Industrial Biotechnology Microbial Cellular Plants and Metabolic Engineering

Editor: Dr. Jörg Kempf

Biotechnologists and chemical engineers work closely together in many fields. One of them is industrial (“white”) biotechnology. Metabolic engineering offers many opportunities for using biotechnological processes.

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Sustainable biotechnological production of bioactive products (Picture: Kristian Barthen/BRAIN)
Sustainable biotechnological production of bioactive products (Picture: Kristian Barthen/BRAIN)

Whoever has ever dealt with organic synthesis probably experienced that special moment between total frustration and unbelieving awe when encountering biochemistry for the first time: An enzyme with an enigmatic abbreviation is introduced, and functionalizations are performed in exactly the right places with exactly the desired stereochemistry in one step where a conventional synthesis with 17 steps was otherwise required. No wonder microorganisms have taken root as little helpers in industrial processes. But nature with its microbes and enzymes does not always exactly meet the chemist’s or pharmacist’s wishes.

Metabolic Engineering Enters the Stage

What is there to do? So far, organisms have been variegated based on haphazard mutations and optimized using trial-and-error-processes until a bacterium had been found that was able to grow and be cultivated and produced the desired substance with acceptable yield. This development can take decades, is expensive, and the result is not necessarily a real optimum.

That’s where metabolic engineering enters the stage. The basic idea: If the metabolism of a microbe is understood well enough, an organism can be designed that does exactly what it is supposed to do. Design wins over mutation.

Unfortunately, adjusting only one screw — meaning one gene — usually does not work. Metabolic processes interact in a very complex way, and optimizing an organism requires to take the whole metabolism into account. In order to achieve this, a couple of methods are available: It is now possible, for example, to isolate a single cell and study its metabolism instead of working with the mean of a large population. Mathematical and statistical simulation models also contribute in identifying the places where genetic manipulation can work. In addition, there exist several approaches to reduce the complexity of the cellular system.

Of course you cannot build walls inside a cell or isolate parts from each other as you would do in a mechanical plant and still have a living cell. A variety of methods can be used to achieve orthogonalization, or the decoupling of metabolic processes.

Development of Bacteria with Minimal Equipment

One strategy consists of the development of bacteria with minimal equipment; Craig Venter’s “artificial cell” that drew attention a couple of months ago represents this line of thinking.

Another interesting approach is to use cell-free in vitro systems. They combine the advantages of in vivo and in vitro systems. First, a cell with the wanted enzyme system is developed. This cell is then broken down and homogenized before unwanted enzymes are removed. This can be done by introducing cutting sites into the enzymes while the cell grows. These cutting sites are designed for specific protein-cutting enzymes, so-called proteases, that cannot access the other wanted enzymes. The protease is then added to the processed in vitro system. The unwanted enzymes are split, while the desired enzymes remain.

Some processes based on “designer-cells” are already competitive, but overall, metabolic engineering makes its way only slowly into large industrial production processes. This is due to the large and time-consuming testing and to the often incomplete knowledge of the detailed metabolism of the organisms used.

But scientists from industry and research institutions are working hard to identify interesting chemical building blocks and train microorganisms to produce them. Thus, this kind of “talent shortage” could soon be history.