‘Can synthetic biology save us?’ and ‘synthetic biology can benefit us all’, are just some of the headlines this emerging scientific field has recently elicited. Lu Rahman speaks to Dr Emily Leproust, Founder and CEO of Twist Biopharma, about the potential that synthetic biology holds within the drug discovery sector.
“Most people today consider synthetic biology to mean the engineering of biology, and the biggest advance here has absolutely been in throughput,” says Emily Leproust, Founder and CEO, Twist Bioscience and Twist Biopharma. “The core technologies that power synthetic biology today were around a decade ago — but on a smaller scale. We had next-generation sequencing machines, microarray DNA synthesis platforms, and even enzymes for gene editing,” she explains.
“Today, sequencing a human genome costs $600, down from over $10,000; DNA synthesis costs $0.07 per base with the Twist silicon-based synthesis platform – down from $0.70-$1 per base ten years ago. And we have CRISPR, which can be used to interrogate the function of thousands of genes in parallel. These are just a few examples, but the point is reading, writing, and editing DNA has never been more accessible,” she adds.
These advances have allowed users to iterate through the design-build-test-learn cycle faster. “Synthetic biologists today start with better designs, informed by NGS and functional genomics, and make faster builds by replacing molecular cloning with inexpensive synthetic DNA. Removing these bottlenecks at the beginning of the cycle means more can be accomplished in a shorter timeframe and for less,” says Leproust.
It is an exciting time for synthetic biology. “We’ve seen many synbio companies funded through significant private and public raises, netting close to $9 billion for the industry in the just the first half of 2021, building on $8 billion in 2020. We’re seeing an evolving ecosystem of companies, with financial backing to support emerging applications and innovations. The opportunities now seem almost limitless,” she adds.
Drug discovery and synthetic biology
Recently synthetic biology has created a lot of attention. “With the increased understanding of biology in the last decade, we now have the ability to engineer biological systems to achieve any number of ends, from manufacturing commercial products to improving agricultural practices and health outcomes. We can preserve the world by making flavours, fragrances, dyes, and materials synthetically. We can engineer bacteria to deliver nitrogen at the root of plants eliminating the need for fertilizers, and we can use pheromones to keep the bugs off the crops rather than using harsh chemicals,” Leproust explains.
There is also more discussion around the importance synthetic biology holds for the drug discovery sector. “We can use gene drives to eliminate mosquito-borne illnesses such as malaria and dengue, gene editing to treat specific diseases, synthetic DNA to read a particular cancer mutation and then create personalised treatment.
“Synthetic biology is beginning to have the same impact on the drug discovery sector. We can now engineer new biocatalysts for complex, highly chiral small molecule synthesis. We can build microbial factories from the ground up to biosynthesize natural products from waste with increased efficiency. And we can precisely synthesize highly diverse libraries of protein variants and screen them with optimised in vitro and in vivo screening systems for faster biologic drug discovery. All of this is just the tip of the iceberg,” she adds.
“Capitalising on these advances, we, and in this case I’m talking specifically about Twist, launched Twist Biopharma a couple of years ago to create an end-to-end antibody discovery and optimisation platform to serve our internal antibody discovery pipeline and the wider biopharma industry. We started by leveraging our ability to make DNA at scale to create high-value synthetic antibody libraries, and we’ve leaned on artificial intelligence to design these libraries,” Leproust reveals.
The business recently acquired Abveris, adding its DiversimAb family of hyperimmune mouse models to Twist’s discovery and optimisation platform. “This acquisition is exciting because it means we will have expertise in all three major approaches to antibody discovery: artificial intelligence, synthetic libraries, and in vivo systems. Through our ability to provide synthetic DNA at scale and our rapidly expanding antibody discovery and optimisation platform, our goal is to supercharge the next revolution in biopharma. And we have synthetic biology to thank for that,” she adds.
The next big thing?
Synthetic biology has been referred to as the ‘next big thing’ for drug discovery. “In my opinion, it is the current big thing!” states Leproust. She says synthetic biology has made massively parallel workflows possible, and pharma companies that are ahead of the game have known for a while that leveraging these workflows increases their speed to market for both biologics and small molecule drugs.
“Developments in synthetic biology will confer knock-on benefits at virtually every phase of the drug development process. Opportunity abounds. Pharma companies can now utilise whole-genome and focused CRISPR screens to validate the vast quantities of genetic sequencing data available and discover new drug targets,” says Leproust. She adds that artificial intelligence is better informing protein library design, and improved recombinant systems for protein library screening mean more protein designs can be parsed at once. “Advanced computational modelling of biological systems is leading to more efficient and sustainable scale-up alternatives for drug production. Next-generation sequencing has vastly expanded the catalogue of available genetic parts, which we can precisely synthesize and integrate into libraries, chassis organisms, and biocatalysts to serve these ends,” she explains.
At the core of this, says Leproust, is the design-build-test-learn cycle, where improving both the speed and parallelisation of iterations leads to decreased drug development time. “This acceleration is made possible with bountiful access to the raw materials for engineering biology, like synthetic DNA,” she says.
The impact of synthetic biology
The advent of synthetic biology has impacted traditional small molecule drug development versus biologics. “An obvious application of synbio in the biopharma space is the discovery and development of new biologics. Biologics are increasingly being produced synthetically from optimised, error-free DNA building blocks. Just as synbio enabled synthetic insulin in the eighties, synbio is now transforming both antibody discovery and T-cell therapy development,” says Leproust.
She explains that the difference between then and now is that the small gene encoding insulin took months to synthesize whereas libraries of tens of billions of antibody genes can now be synthesized in a matter of weeks. “In addition,” she says, “the libraries contain only the sequences that occur in the human repertoire, rather than randomly generated sequences. Screening technology is also advancing, with technologies like single B-cell sequencing and viral display allowing for the rapid testing of drug candidates.”
She adds that we are also seeing a profound shift in how pharmaceutical companies handle the drug development pipeline. “Previously companies primarily focused their development efforts in-house, absorbing the cost to develop the infrastructure to identify new candidate biologics. Now, outsourcing to partner organisations that hold expertise in a specific stage in the discovery pipeline is becoming commonplace as development times and costs can be significantly decreased. Other confounding issues like staffing and rare expertise can also be mitigated,” she says. “We are even seeing some companies going completely ‘lab-free’, outsourcing the entire workflow. By partnering with Twist Biopharma, a pharmaceutical company can screen and identify candidate antibody hits in as little as eight weeks — something in the past that would take years.”
“The application of synbio to small molecule discovery is less obvious but no less important”, says Leproust. “There are many areas in small molecule discovery where traditional methods fall short. Take the production of chiral molecules, for example. Synbio is driving the discovery and evolution of biocatalysts capable of producing enantiomerically pure small molecules, which are preferred by developers for efficacy reasons and regulatory agencies for safety reasons. In addition to being more cost-efficient, these biocatalysts are also a more sustainable solution because they are biodegradable, unlike the harmful solvents and cofactors they often replace.”
And where sustainability is concerned, Leproust points out that synbio is also enabling the production of microbial factories for natural products. “Because agricultural supply chains are vulnerable to disruption, synthetic biologists are turning to scalable organisms like yeast to biosynthesize these natural medicines instead. Creating these microbial factories often involves more than plugging new genes into a microbial chassis. To be used effectively, rapid design-build-test cycles to optimise the production process at a systems level. The rate of progress continues to accelerate and it’s only just the beginning,” she says.
There are always challenges in any area of drug discovery – Leproust has alluded to this – but she adds, speed is always a challenge; how can we make drug discovery faster or improve throughput?
“Part of this stems from the fact that some technologies have evolved faster than others. DNA synthesis technologies have been playing catchup with DNA sequencing technologies for decades. To give some context, the six billion or so base pairs of the human genome were sequenced nearly a decade before the first synthetic genome was generated, which, by the way, was only a 600,000 base pair-long bacterial genome. This gap has closed a fair bit since then but closing it further will help improve the speed and throughput of drug discovery beyond where it is today. The same applies to other technologies, from artificial intelligence to scale-up bioprocesses,” she explains.
Secondary to this challenge is a lack of proven tools for success. “To date, the majority of antibodies discovered by phage display come from only three commercially available libraries. These libraries are very broad-purpose. More libraries would expand the discovery space and allow drug developers to focus their resources on projects that are more likely to succeed. On that front, Twist Biopharma has used the Twist silicon-based DNA synthesis platform to create a diverse portfolio of antibody libraries that we call the ‘Library of Libraries’. With 16 libraries to date — each containing up to ten billion antibodies — we’ve already tripled the commercial antibody discovery space compared to what it was just a few years ago. And we have added significant discovery and optimisation tools to complement the biopharma libraries. And we are not stopping there!” Leproust reveals.
DNA synthesis technology and Twist
According to Leproust, Twist has made huge strides in DNA synthesis technology. “Currently, Twist is the only provider that synthesizes high-quality DNA in highly parallelised and miniaturised reactions. This is what allowed us to expand the antibody discovery space to where it stands today with the Library of Libraries, and our robust antibody discovery and optimisation capabilities.
“We recently demonstrated success with the Library of Libraries in an internal discovery effort aimed at discovering neutralising antibodies against SARS-CoV-2. From our camelid libraries, we discovered a promising candidate that neutralises not only the original SARS-CoV-2 strain but also emerging variants of concern, as demonstrated in a recent paper we published in the journal Science. I’m thrilled to say we recently launched Revelar Biotherapeutics to further develop this candidate with the goal of entering clinical studies in 2022,” she explains.
The company has also evolved its offerings to include antibody discovery, optimisation, and production services aimed at facilitating biologic discovery from design to lead. Leproust adds: “I mentioned before that we recently acquired Abveris. We believe this acquisition will add a powerful tool to the Twist platform: the DiversimAb family of hyperimmune mice. This mouse-based approach complements our display-based in vitro platform: the former harnesses the natural in vivo process of antibody generation and the latter the diversity and control that can only be achieved with a synthetic approach.”
Beyond its internal development pipeline, Twist partners with large and small companies alike. “To name a few recent partnerships, we signed a broad-based research collaboration with Boehringer Ingelheim to use Twist’s proprietary antibody libraries to discover therapeutic antibodies against multiple targets. Takeda Pharmaceuticals licensed the Library of Libraries to assist its discovery efforts for oncology, rare diseases, neuroscience, and gastroenterology; and Serotiny is leveraging our antibody discovery and optimisation platform to facilitate its CAR-T cell therapy development efforts,” she says.
Importance of high-quality DNA
Leproust is clear that the ability to synthesize any sequence of error-free DNA from the human repertoire at scale is very important to antibody development. “More and more therapeutic antibodies are being discovered from antibody libraries. Synthesizing DNA at scale allows more libraries to be built, including target class-specific libraries. To provide a few examples, we offer antibody libraries targeting hard-to-drug target classes such as G protein-coupled receptors and ion channels,” she says.
High-quality DNA lowers the number of useless, nonfunctional, and developmentally risky antibody sequences in these libraries, which can also improve discovery success rates. “Partners are already taking advantage of our libraries to increase their success rates for these hard-to-drug targets, which are poorly served by other commercially available libraries.”
It is also important for end-users to have confidence in high-quality DNA. “It all comes down to efficiency and risk. Precise libraries are efficient libraries, as they require less screening to obtain high-quality hits. This is true regardless of whether we’re talking about identifying a drug target through CRISPR, directing the evolution of a biocatalyst, or screening antibodies. Precise libraries also carry less risk because nonfunctional sequences or manufacturing liabilities can be excluded upfront during library design. Regarding the design-build-test-learn cycle, high-quality DNA shortens both the duration of each iteration and the number of iterations needed to produce a high-value product. Whether the goal is to discover an antibody or engineer a microbial factory, high-quality synthetic DNA is poised to deliver life-changing treatments to the market faster than ever before,” Leproust states.
Volume 23, Issue 1 – Winter 2021/22
About the author
As an early pioneer in the high-throughput synthesis and sequencing of DNA, Dr. Emily Leproust, CEO and co-founder of Twist Biopharma is disrupting markets to enable the exponential growth of DNA-based applications. In 2020, BIO presented her with the Rosalind Franklin Award for Leadership. Foreign Policy named her one of their 100 Leading Global Thinkers and Fast Company named her one of the Most Creative People in Business. She has held positions at Agilent Technologies where she architected the SureSelect product line that lowered the cost of sequencing and elucidated mechanisms responsible for dozens of Mendelian diseases. She also developed the Oligo Library Synthesis technology.