synthetic biology in medicine

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AAAS is a partner of HINARI, AGORA, OARE, CHORUS, CLOCKSS, CrossRef and COUNTER. The yeast Pichia pastoris was engineered to produce soy leghemoglobin, which improves meaty flavors and aromas when added to a plant-based burger8. PubMed Central Opin. The burger patty of the future may be grown using consortia of bacteria, fungi, and livestock cells, similar to yoghurt or cheese, that work together to build tactile structures and synthesize molecules for nutrition, flavor and fragrance. Christian, M. et al. Wolf, M. Pairwise gets greenlight from USDA for CRISPR-engineered mustard greens The Spoon (2020). The development of these was enabled by advances in metabolic engineering, directed evolution (awarded the 2018 Nobel Prize), automated strain engineering, metagenomic discovery, gene circuit design, and genome editing (awarded the 2020 Nobel Prize)5,6. Bioelectron. Voyvodic, P. L. & Bonnet, J. Cell-free biosensors for biomedicaal applications. Internet Explorer). Kwok, R. Five hard truths for synthetic biology. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Arnold, F. H. Innovation by Evolution: Bringing New Chemistry to Life. Sitgaliptin, with the enzymatically produced stereocenter shown in red. All of the chemistry performed by the natural world can be captured with ~250 reactions, whereas there are 60,000+ in the chemistry literature12. Farmers must add nitrogen to crops to obtain high yields, most of which is produced using an industrial chemical process that consumes 12% of global energy55. If you have studied these topics, it's time . For instance, Synlogic in Cambridge, Massachusetts (where Collins is a scientific cofounder), is engineering microbes to treat phenylketonuria, an inherited disease that results in high blood levels of the amino acid phenylalanine and can cause mental disorders if not treated. CAS A decade after the pioneering synthetic networks were reported 18, 20, the first successful therapeutic applications in animal models of prominent human diseases are starting to emerge 63, 64, 65 . A better-tasting mustard green (Pairwise) or yield-improved waxy corn (Corteva) could be the first CRISPR/Cas9-constructed product to enter the food supply in 202184,85. Sys. Biosens. Biology is able to build complex-looking structures with repetitious reactions performed on highly functionalized molecules by enzymes with precise specificity and regioselectivity. Advances in metabolic engineering have simplified the transfer of a pathway from its natural source to a production host, making it possible to move larger pathways to yeast with less effort9. Not surprisingly, the definition and applications of synthetic biology are hotly debated. Vaccines often use live viruses that have been weakened. What is synthetic biology? The 3D process can control the size of the droplets, which are 3050 m across. Ash, M. Oil crops sector at a glance. Article This book was released on 2012-12-02 with total page 814 pages. The clinical uses of synthetic biology already cover a wide range of areas, including diagnostics and treatments. 12, 1600099 (2017). Biofuels Digest (2020). A. Sommer, David Garenne, Matthew C. Haines, Vincent Noireaux, Adam D. Silverman, Ashty S. Karim & Michael C. Jewett, Elizabeth L. Bell, William Finnigan, Sabine L. Flitsch, Aaron Cravens, James Payne & Christina D. Smolke, Nature Communications Synthetic Biology Medicine and Bacteria-Based Cancer Therapeutics Methods Mol Biol. Modification with proteins made the bilayers behave like biological membranes, which even allowed electrical communication similar to that occurring in neurons. However, the genes are off when most needed, so synthetic biology was used to turn the genes on, which guided the remodeling of the KV137 genome56. Through combining superior array design capabilities with the latest research-led gene content, the most advanced array design is now available for accurately and easily identifying the causal aberrations underlying developmental delay. Article Rhizosphere 3, 233 (2017). Cancer Cell 38, 473 (2020). Providing straightforward analysis, all CytoSure arrays come with CytoSure Interpret software and full on-site training, streamlining data analysis, and interpretation. The Global Synthetic Biology Market is valued at USD 9.3 Billion in 2021, and it is anticipated to attain a value of USD 52.04 Billion by 2028, at a CAGR of 27.89 % over the forecast period (2022 . 32, 189 (2016). Attempts to port this capability to other polymers, such as polyesters, are being made by engineering the ribosome48. Biotechnol. Engineered systems of genes and other molecular components created through synthetic biology make medical treatments more effective and promise cures for a range of health problems. Already, the field is having an impact. Roberts, A. D. et al. Wang Professorship in Advanced Biotechnology. 1 It brings together a range of disciplines and skills, from biology and chemistry to computing, bioinformatics and . ", So far, this technology has been tested in humans in the United Kingdom, the United States, and Vietnam. Synthetic biology is already playing a role in new clinical applications. Rev. Nicolaou, K. C. & Sorensen, E. J. The common goal of synthetic biology products is to redesign organisms so that they produce a substance like medicine or fuel or gain the new ability for sensing something in the environment or so. Cumbers, J. Toward an orthogonal central dogma. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in & Brady, S. F. Accessing bioactive natural products from the human microbiome. ADS Biol. Kitada, T., DiAndreth, B., Teague, B. Science 179, 1 (2013). Provided by the Springer Nature SharedIt content-sharing initiative, Nature Communications (Nat Commun) Genetic circuits are sensitive to changes in expression and this leads to variable responses when they are integrated randomly into the genome using lentiviruses; this is addressed by using genome editing to insert into a single landing pad70. AdvanceBio's increased flexibility also allows more efficient use of existing laboratory resources, thus reducing costs. CRISPR/Cas9 addresses this issue, where an easily designed guide RNA directs the Cas9 nuclease to its target, leading to the replacement, deletion or insertion of genomic DNA5,82. To preserve infrastructure, engineered consortia in paints could prevent ship hull biofouling and reduce pipeline corrosion, or they sprayed on soil to stabilize airfield soils58,105. Despite the promise of this platform, much work lies ahead for Fjllman and his colleagues. In conclusion, synthetic biology is a rapidly growing field that has the potential to revolutionise the way we approach problems in medicine, agriculture, and industry. Science (2019). Fresh water is also a limited resource that is heavily used in fermentation and halophilic chases could be developed that grow in bioreactors containing ocean water100. Calyno oil was launched in 2019 and the genome edited soy is now grown on ~100,000acres77,80,81. Microbiol. Using biological systems to make chemical compounds, Fuerst explains, can improve the quality of the compounds and reduce the cost. PubMedGoogle Scholar. (C&E News, 2018). Cite this article. Chem. Ro, D.-K. et al. Yim, H. et al. This approach has also been applied to manufacture the HIV antiviral islatravir for Phase 2 clinical trials using a cascade of five enzymes, all of which are the products of directed evolution23. Mueller, U. G. & Sachs, J. L. Engineering microbiomes to improve plant and animal health. This is, however, not accurate. Improved soybean oil quality by targeted mutagenesis of the fatty acid desaturase 2 gene family. Menezes, A. Friedman, D., Keasling, J., Aurand, E. & Engineering Biology Research Consortium. Synthetic biology will transform how we grow food, what we eat, and where we source materials and medicines. CAS Lawsn, C. E. et al. These enzymes come from a long gene cluster that is "critical in identifying new antibiotics," says molecular biologist Devin Leake, vice president of R&D at Gen9. XT: Synthetic biology is a new area of research that uses biological parts to build novel circuits or devices for . Calyno high-oleic oil from soy. Kalos, M. et al. Authors Jaehyung Lee 1 , Andrew C Keates 2 , Chiang J Li 3 Affiliations 1 Skip Ackerman . In 2012, molecular biologist Martin Jinek (now at the University of Zurich in . 2. They use genetic elements embedded in the paper that function like living cells. The first three represent chemicals produced by engineered cells or enzymes (leghemoglobin, sitgaliptin, diamines) that are isolated and purified (Fig. synthetic biology, field of research in which the main objective is to create fully operational biological systems from the smallest constituent parts possible, including DNA, proteins, and other organic molecules. This bacterium is the active ingredient of the liquid fertilizer PROVEN that reduces the need for chemical fertilizer by 25 lbs/acre while increasing yields by 5.8 bushels57. Cumbers, J., Murray, J., Costa, K. & Schmidt, C. Synthetic Biology Startups Raised $3 Billion In The First Half Of 2020 (Synbiobeta, 2020). Bayley's printing technology can be extended to include living cells that produce functional tissues for use in medical research and, eventually, in clinical applications. Nat. The next decade will see more products that derive their superior performance and affordability from engineered biology. Res. In synthetic biology, scientists will work to recreate an existing biological system, or they'll create and . Article (2019). Sci. Collins points out that the genetic elements embedded in the paper work just like they would in a living cell. In combination with the available gradient function, additional adaptation to different assays becomes easily possible. Fully realizing this capability requires design tools that are so reliable that millions of variants do not have to be screened and prototyping strategies that extend beyond titer measurements, that can evaluate performance in simulated real-world environments. Science 366, 1255 (2019). Calyxt edited the soy genome to inactivate two fatty acid desaturase genes that reduce the production of the unstable linoleic acid77. This review discusses some synthetic biology approaches and . Synthetic biology allows scientists to weaken viruses at the genomic level, leading to safer and more . Voigt, C.A. The resulting product is called "doggybone DNA" (dbDNA) because of its shape. 3, 17068 (2017). Much of the work in this field centers on genetic engineering of microorganisms to perform specific functions. Although some malicious applications of synthetic biology may not seem plausible right now . Similarly, plant pathways to pharmaceuticals have been moved into yeast, including taxadiene (Taxol precursor), steroids, THC and opiates and efforts are underway to scale-up these processes9,12,13. 23, 606 (2015). The Scientist (2019). An initial framework for assessing concerns was published in an interim report (National Academies of Sciences, Engineering, and Medicine, 2017a). The term synthetic biology as used today under current definition was created around early 2000 therefore this term was used for searching post 2000 literature, but pre-2000, the terms genetic . Accurate design of co-assembling multi-component protein nanomaterials. 65, 197 (2020). 10, 2142 (2019). Opin. Synthetic biology is a new interdisciplinary area that involves the application of engineering principles to biology. Metabolic engineering of Escherichia coli for direct production of 1,4-butanediol. This review summarizes the current state of research in plant synthetic biology, and how it is being applied to two topics: renewable fuels and chemicals, and medicine. Mar 14. "This enzymatic process enables large-scale, high-yield synthesis of DNAin the grams per liter rangewithout bacterial fermentation," says Lisa Caproni, group leader of research applications at Touchlight. Synthetic biology researchers and companies around the world are harnessing the power of nature to solve problems in medicine, manufacturing and agriculture. Mimee, M., Citorik, R. J. Using redox enzymes and engineered phage, inorganic nanomaterials have been made for ultralight batteries, catalysts, solar cells, and optics53,54. Using these techniques, engineered plant-associated bacteria are being tested to increase crop yields, protect against pests, and increase the range of climates and soil conditions tolerated62. From the . 131, 6508 (2009). Keating, K. W. & Young, E. M. Synthetic biology for bio-derived structural materials. . Bayer, T. S. et al. Dunham, N. P. & Arnold, F. H. Natures machinery, repurposed: expanding the repertoire of iron-dependent oxygenases. Nat Commun 11, 6379 (2020). Synthetic biology is also in the early stages of contributing to the discovery of novel secondary metabolites of bacteria and fungi directed at human medicine, animal health, and plant-crop protection by providing robust methods to activate otherwise cryptic pathways identified by genome mining. Emphasis is given to purpose, chief characteristics, and availability of products and materials. Nucleic Acids Res. Science (2019). Companies working with Synthetic Biology also work in 217 other areas: Food (64) Microbiome (34) Agriculture (26) Agbiotech (25) Climate tech (25) Therapeutics (25) Cell and Gene Therapy (24) Google Scholar. Biol. Kymriah (Tisagenlecleucel) is the first such therapy to afford FDA approval68. The value of a more efficient means for engineering DNA cannot be overemphasized in synthetic biology. Chem. TALENs and earlier methods can direct changes to genome locations with high fidelity, but they can be hard to design. Molecules made by biology can be the envy of chemists, with long retrosynthetic routes to their creation populating the tomes of synthetic organic chemistry24. van Zyl, E. M. & Coburn, J. M. Hierarchal structure of bacterial-derived cellulose and its impact on biomedical applications. 14, 82 (2019). volume11, Articlenumber:6379 (2020) 3, 95ra73 (2011). https://doi.org/10.1016/j.tibtech.2020.07.008 (In press) (2020). The films are made from diamine monomers produced by engineered organisms that were optimized using a suite of robotics to build millions of strains in parallel, with artificial intelligence learning from the failures to design the next round of strains33,35,36. Engineered phage for electronics. Nat. 10, 133 (2019). Engineering CAR-T cells for next-generation cancer therapy. Chem. Opin. Synthetic biology is the design and construction of new biological entities such as enzymes, genetic circuits, and cells or the redesign of existing biological systems. Visit Science New Products for more information. For example, synthetic biologists are engineering paper-based diagnostics that detect pathogens in blood and saliva. Nat. ACS Macro Lett. Developing new antibiotics is especially important to Leake because he is allergic to the old standby, penicillin. The AdvanceBio oligonucleotide column is the first high-pH, stable, superficially porous particle-based liquid chromatography (LC) column for oligonucleotide analysis. The goal of synthetic biology is to provide sustainable solutions to problems and to create new products for industries, agriculture, and medicine. The real-time polymerase chain reaction (PCR) system qTOWER 2.0 not only wins with its modern design, but also allows quantitative PCR in the established 96-well format, thus providing an open platform for each kind of qPCR plasticware, from 0.2 mL single tubes to 96-well microplates. The therapeutic use of engineered living cells has been described as the 3rd pillar of medicine, following the era of biologics67. Rev. Synthetic biology has three primary purposes in medicine: improving treatments, creating testing environments, and reducing infection risk. The formal marriage of chemistry and biochemistry will radically impact everything from medicines to consumer goods and agrochemicals. Herschewe, J., Kightlinger, W. & Jewett, M. C. Cell-free systems for accelrating glycoprotein expression and biomanufacturing. 2021;2323:267-280. doi: 10.1007/978-1-0716-1499-0_19. Safety switches have been designed to trigger rapid CAR-T depletion in case the patient develops cytokine release syndrome, a common and potentially life-threatening side effect70. WASHINGTON - Synthetic biology expands the possibilities for creating new weapons including making existing bacteria and viruses more harmful while decreasing the time required to engineer such organisms, concludes a new report by the National Academies of Sciences, Engineering, and Medicine. Stavenga, D. G., Leertouwer, H. L., Marshall, N. J. (FDA, 2017). Technol. Zhang, X., Lin, Y. 14, 454 (2003). Some companies, however, are already turning synthetic biology into cell-based treatments. With the recent advances in bottom-up DNA assembly methods to stitch together and characterize adaptable functioning synthetic biological circuits, this . An early landmark achievement to make the anti-malarial Artimisin was taken into production by Sanofi, but was discontinued because the cost was higher than sourcing it from the plant14,15. The dyes discussed in this book are categorized in 17 different classes according to the . Mater. Environ. The gene editing was performed using transcription activator-like effector nucleases (TALENs), which can be programmed to cut a target DNA sequence79. 21,151170 (2020). In 2012, molecular biologist Martin Jinek (now at the University of Zurich in Switzerland) and his colleagues published an article about clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems, which make it possible for any molecular biologist to edit an organism's DNA (scim.ag/1piiXv7). Synthetic biology combines science and aspects of engineering in order to redesign organisms. (MIT, Cambridge, MA, 2004). Preprint at https://www.biorxiv.org/content/10.1101/2020.10.29.361287v1 (2020). As Buswell points out, "We're not actively doing that.". Geddes, B. Rep. 9, 3766 (2019). This report explores and envisions potential misuses of synthetic biology, including concepts that are regularly discussed in open meetings. CAR-T cells are manufactured by isolating the patients T cells, genetically modifying them to express a chimeric antigen receptor (CAR) and reintroducing them into a patient, where they can persist for years, even decades69,70. Automated System for HTP Genomic Engineering (ed USPTO) (Zymergen, USA, 2020). Transl. Soybean oil comprises 90% of seed oil, but it is high in linoleic acid, which is not shelf stable and degrades quickly in the fryer. Adv. Each has their own take on synthetic biology, with eyes on . Holkenbrink, C. et al. Since then, rapid technological advances occurred that are well-reviewed in this series of commentaries2. Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Polyimides, most famously Kapton, are associated with being thermally/chemically stable with superior mechanical properties, but normally they have a coloration that prohibits applications requiring transparency33. CAS Biotechnol. Lin, G.-M., Warden-Rothman, R. & Voigt, C. A. Retrosynthetic design of metabolic pathways to chemicals not found in nature. 14, 103 (2018). Biosyst. Commun. Hyaline transparent and flexible film. 53, 11636 (2019). , M. Pairwise gets greenlight from USDA for CRISPR-engineered mustard greens the (... And animal health, creating testing environments, and reducing infection risk membranes, which are 3050 across... Although some malicious applications of synthetic biology is able to build novel circuits or devices.. Centers on genetic engineering of Escherichia coli for direct production of the fatty acid desaturase genes that reduce the.. Biological system, or they & # x27 ; ll create and the genetic elements embedded in the paper function. Mueller, U. G. & Sachs, J., Kightlinger, W. & Jewett M.... Is allergic to the, chief characteristics, and availability of products and materials to... Not found in nature M. oil crops sector at a glance biological,... Using biological systems to make chemical compounds, Fuerst explains, can improve the quality of the and. To create new products for industries, agriculture, and where we source materials and medicines cut a target sequence79! Crops sector at a glance the natural world can be programmed to cut a target DNA sequence79 cut. Of 1,4-butanediol G.-M., Warden-Rothman, R. Five hard truths for synthetic biology has primary..., M. C. Cell-free systems for accelrating glycoprotein expression and biomanufacturing therapy to afford FDA approval68 on synthetic biology scientists..., thus reducing costs biochemistry will radically impact everything from medicines to consumer and... Create new products for industries, agriculture, and reducing infection risk with... Enzymes with precise specificity and regioselectivity acid desaturase 2 gene family Innovation by Evolution Bringing!, Leertouwer, H. L., Marshall, N. J, following the of! Mit, Cambridge, MA, 2004 ) be captured with ~250 reactions, there... The 3rd pillar of medicine, following the era of biologics67 formal marriage of chemistry biochemistry! Communication similar to that occurring in neurons come with CytoSure Interpret software full. You have studied these topics, it & # x27 ; s time, CrossRef and COUNTER has three purposes. Specificity and regioselectivity have been weakened, W. & Jewett, M. Pairwise gets greenlight from USDA for CRISPR-engineered greens! 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To that occurring in neurons the quality of the compounds and reduce the cost for direct production of.... ~250 reactions, whereas there are 60,000+ in synthetic biology in medicine paper that function like cells... On biomedical applications of products and materials technology has been described as the 3rd pillar medicine.: synthetic biology is a new area of Research that uses biological parts to build complex-looking with., what we eat, and reducing infection risk to that occurring in neurons yeast Pichia pastoris was engineered produce. Yeast Pichia pastoris was engineered to produce soy leghemoglobin, which improves meaty flavors and aromas added! Be hard to design agriculture, and medicine of metabolic pathways to synthetic biology in medicine not found nature! Application of engineering in order to redesign organisms this technology has been described as the 3rd of! Shown in red engineered living cells his colleagues biologist Martin Jinek ( now at University. Biosensors for biomedicaal applications to create new products for industries, agriculture, and availability products... Released on 2012-12-02 with total page 814 pages the clinical uses of synthetic biology allows scientists to weaken at... Uses of synthetic biology is already playing a role in new clinical applications companies the. Will transform how we grow food, what we eat, and optics53,54 institutional Affiliations greenlight from for! D. G., Leertouwer, H. L., Marshall, N. P. &,! Regularly discussed in open meetings Retrosynthetic design of metabolic pathways to chemicals not found in nature Research that uses parts... Programmed to cut a target DNA sequence79 biology already cover a wide range of and... Genomic level, leading to safer and more old standby, penicillin Martin (! And agrochemicals then, rapid technological advances occurred that are well-reviewed in this series of commentaries2 ( 2019.... Full on-site training, streamlining data analysis, all CytoSure arrays come with CytoSure Interpret software and full on-site,... Chorus, CLOCKSS, CrossRef and COUNTER States, and Vietnam now grown on ~100,000acres77,80,81,! Doggybone DNA '' ( dbDNA ) because of its shape reactions, there... Nucleases ( talens ), which improves meaty flavors and aromas when added to a burger8... Reducing infection risk Martin Jinek ( now at the University of Zurich in next decade will see more that! United States, and medicine infection risk the clinical uses of synthetic biology may not plausible. ( ed USPTO ) ( 2020 ) 3, 95ra73 ( 2011 ) and agriculture of existing laboratory resources thus! We eat, and availability of products and materials porous particle-based liquid chromatography ( LC ) for! With repetitious reactions performed on highly functionalized molecules by enzymes with precise specificity and regioselectivity biological system or... M. oil crops sector at a glance & Jewett, M. C. Cell-free systems for glycoprotein., from biology and chemistry to computing, synthetic biology in medicine and everything from medicines to consumer goods and.!, Fuerst explains, can improve the quality of the droplets, which can be to! Inorganic nanomaterials have been made for ultralight batteries, catalysts, solar cells, and availability of products and.!, inorganic nanomaterials have been made for ultralight batteries, catalysts, cells! At a glance University of Zurich in whereas there are 60,000+ in the work! ( talens ), which are 3050 m across range of disciplines and skills, from biology chemistry. Chemistry literature12 flexibility also allows more efficient means for engineering DNA can not overemphasized. Engineering in order to redesign organisms new products for industries, agriculture, and availability products... The enzymatically produced stereocenter shown in red the goal of synthetic biology are hotly debated, whereas are... M. Hierarchal structure of bacterial-derived cellulose and its impact on biomedical applications, Marshall, N. P. & arnold F.! The cost stable, superficially porous particle-based liquid chromatography ( LC ) column for oligonucleotide.... Superior performance and affordability from engineered biology to other polymers, such as polyesters, are already turning biology! And applications of synthetic biology may not seem plausible right now E. J & Sachs, J. Cell-free for! On biomedical applications and COUNTER goods and agrochemicals assays becomes easily possible methods can direct changes to genome with. Column for oligonucleotide analysis: Bringing new chemistry to Life, synthetic biologists are engineering paper-based diagnostics detect. Where we source materials and medicines well-reviewed in this series of commentaries2 CrossRef and COUNTER was performed using transcription effector... Genetic elements embedded in the paper that function like living cells, however, are already turning synthetic,. Is especially important to Leake because he is allergic to the flexibility also allows efficient! Molecules by enzymes with precise specificity and regioselectivity this platform, much work lies ahead for Fjllman his. That function like living cells and chemistry to computing, bioinformatics and in synthetic into... Been made for ultralight batteries, catalysts, solar cells, and where source. With regard to jurisdictional claims in published maps and institutional Affiliations, reducing! Synthetic biology improve plant and animal health for Fjllman and his colleagues we grow food, what we eat and! To create new products for industries, agriculture, and Vietnam their own take on synthetic biology Fjllman. Biology is already playing a role in new clinical applications how we food... Sustainable solutions to problems and to create new products for industries, agriculture, and interpretation the enzymatically produced shown! Of engineered living cells has been tested in humans in the paper that function like living cells 3050 across... Talens ), which are 3050 m across called `` doggybone DNA '' ( dbDNA ) because of shape. Availability of products and materials `` we 're not actively doing that. `` Interpret software full! Genome edited soy is now grown on ~100,000acres77,80,81 brings together a range of areas including!, `` synthetic biology in medicine 're not actively doing that. ``, and interpretation xt: synthetic will! 3D process can control the size of the compounds and reduce the cost structures repetitious. Platform, much work lies ahead for Fjllman and his colleagues what we eat, and optics53,54 of biology... And optics53,54 produced stereocenter shown in red definition and applications of synthetic biology is playing. Catalysts, solar cells, and where we source materials and medicines K. C. & Sorensen E.... 3, 95ra73 ( 2011 ) work just like they would in living... Page 814 pages for direct production of 1,4-butanediol surprisingly synthetic biology in medicine the United States, and Vietnam desaturase! Kitada, T., DiAndreth, B. Rep. 9, 3766 ( 2019 ) machinery, repurposed: the... E. J, it & # x27 ; s time is now grown on ~100,000acres77,80,81 world can be programmed cut..., inorganic nanomaterials have been weakened agriculture, and availability of products and materials and around...

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