Synthetic Biology Is Set To Explode, But Only Once This Huge Bottleneck Is Gone

What better way to celebrate DNA Day than to get up close and personal with the four letter code with trillion dollar potential? And a startup that may have a key to unlock it.

“Elegen is going to provide the manufacturing capability to allow other companies to do whatever they want.”

That’s the vision of Matt Hill, CEO and Founder of Elegen Bio, who I’m catching up with ahead of his talk at the SynBioBeta Conference this May.

Hill and Elegen are on a mission to remove a huge bottleneck from synthetic biology. The DNA code that we’re still to fully crack.

“It’s worse than punch cards,” he says, equating synthetic biology now to computing almost a century ago. “It’s slow, it’s expensive, it’s cumbersome.

“The manufacturing of DNA is a critical bottleneck, and it’s holding back the entire field of synthetic biology as well as the rest of the life sciences.”

Hill believes that long DNA, written with speed and accuracy, is what synthetic biology needs – and that’s exactly what Elegen offers.

Long DNA like no other

Elegen is a company that writes DNA. They’re among a suite of companies such as Twist Bioscience, Genscript, Integrated DNA Technologies and more.

Writing DNA involves replicating the sequence of DNA code, made up of the bases we know as A, T, G and C. Accuracy is key to ensure the correct products, like enzymes, are made in cells.

Hill says Elegen’s ENFINIA DNA technology – a modular, systems based approach that targets methods, hardware and software alike – sets them apart.

“We produce full length DNA up to 7000 bases with 99.999% per base accuracy in seven business days,” he says. “Right now there’s nothing on the market that comes even close to that.”

Hill explains that complexity is another thing Elegen is tackling, writing the parts of DNA that are tough to manufacture but can play an important role in a living cell.

“There are certain features of DNA such as runs of the same DNA bases, or repeats, that are difficult to make,” explains Hill. “We have technologies in development that can improve on this. It’s a big deal for a lot of companies. Instead of having to reconfigure the DNA, to get the molecules that they actually need.”

Why is long DNA so useful?

A big barrier for making DNA is cloning, which despite decades of advances to date is still a hugely time consuming task for many synthetic biology startups.

A lot of the useful products that can be made using synthetic biology, new cancer medicines for example, can require five, ten, twenty or even more biochemical steps. Multiple enzymes working together.

More or less the same number of genes need to be stitched together, along with the other DNA ingredients that turn them on in the cell, to produce the desired enzymes that go on to make the medicines we want.

“We have new methods that streamline the cloning step dramatically and make it very high throughput,” says Hill. “When you’re talking about things like biosynthetic gene clusters, that’s absolutely an area where we unlock capability and speed.”

Long DNA takes the load off startups

I spoke to Quentin Dudley, an expert in metabolic engineering at Speculative Technologies, an organization I wrote about earlier this year that’s pioneering new innovation systems. He told me how useful this could be for startups.

“When you want to metabolically engineer an organism, you often make genetic constructs that are ten thousand or more DNA base pairs,” says Dudley. “When you have a long metabolic pathway or very large multi domain enzymes, it’s really hard to order DNA parts that big off-the-shelf so you need to stitch various DNA fragments together yourself.”

He explains that synthetic biology startups often do this sort of thing in house with limited resources, which takes time.

A lot of the existing assembly strategies are hierarchical,” Dudley explains. “It can take up to a month to deliver a final vector with several rounds of assembly and quality control steps. When you can custom order 7000 base pairs of DNA with very few errors, maybe you have to stitch just two or three components together in one step instead.

“You’re shaving half the time off at least.”

It’s a boost that Hill believes will allow startups to focus more on the product.

“Manufacturing DNA is not something that needs to be replicated across a thousand companies,” says Hill. “You have all these young companies out there trying to solve really challenging clinical problems.

“Our technology allows them to progress very quickly from screening onto scale up and very rapidly into the clinic.”

Solving big problems

Hill stresses that this technology is going to help some of society’s biggest problems.

“This really unlocks areas like personalized cancer vaccines,” says Hill. “You don’t have 18 or 24 months to make these things, you have to act quickly. You need to create the molecules in an order of weeks to help the patient.”

mRNA vaccines, too, could be brought much faster to clinical use.

“The companies we work with in pharma see DNA as a key bottleneck in being able to rapidly move from the earliest stage to a clinically deployable vaccine,” he continues. “The potential is huge.”

But how big can Elegen go?

For plant biotechnology, getting molecules that are even bigger could be game changing.

“The bacteria that you use to introduce genes into plants, Agrobacterium, the size of those DNA inserts natively can be up to 60 thousand DNA base pairs,” explains Dudley. “For plant engineering, we haven’t necessarily been doing that because we run into size limits of what our DNA assembly strategies and organisms can handle. The maximum size plasmid you can get in E. coli is 15 or 20 thousand.

“With large fragments of DNA on order, we can can get to that 60 thousand size.”

For Hill, that sort of length is certainly within scope.

“Right now, we can get up to 20 thousand in a roughly similar time frame, about a week and a half,” says Hill. “When you talk about very, very long DNA, 30, 40, 50 thousand DNA bases, this is an ideal material to be used in that process.”

Crucially, for Hill and Elegen, the most important thing of all is creating a platform for companies to thrive.

“I don’t think we can comprehend how rapid high quality DNA and programmability in biology will actually transform everything,” says Hill, positioning synthetic biology on a cusp similar to that of computer technology not so long ago. “Elegen is solving a crucial part of the supply chain.”

Thank you to Peter Bickerton for additional research and reporting on this article. I’m the founder of SynBioBeta and some of the companies I write about, such as Elegen, are sponsors of the SynBioBeta conference and weekly digest.