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Expert View: How China is catching up with the US in new applications of synthetic biology.

Additionally, Cargill and Calysta Biosystems are working jointly to convert another greenhouse gas, methane, into fish food. As the application and understandings around synthetic biology continue to broaden over the next 25 years and beyond, BIO will continue to work with industry to advance the science. Each year, BIO hosts the annual World Congress on Industrial Biotechnology, which provides a platform for industry leaders to partner and share insights with each other on innovations such as synthetic biology.

The tri-state region Delaware, New Jersey, Pennsylvania ranks as one of the top markets for biotechnology research. Outside of work, Connor can be found taking a stroll down the National Mall with Jax, his brindle-striped dog, in the kitchen testing out new recipes or cheering on one of his favorite sports teams.

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By Karen Batra, September 18, Download preview PDF. Skip to main content. Advertisement Hide. Taking Care in Synthetic Biology. This process is experimental and the keywords may be updated as the learning algorithm improves. This is a preview of subscription content, log in to check access. Endy, D. CrossRef Google Scholar. Royal Society of Chemistry. National Research Council. Google Scholar.

This heightened attention to the security dimensions of synthetic biology is likely connected to several broader events around the turn of the twenty-first century, including the anthrax letters and the terrorist attacks of September 11, ; several popular books centered on bioterrorism; and new laws that changed the governance of biological agents. See Alibek, K. New York: Delta; Google Scholar. Preston, R. The Cobra Event. New York: Ballantine Books. Garfinkel, M. CDC 21—, See also Google Scholar. Marris, C. In a different strategy, synthetic mobile genetic elements that can invade mosquito populations as recently shown for human malaria mosquitoes [ 41 ] could provide a tool capable of rapidly spreading genetically-engineered parasite resistance among mosquitoes in the field [ 41 ].

The generation of chimeric antigens exemplifies a relatively straightforward approach to construct novel diagnosis tools for pathogens e. Lyme disease involving DNA-synthesis [ 42 ].

Applications

Rather complex DNA-synthesis and genome-assembly techniques have been used to generate entire viral genomes and to address the etiology and pathogenicity mechanisms of corresponding viruses, including the viruses that caused the influenza pandemic or that are responsible for SARS [ 43 , 44 ]. Similarly, such synthetic genomics technology can be exploited to introduce hundreds of base-pair changes in codon pairs in order to produce live attenuated viral vaccines by means of computer-aided rational design. This approach has been demonstrated to rapidly generate safe and effective influenza vaccine candidates in mice [ 16 ] Fig.

The production of naturally occurring drugs especially the anti-malaria compound artemisinin through assembled complex metabolic pathways in microorganisms has become one of the best-known applications linked to synthetic biology [ 2 , 3 ]. Crucial precursors for plant-derived drugs like artemisinin, which is effective against multi-resistant forms of malaria in combination therapy [ 45 ], or for one of the most important cancer drugs, taxol paclitaxel [ 46 ], can so be produced in yeast and E. In both cases, new pathways leading to the desired products were assembled from a native upstream part, involving yeast and E.

The flux through these composite pathways was increased mainly by upregulation of several rate-limiting pathway components. However, also synthetic biology approaches including non-natural amino acids and expanded genetic codes have been envisaged for the biosynthesis see, e. The toxic contamination of soil and water and an increase in atmospheric greenhouse gases GHGs due to human activities, including industrial production processes and the use of fossil fuels, have become major environmental issues on a global scale [ 49 ].

These may be addressed by several approaches related to the synthetic biology idea summarized in Fig. Synthetic biology approaches to environmental applications. Whole-cell biosensor array that is frequency-modulated by arsenite [ 55 ]. The array consists of multiple E. Cells contain an oscillator module based on genetic quorum-sensing circuits light green , producing synchronized oscillations of the expression of H 2 O 2 and of green fluorescent protein GFP.

H 2 O 2 can migrate between colonies and synchronize them by affecting the oscillator module. This genetic oscillator was coupled to one of two arsenite sensor modules 1 or 2 containing parts of the oscillator luxR or luxl genes under the control of an arsenite-responsive repressor protein ArsR and its cognate promoter element yellow box. Generation of synthetic riboswitches to generate bacteria that detect, follow and can destroy the herbicide atrazine [ 53 ].

Current Uses of Synthetic Biology – BIO

A library of atrazine-binding small RNAs aptamers selected in vitro was inserted into the 5'-untranslated region of the cheZ gene that controls E. Together with an aptamer, the randomized sequence can become part of a riboswitch element that couples ligand binding and translational control of cheZ mRNA. By functional screening, riboswitches were selected that mediated atrazine-dependent cell motility bottom panel. When an atrazine-degrading enzyme is introduced, the cells migrate towards atrazine and degrade it.

Interestingly, a recent more sophisticated approach guided by computational modeling combines synthetic arsenite-sensing gene circuits with an oscillating circuit in E. At the same time, a large number of these fluorescent biosensor cell colonies were coupled and synchronized via a rapidly diffusible, long-range output signal hydrogen peroxide generated by the synthetic circuits [ 55 ] Fig.

Such synchronization and integration of signals from millions of cells could prove generally applicable to overcome an important issue in the construction of robust circuits, namely the considerable intercellular variability in circuit behavior due to noisy processes. These include random bursts of transcription and translation, or differences in the growth state of individual cells see [ 54 , 55 ] and references therein.

While decontamination of water or soil by microorganisms bioremediation is a process that can occur naturally intrinsic bioremediation , it may be enhanced by the addition of nutrients biostimulation , additional microorganisms bioaugmentation or by plants phytoremediation [ 56 ]. Approaches adopting synthetic biology principles include the construction of hybrid proteins combining bacterial and mammalian protein domains, or proteins generated by directed evolution that upon transfer in bacteria provide new or enhanced functions in binding or reducing heavy metal ions and radionuclides [ 57 , 58 ].

Thus, a novel and complex catabolic pathway for the degradation of the organic pollutants methylphenols and methylbenzoates have been constructed in Pseudomona sp. Similarly, though somewhat less complex, a new pathway for biodegradation of 2-chlorotoluene was assembled from segments of distinct catabolic pathways [ 60 ].

More recently the function to seek and degrade a pollutant was generated by coupling in E. Additionally, these cells were equipped with an atrazine chlorohydrolase gene atz A for atrazine degradation, derived from Pseudomonas sp. Based on multiple genes from different organisms, pathways have been constructed and optimized by metabolic engineering [ 8 ] to efficiently produce chemicals in microorganisms and plants. For instance, in an attempt to produce biodegradable plastics, a pathway to synthesize lactic acid from sugar was generated in E.

Likewise, a complex pathway made of an optimized plant gene and 8 genes from yeast was transferred to and expanded in E.

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Interestingly, a new efficient pathway for the biosynthesis of a chemical that is produced in nature in trace amounts only was constructed by adding a single enzyme activity to an organism. Thus, an artificial pathway for the efficient production of isobutene, a chemical that can be used to synthesize plastics, rubber or fuels, has been generated in E.

Finally, we would like to acknowledge the recent generation of E. This example is especially noteworthy since compared to the previous examples it has moved metabolic pathway engineering closer towards a central synthetic biology concept, namely the application of rational computer-based design and modeling to generate biological functions not present in nature or, in future, to build entire new organisms.

Moreover, this new pathway was constructed involving a high degree of rational design based on in silico algorithms predicting and ranking possible pathways from E. This was followed by optimizing the strain to channel carbon and energy sources into the new pathway via gene deletions guided by an E. In an attempt to create renewable and sustainable carbon-based fuels, first-generation biofuels have been developed that are based on plant oils biodiesel or on cane sugar and crop starch ethanol ; see Fig.

New generations of biofuels based on non-edible, lignocellulosic plant parts, special energy grasses or microalgae have thus been envisaged [ 17 , 68 - 70 ] Fig. These are based on synthetic hydrocarbons or higher-chain alcohols like butanol with high energy content, allowing gasoline, diesel and even aviation fuels to be replaced [ 67 , 71 ].

In addition, strategies have been devised that use microorganisms to produce hydrogen [ 72 ]. All these approaches involve synthetic biology ideas and can be ascribed to one of two fundamental strategies: the microbial synthesis of fuels from materials produced by plants see i and ii , below or their direct microbial photosynthesis from CO 2 and water iii and iv see also overview in Fig.

Approaches involving synthetic biology concepts to generate biofuels. A synthetic pathway for high-level production of n -butanol from glucose in E. It includes the generation of an enzymatic reaction mechanism rather than a physical one as a kinetic control element to achieve high yields shown in orange. The origin of genes is indicated by color: blue, R.

Synthetic Biology: Industrial and Environmental Applications

Generation of cyanobacteria for direct photosynthetic production and secretion of hydrocarbon fuels n-alkanes involving waste CO 2 and non-potable water [ 17 - 86 ] The introduction of as few as two heterologous genes, encoding acyl-ACP reductase AAR and alkanal decarboxylative mono-oxygenase ADM activities, from other cyanobacterial species can confer, or enhance, n-alkane C 10 - C 20 synthesis dependent on the host cell and directs product secretion for easy recovery without the need to extract cells [ 86 ].

The transfer of multiple genes from different organisms into E. Of special interest with regard to the synthetic biology idea is that these include synthetic pathways based on computer-aided design with enzyme-based kinetic control mechanisms, allowing the efficient production of the non-native alcohol products [ 14 , 74 ] Fig. The generation of new pathways based on combining different genes from distinct organisms also allowed biodiesel and alkanes to be synthesized from sugar in E.

Noteworthy, for biodiesel production a first sensor-regulator system was designed and integrated in E. Since these approaches use available sugar e. At the same time, they allow to synthesize drop-in fuels see above. Several pathway engineering approaches aim to synthesize biofuels from lignocellulosic polysaccharides cellulose, hemicellulose , making available non-edible plant parts. For example, a pathway to produce isobutanol was constructed in a native cellulose-degrading bacterium using various genes from different organisms [ 78 ].

Similarly, genes to make use of cellulose or hemicellulose were transferred into different microorganisms, some of them containing one or several exogenous genes, in order to synthesize butanol, biodiesel or hydrocarbons [ 77 , 79 , 80 ]. Higher photosynthetic yields per area, less need for arable land or the use of brackish or sea water [ 81 ] have inspired various approaches aimed at producing biofuels in microalgae. These include the generation of new metabolic pathways by combining genes from distinct organisms in cyanobacteria to synthesize products that can be converted to or act as drop-in fuels, such as isobutyraldehyde or butanol derivatives [ 82 - 84 ].

Cyanobacteria have also been metabolically engineered to efficiently produce and secrete fatty acids to synthesize biodiesel [ 85 ] or alkanes [ 86 ], with secretion allowing continuous and energy-saving production schemes [ 17 ]. In contrast to the previous examples, in the case of alkane synthesis and secretion, introducing as few as two genes from other cyanobacteria was sufficient to build a pathway for linear alkane synthesis and a module for alkane secretion, allowing to generate these functions in robust cyanobacterial genera that may be exploited for industrial use [ 86 ] Fig.

However, although different studies have suggested the technical feasibility and economic viability of industrial-scale biofuel production by microalgae e. Direct photosynthetic production of biofuels may strongly benefit from higher efficiencies in solar light conversion and by reducing the amount of biomass that has to be grown. A nascent concept taking these factors into account is microbial electrosynthesis, which may be described as an artificial form of photosynthesis to produce organic compounds and energy-rich fuels [ 89 ].

Here the higher efficiency in photovoltaics to harvest light energy compared to natural photosynthesis can be used to supply electrons via electrodes to certain microorganism in order to reduce CO 2 to multicarbon products. Recently, electrosynthesis of isobutanol and 3-methylbutanol which can be used as drop-in fuels has been achieved by introducing a synthetic metabolic pathway to these products previously constructed in E.

The prospective use of hydrogen as a non-carbon fuel has raised interest in certain photosynthetic microorganisms, such as algae and cyanobacteria, that can produce hydrogen from water and light [ 72 ].

Synthetic Biology

Effective production, however, is limited by several issues, including the oxygen sensitivity of hydrogenases the enzymes that can reduce protons and release molecular hydrogen and inefficiencies in utilisation of solar light energy. So far, several approaches based on alteration of the expression of genes, including those for light-harvesting proteins, or the introduction of heterologous hydrogenase genes have aimed to improve hydrogen production by increasing the efficiency of light conversion or by reducing oxygen production or sensitivity in green algae [ 91 , 92 ] and cyanobacteria [ 93 , 94 ].

With respect to public health see overview in Fig. Furthermore, synthesizing drugs by metabolically-engineered microbes may provide more affordable alternatives to expensive chemical synthesis or extraction from precious natural sources, as in the case of the anti-cancer drug taxol [ 95 ]. Finally, viral vaccines e. Nonetheless, a number of challenges and concerns related to these approaches in the health area see Fig. These include potential biosafety issues linked to the use of genetically engineered organisms as therapeutics. Similarly, while the strategy underlying the use of genetically-engineered mosquitoes to combat dengue fever [ 40 , 99 ] may provide a species-specific means of controlling insect vectors for important diseases, various concerns have been pointed out.

These include potential hazards for human health by synthetic gene products injected by bites of surviving female mosquitoes , potential ecological consequences e. Nonetheless, initial field-release experiments have recently been performed in the Cayman Islands, Malaysia, and in Brazil [ 99 , ]. Finally, sequence information and knowledge about pathogen genomes, coupled with advanced and relatively cheap custom DNA synthesis and genome assembly, has raised biosecurity concerns regarding potential misuse for a recent review, see [ 20 ]; and also below.

Hopes in the field of the environment see overview in Fig. Furthermore, an industry based on the environmentally-friendly and sustainable biosynthesis of chemicals and materials could reduce the depletion of and dependence on fossil resources and mitigate climate change. These hopes have so far been countered above all by concerns about biosafety and sustainability see Fig. For example, in situ applications of GEMs for biosensing and bioremediation will require GEMs to be released into the environment and some experiments point to possible impacts on indigenous organisms through horizontal gene transfer of recombinant DNA or via indirect effects, e.

Besides technical challenges relating to in situ efficacy including survival and competition with indigenous microorganisms , such environmental concerns, and problems with solutions that were able to unequivocally alleviate them e. Upcoming approaches based on systems and synthetic biology could improve the issue of poor in situ efficiency of GEMs [ ] and could thus make the release of GEMs for bioremediation applications more attractive.

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At the same time synthetic biology will allow to introduce increasingly complex genetic changes in organisms to generate new functions and possibly to generate even entirely new organisms which may, however, be also associated with the emergence of unexpected traits. These mechanisms include non-natural nucleic polymers [xeno nucleic acids, XNAs ] as genetic material that cannot be read or duplicated by natural DNA or RNA polymerases , expanded or alternative genetic codes that may encode both natural or non-natural amino acids , and cells dependent on xenobiotic chemicals for recent review, see [ ].

Interestingly, in vitro work lately demonstrated storage in and recovery of genetic information from various XNAs as well as the evolution of XNA aptamers, using enzymes that are able to convert DNA into XNA and vice versa. These enzymes had been generated by directed evolution from an already mutated variant of a replicative Thermococcus polymerase [ ].

Though several point mutations were necessary to finally generate these converting enzymes [ ], the findings may implicate the natural evolution of such enzyme activities, which would undermine a solely XNA-based firewall. In combination with the stable interaction of certain XNAs with DNA and RNA, which can experimentally and therapeutically be exploited to inhibit gene expression in various ways [ , ], potential effects on native organisms related to increased XNA stability might be worth considering.

As regards the environmental benefits to be gained from the industrial production of chemicals based on renewable sources, a reduction of energy needs and GHGs would indeed appear possible [ - ], though environmental impacts e. Furthermore, large-scale production of bio-based chemicals including fuels may result in competition for land needed to grow food crops and may lead to GHG emissions from land-use change [ , ] see also biofuel debate below. Climate change mitigation and improved energy security could be the key assets of new generation of biofuels, if their production and use resulted in a net reduction of total GHG emissions.

At the same time, they may reduce the need for land and competition for food as compared to first generation biofuels see below. Moreover, competition with food crops can become a factor with a negative impact on food security and food prices [ ]. These issues may be reduced or avoided if plant feedstock can be grown on agriculturally-degraded or abandoned land with little or no fertilizer input [ - , , ]. Though biofuels produced via photosynthetic microalgae may avoid these issues in principle, their benefits will depend on answers to crucial issues: namely the amount of water and energy with associated GHG emissions needed to grow and process algae, and the supply of CO 2 and nutrients fertilizer [ 68 , ], the latter of which could bring algae-based strategies into conflict with food-crop production [ 68 , 81 ].

Possible solutions include the use of wastewater as a nutrient source , flue-gas CO 2 and energy generation from spent algal biomass [ 81 ]. Furthermore, genetic engineering attempts to enhance light conversion efficiencies see, e. Similarly, calculations of the proportion of fossil fuels that can be replaced by these new biofuels vary greatly depending on the development of yields, feedstock, products or land use [ 87 , ], lignocellulosic and algal biofuels possibly being able to replace the most substantial proportions [ 87 , ].

Additional factors that can affect the equitable distribution of benefits and risks may include intellectual property rights and potential effects on the environment due to biosafety issues. The way patents for synthetic biology solutions are organized and applied may therefore influence the extent to which poor countries in the global south — which are likely to be the main areas for plant-derived biomass production [ ] — have access to biofuel feedstock and technologies [ ].

Furthermore, concerns have been raised that genetically engineered microorganisms such as microalgae could pose environmental risks if they escape, by becoming invasive and evolving rapidly [ ]. Synthetic genomics and synthetic biology, their potential implications on society as well as possible needs or options for their governance have been the topic of a number of reports by scientific organizations, policy advice institutions, civil society organizations and other players since the mids see [ ] and references therein.

There appears to be broad consensus that it is paramount to maintain the trust of the public and policy regulators and that hype and exaggerated claims are counterproductive to developing regulatory models which respond to concerns of stakeholders and the public [ ]. However, while some actors propose that current regulatory frameworks for recombinant DNA technology are still appropriate and the development of synthetic biology technologies and products should continue under these frameworks see, e.

Others argue for significant public funding of ecological risks research on synthetic organisms and close cooperation between ecologists and synthetic biology researchers [ ]. As we have tried to outline in this article, there exists a wide spectrum of approaches currently connected to and discussed with the synthetic biology idea, ranging from simple genetic circuits to the generation of new metabolic pathways or synthetic viruses altered on the scale of the whole genome. In addition, these approaches can be part of different application schemes, including the production of chemicals from plant feedstocks in closed systems by GEMs, strategies that would require the release of GEMs e.

On the one hand, certain general aspects of application schemes appear to be decisive rather than synthetic biology-related issues.


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  4. Similarly, broad patents and patent thickets — the number of which may increase as a result of synthetic biology approaches [ , ] — already pose a challenge in the biopharmaceutical industry [ ]. Curbing negative consequences of this kind on a global scale may require products or applications to be subjected to broadly applicable and effective environmental, socio-economic and ethical standards, irrespective of the exact nature of the underlying technical approach.

    In this way, negative impacts from bio-based chemicals or fuels could be mitigated by applying international sustainability and human rights standards to their production [ 22 ], and intellectual property issues could be addressed by international governmental organizations and industry within the framework of collaborative licensing models [ , ]. Various governance options have been suggested both within and outside the field, concerning screening procedures for DNA synthesis, its equipment and reagents, or ethical training of researchers for recent overviews, see [ 20 , ].

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    Still recent experiments, involving directed evolution and genetic-engineering, into the airborne transmission of the deadly bird-flu virus H5N1 in ferrets a model to study influenza transmission in humans [ , ] have revigorated debates about conditions for publication of biosecurity-sensitive data [ ]. This issue may become more significant as the areas of synthetic genomics and synthetic biology progress and it remains to be seen whether synthetic biology-derived containment strategies including xenobiotic mechanisms can contribute to solve biosafety issues in future.

    Risk assessment may thus need to shift from prediction-based assessment to more real testing. Given this situation, effective governance should be informed by the most pluralistic expertise and perspectives available. Therefore, various actors may be involved by creating conditions that encourage and allow them to take on and evolve responsibilities regarding the development of scientific knowledge and the various levels of risks that may be associated with its use.

    The author s confirm that this article content has no conflicts of interest.