Tapping into the power of nature

The ambition to adapt, modify, and even bend nature at times sets humans apart from other species. It’s not exactly natural for edible plants to spring up and thrive in a tightly packed land just so that we can conveniently nurture, harvest, and feed our kind at scale. But that’s what our ancestors accomplished. 

The level of sophistication in which we bend nature becomes more complex over time, parallel to an ever-growing understanding of how the system works. So, by the time genome/DNA sequencing, gene editing, and molecular tools entered the scene, nature bending went down to the genomic level. 

Microbial cell factory

The most intuitive engineering target is one with the simplest form of life: single-celled microorganisms. Each cell possesses self-sufficient functions and can pass down its genetic material to the next generation. Their genomes are also substantially smaller than complex organisms, some by ~1000x, making them simpler to manipulate. 

One of the most well-known single-celled microorganisms is Saccharomyces cerevisiae, also known as baker’s or brewer’s yeasts. The concept is simple: the yeasts act as catalysts, turning sugars such as glucose into ethanol and carbon dioxide. They help bread rise during the baking process and make beers alcoholic and bubbly.

The yeasts’ ability to catalyze is thanks to their genetic codes, programmed to make thousands of proteins, which take part in a highly interconnected metabolic pathway.

This metabolic pathway can be engineered by introducing new enzymes and/or deactivating existing ones. If you’ve tried ImpossibleTM Burger, it contains a heme molecule made from such a process. Impossible’s yeasts are engineered to make soy leghemoglobin, naturally found in the roots of soy plants. The technology isn’t entirely new. Genentech introduced a new way of producing insulin from engineered bacteria in 1982, revolutionizing how insulin is made now.

Market pull vs. technology push

The two cases above are great examples of market pull opportunities. Heme contributes to the meaty flavor profile of Impossible’s products, but its supply is limited. It’s the same thing with Genentech’s insulin:

At the time, it took 8,000 pounds of pancreas glands from 23,500 animals to make one pound of insulin. Diabetics lack this hormone, which regulates the amount of glucose in the blood. The manufacturer, Eli Lilly, needed 56 million animals per year to meet the increasing U.S. demand for the drug. They had to find a new insulin alternative, fast.

The engineered microbes provide executable solutions to their specific market pull problems.

But it’s not as easy as it sounds. It’s incredibly difficult to engineer the cells to do precisely what you need them to. After all, they are living things and they have their own underlying nature.

It’s a question of what may be possible from the existing internal metabolic pathway. Insufficient nutrient flow to central metabolism, metabolic burden from excessive recombinant expressions, and toxicity could all prove problematic. The potential for failure goes on.

The system is also far from static. They can pick up mutations over time, and those may revert the original engineering, reduce yield, and/or decrease productivity – all affecting the bottom line costs.

Again, no matter how small or simple these organisms are, they have their own will to survive and thrive. Their incentives are not to make desired products based on human engineering schemes. 

Challenge of Scale

Beyond cellular metabolism constraints, scale is a well-known, inevitable challenge. The system performance measured by yield and productivity is rarely consistent when the catalytic process is scaled up or down. 

Unlike the scaling of physical properties, scaling biology has many unpredictable factors. They’re typically done in a step-wise fashion, learning and adjusting the system as they go.

A notable approach to address both cellular constraints and scale problems is cell-free synthetic biology. Instead of relying on preexisting metabolic pathways, specific enzymes are extracted and put to work in vitro. With no live cells involved, higher predictability follows, though not without challenge.

Enzymes are not the most stable molecules and need to be kept in their preferred environment to perform. They also need to be produced and extracted, which are often costly and technologically challenging. Additionally, they rarely perform on a standalone basis. Many of them require co-substrates such as the energy molecule, ATP, or other co-factors such as NADP/NADPH – all of which are not cheap. 

While cell-free synthesis has its upside, it faces the kind of troubles that are more readily addressable in a cell-based system.

Eyes on the prize

The microbial cell factory approach has its limitations. One cannot simply dream up a product and drop in a standalone synthetic pathway. It must co-exist with the cells’ underlying genetics. Still, that is not a convincing excuse to overlook the search for market demand and driving force to adopt.

In fact, because it is so difficult to get the engineering and the scale to work seamlessly, having a solid rationale on why the target product has a good shot at conquering the market is critical.

The cautionary tales of Ginkgo Bioworks and Zymergen on the “platform” promises for cell engineering are already well laid out by Antonio Regalado and by Amy Feldman and Angel Au-Yeung, respectively. Neither company has a sufficiently strong product to justify their valuations. In fact, both of their core products are more of a service for other cell microbial factory companies, which isn’t tremendously helpful when only a handful of them have found their product-market fit and even fewer are willing to hand off their cells to a third party for optimization.

Final Thoughts

As someone who spent years doing synthetic biology, I believe in the possibilities and our ambitions to tap into the power of nature. Though the field has seen some tough months, not living up to its promises and failing public expectations, it’s important to remind ourselves that it is a tool, just like any other technology.

Despite and because of all the challenges lined up between bench-top and commercialization, it is critical to take a market-driven approach when picking a synthetic biology product.

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