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Harnessing the methods of metabolic engineering, Xixian Chen is blazing a trail toward sustainable production of industrially important compounds.

© A*STAR Research

Streamlining operations of life’s fundamental factories

20 Sep 2022

Harnessing the methods of metabolic engineering, Xixian Chen is blazing a trail toward sustainable production of industrially important compounds.

One of the first things we are told in biology class is that the cell is the most basic, fundamental unit of life. Not many people know, however, that cells can function as factories too, working overtime and at top efficiency to produce a wide variety of compounds—anything from biofuels to preservatives, from wine and cheese to life-saving drugs.

The process of turning cells into these production lines is called metabolic engineering. By tinkering with the cell’s genetic material, metabolic engineers hope to optimise the many different cellular processes that yield the particular substance of interest. Single-celled microbes such as baker’s yeast and E. coli bacteria are often used as they grow well on cheap food sources, making large-scale cultivation easier.

If the field wholly rises up to its promise, it can potentially transform many industries. Still, many roadblocks remain. For one, optimisation is a delicate balancing act. Rather than simply ramping up gene expression, metabolic engineers look for the ideal middle-ground between production volume and cellular viability.

Another barrier is that the biosynthesis routes involved in the production of many compounds of interest remain incompletely elucidated or completely unknown. Without mapping these out in full, efforts to optimise the cell factories could prove futile.

At A*STAR’s Singapore Institute of Food and Biotechnology Innovation (SIFBI), scientists like Junior Principal Investigator Chen Xixian are working around this limitation, developing completely new and sustainable pathways to help metabolic engineering meet its potential.

In this interview with A*STAR Research, Chen talks about her enduring fascination with metabolic engineering, her cutting-edge work at SIFBI, and how A*STAR helped her develop as a well-rounded scientist.

Q: What drives your interest in tinkering with cellular and molecular processes?

Metabolic engineering is a very exciting and interdisciplinary field that requires knowledge of engineering, biochemistry and microbiology, among others. More importantly, it can be used to produce compounds that are difficult to synthesise naturally or chemically.

I have a strong interest in organic chemistry, particularly in making organic compounds. Cells are the best organic chemists because they can make many complex compounds using only simple starting materials and even at mild reaction conditions. Instead of relying on heavy metals, cells use enzymes, the green catalysts that can transform a substrate into different products.

Q: How might metabolic engineering help our search for more sustainable ways to produce food?

Metabolic engineering is the optimisation of pathways in host organisms, like baker’s yeast, to achieve high TRY (titre, rate, yield) of target compounds. However, it is not as simple as just overexpressing a group of genes, but a complex engineering process to maximise the product output while causing minimal impact on the fitness of the host. This includes fine-tuning each enzyme’s activity, balancing co-factors and preventing the accumulation of toxic or unstable intermediates. Some metabolically engineered hosts or microbes can be cultured in bioreactors and scaled up to more than 1,000 litres to produce desired compounds.

The food industry can greatly benefit from metabolic engineering. For instance, compounds used for food applications, such as flavourants, colouring agents or natural preservatives, are usually highly chiral; that is, only one form of the molecule is useful. Thus, these compounds tend to be difficult to produce through chemical means. Moreover, the starting materials for their chemical synthesis are usually derived from non-renewable, and highly unsustainable, petrochemicals. Another option is to extract these compounds from natural sources, but this requires agricultural land and water.
Metabolic engineering enables the production of functional molecules using renewable carbon sources while taking up significantly lesser land and water.

Q: At A*STAR’s SIFBI, how have you harnessed metabolic engineering to sustainably produce food or cosmetic compounds?

Our goal is always to achieve higher TRY for the molecules that we work on. We’ve achieved near-theoretical levels of yield for some natural products (that is, the maximum yield possible given the chemical reactions involved).

A prerequisite of metabolic engineering is that the target molecule’s biosynthetic pathway is known. Unfortunately, many food and cosmetic molecules’ pathways have yet to be elucidated. As a workaround, we are currently developing capabilities to design new-to-nature pathways based on chemical and biochemical rules. This will be our competitive edge in producing food and cosmetic molecules from renewable carbon sources using metabolic engineering strategies.

Aside from scientific advancement, A*STAR also helps us to commercialise our technology. Through this support, our patented technology has been licensed to the spin-off company Fermatics.

Q: Could you explain how Fermatics’ core technology works?

Multidimensional heuristic process, or MHP, is a platform technology by Fermatics that enables us to balance the activities of the multiple enzymes we have introduced into a host. By quickly identifying the highest-producing host strain, MHP reduces the number of trial-and-error.

The idea behind it is simple: Instead of modulating individual enzymes, of which there are usually more than 10, MHP first groups several enzymes together, thereby reducing the overall number of combinations we have to test. This allows us to identify which group of enzymes is the bottleneck. We can then zoom into this group and focus our efforts there to enhance their efficiencies.

We spent the last ten years building the molecular biology tools to make MHP work.

Q: How has A*STAR helped you to grow as a research scientist?

A*STAR provides a conducive and supportive environment for me to conduct industrially relevant research. Even during the very early stages of my career, my colleagues would include me in brainstorming sessions to tackle problems identified by industry colleagues.
SIFBI also allowed me to head a few industrial projects in partnership with multinational companies. All of these broadened my perspectives and made me more aware of industrial needs, as well as of the gaps that basic research needs to fill.

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This article was made for A*STAR Research by Wildtype Media Group