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High value products and energy production through metabolic engineering

by Dr Yalun Arifin

Biotechnology is a multidiscipline in science and technology that has developed rapidly in the 21st Century. It is a technological application that utilises biological systems for production of desired products.

The history of biotechnology can be traced back to 8,000 BC when humans started to domesticate plants and livestock, and also when the Egyptians started to make wine around 4,000 BC.

Biotechnology is vital to our existence as it is used in the production of a wide range of products from food and pharmaceuticals to industrial chemicals and bioenergy. It also key to environmental protection, for example, in wastewater treatment.

Basically, this technology is essential for a myriad of issues such as food security, environmental degradation, energy crises, global warming and health, including the fighting of infectious diseases and degenerative diseases.

Advances in physics, mathematics, engineering and information technology have allowed the rapid development in biotechnology, including the strategies used to achieve its objectives. One of the main objectives in biotechnology research is to obtain a superior organism that allows efficient production process for achieving high productivity. The superior organism can be generated by modifying its gene or inserting foreign DNA.

In the past, modification was done by performing classical random mutagenesis. In this method, the targeted organism is treated with a mutagen such as UV radiation or a chemical ethyl methanesulfonate. The mutants developed are further screened to pick the desired ones. This method’s random nature means a very high number of mutants have to be screened and is therefore considered inefficient.

An improved method called metabolic engineering was first developed in the 1990s. Pioneered by leading scientists and engineers such as Gregory Stephanopoulos, Jens Nielsen and Sang Yup Lee, it is now widely applied by bioengineers to obtain superior organisms.

Compared to the old methods, metabolic engineering is more systematic and precise. It is based on the extensive understanding of the characteristics of the organism. Recently, metabolic engineering was included as one of top 10 emerging technologies of 2016 by the World Economic Forum.

A simple illustration of metabolic engineering is the analogy of shooting an Indian wolf surrounded by a pack of Eurasian grey wolves. These two subspecies of wolf are similar and often an expert eye is needed to tell them apart. Using the classical random mutagenesis method is like using a shotgun or machinegun to shoot the wolves and hoping some of the bullets will strike the target. As a result, there will probably be a mass of dead wolves and the ensuing selection process to find the right one will be time consuming.

When the metabolic engineering principle is applied, the shooter needs to understand the target’s unique characteristics and its surroundings. A sniper rifle is used instead of a shotgun to ensure a minimal number of bullets will be used. While the strategy may not eliminate the possibility of accidentally shooting Eurasian grey wolves, the number would certainly be lower.

Metabolic engineering involves modern analytical techniques that provide data from the genome to the metabolite level. By using state-of-the-art genetic engineering techniques assisted by the use of software for modelling, scientists can perform more accurate and efficient genetic modifications to obtain the desired superior organisms.

One example of metabolic engineering application is a study conducted for efficient lactic acid production in the bacterium Escherichia coli (E. coli). Lactic acid is normally used as a food or detergent additive, in pharmaceuticals preparation, and in recent times, for the production of poly-lactic acid, a biodegradable plastic. Previously, lactic acid was produced by lactic acid bacteria such as Lactobacillus. However, E. coli has advantages over Lactobacillus in terms of nutrition requirements.

A comprehensive understanding of E. coli potentials has allowed for precise genetic modification for efficient lactic acid production. Under anaerobic conditions, E. coli performs mixed acid fermentation to produce ethanol, acetate, formate, succinate and lactate (lactic acid).

Metabolic engineering can be applied to modify the E. coli, such as deletion of the genes for production of undesired products, allowing production of lactic acid only. The fermentation productivity achieved is comparable to the current process using Lactobacillus, making it a potential alternative for lactic acid production technology.

There are actually many more cases where metabolic engineering has been successful. Metabolic engineering of yeast has allowed for ethanol production from xylose, one of the main sugars found in lignocellulose biomass. 1,4-Butanediol, an important chemical for polymer industries, is produced from metabolic engineered E. coli. Several Bacillus and Streptomyces bacteria are metabolic engineered for production of drugs and drug precursors.

Metabolic engineering research work is still concentrated in countries such as the United States, the United Kingdom, Germany, Netherlands, Japan, South Korea and China. Biomass for fermentation to produce chemicals, however, is produced in very large quantities in developing countries including Malaysia, Indonesia and Thailand.

Several research groups in Malaysia, including those at Curtin Malaysia and Universiti Putra Malaysia, as well as groups in Singapore, Indonesia and Thailand, have started to focus on metabolic engineering. It is expected that their research as part of the global research led by leading metabolic engineering groups will bring about greater advances in the engineering of biological systems for the production of high value chemicals and energy.

Dr Yalun Arifin is a former senior lecturer of Curtin Malaysia’s Faculty of Engineering and Science.