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Can Engineered Tobacco Plants that Make Human Sugars Improve Infant Formula and Plant-Based Milks?

In an eclectic application of transgenic technology, researchers at the University of California at Berkeley and Davis describe retooling cells of a tobacco relative to produce enzymes required to synthesize the short sugars (oligosaccharides) found in human milk. The work appears in Nature Food.

Transgenic Technology

Plants have been genetically modified since the 1980s, programmed to produce molecules of use to us. In contrast to the controlled breeding of conventional agriculture, genetic modification inserts or removes specific genes, crafting a plant variant with some use for us.

Plants aren’t only genetically modified to create or enhance fruits and veggies, or make them easier to cultivate or protect from pests and pathogens, but also to manufacture the enzymes required to catalyze biochemical reactions behind the synthesis of such ingredients as corn syrup, cornstarch, corn oil, soybean oil, canola oil, and even sugars.

The alterations aren’t direct, for genes encode proteins, not carbohydrates or oils. Instead, the genomes of plant cells cultured in a lab receive the DNA sequences – genes – that enable them to manufacture specific enzymes required for the biochemical pathways to produce certain molecules of value to us. The researchers deployed a commonly used soil bacterium, Agrobacterium tumefaciens, to deliver select genes into plant leaves

An organism harboring DNA from another species is termed transgenic, which uses recombinant DNA tools on a multicellular organism. Human interferon-α was the first recombinant plant-derived pharmaceutical protein, produced in turnips in 1989.

Transgenic plants have diverse applications. They include making:

• human growth hormone from tobacco
• protein antigens used as vaccines against HIV (from tobacco) and hepatitis B (from lettuce)
• colony stimulating factor in rice
• protease inhibitor against HIV infection in corn
• enzymes such as lysozyme and trypsin
• interferon and interleukins from potatoes
• vaccines and antibodies to against COVID-19

Mimicking Milk

The researchers call their retooled cells of Nicotiana benthamiana (aka benth or benthi), a close relative of the tobacco plant from Australia, a “photosynthetic platform for the production of diverse human milk oligosaccharides.” The goal is to mimic the difficult-to-synthesize unique blend of sugars required for commercial infant formula to be as close to the real thing, nutritionally, as possible.

Worldwide, about 75% of babies drink infant formula in their first six months, either as a sole source of nutrition or as a supplement to breastfeeding. But molecule-by-molecule, formula isn’t exactly the same as the real deal.

The 200 or so short sugar molecules in human breast milk are precursors to molecules that support the establishment and maintenance of a gut microbiome that eases digestion, while also preventing disease. But the same sugars that a plant cell easily produces are challenging, sometimes impossible, for food chemists and microbiologists to synthesize in a lab.

Enter transgenic technology.

Using genetic modification to control the composition of milk may improve not only infant formula, but plant milks too.

“Plants are phenomenal organisms that take sunlight and carbon dioxide from our atmosphere and use them to make sugars. And they don’t just make one sugar — they make a whole diversity of simple and complex sugars. We thought, since plants already have this underlying sugar metabolism, why don’t we try rerouting it to make human milk oligosaccharides?” said study senior author Patrick Shih.

The complex milk sugars – oligosaccharides – are built from simple monosaccharides that link them into straight as well as branched chains. Enzymes catalyze the reactions that link the simple sugars of human milk, complex enough to challenge the synthetic skills of chemists – but not of plants.

The transgenic tobacco plant cells are endowed with the genes that encode the enzymes necessary to craft 11 human milk oligosaccharides, and other complex sugars.

That’s quite a feat. “We made all three major groups of human milk oligosaccharides. To my knowledge, no one has ever demonstrated that you could make all three of these groups simultaneously in a single organism,” said Shih.

One milk sugar in particular is of great value – LNFP1.

“LNFP1 is a five-monosaccharide-long human milk oligosaccharide that is supposed to be really beneficial, but so far cannot be made at scale using traditional methods of microbial fermentation. We thought that if we could start making these larger, more complex human milk oligosaccharides, we could solve a problem that that industry currently can’t solve,” said lead author Collin R. Barnum, who was a graduate student at UC Davis.

It’s possible to make a few human milk sugars in bacteria, but isolating them from toxic byproducts is costly. So most infant formula brands leave these valuable sugars out of their recipes.

The transgenic tobacco approach to making human milk sugars is also scalable, an important consideration for products consumed by millions. Collaborator Minliang Yang, from North Carolina State University, estimated that manufacturing human milk sugars from GM plants at an industrial scale would likely be cheaper than using traditional processes.

Summed up Shih, “Imagine being able to make all the human milk oligosaccharides in a single plant. Then you could just grind up that plant, extract all the oligosaccharides simultaneously and add that directly into infant formula. There would be a lot of challenges in implementation and commercialization, but this is the big goal that we’re trying to move toward.”

I wonder about the implications for making ice cream.

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