A Systematic Review of Synthetic Biology - A New Era in Biopharmaceutical Drug Development

Biotechnology is a technology that strategically aims to convert
raw materials into more useful products with the help of organisms...


Biotechnology: A Historical Perspective
Biotechnology is a technology that strategically aims to convert raw materials into more useful products with the help of organisms.
This definition of biotechnology relies mainly on the early understanding of fermentation in the 1900s, which put forward the importance of the microbial fermentation technology on the purification and production of a number of organic molecules at industrial level [1]. This strategic movement in industry led to production of vital primary metabolites such as lactose, ethanol, amino acids, antibiotics such as penicillin, which were produced and purified in large quantities. In addition, different enzymes, or proteins, which possess commercial value, were extracted using increased knowledge at industrial utilization of biotechnologybased tools [2]. The successful industrial progress based on biotechnology was one of the important revolutions for bio-based economies, however biotechnology as a term was not coined until

1919.
Modern biotechnology became a more powerful tool with the help of recombinant DNA technology that was developed in late 1970s, which enabled researchers to express genes from one organism in another host organism. In particular, technologies that enable sequencing and altering the genomes of microbial organisms promised more valuable products at different industry sectors such as pharmacy, food, and agriculture [3].
All these efforts not only increased the knowhow about biotechnological product development process but also significantly decreased cost of production, bypassing the challenges to obtain purified and large-scale bio-based products using earlier

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technologies. Therefore, modern biotechnology can be accepted as the second revolution in industrial and medical biotechnology.
Towards the 1990s, the genetics of microorganisms were modified with the use of recombinant DNA technology, which enabled the protein coding region obtained from any organism to be produced in the desired organism as a result of cloning into a carrier DNA vector, thereby enabling the production of human proteins in the host organism (e.g. bacteria) [4]. During this period, many biotechnology companies, such as Genentech that commercialized the recombinant human growth hormone, were founded, and commercialization of biotechnology started [5] (Figure 1).

Synthetic Biology Era
With the completion of the human genome project in the early 2000s, synthetic biology underlined the possible third revolution of industrial and medical biotechnology as a game changer, which allowed the production of novel molecules in living organisms and also manipulation of organisms as live biosensors. Of course, this required a series of technological advances such as Next Generation Sequencing, omics technologies, and genome editing techniques ( Figure 1). Protein engineering, enzyme engineering and metabolic engineering fields can be assumed as predecessors of synthetic biology -enabling researchers to alter the sequence and function of proteins or enzymes, or indeed entire metabolic pathways, paved the way to a more flexible and unhindered Lego brick-based attitude of synthetic biology that followed [9,10].
While enzyme engineering was first performed with immobilization methods and complemented with detailed kinetic studies in 1980s, the use of recombinant DNA technology to optimize proteins or enzymes for particular desired phenotypes or properties became mainstream in 1990s, mainly relying on technologies such as random or site-directed mutagenesis, phagedisplay and other [11,12]. Nobel Laureate Prof Frances Arnold is most renowned for her work on directed evolution of enzymes for industrial production of metabolites and commercial application of such catalysts and their use in this field have become possible [13,14]. These all efforts might be critical in the restoration of biodiversity for a sustainable blue planet. , systems biology can be critical approach with its novel approach and application strategies for the sustainability of bioresources and restored the required biodiversity for a live planet. was approved for ADA deficiencies (Table 1) [17] (ADA enzyme has also been used in the gene therapy of Severe Combined Immunodeficiency (SCID), a pioneer in gene therapy trials [18,19].

Biopharmaceuticals and Synthetic Biology
Extracting such bio valuables from natural producers (such as bacteria, human cells, yeast, or plants) present challenges, the most important being limited availability of such bioresources, and the threat of industrial harvesting or cultivation on biodiversity.
Recombinant cells, on the other hand, show higher performance as bio factories in production of the desired product, in theory without the need for collecting from nature (such as trypsin from pancreas etc) [20]. In 2018, FDA has approved 59 novel drugs, including many monoclonal antibodies, hormones, or RNAi drugs [21,22].  (Table 1) [23,24].
In countries such as Turkey, due to the high cost of generating a biopharmaceutical or biological drug from research to market approval, many biotechnology companies prefer to focus on biosimilars. Unlike a generic drug, which is chemically identical to the original branded drug, biosimilars are "highly similar" to the original biological drug, and since these are produced in host organisms as described above, they may have minor differences in active ingredients while no significant clinical differences [25]. However, since the tests required to show such high level "similarities" are numerous and complex, biosimilars are only 15-20 % cheaper than the original drug, as opposed to generics cost almost 40 to 50 % less than the original drug. FDA has approved 12 biosimilars, including Filgrastim and Bevacizumab, and has also rejected quite a number of applications, which adds to the overall cost of biosimilar development and production [26]. (do-it-yourself) kits so that they can be made at home by ordering from online sites also push biotechnology in different directions [31].

Synthetic Biology
In the late 1990s, the field of synthetic biology was built on the use of cells, proteins, genes, and promoters to design and manufacture entirely new circuits and systems not found in nature, with the idea that engineering concepts could be applied to biological systems [32]. Synthetic biology briefly works on the principle of combining the mentioned bio Bricks-like "standardized" parts with desired combinations like the same lego toys and converting them into "output" by processing logic gates (input / output, I / O) ( Figure  2). Synthetic biology, which was previously used to create more biosensor systems, is now being used to produce the desired biotechnological product with more efficient processes and less costmore product principle. Because with this method, the production of the desired biotechnological product ("output") can be produced with the desired stimulus ("input") in the desired organism by designing completely original and often non-natural circuits and pathways. Knowledge from synthetic biology is transferred to generation of different product types such as environmental biosensors, which is used as diagnostic or monitorization of field studies. In a similar understanding the developed biosensors are used in in vivo systems to diagnose or track the diseases. One of the promising developments is the generation of the novel nanobots, which enter the circulation system to diagnose and report tumorigenesis real-time.