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The Future of Food Starts With Better Cells: Why We Invested in Triplebar

• Investment • Opinion

Triplebar and Synthesis team

The future of food starts with better cells

Nature’s biological processes are both complex and powerful. They have been optimised over billions of years by a guiding force called evolution. Humans have spent the better part of the last century trying to tap into the power of biology. In recent years, Synthetic Biology (“SynBio”) – the re-writing of life’s code to build biological systems that serve our needs – has promised to revolutionise manufacturing for almost everything we consume, from fuels and materials to foods and novel drugs.

Despite the enormous potential, SynBio companies have found it challenging to date to fulfil such ambitions. Successfully scaling up and operating a commercially viable SynBio business has proved difficult - the untimely downfall of pioneering companies Zymergen and Amyris is testament to the hurdles the sector continues to face. Part of the problem is that it takes too many R&D dollars to identify the cell variant(s) that will deliver viable production yields at scale. While innovation is required in multiple areas (better bioreactors, more efficient bioprocesses, cheaper growth media etc.), it will amount to little if the starting cells are sub-optimal.

Lower cost and larger scale are the most important pre-requisites for food system disruption. To unlock this, precision fermentation processes need to use microbes that that yield as much of the target protein as possible per litre of fermentation capacity and cultivated meat producers need to culture cells that proliferate quickest and at higher densities. In both examples, the cells (whether microbial or animal) need to be optimised to behave in specific ways.

Traditional methods to screen for better cells are not good enough

SynBio applies a core engineering principle (“design–build–test–learn”) to biology. However, the sheer complexity of cell behaviour, as defined by its genetics, can make it challenging to design effectively at the outset. A so-called “rational design” approach to cell engineering relies on a strong working knowledge of the genes and/or pathways one wants to manipulate. It is a powerful approach, particularly with the advent of modern gene-editing tools. It is less helpful however, when you are not clear on what you want to edit or if the desired outcome requires modification of many genes across multiple pathways. This is often the case in applications for alternative protein, where rational design is akin to a shot in the dark.

“Directed evolution” provides us with an alternative for applications where we understand less about the relationship between genetics and the increasingly complex phenotypes we require cells to display. Instead of rationally engineering a strain, random mutagenesis (a tool for quickly producing millions of mutant single-cell variants) is used to create a large library of candidates. Each candidate is screened against a set of criteria to determine the best performing variants. Much of the success of directed evolution relies on the throughput and accuracy of the screening method. Large cell libraries (with hundreds of millions of mutants) become difficult to viably screen without an appropriate high-throughput screening tool. The plethora of variables to consider means the volume of testing required is orders of magnitude higher than what is possible today.

Traditional high-throughput screening methodologies using 96-well microtiter plates can screen roughly 10,000 cell variants per day. In a scenario that requires ~300 million variants to be screened, traditional approaches would take several decades and require billions of dollars in funding [1]. Scaling up 4x to 384-well plates, while an improvement, still fails to provide enough leverage to make the screening process viable. Instead, companies are forced to work with very small cell libraries that do a poor job of testing enough variants that perform meaningfully better.

Lower cost and larger scale are the most important pre-requisites for food system disruption.

Triplebar’s screening platform combines remarkable throughput with high accuracy and versatility

Enter Triplebar. Their Hyper-throughputTM Screening platform (”HyTS”) dramatically reduces the time and cumulative cost of finding the best performing strains. The HyTS shrinks the test tube down to picolitre-scale droplets (1 picolitre = a billionth of a millilitre!) that recreate a multitude of complex micro-environments in which single cells are tested. The platform screens entire libraries containing millions of mutant strains in as little as a day, to identify the best performing ones. Triplebar’s technology stands out among its competitors by scoring highly on three important categories for cell screening platforms:

A. Throughput: A crucial variable when it comes to strain optimisation. The benefits of directed evolution are impossible to leverage without higher throughput platforms. HyTS can screen at a throughput several orders of magnitude higher than traditional approaches that use 96-well plates and liquid-handling robots, allowing Triplebar to sift through large libraries at a fraction of the cost.

B. Accuracy: Throughput on its own will not necessarily lead to a desirable outcome. Assay quality – the ability to accurately test for a specific cell behaviour or protein functionalities – is crucial to help “pick the winners.” Triplebar’s platform maintains exceptionally high throughputs without sacrificing assay quality. The HyTS platform boasts noise characteristics enviable at the 96-well plate scale and has already been able to demonstrate predictability at larger scales – a key aspect of reducing the time and cost of developing commercially robust cell lines.

C. Versatility: The applicability of Triplebar’s platform stretches far beyond a single product vertical or cell type. HyTS works effortlessly across a suite of organism hosts with no real changes required to the benchtop hardware system. The platform is modular, easily scalable, and low-cost. Triplebar is helping produce bioproducts not just for food but for pharma as well. HyTS can be used to discover novel antibodies using a function-first approach, versus the traditional method of screening antibody candidates for binding. Versatility allows Triplebar to efficiently risk-manage its product portfolio as it grows the business over time.

A world-class leadership team with a product-first approach

We often encounter companies building platform technologies that spread themselves unnecessarily thin with their commercial strategies in a bid to demonstrate broad end-market applicability. In practice such a strategy is difficult to execute, particularly if you are a start-up building the proverbial plane while trying to fly it. Product-market-fit is harder to find without a clear focus on the subset of customers you want to sell to and the specific nature of the problems they face today that your platform can address.

Triplebar’s leadership team have demonstrated that they understand the pitfalls of not focusing on the right commercial partners and/or products when going to market, and bring with them an optimal mix of skills and decades of valuable experience in biopharma and SynBio. Taking a targeted approach to the product verticals prioritized through their commercial strategy, Triplebar optimises for partners best placed to scale-up and profitably commercialise bioproducts, thereby maximising the company’s likelihood of securing royalties over time. Triplebar’s cornerstone partnership with FrieslandCampina to bring to market cell-based proteins using precision fermentation is an early but significant validation of the platform.

At Synthesis, we are thrilled to partner with the amazing Triplebar team and to have led the company’s recent Series A round. We are excited about the potential for HyTS to deliver a much-needed step-change in commercial outcomes for SynBio businesses, and to help build strong foundations for the future food system through better cells.

[1] Assuming $30 cost per variant (from Ginkgo’s publicly available data), this would cost $9B

by Shrav Shah