Designer proteins…made to order? Tierra Biosciences unlocks the potential of cell-free protein synthesis with an online ordering platform

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The San Leandro-based startup – which was founded in 2015 by academics* from Caltech and Harvard in 2015, when it was known as Synvitrobio – is part of a new wave of synthetic biology companies expressing proteins using some of the bio-machines found inside the cells of microbes such as E.coli​, without having to keep the cells alive, hence the term “cellless”.

This allows companies to produce ingredients that are currently difficult or impossible to manufacture inside, for example, a yeast or bacteria cell, and significantly speed up the discovery process, says Tierra, who comes from launch the Tierra Protein Platforman online portal for customers to obtain custom proteins”synthesized, validated and dispatched in a few clicks.

Custom protein…made to order

Customers enter numerical sequences of proteins (“chains of amino acid letters”​) in Tierra’s online portal, which then evaluates their properties and the most efficient ways to biosynthesize them, explained co-founder and CSO Dr. Zachary Sun.

From there, the company uses a cell-free manufacturing process to express the final proteins, which are then shipped to customers for testing, he told FoodNavigator-USA.

Partners such as those based in San Diego Beginning Biotech have since used these proteins (in the case of Debut, enzymes) to optimize their own cell-free biomanufacturing platforms (Debut uses immobilized enzymes to convert low-value materials such as glucose into high-value ingredients such as colors and flavors, in a continuous process).

Why no cell?

But why abandon the cell?

It all depends on the proteins you want to produce, said Sun, who noted that traditional microbial fermentation systems use a batch (rather than continuous) production process and can have low yields and high costs because the target ingredients are either secreted into the reservoir, thus requiring further purification, or are enclosed in cells, requiring an extraction process, for example.

Abandon the cell, but retain some of its internal machinery, and you can operate under a wider range of conditions (pH, temperature, etc.) and allow metabolic transformations that are not possible in cellular microbial fermentation systems, he asserted.

Cells can offer distinct advantages when you’re trying to make a lot of protein of a specific type, but the fundamental realization that we had at Tierra is that before we get to that there’s all this work prior R&D to try to identify the protein you want to make and how you want to make it; it’s about trying things out and figuring out what your best candidate is, and for that, cell-free approaches offer advantages, because you don’t have to fight biology to extract that protein.

“So what we have is actually a liquid that you can put synthetic DNA in, which is a type of protein that you want to make, and you’re not limited by toxicity or things that the cell needs to grow, allowing you to really get protein fast in small amounts, allowing you to power innovation.

the E-Coli the strains used by Tierra are “no different from those used in traditional fermentation,” noted CEO Dr. Corinna Chen. “The basic difference is that in fermentation the cell is alive and bound, while in celllessness we use the molecules and compounds inherent in the cell, we just don’t need the cell to be really alive.”

The E Coli strains used by Tierra are “no different from those used in traditional fermentation,” says CEO Dr. Corinna Chen. “The fundamental difference is that in fermentation the cell is alive and bound, while in acellular [manufacturing]we use the molecules and compounds inherent in the cell, we just don’t need the cell to be actually alive…’ Image credit: Tierra Biosciences

“There’s a huge upside to being able to help people innovate faster”

As a practical example, she says, take something like red cochineal (crushed insects). Food companies love the stability and bright red color, but they don’t want to put bugs in their smoothies, so they’re exploring ways to biosynthesize red colors with similar properties, without the unfriendly label. Cell-free approaches can help them achieve this.

“So companies know what that red is,” said Chen. “So they can enter a bunch of variants or sequences into our platform, so they may want more pH or temperature stability depending on the application they’re targeting, so we can create those variants for them. If they did that​ [in-house] it could take years. There’s a huge upside to being able to help people innovate faster and find that needle in the haystack sooner.

Tierra cell free expression
By removing the protein-synthesizing elements of living bacteria, reliance on these organisms is eliminated and efficiency and throughput are increased, claims Tierra Biosciences. Image credit: Tierra Biosciences

The business model

So what is the business model for Tierra, which has so far raised just over $6 million in seed funding and is currently gearing up for a Series A?

“Initially, we offer customers many options”, said Chen, who said Tierra sees particular interest from companies looking for meatier flavors in meat alternatives.

“But we intend to grow with our customers and their needs, so that while now we can only provide a preview, in the future we could provide larger quantities, and potentially a route to manufacturing. One of the benefits of cellless​ [biosynthesis] is that it should be much easier to transfer technology from R&D scale to commercial scale.

“Customers can already go to our e-commerce site and order protein and we’ve already seen commercial revenue and worked with several companies, from synthetic biology startups in food and flavor, to very large corporations.”

Microbial fermentation may be the best option for biosynthesizing many proteins, while cell-free production may be more efficient for others, she said. “Some compounds are made easier and more readily by microbes and some are not.​.

“But this​ [microbial fermentation] uses a lot of water and you need a lot of space in commercial scale bioreactors,” added Chen. “While this is not the case in a cellless system, for example.”

Cell-free protein synthesis and alternative proteins

Asked about the broader potential of cell-free biomanufacturing in food and beverages, Synthesis Capital co-founder Dr. David Welch (who was formerly director of science and technology at the Good Food Institute) told us says he saw a lot of opportunities in the alternative protein field.

In particular, the flexibility of cell-free platforms allows for the synthesis and manufacture of a wider range of proteins, some of which may be more technically or economically difficult to produce by conventional microbial fermentation.

“Second, once at scale, these platforms could reduce the manufacturing footprint and complexity required for the production of recombinant proteins, which will become increasingly important as demand for these ingredients grows.”

*​ Dr Zachary Sun, Dr Richard Murray (Caltech) and Dr George Church (Harvard).

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