. Many genes and genetic elements have been underexplored simply because they’re difficult to synthesize. With our platform, these elements are now in play and can be readily used for functional genomics, genetic engineering, and drug development. Additionally, with AI-guiding protein engineering efforts, there has been a growing desire for custom DNA sequences that show promise in silico, but which have been untested due to the difficulties of their synthesis. I am excited to see this technology effectively applied to the RNA therapeutics and antibody therapeutics market. Here, too, complex gene synthesis will be transformative.
Additionally, the future will see still more improvements in the speed and reliability of synthesis technologies and their platforms. It’s the nature of this field: we’re in the pursuit of perfection and will never stop innovating to meet the field's evolving needs.
