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Synthetic Microbes as Efficient Cell Factories
Scientists are trying to play God, it seems.

Rather than replicating existing genomes and modifying existing microorganisms, scientists now aim to create “synthetic life” from scratch.

They are conducting researches on the construction of custom-made microorganisms which are pre-designed to efficiently carry out specific tasks. These microbes will carry programmed genomes which will make them behave in a predictable manner similar to that of synthetic machinery. These ‘biological machines’ will be more competent than genetically engineered microorganisms and will be able to perform a vast range of metabolic activities which are not yet achievable with the natural or genetically altered microorganisms.

A Minimal Genome

In fact, scientists have come halfway through their goal. They have already identified the genes which are crucial for the basic cellular functions of a bacterium. This ‘minimal genome’ enables the bacterium to survive, grow and reproduce without involving in other non-essential energy wasting cell functions. Insertion of another few pre-programmed genes will convert such minimal bacterium into an efficient biological machine capable of self-replication and self-assembly while accomplishing the desired tasks with maximum productivity.

In 1995, a group of researchers at the J. Craig Venter Institute, California completely sequenced the genome of the bacterium Mycoplasma genitalium, the smallest genome of a natural free living organism. They identified that of some 500 genes only 206 genes, approximately, are required for the viability of the cell.

A Man-made Genome

In 2010, they succeeded in the construction of a ‘semi-synthetic bacterium’ by transplanting a synthetic genome into a host bacterial cell.
In the process of creating this bacterium, the scientists first sequenced the genome of the donor bacterium, Mycoplasma mycoides and then designed a computer model of a new genome by purposely deleting some of its genes and adding a few ‘watermark genes’ which enabled to distinguish between the synthetic and natural genomes. Then they chemically synthesised this genome in the lab in the form of several gene fragments with sticky ends. These gene fragments were then put together to form the complete genome. The re-assembly was done in yeast cells.
This completed synthetic chromosome was inserted into another host bacterium of the same genus, M. capricolum, where it replaced the natural genome and replicated successfully.

Read the complete process of the “Creation of a Bacterial Cell Controlled by a Chemically Synthesized Gnome” in detail.

Gibson, D. G., Glass, J. I., Lartigue, C., Noskov, V. N., Chuang, R. Y., Algire, M. A., ... & Venter, J. C. (2010). Creation of a bacterial cell controlled by a chemically synthesized genome. science, 329(5987), 52-56.

An Ideal Cell Factory

Equipped with this knowledge, scientists are currently conducting research with the hope of manufacturing an ideal microbial cell factory to be used industrially. This model cell will contain a collection of genes that are essential for the metabolism, growth and reproduction of the microbe along with the tailored genes for carrying out the required job.

Such a cell is hoped to maximise bioprocess efficiency by eliminating unnecessary cellular processes and focusing only on the essential activities. For instance, deleting the genes required for alternative metabolic pathways will make product formation a favourable condition to the cell viability, thus enhancing production efficiency.

A smaller genome will also be beneficial since it will reduce the rate of mutations- probably due to the removal of transposons- consequently increasing the genetic stability of the strain.

Another favourable characteristic will be improved resistance of the bacterium to the physical and stresses such as sheer force or osmotic stress as well as resistance to toxicity by products or substrates. For example, an ideal microbe designed to be used in ethanol fermentation will have higher alcohol tolerance; hence will be able to produce higher ethanol yields without being suppressed by elevated alcohol concentrations.

This perfect microbial machine will be programmed in such a way that its reproduction will be carried out in an effective manner without generating waste biomass i.e., non-viable, non-product forming daughter cells. This will result in higher product yields per unit mass of substrate. Furthermore, it will have higher growth rates accounting for short productions runs, ultimately boosting the overall productivity.

A Dream Come True

The array of possibilities a programmed organism offers is unimaginable.
This will open up new avenues of research and industrial processes such as biofuel research, production of industrial enzymes, pharmaceuticals, bio-based chemicals, etc. These man-made organisms can be programmed with higher resistance to the toxins making them suitable for clearing up chemical spills.

There will be microorganisms with laboratory-designed metabolic pathways capable of utilising new, renewable substrates. And those microbes will have increased resistance for products and inhibitors thus resulting in improved product yields. Moreover, new microorganisms will be constructed to manufacture completely new end products.

Such a microorganism is the dream of industrialists as well as the researchers. With the advancement of technology, this dream will be realised sooner or later. For instance, the ‘de novo’ construction (meaning from the beginning) of the synthetic DNA which cost more than 20 years and approximately $40 million in 2010 is now feasible at a much lower price today and takes much lesser time.

Research On-going

However, the ever inquisitive scientific mind is not satisfied with the creation of a semi-synthetic bacterium. Researches are being conducted to construct an entirely man-made ‘biological machine’ with a complete set of programmed genes as well as a synthetic ‘chassis’ housing those genes. Such a framework will be more durable than the delicate bacterial outer membranes and will have improved features including selective permeability and affinity.


Foley, P. L., & Shuler, M. L. (2010). Considerations for the design and construction of a synthetic platform cell for biotechnological applications. Biotechnology and bioengineering, 105(1), 26-36.
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In the 80’s the cell factory concept was fully established through the intensive public and private investment. The factories of cells have been exploited for the controlled production of interest for food, pharma and biotech industries.
The principle of controlled biological production as a convenient source of difficult to obtain molecules deeply penetrated the industrial tissue, soon becoming a widespread platform aiming at cost effective large production.

The first generation which was mainly composed from bacterium Escherichia coli ant Saccharomyces cerevisae were soon replaced by engineered variants. Resulting from the application of untargeted mutagenesis and phenotypic selection, conventional genetic modification, and by systems metabolic engineering that integrates metabolic engineering with systems biology and synthetic biology. New strains had much enhanced performance and have been progressively developed.

Mammalian and insect cells have been used for production of high quality proteins and other microbial species. On the other hand a set of food grade lactic acid bacteria are under development as emerging platforms in food microbiology and also as a new source of metabolites and proteins.

The physiological diversity of the microbial world offers an intricacy of biosynthetic pathways from which novel bio-products, including nano- or micro-structured. Still, many substances and materials of industrial interest are nowadays produced by chemical synthesis, and the number of proteins approved for therapeutic use hardly reaches 200, a figure much lower than that initially presumed. However, both environmental concerns and medical and industrial needs strongly push towards a fully sustainable bio-production of a larger spectrum of substances.

Then some questions arise like how much limited is the economic feasibility of microbial production or have the cell factories reached a plateau in their development.

Systems metabolic engineering offers a set of methodological and strategic tools for the design and
optimization of metabolic and gene regulatory networks for the efficient production of chemicals and materials from plastics to high value materials.
Furthermore, creation of new metabolic pathways and fine tuning of the existing ones have become possible.
Sasa Milosevic
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