Could GMO plants unlock full-spectrum human milk oligosaccharide production?

The company has been selected as one of three winning Probiota Pioneers for its work in HMOs, the complex sugars in breast milk that act as crucial prebiotics that promote good gut bacteria, block pathogens, and strengthen the gut barrier. Currently, over 200 structures of HMOs have been identified.

Scientist-turned-entrepreneur CEO Leila Strickland told NutraIngredients that only a small number of very simple HMOs can be produced at scale using fermentation technologies, and these processes are often expensive. Furthermore, the microbes used, often genetically engineered E. coli grown in bioreactors, can often be metabolically unsuitable for making the complex carbohydrates found in breast milk, according to Strickland.

“As a result, there’s been a longstanding interest in expanding the range of HMOs that can be produced to better reflect the complexity and diversity of those found naturally, while also dramatically improving the cost profile,” she said. “That’s essential if these ingredients are going to reach more babies—and ultimately more people—for a wide range of health applications.”

The plant advantage

Patrick Shih, CSO and co-founder of Totality Biosciences, is a plant molecular biologist and professor at UC Berkeley. He is “deeply interested in engineering plants to do what they already do best,” Strickland said. “One of those things is producing complex carbohydrates, which HMOs are.”

The business was founded on the concept that plants might be a sound platform for producing HMOs, both economically and in terms of molecular complexity and structural diversity.

Shih particularly believed plants could get much closer to producing the full spectrum of HMOs found in breast milk than the current method, and it was in the lab at Berkeley that the first genetically engineered plants expressing the enzymes needed to synthesize HMOs were created.

“Plants are metabolically optimized to create exactly this type of molecule,” Strickland said. “By giving them the right enzymatic instructions, the plants could generate a very complex HMO profile, and potentially the full spectrum of 200 HMOs found in breast milk.

“Today, by contrast, only five or six are produced at scale.”

Economics and accessibility

The increase in molecular diversity is one part of the story; another key component of the business model is about reducing the cost of HMOs, Strickland explained.

“When you move from expensive bioreactors to plants, the cost structure changes completely,” she said. “Based on technoeconomic analyses, we believe we could reduce the cost of HMOs by an order of magnitude or more.”

Its first product is therefore about proving the point that they can “make the most common HMOs much more cheaply than today’s manufacturers”.

The project began with 2-fucosyllactose (2FL), typically the most abundant HMO, with the gene program responsible for its production introduced and now being expressed in soybean. The goal is to have a 2FL-producing soybean by the end of 2026, Strickland said.

While economics are difficult to project, the Totality Biosciences team forecasts that when reasonable production levels are met, 2FL should be available at approximately half the current market price.

In the future, this could result in all formula-fed babies having access to HMOS, Strickland noted, something that is not currently possible due to the premium price point of the ingredient.

Furthermore, beyond infant formula, agricultural-scale HMO production could make these compounds accessible to other user demographics across multiple health applications.

“It’s a very important message that HMOs are not just for babies,” Strickland said.