From synthetic biology to synthesising DNA: helping advance research 

Evonetix is reimagining biology. Dr Vijay Narayan, Head of Physics, Dr Stuart Crosby, Head of Synthetic Chemistry, and Daniel Bygrave, Principal Software Engineer, offer insight into the technology being developed by the company and its relevance for researchers. 

“I have always been intrigued by interdisciplinary environments,’ says Dr Vijay Narayan, Head of Physics, Evonetix. “This is what initially drew me to synthetic biology, as it combined aspects of physics and biology that I enjoyed working in. When I first read about Evonetix, I could see the potential that the company’s technology offered toa the field, and its ambitious goals and vision really resonated with me. The opportunity to make a chip that would have applications in biology and chemistry seemed unique and exciting.”  

Evonetix says it has a different approach to gene synthesis – a platform to synthesize DNA at unprecedented accuracy, scale and speed. This will allow the rapid prototyping of new genes and pathways to harness biology to address challenges such as the need for novel treatments. The company believes its work will place DNA synthesis in the hands of every researcher and change how DNA is accessed, made and used, creating a new paradigm for gene synthesis. The technology is based on a novel silicon array, manufactured with semiconductor microfabrication techniques and capable of independent control of up to 10,000 miniaturised reaction sites. 

“When I first joined Evonetix, synthetic biology was still developing as a concept, albeit one with massive potential,” says Dr Stuart Crosby, Head of Synthetic Chemistry, Evonetix.  Crosby found the company’s proposition attractive “because it was completely novel and cutting-edge. I was interested in the idea of applying engineering principles to biological systems and the potential impact of synthetic biology applications was extremely exciting.” 

Having first come across synthetic biology when he was working at Cambridge Consultants on a project using PCR technology to amplify DNA, Daniel Bygrave, Principal Software Engineer first worked with DNA at Evonetix. “I found it fascinating. We then started thinking of how we could apply similar technology to synthesize DNA, and from there my interest only grew,” he reveals.  

The technology uses thermal control to synthesize DNA. Bygrave says this is a fundamentally different approach to conventional DNA synthesis. “What makes this technology unique is our ability to reject errors as we synthesize.” 

The process has not been without issues. “One of the big challenges that faces standard DNA synthesis is a high error rate (around 1 in 200 bases added) when building long strands. Thermal control allows us to selectively grow DNA on different sites simultaneously, while enabling the rejection of errors during the subsequent assembly process,” says Bygrave. 

The process required the development of custom chemistry that is thermally activated. “When we began the project, we didn’t know what this would look like, and so this presented a major challenge. We overcame it with a flexible approach and by working across the scientific disciplines to problem-solve together. 

“Another challenge we faced was the need to be able to predict the behaviour of DNA under different thermal conditions. The number of potential combinations of DNA meant that gathering this information empirically would be impractical, therefore we adopted a machine learning approach. By capturing a representative subset of possible data, we train an algorithm to be able to predict behaviour for any arbitrary DNA sequence,” he says.  

This was not the only challenge – technical and manufacturing-related  – the team faced. However, as Narayan explains: “Our biggest asset here is having such a wealth of expertise within the company and through our excellent collaborators which has enabled us to find solutions to each of these challenges.” 

According to Crosby one of the most fundamental research challenges they are trying to address is access to DNA. “Currently DNA is relatively easy and inexpensive to read and edit thanks to Next-Generation-Sequencing (NGS) and CRISPR. But it is still very costly and labour-intensive to write long, gene-length DNA at the low error-rates required for incorporation into biological systems. There has not yet been the orders-of-magnitude drop in the cost and time for DNA writing that NGS delivered for DNA reading, and the only way to do that is to make DNA in a parallel way with an automated error-detection/removal process,” he says.  

Bygrave adds: “The main challenge and current bottleneck is getting good quality DNA into researchers’ hands. The process of obtaining DNA slows down research. This could be preventing breakthrough ideas reaching realisation if scientists are waiting weeks to get hold of DNA and begin their experiments.” 

The technology addresses this by using the fine temperature control built into each synthesis site and the fact that a mismatched DNA duplex has a lower melting point than the equivalent homoduplex. A combination of laminar flow and specially designed electrodes moves DNA from one synthesis site and traps it at the next, where it is annealed to a partially overlapping complementary strand. By raising the temperature to just below the homoduplex melting point any sequences with a mismatch are melted and removed from the pool. Repeating this process multiple times grows the dsDNA strand while purifying out most of the errors. Completing this on the surface of a chip takes around three days from start to finish instead of the three weeks often needed by conventional approaches. 

Synthetic DNA potential 

Crosby feels that biologics will increasingly take over from small molecules in pharmaceutical chemistry, and this will be further accelerated by synthetic biology. “A great recent example of this is the development of mRNA vaccines for SARS-CoV-2,” he explains.  

Bygrave too, sees many possibilities within medicine. “And we’ve seen recently in the news examples of machine learning algorithms predicting protein structures. There is potentially a whole realm of possibilities that nobody has even thought of yet. It is exciting to think of what may emerge once DNA synthesis technology is readily available and accessible in all laboratories – it is difficult to predict what this will enable in the coming years,” he adds. 

“The whole field of synthetic biology is reliant on access to long and accurate DNA, so I think Evonetix provides endless opportunities,” says Narayan. “Being able to make accurate tailor-made sequences could revolutionise research from sectors such as agriculture by improving drought resistance in crops, to pharmaceuticals by producing synthetic microbes that act as drug delivery system.” 

Opportunities for drug discovery 

Synthetic biology has the potential to create opportunities for drug discovery research.  

In drug discovery, the development of mRNA-based vaccines and therapies requires multiple iterations of sequence design to optimise performance. In the race to the optimal sequence, cutting the production time for each new iteration can take months off the development timeline. In antibody discovery, screening pools of synthetically prepared sequences against therapeutic targets is driving the development of new therapeutics and in cell and gene therapy, where each patient may ultimately require a different, specifically tailored gene modification. The ability to provide high quality synthetic DNA quickly and close to the point of use will help drive the broad availability of personalised medicine. 

Volume 23, Issue 1 – Winter 2021/22 

Image credit: Richard Marsham/RMG Photography

About the authors 

Dr Vijay Narayan, Head of Physics, joined Evonetix in April of 2018 as a Senior Engineer. He took on the role of Head of Physics in October 2020. 

Daniel Bygrave, Principal Software Engineer, joined Evonetix at its founding in 2015. He previously worked as a Principal Software Engineer at Cambridge Consultants. 

Dr Stuart Crosby, Head of Synthetic Chemistry has over 20 years’ experience working in synthetic chemistry and drug discovery. He is now Head of Synthetic Chemistry at Evonetix where he is developing the chemistry that underpins Evonetix’s third generation DNA synthesis platform. 

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