Synthetic Biology
Synthetic Biology - An Overview
For thousands of years, humans have been deliberately breeding animals and plants with certain beneficial traits. The decryption of the DNA code, the discovery of sequence-specific DNA-cutting proteins, the establishment of DNA sequencing and DNA synthesis in vitro, and the improvement of DNA transfer into cells provided the basis for targeted DNA modifications. With all these advances, researchers are now able to transfer the genetic information associated with desirable traits from one organism to another. It is also possible to generate new DNA building blocks from scratch to create organisms with new traits.
What is Synthetic Biology?
Behind the ideas and methods that deal with genome modifications, a new concept is emerging in the life sciences: Synthetic Biology. It goes beyond traditional (molecular) biology, as it combines engineering design strategies with the construction of biological systems and cells at the genetic level. Bioinformatic methods are used to model changes and their effects, and the use of standardized parts, called modules, is intended to increase the predictability of the results. Overall, Synthetic Biology uses methods from many different scientific disciplines to create a broad range of potential applications. It should be emphasized that a method generally cannot be assigned to Synthetic Biology per se, but the resulting development can, if it follows the engineering concept.
Synthetic Biology serves basic and applied research. It opens up new ways of exploring the origin of life and its basic processes. One goal is to produce and use biological systems with customized functions. This includes systems that process information, produce or modify chemicals, generate materials and structures, and generate energy. New pharmaceuticals, vaccines or food additives are expected to be produced with the help of Synthetic Biology. Synthetic biology can help relieve natural resources by, for example, producing alternatives to fossil fuels and improving human health.
The significance and opportunities of Synthetic Biology are also reflected in the fact that more and more scientists are working in this area of research.Since the beginning of the 21st century, the number of scientific publications covering Synthetic Biology has risen from about 500 per year to more than 4,000 per year in 2017 (source: PubMed with the keyword ‘Synthetic Biology’). An overview of key developments in Synthetic Biology can be seen in Figure 1.
Some applications of Synthetic Biology already have a marketing authorization and are available here.
Figure 1: Timeline of Key Developments in Synthetic Biology
The development of basic technologies in genome and molecular biology paved the way for the rapid development of Synthetic Biology. After the initial construction of fairly simple modules, the research and potential applications have become more and more complex. Each of the different colours represent one of the five research fields in Synthetic Biology. Numerals give reference to the original literature or reviews (number in blue circle); E. coli - Escherichia coli, S. cerevisiae - Saccharomyces cerevisiae
Key Research Areas of Synthetic Biology
There is no universal definition of Synthetic Biology. Synthetic Biology is not a limited field of research; instead it is considered a conceptual approach in science. The fields of application of Synthetic Biology are often divided into five areas. An overview and application examples are shown below.
| 1. Synthesis of genes and genomes |
| Design and synthesis of (artificial) genes and chromosomes all the way to complete genomes and introduction into an organism > Optimization and synthesis of microorganisms for vaccines > Design of optimized production organisms for biotechnological applications and basic research |
| 2. Design of genetic circuits |
| Assembling components of signalling systems of different organisms into novel circuits; defined signal leads to desired reaction of the cell > Biological sensors that respond to environmental stimuli or metabolic products in the animal or human body, thereby releasing a specific product: - Diabetes: Glucose-detecting cells that deliver insulin as needed - Food industry: rotten meat triggers dye production > adapted regulation for the production of goods through microorganisms significantly increases the yield |
| 3. Design of customized metabolic pathways |
| Introducing a variety of genes of new or alternative metabolic pathways into an organism to produce a desired product > Microorganisms that produce biofuels or pharmaceutical compounds > biological decontamination, removal of toxins from the environment |
| 4. Minimal cells: Genome reduction and generation of protocells |
| Simplifying a cell so that it only retains the essential genes for survival; special focus area: Construction of protocells from chemical components > simplified model organisms for the study of cell function and origin of life > simplified production organisms for biotechnological applications lead to higher yields |
| 5. Xenobiology |
| Construction of organisms that coexist with the natural ones and ideally do not interact with them, because they have an altered genetic code or non-natural amino acids in their proteins > Organisms that serve as safety strains, which require artificial conditions for their growth > Proteins with new traits |
_____________________________________________________________________________________________
Overview of the Research Areas of Synthetic Biology
Research on gene drives is not considered part of Synthetic Biology because it is a modern variant of traditional genetic engineering and does not pursue a particular engineering approach.
The research landscape is diverse and international meetings are held frequently. Various research centres and networks with focus on Synthetic Biology projects have established themselves in recent years. Recently, the German Association of Synthetic Biology (GASB) was founded. For science students, there is a large international competition, the International Genetically Engineered Machine (iGEM), which by now has more than 300 teams participating from around the world.
Statutory Regulation of Synthetic Biology
There is no specific regulation in Germany or Europe for the risk assessment of Synthetic Biology. Since most research approaches in Synthetic Biology generate genetically modified organisms (GMOs), their potential risk can be assessed using existing methods. These can be found in the European Directives 2009/41/EC (contained use) and 2001/18/EC (deliberate release), which have been implemented in the German Genetic Engineering Act (GenTG), as well as the Cartagena Protocol on Biological Safety to the Convention on Biodiversity, an international agreement between 196 countries.
The Federal Ministry of Food and Agriculture (BMEL) has commissioned the ZKBS to monitor developments in the field of Synthetic Biology in order to competently and critically monitor current scientific developments in the various fields of research. This monitoring also serves to identify potential biosafety implications that would require adaptation of existing regulations. In this context, the ZKBS examines whether the research projects are covered by the applicability of the GenTG. The ZKBS published its first Monitoring Report on Synthetic Biology in Germany in 2012. The second ZKBS report was published in 2018, summarizing the state of research in the various fields of Synthetic Biology worldwide.
Both reports identify that current research approaches in Synthetic Biology are covered by existing legislation, in particular the Genetic Engineering Act (GenTG). According to GenTG, the risk assessment is carried out by comparing the nucleic acid sequence of the resulting organism with the sequences of the starting organisms that were used for the production of the organism. The created organism is a GMO if (compared to the parental organisms) there are genetic modifications that could not have occurred naturally by crossing and/or natural recombination.
Accordingly, the GenTG applies to both the introduction of genes for new signalling pathways and new metabolic reactions and to any modifications made in the genome. The introduction of a genome, which was completely manufactured in the laboratory, into an organism (and possibly a simultaneous, sometimes extensive, change, e.g. reduction of the genome) results in a GMO according to GenTG, since these synthetic genomes are based on a natural model (see position statement from the ZKBS regarding Mycoplasma mycoides JCVIsyn2.0 and JCVI-syn3.0).
Conversely, modifications of the genome, which could also occur naturally, as well as DNA synthesis in the laboratory (outside of cells) and individual research areas for the creation of artificial systems that take place outside of living systems do not fall within the jurisdiction of the GenTG. Tight regulation like that of the GenTG is not necessary here, because these experiments do not pose any risk potential as defined in the GenTG, since they are carried out without living organisms and therefore fall under other regulations.
At this time, it is not yet possible to produce viable, artificial biological systems. Rather, components are examined separately. If production of self-replicating protocells ‘from scratch’ proves to be successful one day, there will be no natural comparator for them. Thus, the risk assessment according to the GenTG, which is based on the comparison with naturally occurring (parental) organisms, cannot be performed. Viable protocells would therefore require new risk assessment criteria. However, protocells possess only basic genetic information and contain no virulence factors, so that no increased risk potential is to be expected. To anticipate the need for a potential expansion of the risk assessment for the future, any progress in this area will be closely monitored and assessed.
In summary, current research on Synthetic Biology in Germany or globally does not present any risks for biological safety other than those already assessed for ‘conventional’ genetic modification using the GenTG and other international regulations.
Research Trends and Social Discussion
As the previous text demonstrates, the Synthetic Biology research field is very diverse. Aiming to simplify Synthetic Biology and make it more predictable, there is currently a strong emphasis on standardization, automation and computer modelling. There is even a separate language for computer-generated biological concepts, the Synthetic Biology Open Language (SBOL).
The potential ethical, legal and social implications of Synthetic Biology and its future applications (e.g. for healthcare) are an important issue in politics and society and are accompanied by ongoing discussions on the benefits and risks to biosafety.
The ZKBS will continue to follow developments in the field of Synthetic Biology. Relevant publications and a risk assessment thereof are regularly provided to the interested public on the homepage.
Further reading
1 Cello et al., 2002. Chemical synthesis of poliovirus cDNA: generation of infectious virus in the absence of natural template. Science 297(5583):1016-8.
2 Chien et al., 2017. Advances in Bacteria Cancer Therapies using Synthetic Biology. Curr Opin Syst Biol 5:1-8.
3 Gibson et al., 2010. Creation of a bacterial cell controlled by a chemically synthesized genome. Science 329(5987):52-6.
4 Annaluru et al., 2014. Total synthesis of a functional designer eukaryotic chromosome. Science 344(6179):55-8.
5 Alvarez & Fernandes, 2017. Sustainable therapies by engineered bacteria. Microb Biotechnol 10(5):1057-61 und Haellman & Fussenegger, 2016. Synthetic Biology-Toward Therapeutic Solutions. J Mol Biol 428(5 Pt B):945-62.
6 Acevedo-Rocha & Budisa, 2016. Xenomicrobiology: a roadmap for genetic code engineering. Microb Biotechnol 9(5):666-76.
7 Caschera & Noireaux, 2014. Integration of biological parts toward the synthesis of a minimal cell. Curr Opin Chem Biol 22:85-91.
8 Kung et al., 2018. Approaches and Recent Developments for the Commercial Production of Semi-synthetic Artemisinin. Front Plant Sci 9:87.
9 Ostrov et al., 2016. Design, synthesis, and testing toward a 57-codon genome. Science 353(6301):819-22.
10 Pardee et al., 2014. Paper-based synthetic gene networks. Cell 159(4):940-54.
11 Galanie et al., 2015. Complete biosynthesis of opioids in yeast. Science 349(6252):1095-100.
12 Hutchison et al., 2016. Design and synthesis of a minimal bacterial genome. Science 351:aad6253.
13 Richardson et al., 2017. Design of a synthetic yeast genome. Science 355(6329):1040-44.
14 Shipman et al., 2017. CRISPR-Cas encoding of a digital movie into the genomes of a population of living bacteria. Nature 547(7663):345-9.
published: September 2018
Monitoring of Developments in Synthetic Biology
In 2012, the ZKBS compiled a 1st Monitoring Report on Synthetic Biology in Germany.
The 2nd ZKBS Report on Synthetic Biology was published in 2018 and summarizes the international literature on research conducted under the term Synthetic Biology. It describes the progress in each of the fields of Synthetic Biology and examines whether the activities give rise to hazards that are not regulated by the Genetic Engineering Act or the European legislation on genetic engineering.
Continuous monitoring of developments in the field of Synthetic Biology is performed by the ZKBS. Relevant publications and a risk assessment will be made available here in the future.