Synthetic Biology and its Potential Implications for BioTrade and Access and Benefit-Sharing

AT SYNTHETIC BIOLOGY AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING UNCTAD/DITC/TED/INF/2019/12 ©2019, United Nations Conference Trade Development. rights reserved. trends, figures views expressed publication UNCTAD necessarily represent views member States. designations employed presentation material map work imply expression opinion whatsoever part United Nations legal status country, territory, city area authorities, delimitation frontiers boundaries. study freely cited acknowledgment UNCTAD. information UNCTAD’ BioTrade Initiative consult website: http://www.unctad. org/biotrade contact : biotrade@unctad.org publication formally edited. iiiAND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING Contents Acknowledgements ................................................................................................................................ iv Abbreviations ........................................................................................................................................... EXECUTIVE SUMMARY ............................................................................................. vi SECTION 1: INTRODUCTION TO BIOTRADE, SYNTHETIC BIOLOGY AND SYNTHETIZATION . 1 1. BioTrade ............................................................................................................................................ 1 2. Defining synthetic biology .................................................................................................................. 2 3. Synthetic biology approaches ............................................................................................................ 4 Genome engineering ................................................................................................................... 4 Metabolic engineering ................................................................................................................. 5 Implications BioTrade ABS .............................................................................................. 5 4. difference chemical synthesis biosynthesis .......................................................... 6 Chemical synthesis ..................................................................................................................... 6 Biosynthesis ................................................................................................................................ 6 Implications BioTrade ABS .............................................................................................. 7 SECTION 2: CASE STUDIES ON NATURAL PRODUCTS, SYNTHESIZATION AND SYNTHETIC BIOLOGY ............................................................................................................ 8 1. Flavours fragrances .................................................................................................................... 8 Vanilla ......................................................................................................................................... 8 Patchouli ................................................................................................................................... 10 Orange ...................................................................................................................................... 10 Stevia ....................................................................................................................................... 10 2. Pharma phytopharmaceuticals ................................................................................................. 12 Artemisinin ................................................................................................................................ 12 SECTION 3: LAW AND POLICY ISSUES AT THE INTERFACE OF BIOTRADE AND SYNTHETIC BIOLOGY .......................................................................................................... 14 1. Food labelling .................................................................................................................................. 14 United States ............................................................................................................................ 14 European Union ........................................................................................................................ 14 2. Cosmetic products .......................................................................................................................... 15 United States ............................................................................................................................ 15 European Union ........................................................................................................................ 15 3. Voluntary certification ....................................................................................................................... 16 -GMO certification .............................................................................................................. 16 COSMOS .................................................................................................................................. 16 NATRUE.................................................................................................................................... 16 SECTION 4: CONCLUSIONS ON IMPLICATIONS OF SYNTHETIC BIOLOGY FOR BIOTRADE AND ABS ......................................................................................................... 18 1. General conclusions implications SynBio BioTrade ............................................... 18 2. Potential implications SynBio ABS .......................................................................................... 20 3. Recommendations BioTrade ........................................................................ 20 iv SYNTHETIC BIOLOGY Acknowledgements study prepared . Frederic Perron-Welch, Access Benefit-Sharing (ABS) Consultant BioTrade Initiative Trade, Environment, Climate Change Sustainable Development Branch UNCTAD. study greatly benefited peer reviews substantive inputs : Ms. Lorena Jaramillo, Economic Affairs Officer, . David Vivas Eugui, Legal Officer, Trade, Environment, Climate Change Sustainable Development Branch (TED) UNCTAD; Ms. Anne Schick (Swiss State Secretariat Economic Affairs SECO); Molly Bond (Bristol University); Dr. Marco ’Alessandro (Swiss Federal Institute Intellectual Property (IPI)); Dr. Hartmut Meyer, (ABS Capacity Development Initiative); Ms. Maria Julia Oliva (Union Ethical BioTrade (UEBT)); Dr. Balakrishna Pisupati (Forum Law, Environment, Development Governance (FLEDGE)); . Andrew Wilson (Helvetas Swiss Intercooperation). Desktop formatting . Rafe Dent UNCTAD. UNCTAD gratefully acknowledges support SECO development study Global BioTrade Programme: Linking trade, biodiversity sustainable development. 2 October 2019 ANNEX :DEFINITIONS OF SYNTHETIC BIOLOGY ......................................................... 24 ANNEX II: SELECTED SYNTHETIC BIOLOGY TOOLS AND TECHNIQUES .......................... 25 1. BioBrick engineering ........................................................................................................................ 25 2. Bioinformatics .................................................................................................................................. 25 3. Design tools .................................................................................................................................... 26 4. Construction tools ........................................................................................................................... 27 Genome-editing technologies ................................................................................................... 27 Gene synthesis technologies ..................................................................................................... 27 Biofoundries .............................................................................................................................. 27 GLOSSARY ............................................................................................................ 28 Notes .................................................................................................................................................... 30 Figures Figure 1: SynBio ingredient production genetically modified yeast ......................................................... 6 Figure 2: Examples methods obtaining vanillin ........................................................................ 9 Figure 3: Dried leaf artemisia phytomedicine .............................................................................................. 12 Figure 4: GenoCAD online platform ............................................................................................................ 26 Figure 5: Traditional Twist Bioscience DNA synthesis platform ............................................................... 27 Figure 6: architecture typical biofoundry ....................................................................................... 28 Tables Table 1: BioTrade sectors prioritized countries partners ................................................................... 2 Table 2: Examples SynBio products replace naturally sourced biological resources .............. 13 vAND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING Abbreviations ABS Access benefit-sharing AHTEG-SB Ad Hoc Technical Expert Group Synthetic Biology BBF BioBricks Foundation BioCAD Computer-Aided Design software environments biology BLAST Basic Local Alignment Search Tool BPA BioBrick Public Agreement BT & BioTrade Principles & Criteria CAD Computer-Aided Design Cas9 CRISPR- Protein 9 CBD Convention Biological Diversity CITES Convention International Trade Endangered Species Wild Fauna Flora COP Conference Parties COSMOS COSMetic Organic Standard CRISPR Clustered regularly interspaced short palindromic repeats DDBJ DNA Data Bank Japan DNA Deoxyribonucleic acid DSI Digital sequence information ECSC European Commission Scientific Committees EFSA European Food Safety Authority EGGenTDurchfG German Genetic Engineering Implementation Act EMBL-EBI European Bioinformatics Institute European Molecular Biology Laboratory FAO United Nations Food Agriculture Organization FDA United States Food Drug Administration FCI France Chirurgie Instrumentation ... Gates Foundation Bill & Melinda Gates Foundation GMOs Genetically modified organisms GRAS Generally recognized safe iGEM International Genetically Engineered Machine Competition IFF International Flavors & Fragrances INSDC International Nucleotide Sequence Database IUCN International Union Conservation Nature JECFA Joint FAO/WHO Expert Committee Food Additives LMOs Living modified organisms MAGE Multiplex Automated Genome Engineering MAT Mutually agreed terms NCBI National Center Biotechnology Information NGS generation sequencing NIH National Institutes Health OECD Organisation Economic -operation Development Online Forum Open-ended Online Forum Synthetic Biology Open MTA Open Material Transfer Agreement PIC Prior informed consent SBSTTA Subsidiary Body Scientific, Technical Technological Advice SCCS European Union Scientific Committee Consumer Safety SCENIHR European Union Scientific Committee Emerging Newly Identified Health Risks SCHER European Union Scientific Committee Health Environmental Risks SDGs Sustainable Development Goals SSA Semisynthetic artemisinin SynBio Synthetic biology TALEN Transcription Activator- Effector Nuclease WHO World Health Organisation WIPO World Intellectual Property Organisation ZFN Zinc-finger nuclease vi SYNTHETIC BIOLOGY EXECUTIVE SUMMARY Synthetic biology identified emerging issue meriting research meeting UNCTAD BioTrade Initiative Stakeholder Steering Committee meeting 2018. study implications synthetic biology BioTrade developed based request order provide guidance comprehension topic, implications BioTrade. BioTrade partners expected support line work enhance knowledge provide practical experiences enrich findings study. universally agreed definition term ‘synthetic biology’, 13th Conference Parties (COP) Convention Biological Diversity acknowledged definition starting point continued discussions: “ development dimension modern biotechnology combines science, technology engineering facilitate accelerate understanding, design, redesign, manufacture / modification genetic materials, living organisms biological systems.” , falls scope Convention Protocols biosafety access benefit-sharing (ABS). study, case studies, UNCTAD aims show potential implications synthetic biology BioTrade ABS. research carried , appears synthetic biology direct impacts BioTrade sectors, existing technologies target specific market sectors cosmetics sector, food fragrances sector, pharma/phytopharmaceutical sector. foreseeable consequence BioTrade displacement naturally sourced ingredients ingredients produced synthetic biology. , displacement BioTrade sector limited, consumers purchasing products BioTrade ingredients purchase products produced line economic, social environmental sustainability criteria influenced cost savings resulting synthetic biology ingredients. trend strong younger consumers. implications synthetic biology BioTrade remain prospective synthetic biology companies producing economically competitive products. , opportune time BioTrade actors proactive approach matter. Based analysis conducted study, recommendations BioTrade . recommendations offer approaches addressing synthetic biology revised BioTrade Principles Criteria (BT &), addressing implications sustainable biodiversity broadly. Recommendations: 1. Provider countries conducting socioeconomic impact assessments nationally important chains synthetic biology alternative appears market order determine potential impact jobs livelihoods. 2. significant risk jobs livelihoods, provider countries assist producers transition BioTrade chains prevent impact livelihoods biodiversity result shift existing chain. 3. potential implications defining “natural product” “goods services derived native biodiversity” context BioTrade. challenging undertaking preferable leave national decision makers standard-setting bodies. 4. addressing BioTrade Principles Criteria address specific types technologies products falling broad scope synthetic biology. include question broad approach preferable, case--case approach based sustainability criteria . 5. case--case approach products fabricated genetically modified/ synthetic biology organisms BioTrade products demonstrably sustainable naturally derived counterparts (.. trade ban CITES, listed International Union Conservation Nature (IUCN) Red List). 6. case--case approach adopted, development traceability mechanism ingredients derived CITES-listed species prove fabricated SynBio processes species. 1AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING SECTION 1: INTRODUCTION TO BIOTRADE, SYNTHETIC BIOLOGY AND SYNTHETIZATION emerging issues study implications synthetic biology (SynBio) BioTrade developed request BioTrade Initiative partners, requested guidance understanding topic SynBio potential implications BioTrade. section addresses concept BioTrade, field SynBio, differences chemical synthesis biosynthesis. 1. BioTrade BioTrade involves collection, production, transformation commercialization goods services derived native biodiversity (species ecosystems) environmental, social economic sustainability criteria— BioTrade Principles Criteria (BT &). underlying premise BioTrade biodiversity based products — sourced elaborated respect equity, fairness sustainability principles — provide strong basis local livelihoods, respect traditional practices values, conservation sustainable biodiversity. distinction drawn BioTrade takes place line BT &, broader trade biodiversity- based products, commercial biological resources sustainable.1 BioTrade implemented sectors personal care, pharmaceutical (phytopharma); food; fashion; ornamental flora fauna; handicrafts; textiles natural fibres; sustainable tourism; forestry-based carbon credit activities.2 Specific examples BioTrade products Table 1 (page 2). relevant BioTrade sectors, synthetic biology (SynBio) products impact BioTrade chains sectors: personal care; pharmaceutical (phytopharma); food; fashion; textiles/natural fibres. Case studies existing emerging SynBio products cosmetics flavourings fragrance sectors presented report order demonstrate potential impacts BioTrade chains, developed greatest potential impact. Box 1: Sample BioTrade case 2009, Weleda, Swiss-based company producing natural organic beauty products anthroposophic medicines, [Union Ethical BioTrade] member, launched project organic sustainable cultivation sandalwood Sri Lanka. Sandalwood essential oil fragrance range Weleda products… Weleda, fundamental sandalwood oil organic sustainable sources, contributes increasing number sandalwood trees Sri Lanka livelihoods local communities. context, Weleda formed partnership local family-owned company. , , abandoned tea plantation highlands Sri Lanka. , 100-year- tea bushes, grew 1000 sandalwood trees, including young saplings. trees spread naturally birds carrying seeds thrived steep terrain protected wide root systems tea bushes. support Weleda, company invested land techniques organic sustainable harvesting sandalwood… line Ethical BioTrade Standard – based BT & – Weleda sandalwood project strong social component. Weleda signed agreement committing project sourcing exclusively company number years. supported creation plant nursery training education centre collectors. centre focuses sandalwood, cultivation vegetables, tea cinnamon trees. ensure variety crops cultivated – key local food security diversifying local incomes. , local company independently harvests commercializes crops, organic certification. Source: 20 Years BioTrade: Connecting People, Planet Markets, pp. 24-5. 2 SYNTHETIC BIOLOGY 2. Defining synthetic biology SynBio rapidly developing field emerged developments genetic engineering decades.3 builds advances molecular biology, genetic engineering microbiology,4 moving fields embrace “techniques ideas biology, engineering, chemistry materials sciences.”5 SynBio genetic engineering technologies, aims faster easier process.6 , understood “ umbrella term … gathers set activities ranges basic sciences innovative technology, scientific paradigm.”7 “ toolbox, .”8 activities place field SynBio distinct earlier technologies fall broad definition biotechnology Convention Biological Diversity (CBD),9 : “ technological application biological systems, living organisms, derivatives thereof, modify products processes specific .”10 , commonly agreed definition SynBio. Annex short summary definitions international expert groups, commonalities definitions. rapid ongoing evolution field SynBio, study establish definitive definition term, potential implication BioTrade. , study carried horizon scan methodology, defined OECD “ technique detecting early signs potentially important developments systematic examination potential threats opportunities, emphasis technology effects issue hand.”11 decade, SynBio “ key part 21st century bioscience biotechnology.”12 Advances reading DNA (sequencing) writing DNA (synthesis) “ led development ground-breaking technologies design, assembly, manipulation DNA encoded genes, materials, circuits, metabolic pathways, allowing greater manipulation biological systems entire organisms.”13 generation sequencing (NGS) technologies DNA synthesis technologies “form foundational technologies driving synthetic biology efforts eventually instill predictability reliability engineered biological systems chemical engineering brought chemical systems.”14 Due NGS technologies, boom DNA sequence repositories, improvements bioinformatics techniques software.15 Technological developments subsequently “ ‘’ genetic data wide variety organisms synthesize genetic constructs modify function living organisms.”16 growing number databases “digital sequence information”17 (DSI) form “ enormous potential catalogue natural ‘parts’—functional units DNA— high- chemical pathways discovered created.”18 widespread availability DSI great significance SynBio, “[] rise DNA Table 1: BioTrade sectors prioritized countries partners Sector Type product Personal care Essential oils, natural dyes, soaps, cream butters, cosmetics, . Pharmaceutical (phytopharma) Extracts, capsules infusions medicinal plants, Food Fruit pulps, juices, jams, biscuits, sauces, spices, nuts, tubers, snacks, food supplements, meat caiman fish, . Fashion Skin belts, bags Caiman yacare, . Ornamental flora fauna Heliconias, orchids, butterflies, Handicrafts Jewellery, decorative objects based native species, garments, Textiles natural fibres Furniture decorative objects based natural fibres, bags, shoes, . Sustainable tourism Ecotourism, nature-based tourism, community-based tourism, . Forestry-based carbon credit activities Reducing Emissions Deforestation Forest Degradation, conservation, sustainable management forests enhancement forest carbon stocks (REDD+), greenhouse gas (GHG) emissions mitigation strategies specific chains, . Source: Jaramillo & Onguglo, “BioTrade — harmonizing trade, biodiversity livelihoods” 20 Years BioTrade: Connecting People, Planet Markets, United Nations Doc. UNCTAD/DITC/TED/2016/4, 3. 3AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING synthesis moved biology information science DNA reconstructed sequence information , eliminating physical transfer enabling direct access biological functions encoded sequence databases.”19 overview developments Annex II. 2012, Conference Parties (COP) CBD SynBio context work emerging issues relating conservation sustainable biodiversity.20 examination based “ potential positive negative impacts components, organisms products resulting [SynBio] techniques conservation sustainable biodiversity” application precautionary approach.21 Parties COP 11 initiated enquiry requesting Secretariat compile “relevant information components, organisms products resulting synthetic biology techniques impacts conservation sustainable biological diversity social, economic cultural considerations”22 order assess qualifies emerging issue. information compiled synthesized Secretariat,23 gaps overlaps applicable provisions CBD, Protocols relevant agreements related components, organisms products resulting synthetic biology techniques considered,24 synthesis information peer review subsequent consideration meeting Subsidiary Body Scientific, Technical Technological Advice (SBSTTA) prior COP 12. include analysis criteria set emerging issues apply synthetic biology. criteria25 : . Relevance issue implementation objectives Convention existing programmes work; . evidence unexpected significant impacts biodiversity; . Urgency addressing issue/imminence risk caused issue effective implementation Convention magnitude actual potential impact biodiversity; . Actual geographic coverage potential spread, including rate spread, identified issue relating conservation sustainable biodiversity; . Evidence absence limited availability tools limit mitigate negative impacts identified issue conservation sustainable biodiversity; . Magnitude actual potential impact identified issue human -; . Magnitude actual potential impact identified issue productive sectors economic - related conservation sustainable iodiversity.”26 SBSTTA considered proposal COP 11 SynBio emerging issue, concluded SynBio relevance CBD, insufficient information finalize analysis criteria decide emerging issue.27 affirmed COP 12, established Ad Hoc Technical Expert Group Synthetic Biology (AHTEG- SB) carry research report meeting SBSTTA prior COP 13.28 tasks assigned AHTEG-SB work operational definition SynBio,29 issued 2015, stating SynBio “ development dimension modern biotechnology combines science, technology engineering facilitate accelerate understanding, design, redesign, manufacture / modification genetic materials, living organisms biological systems.”30 COP 13 acknowledged outcome work AHTEG-SB operational definition, considered starting point facilitating scientific technical deliberations CBD Protocols.31 COP 13 extended mandate AHTEG-SB, requesting recommendations SBSTTA preceding COP 14 order facilitate future discussions actions SynBio analysis based criteria Synthetic biology “ development dimension modern biotechnology combines science, technology engineering facilitate accelerate understanding, design, redesign, manufacture / modification genetic materials, living organisms biological systems” 4 SYNTHETIC BIOLOGY emerging issues.32 reasons, preliminary analysis presented SBSTTA,33 COP 14 extended mandate AHTEG- SB contribute completion assessment requested COP 12, building preliminary analysis presented SBSTTA 2018.34 part latest mandate, AHTEG-SB expected review current state knowledge analysing information potential positive negative environmental impacts, account human health, cultural socioeconomic impacts, regard biodiversity indigenous peoples local communities, current -future applications synthetic biology,35 prepare report outcomes work SBSTTA preceding COP 15.36 UNCTAD study intended contribute state knowledge SynBio’ impacts objectives CBD, building invitation COP 12 relevant United Nations organizations implications SynBio relates mandates.37 AHTEG-SB operational definition SynBio facilitate technical deliberations context CBD, BioTrade intended aligned CBD, exercise carried study rely definition AHTEG-SB clarify nature SynBio applications products implications BioTrade. horizon scanning exercise carried study based review analysis academic literature, government reports, interviews public private actors active SynBio BioTrade. study address subjects, fall scope BioTrade: • SynBio products intended environmental release agricultural production (.. living modified organisms (LMOs) covered Cartagena Protocol); • SynBio healthcare applications (gene therapy, cell-based therapy, antibody therapy, vaccines, antibiotics, vitamins, probiotics, ); • SynBio biofuels (derived algae, yeast, bacteria, ); • SynBio environmental applications (environmental monitoring biosensors, bioremediation, waste treatment, gene drives, ); • SynBio industrial chemicals (feedstocks, polymers, enzymes, surfactants, ); • Risk assessment risk management LMOs resulting SynBio. 3. Synthetic biology approaches meta-analysis scientific literature carried Raimbault, Contet Joly 2016 identifies dominant approaches closely concept SynBio:38 1. BioBrick engineering (DNA biological parts standardised prefix suffix DNA sequences routinely assembled); 2. Genome engineering ( rational -writing, editing complete design genomes); , 3. Metabolic engineering ( directed modification metabolic pathways microbial synthesis products). interest study, basis innovations discussed section study discussed . BioBrick engineering summarized Annex II play larger role commercial SynBio applications future. Genome engineering genome defined “ totality hereditary material stored nuclei, organelles mitochondria, living cells, form [DNA].”39 Genome engineering involves “rational -writing, editing complete design genomes.”40 , consequential organism earlier genetic engineering technologies based recombinant DNA, intended induce limited modifications specific genes. AHTEG- SB noted late 2017, stating “[]ynthesis genomes chromosomes significant implications modification organisms .”41 driven “ prevailing approaches: genome synthesis genome editing.”42 -genome synthesis combines “de novo DNA synthesis, large-scale DNA assembly, transplantation, recombination, [permitting] de novo construction user-defined double-stranded DNA genome.”43 Advances decades “ created possibility engineering organisms genome substantially altered consist largely DNA sequences chemically synthesized.”44 , technologies allowed increased number organisms 5AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING manipulated genetic engineering technologies, types manipulations . noted participants Open-ended Online Forum Synthetic Biology (Online Forum) convened Biosafety-Clearing House 2017, techniques “expand range host organisms living beings, range organisms successfully modified traditional modern biotechnology tools.”45 greatly “expanded types number products developed biotechnology.”46 , “[]lthough synthesize entire genomes, write scratch bottom . current state art top- ‘editing’ existing genomes technologies MAGE CRISPR [discussed Annex II] introduce incremental natural genome.”47 remain case perpetuity, predicted “[]enome-scale engineering, designs composed thousands genes assembled bottom , norm.”48 time , remains significant overlap practice ‘genetic engineering’ practice ‘genome engineering’. Metabolic engineering Metabolic engineering discipline commonly included SynBio toolbox. field focused “designing, engineering, optimizing pathways production variety products.”49 involves “ purposeful modification metabolic, gene regulatory, signaling networks achieve enhanced production desired chemicals.”50 central commercial future SynBio, “[] metabolic engineering microorganisms production small organic molecules fuel, chemical, materials, pharmaceutical applications represents promising opportunities synthetic biology.”51 , established 1990s, based genetic engineering technology application “systems network analyses challenge engineering productive strains.”52 early date, goal improving performance cells metabolic pathways pursued means “included synthetic genetic constructs (networks circuits) regulated performance metabolic network. circuits constitute today main activity synthetic biology, , , advanced context metabolic pathway optimization metabolic engineering.”53 overlaps synergies SynBio metabolic engineering, fields remain distinct.54 , metabolic engineering carried microbial strain improvement genetic engineering techniques. development significant future emergence cell-free SynBio metabolic pathways biosynthesis natural products.55 order address shortcomings cell-based production simplify research development, “ vitro, cell-free, platforms developed emerging powerful systems biomanufacturing therapeutic proteins, - biocommodities, -added chemicals.”56 participants Online Forum expressed concern platforms, noting “ cell-free systems genetic resources ‘bioparts’ potentially scaled produce compounds replace naturally sourced products, impacting sustainable equitable sharing benefits biodiversity.”57 Implications BioTrade ABS SynBio tools approaches discussed evidently implications BioTrade ABS. Metabolic engineering genome engineering technologies impact products BioTrade, organisms designed produce biochemical compounds BioTrade chains (examples case study section ). Rapid developments fields information technology (bioinformatics design tools) biotechnology (genome sequencing, genome editing, gene synthesis biofoundries) significantly accelerated Design–Build-Test–Learn cycle discovery optimization metabolic pathways, including artificial intelligence (machine learning).58 resulted faster research development process, quicker placement market biochemical products compete BioTrade products. ABS, aforementioned approaches tools boon naturally sourced genetic resources SynBio research development. , lead 6 SYNTHETIC BIOLOGY reduction reliance naturally sourced genetic resources research development relies DSI DNA synthesis. technologies approaches faster development products based ABS, leading benefit-sharing, faster development products bypass ABS requirements. remains actual impacts , technologies rapidly advancing, faster product development commercialization foreseeable result.59 4. difference chemical synthesis biosynthesis Chemical synthesis Chemical synthesis “ construction complex chemical compounds simpler .”60 step involves chemical reaction, reagents conditions designed give adequate yield pure product work . based simple, commercially petrochemical natural precursors. Synthesis applied produce organic -organic compounds, economically valuable substances obtained process (pharmaceuticals, flavours, fragrances, ).61 “involve considerable number individual reactions leading sequence starting materials desired product.”62 Biosynthesis Biosynthesis multi-step process precursor compounds converted complex products living organisms, metabolic pathways. occurs living organisms, nature engineered lab. production high chemicals, sourced natural products, “benefit specificity biological synthesis, leading high-purity products, produced high yield pathways minimize -product formation.”63 , complex natural products, “ existing chemical method commercial manufacture. , biological route provide access target semisynthetic intermediate.”64 demonstration genetically modified microbe prvided Figure 1 . Figure 1: SynBio ingredient production genetically modified yeast Source: Adapted Linda Wang, “Manus Bio” (2018) 96:44 Chemistry & Engineering News 42 43. 7AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING Biosynthesis carried industrial fermentation processes, naturally sourced precursors produce high biochemicals genetically modified -genetically modified microorganisms carefully designed conditions.65 process bioconversion. bioconversion process case study Vanillin Section 2. Chemical synthesis biosynthesis necessarily exclusive, “[] future production chemicals, industrial chemical synthesis frequently advantage biosynthesis traditional chemical synthetic steps, employing optimize synthetic pathway.”66 case SynBio process production artemisinin artemisic acid Section 2. Implications BioTrade ABS Chemically synthesized products competing natural products century . , “ synthesis indigo Adolf von Baeyer 1867… led explosive growth German Swiss dye industry, simultaneously dismantling import indigo natural dyes distant tropical locales.”67 , market segments, products labeled “artificial” (.. artificial flavours artificial colours foods). Consumer pressure leading companies move products, opening opportunities naturally sourced ingredients biosynthesized analogues ( discussed sections ). present, ingredients produced biotechnological processes labelled ‘natural’ products production process (discussed ), long final product genetically modified organisms (GMOs). consequences BioTrade, blurring lines regard constitutes natural product. discussed greater detail . 8 SYNTHETIC BIOLOGY SECTION 2: CASE STUDIES ON NATURAL PRODUCTS, SYNTHESIZATION AND SYNTHETIC BIOLOGY SynBio research development “evolutionary, revolutionary, involving tweaking existing organisms copying natural products.”68 , targeting biochemicals derived natural sources. section address SynBio organisms designed contained , prominent SynBio produce natural product analogues. organisms “ industrial fermentation produced sealed environments laboratories ponds … [ ] produce commodity chemicals, fuels, specialty chemicals intermediates, enzymes, polymers, food additives, flavours.”69 products resulting applications taste smell identical natural product, market. commercially significant, manufacturers moving artificial ingredients products 2015 natural substitutes due consumer pressure.70 Proponents argue resulting products natural existing chemical ingredients, naturally sourced products satisfy market demand. hand, natural products qualities SynBio products , multiple biochemical compounds effects isolated biochemical compound. addressed case studies . 1. Flavours fragrances Biotechnology-derived production flavours fragrances expanded rapidly years.71 main economic driver trend “desire establish reliable economically profitable production systems environmentally benign comparison classic production approaches based large-scale organic chemical synthesis.”72 important driver legislation European Union United States America compounds produced living organism labelled ‘natural’ artificial.73 section present case studies naturally sourced products flavour fragrance industries competing ingredients produced SynBio organisms. Vanilla Naturally sourced vanilla flavour obtained species vanilla orchid, Vanilla planifolia Vanilla tahitensis.74 labour-intensive crop, estimated 200,000 people involved annual production.75 80 cent world’ vanilla smallholder farms Madagascar, vanilla orchids pollinated hand pods traditionally cured.76 Yield , 600 hand-pollinated blossoms required produce 1  kg cured pods, approximately 500 kg pods needed produce 1 kg vanilla bean extract.77 extract 250 flavour aroma compounds, vanilla beans taste potency profiles based grown.78 Due yield mentioned , 1 cent vanilla flavour world markets actual vanilla orchids. Synthesized substitutes vanilla flavour existed decades, vast majority labelled natural flavour ingredient. years, roughly 18,000  tonnes food grade vanilla flavour produced annually, 85 cent vanillin synthesized petrochemical precursor guaiacol.79 remainder derived lignin, waste product pulp paper industry. , processes significant environmental consequences. Chemical synthesis vanillin requires organic solvents hazardous chemicals, synthesis lignin calculated require safe disposal 160 kg waste 1 kg vanillin obtained.80 lignin- derived production ceased Canada United States due environmental concerns, leaving major supplier Norway (Borregaard).81 processes produce vanillin shwn Figure 2. Specialized fermentation processes - genetically engineered organisms (yeast, fungi bacteria) produce vanillin based natural ingredient, processes based eugenol isoeugenol (extracted clove oil) ferulic acid (extracted rice bran oil).82 products command price premium market labelled natural, production limited precursors products significantly expensive synthetic precursors.83 processes face limitations due toxicity 9AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING eugenol ferulic acid microbes, -vanillin -products created process (.. vanillin alcohol vanillic acid).84 biotechnology firm Evolva developed SynBio approach producing vanillin based glucose. microbe expresses Evolva’ vanillin considered processing aid, product flavour fall United States artificial flavouring labelling requirements, allowing ‘ artificial ingredient’ claims.85 Evolva partnered International Flavors & Fragrances (IFF) 2011 develop commercialize SynBio production process vanillin. brought market IFF mid-2014 trade Vanilla.™ , reference product IFF website, United States trademark abandoned 2015.86 suggest product commercially successful continued marketing partnership Evolva’ website.87 market research company suggests IFF concerned consumer backlash compounds SynBio. supported fact ice cream chocolate industries comprise 75 cent market vanillin,88 large-scale campaign launched SynBio vanillin ice cream IFF launched product.89 Evolva’ 2018 Annual Report “[] introduction, IFF significantly widened range blends vanillin. , volumes remain compared original expectations market potential.”90 Proponents SynBio techniques producing vanillin assert aiming compete synthesization methods,91 advantage trend ‘natural’ food products. argued labelling SynBio vanillin ‘natural’ lead competition vanilla bean extract.92 , naturally sourced vanilla remains highly valued, consumers prefer complex flavour profile. consequence, naturally sourced product continue appeal international markets , , SynBio vanillin significant consequences BioTrade product. SynBio vanillin compete ‘natural’ vanillin resulting bioconversion. Figure 2: Examples methods obtaining vanillin Source: MM Bomgardner “ problem vanilla: vowing natural, food brands face shortage favored flavor” (2016) 94 (36) Chemical & Engineering News 38 40. 10 SYNTHETIC BIOLOGY Evidence supporting view flavour manufacturers Symrise, Givaudan, Mane IFF set programs assist producers providing high quality sustainable supply vanilla satisfy consumer demand.93 actions response wild price fluctuations years poor harvests caused disease challenging climactic conditions ( threatening BioTrade naturally sourced vanilla SynBio vanillin). order increase revenue, farmers obtaining organic, fair-trade Rainforest Alliance certifications,94 consistent BT &. conclusion, food makers “commit roller coaster natural vanilla”95 order benefit natural ingredient trend, carry organic voluntary certification label, sell products specialty retailers, relying SynBio vanillin solution. Patchouli Patchouli essential oil traditional fragrance product, fragrance industry remains strongly dependent characteristics cosmetics, air fresheners, laundry detergents household scented products.96 traditionally extracted plant Pogostemon cablin, cultivated estimated 12,000 farm families countries including China, Indonesia, India, Malaysia Philippines.97 Indonesia largest producer, supplying estimated 80 cent global market.98 Competing SynBio products emerged, patchoulol, commercialized biotechnology company Amyris, partnership Firmenich ( Swiss flavour fragrance company). ingredient launched 2014, marketed trade “CLEARWOODTM” stated incorporated leading fragrances.99 , Firmenich claims CLEARWOOD replace natural patchouli essence, complement ingredient complex mix biochemicals.100 remains case. Orange Orange oil natural product widely flavour fragrance industry obtained inexpensively orange peels. primary compound valencene, orange scent flavour products. - product juice industry, cold pressed peel fruit juice extraction. Beverage flavouring primary application (including juice juice concentrates),101 valencene fragrances.102 production valencene requires large quantities orange oil, 0.5 cent oil . main drawbacks production method. , quality quantity ingredient highly dependent weather conditions contamination plant protection products orange production.103 , citrus greening disease (huanglongbing) emerging major threat orange production important production regions.104 companies emerged SynBio versions valencene: Isobionics105 Evolva.106 advantage products “unlimited guaranteed availability, constant quality, high purity price.”107 Evolva partnered France Chirurgie Instrumentation ... (FCI) expand European sales, marketing distribution valencene,108 Isobionics partnered DSM Nutritional Products worldwide distribution.109 Stevia Stevia member Asteraceae plant family. 230 species genus Stevia, “ species rebaudiana phlebophylla produce steviol glycosides.”110 traditional stevia hot water extract powdered leaf, containes variety biochemical compounds including stevia glycosides. Purified stevia glycosides main commercial product products world. classified calorie, high- intensity sweetener (250–300 times greater sugar) comparable synthetic sweeteners acesulfame , aspartame, saccharin sucralose.111 rapidly increasing global demand stevia glycosides sweeteners, sugar substitutes dietary supplements.112 extracted farm-raised stevia rebaudiana plants, stevia glycosides fastest growing segment sweetener market today, “ hundreds food beverage products, including cereals, teas, juices, flavoured milks, yogurts, carbonated soft drinks.”113 , crop predominantly produced smallholders Asia Latin America ( 80 cent grown China 3 cent Paraguay, country origin).114 glycoside extraction process carried chemical physical processes, 11AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING environmentally friendly leave contaminants final product.115 countries national guidelines prohibit labelling purified steviol glycosides “stevia” ‘natural’ misleading consumers (.. Germany, Switzerland Austria).116 Stevia leaf crude stevia extracts considered generally recognized safe (GRAS) United States approved United States Food Drug Administration (FDA) food.117 consequence, subject import alert United States, means seized border “ product labelled dietary supplement solely dietary ingredient manufacture dietary supplement product.”118 Prior 2017, European Union considered stevia leaf fell scope Food Regulation . 258/97, prohibits products entering European Union market undergone safety evaluation European Union scientific committee approved European Commission, authorized .119 European Union changed position stevia leaves, recognizing sold consumed significant degree European Union 1997, change position pertains tea, herbal fruit infusions. stevia leaf extracts sweetener flavouring falls scope Regulation 1333/2008 food additives Regulation 1334/2008 flavourings.120 Steviol glycosides approved food additive European Union 2011 -number 960 ( 960) based safety assessment carried European Food Safety Authority.121 companies developed SynBio pathways producing steviol glycosides. Evolva developed biosynthetic pathways producing steviol glycosides (Rebaudioside Rebaudioside ), partnering multinational Cargill . launch product brand EverSweetTM.122 2016, Cargill . submitted GRAS exemption claim FDA “Steviol Glycosides Saccharomyces cerevisiae Expressing Steviol Glycoside Biosynthesis Pathway”,123 FDA responded “ questions time Cargill’ conclusion [Steviol Glycosides ] GRAS intended conditions .”124 Cargill partnered Royal DSM grow line business, establishing joint venture named Avansya scale production.125 Amyris markets SynBio stevia glycoside product brand Compromise™ Sweetness. commercialization, joined “ASR Group, cane-sugar refiner owns Domino Sugar & Sugar brands [] Camil Alimentos, [] market sweetener retail customers Brazil. production, Amyris established manufacturing partnership Brazilian cane sugar producer Raizen. [Brazilian consumers] tabletop sweetener version [Rebaudioside ], Swiss flavour firm Givaudan.”126 apparent inconsistency treatment natural product, Paraguay “moving change international standards defined Joint United Nations Food Agriculture Organization (FAO)/ World Health Organization (WHO) Expert Committee Food Additives (JECFA) ( extension national standards United States European Union), longer discriminate favour chemically purified synthetically produced steviol glycosides.”127 inability stevia producers sell stevia leaf products markets, prohibition labelling stevia glycoside extracts ‘natural’ markets, real risk displacement supply chain naturally sourced Stevia. Due ability SynBio firms market stevia glycoside products natural, “products additives marketed consumers product sweetened extracts real stevia leaves.”128 , appears time , steviol glycosides obtained stevia leaf. decades- long head start, price sugar high fructose corn syrup. Plant-based stevia glycoside extracts pure (95-98 cent), scale production limitation ( vanilla extract).129 Stevia glycosides advantage synthetic sweeteners consumer preferences, “Amyris Avansya, taste important cost appealing food beverage formulators … concept pure molecules tasting plant-derived counterparts proven marketplace.”130 12 SYNTHETIC BIOLOGY 2. Pharma phytopharmaceuticals Artemisinin Natural product Artemisinin derived qing hao (Artemisia annua sweet wormwood), annual shrub.131 medicinal plant Traditional Chinese Medicine 2,000 years.132 traditional preparation global scale treatment malaria, shown dried leaf tablets . annua leaf form effective phytomedicine ( Figure 3).133 argued traditional preparation superior isolated molecule due synergy multiple active components.134 Artemisinin-based combination therapy recommended World Health Organization (WHO) - -line treatment types malaria 2002.135 WHO recommendation 2002, “ availability price artemisinin fluctuated greatly, ranging supply shortfalls years oversupply .”136 progress artemisinin production selection breeding high-yielding cultivars,137 program undertaken Switzerland resulted high-yielding cultivar Artemis.138 pathways artemisinin production, natural source artemisinin continues supply 75 cent world market drug.139 2013, sourced estimated 100,000 small farmers Asia ( China Viet Nam) Africa grow . annua.140 Scientists began investigating potential total synthesis artemisinin chemical structure molecule understood. total synthesis reported 1983, pathways identified. , pathways involve steps result yield. , pathways provide cost-effective method large-scale production, extraction . annua plants remains main source drug.141 address price supply fluctuations resulting natural production,142 significant work carried 2004 SynBio production techniques. 2005, Bill & Melinda Gates Foundation (Gates Foundation) granted funds Institute OneWorld Health finance development Amyris genetically engineered yeast artemisinic acid, precursor compound chemically synthesized artemisinin.143 preliminary work complete, Amyris intellectual property Sanofi royalty-free basis, commercialized process semisynthetic artemisinin (SSA) 2013. Sanofi built production plant capacity meet global demand, anticipated quantities produced process cost-effective Sanofi sold plant 2016.144 process efficient,145 total global production SSA equivalent 25 cent global artemisinin demand.146 demand artemisinin expected increase 176 tonnes 221 tonnes 2017-2021, “ race synthetic artemisinin .”147 Amyris continues Figure 3: Dried leaf artemisia phytomedicine Source: NB Daddy al “Artemisia annua dried leaf tablets treated malaria resistant ACT .. artesunate: Case reports” (2017) 32 Phytomedicine 37–40. 13AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING work improving process artemisinin support Gates Foundation, biotechnology companies won grants Gates Foundation develop sustainable -cost supply SSA.148 long-term implication SynBio artemisinin farmers sweet wormwood profound, eventually eliminate, significantly reduce, market natural product.149 , depends SynBio product compete natural product basis price. highly efficient flow method artemisinin biosynthesis developed 2018 based waste products . annua.150 commercialized company ArtemiFlow. price naturally sourced artemisinin SynBio variety, provide additional economic incentive farmers continue producing . annua plant material provide pathways artemisinin production.151 strongly promoted -cost substitute naturally sourced artemisinin, time , SSA supplemental source fill gaps production spikes demand.152 , Gates Foundation reaches aim SSA production $100 kg, “ significant uptick SSA.”153 Table 2: Examples SynBio products replace naturally sourced biological resources154 Compound Natural source Status BioTrade sector β-ionone Rose (Rosa damascena, Rosa centifolia) development Flavour/Fragrance Agarwood aromatic compounds Agarwood (Aquilaria malaccens) development Personal Care/ Cosmetic Artemisinic acid Sweet wormwood (Artemisia annua) Commercialized Pharmaceutical Cinnamaldehyde Cinnamon tree (Cinnamomum zeylanicum) development Flavour/Fragrance Cocoa butter Cocoa tree (Theobroma cacao) development Food Forskolin Coleus forskohlii development Pharmaceutical Geraniol Madagascar periwinkle (Catharanthus roseus) development Fragrance Ginsenosides Ginseng (Panax ginseng, Panax quinquefolius) development Pharmaceutical Limonene Citrus development Fragrance Linalool Variety plants development Fragrance Nerolidol Variety plants development Fragrance Nootkatone Grapefruit (Citrus paradisi) Commercialized Fragrance Patchoulol Patchouli (Pogostemon cablin) Commercialized Fragrance Raspberry ketone Raspberries, cranberries, blackberries development Fragrance Resveratrol Red grape (Vitis vinifera) Commercialized Pharmaceutical Sabinene Comb bushmint (Hyptis pectinata) development Flavour/Fragrance Saffron Saffron crocus development Flavour Santol Sandalwood (Santalum album) development Fragrance Shikimic acid Star anise Commercialized Pharmaceutical Shinorine Algae (Porphyra umbilicalis) development Cosmetics Steviol glycosides Stevia (Stevia rebaudiana) Commercialized Food Squalene Olive oil, Shark liver Commercialized Personal Care/Cosmetic Valencene Orange (Citrus sinensis) Commercialized Fragrance Vanillin Vanilla orchid (Vanilla planifolia, . tahitensis) Commercialized Flavour/Fragrance Vetivone Vetivier (Chrysopogon zizanioides) development Fragrance 14 SYNTHETIC BIOLOGY SECTION 3: LAW AND POLICY ISSUES AT THE INTERFACE OF BIOTRADE AND SYNTHETIC BIOLOGY 1. Food labelling labelling SynBio products important issue terms implications BioTrade. primary question SynBio product considered natural ingredient due production living organism. United States Europe, SynBio products labelled ‘natural’ ingredients, necessarily consistent consumer perceptions. demonstrated survey conducted Consumer Reports 2014, consumers widely misunderstand term ‘natural’ “[]bout -thirds [ consumers] [ term] means processed food artificial ingredients, pesticides, genetically modified organisms, 80 cent .”155 section address legal framework food labelling relates SynBio ingredients jurisdictions. United States regulatory missions FDA protect consumers misleading claims food labels.156 early 1990s, FDA issued informal guidance term ‘natural’, stating views term meaning “ artificial synthetic (including colors source) included , added , product expected .”157 internal policy, carries weight advisory opinion legal force.158 policy established, “ intended address food production methods, genetic engineering forms genetic modification … explicitly address food processing manufacturing methods…”159 , “fails address effect processing food technology advances ‘naturalness’ food.”160 question SynBio ingredients labelled ‘natural’ falls scope policy. 2015, FDA sought public comment definition term ‘natural’ human food products, including foods genetically engineered ingredients produced genetic engineering.161 response citizen petitions, “ Federal district courts [] referred , administrative determination 21 CFR  10.25(), question food products ingredients produced bioengineering labelled ‘Natural,’ ‘ Natural,’ / ‘100% Natural.’”162 public comment period closed 10, 2016, FDA’ steps unclear. , FDA statement subject, adjustment policy, administrative determination, restated accordance original guidance, “ object term natural ‘ products “added color, artificial flavours, synthetic substances.”’163 late 2018, United States Department Agriculture published final rule implementing National Bioengineered Food Disclosure Standard (NBFDS) signed law 2016.164 NBFDS pre- empted state local genetic engineering labelling requirements charged Agricultural Marketing Service developing mandatory national standard disclosing presence bioengineered food. rule effect 19 February 2019 phased years.165 NBFDS requires food manufacturers, importers food labelled retail sale United States United States retailers disclose foods ingredients produced foods bioengineered. final rule defines bioengineered food food “ genetic material modified vitro recombinant [DNA] techniques modification obtained conventional breeding nature,’ excludes genetically modified material ‘ detectable.’ -detectable amounts modified genetic material require ... labelling.”166 SynBio products fall definition bioengineered food, list bioengineered food products, affected labelling requirements NBFDS. European Union European Union, foods state label consist GMOs, ingredients produced GMOs. , foods produced genetically modified microorganisms (.. SynBio products) labelled.167 ‘natural’ label flavouring substances regulated strictly European Union 15AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING United States. Flavoring substances termed ‘natural’ “obtained physical, enzymatic microbiological processes material vegetable, animal microbiological origin raw state processing human consumption traditional food preparation processes… Natural flavouring substances correspond substances naturally present identified nature.”168 SynBio ingredients correspond substances naturally present identified nature, obtained microbiological processes material vegetable origin. suggest labelled natural flavouring substance Regulation. 2011, European Parliament Council adopted Regulation 1169/2011 provision food information consumers. Regulation modifies existing food labelling provisions European Union aim allowing consumers informed choices safe food, ensuring free movement legally produced marketed food. Article 7(1)() “[]ood information misleading suggesting, means appearance, description pictorial representations, presence food ingredient food, , reality, component naturally present ingredient food substituted component ingredient.” obligation triggered “ considered average consumer expect food produced ingredient ingredient naturally present food substituted component ingredient.” Commission examples: “ food ingredient food substituted component ingredient; [] food component naturally present food substituted component ingredient.” substitution ingredient , “ product close proximity substitution ingredient(), printed package label ensure clear legibility… food business operator find substitution food accordance rules food.”169 2. Cosmetic products United States Federal Food, Drug Cosmetic Act, cosmetic products ingredients ( color additives) FDA pre-market approval placement market.170 Food, Drug, Cosmetic Act , , FDA regulate marketing adulterated misbranded cosmetics interstate commerce.171 context, misbranding refers “violations involving improperly labelled deceptively packaged products … [ ] labelling false misleading .”172 Misbranding result failure provide material facts.173 FDA approve cosmetic products placement market, “ pursue enforcement action products market compliance law, firms individuals violate law.”174 United States Federal Trade Commission issued number administrative complaints ( reached settlements ) companies claimed products ‘100% natural’ ‘ natural’ contained synthetic ingredients,175 unclear decisions relevant cosmetic products ‘natural’ SynBio ingredients. European Union European Union harmonized definition term ‘natural’ personal care cosmetics industry. requirement labels true misleading nature. Commission Regulation 655/2013 requires claims cosmetic products conform common criteria: 1) legal compliance; 2) truthfulness; 3) evidential support; 4) honesty; 5) fairness; , 6) informed decision-making. common criteria equal importance.176 common criteria aimed defining wording cosmetic product claims, , message communicated compliance common criteria consistent documentation supporting claim.177 aspects relevance SynBio products arise Regulation. , ‘truthfulness’ criteria, “[] claimed product specific ingredient, ingredient deliberately present.”178 ‘fairness’ criteria, “[]laims cosmetic products objective denigrate competitors, 16 SYNTHETIC BIOLOGY denigrate ingredients legally , [] []laims cosmetic products create confusion product competitor.”179 terms ‘informed decision-making’, “[]laims clear understandable average user … [] information allowing average user informed choice … [] [] arketing communications account capacity target audience (population relevant Member States segments population, .. users age gender) comprehend communication. Marketing communications clear, precise, relevant understandable target audience.”180 3. Voluntary certification lack regulatory guidance ‘natural’ claims resulted appearance -party certifications food cosmetics industries, ‘natural’ requirements. Examples certifications application SynBio products discussed . -GMO certification -GMO Project operates voluntary certification scheme aiming “preserve build sources - GMO products, educate consumers, provide verified -GMO choices.”181 certification scheme aimed food products, expanded include products personal care cosmetic products.182 section ingredient classification, -GMO Project Standard “[] ingredients allowed direct product genetic modification:  1) finished retail goods, listed ingredient panel; 2) products sold retail labeling, listed input disclosure documentation: … Products synthetic biology (synbio).”183 German ‘Ohne Gentechnik’ label applies labelling food produced “ genetic engineering processes.” statutory basis Genetic Engineering Implementation Act (EGGenTDurchfG).184 standard includes requirement “ vitamins, aromas, enzymes food additives manufactured GMOs.”185 Specifically, “[] production/processing “ohne Gentechnik” products, processing aids substances meaning Sec. 3a (5), EGGenTDurchfG , consist , produced GMOs labelled accordance Regulation 1829/2003 1830/2003, labelled circulation.”186 COSMOS COSMOS (COSMetic Organic Standard) Europe- wide voluntary standard organic natural cosmetics. Version  3.0 standard entered effect 2019. standard addresses subject SynBio products, stating “[]rimary raw materials ingredients GMOs derivatives GMOs forbidden. Contamination primary raw materials ingredients genetically modified material 0.9% primary raw material ingredient, reliable detection limit 0.1% adventitious technically unavoidable.”187 Standard defines derivative “ substance produced GMO GMO source organism substance involved process accomplishes essential conversion substance”188 (emphasis added). , “[] manufacturer chemically processed agro-ingredients … ingredients derived culture fermentation - GMO biotechnology [] cultures feedstock natural vegetable microbial raw materials [GMOs] derivatives”189 (emphasis added). provisions intended exclude SynBio products processes cosmetic products covered COSMOS standard. NATRUE NATRUE ( International Natural Organic Cosmetics Association) -profit association committed promoting protecting natural organic cosmetics benefit consumers worldwide. categories certification NATRUE standard: 1) natural cosmetics; 2) natural cosmetics organic portion; 3) organic cosmetics. NATRUE standard establishes prohibition GMOs covers SynBio products. Specifically, “finished products starting materials, enzymes microorganisms comply criteria laid European Union Eco-regulation (Regulation 834/2007). requirement applies substances covered 17AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING Regulation (.. -organic certified ingredients, - food —feed substances).”190 derogation exists enzymes, : “[] justifiable, due current technical unavailability alternatives / improved sustainability, isolated enzymes recombinant microorganisms (recombinant enzymes) manufacture processing substance recombinant host grown regulated contained conditions (cf. Directive 2009/41/EC), including post-production treatments required assigned containment level protective measures.”191 Bioconversion -genetically modified microorganisms allowed standard, “[]nzymatic microbiological reactions permitted exclusively naturally occurring microorganisms enzymes obtained thereof , products identical occur nature.”192 prohibition SynBio products clear, section derived natural ingredients, standard “[] recombinant microorganisms … production recombinant enzymes justified … prohibited.193 18 SYNTHETIC BIOLOGY SECTION 4: CONCLUSIONS ON IMPLICATIONS OF SYNTHETIC BIOLOGY FOR BIOTRADE AND ABS 1. General conclusions implications SynBio BioTrade emergence field SynBio raises significant economic, social, environmental regulatory issues. noted AHTEG-SB, “ aspect relationship synthetic biology biological diversity noted potential positive negative indirect effects, account adoption organisms, products components synthetic biology order ensure sustainable biodiversity maintained.”194 , AHTEG-SB members “noted [] regard international regimes: () provisions address socioeconomic impacts components products synthetic biology.”195 , present, COP resolve scope issues relation SynBio.196 means States develop national responses advent SynBio technologies discussions continue international level. present, discussions continue extended AHTEG-SB.197 SynBio potential positive effects society biodiversity, “cures numerous diseases, [providing] stable supplies therapeutic compounds [enabling] creation organisms products limited human imagination.”198 Proponents SynBio argue technique benefit companies consumers reducing swings price, product availability quality dependence natural production.199 focus rare natural compounds, contribute conservation sustainable biodiversity reducing pressure overharvested, unsustainably managed, illegally sourced wild flora, continuing provide market desired final product.200 Products produced SynBio potential negative effects biodiversity ingredients. , concerns raised potential impacts developing countries, impacts livelihoods rely growing harvesting natural products, due increased competition cost products.201 “farmers … depend robust markets natural products economic survival.”202 risk posed livelihoods forthcoming products, “ mere prospect competition prompt farmers stop planting crop, producing shortage [SynBio] product .”203 number cases, products announced private sector market years product development. , main feedstocks today SynBio require extensive agriculture, leading threat global biodiversity.204 SynBio “increasingly accessible, practices shift large-scale cultivation crops single fragrance flavouring … cultivation crops sugarcane, crop efficiently processed feedstock supply carbon microbial fermentations.”205 Farmland developing countries converted sugarcane production meet SynBio companies. conversion “impact food prices availability vulnerable populations.”206 , SynBio applications aiming “convert ‘-’ forests agricultural products feedstocks”207, harmful effects biodiversity. SynBio products promised benefits, “ environmental impacts, biological feedstocks sustainably, operate high safety standards respect humans, animals, environment.”208 Lastly, traceability concerns biochemicals produced SynBio techniques species listed annexes Convention International Trade Endangered Species Wild Fauna Flora (CITES).209 Greater availability SynBio product “ lead increased demand product, driving suppliers mix wild- sourced products market.”210 products virtually indistinguishable derived CITES-listed species, “ unscrupulous dealers attempt pass- launder original product synthesised modern techniques.”211 19AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING negatively impact legitimate BioTrade CITES-listed products. order address issue, suggested “[] direct link product CITES regulated species, product chemically identical ( identical) derived listed species certification permit system differentiating product essential.”212 Developments SynBio “raise environmental human economic development concerns reminiscent previous economic transitions attendant potential severe unintended consequences.”213 , “ grand promise dire perils synthetic biology fully realized … [ SynBio ] viewed retrospectively … technological development providing incremental advances fully manageable drawbacks.”214 significant technological developments occurred years, SynBio revolutionary incremental development, ultimate impacts .215 “ potential problems significant roadblocks [SynBio] developments”216 demonstrated number products announced companies commercialized. “[]etabolic pathway engineering microbial fermentation technically economically viable flavour/fragrance compounds … []hat technology exists doesn’ commercial logic exists.”217 time, SynBio “chemical manufacturing attained widespread specific sectors, comparison traditional chemical manufacturing small market.”218 number types SynBio products future predictable, “[] increased rate product ideas means types number biotechnology products 5–10 years significantly larger current rate product introduction.”219 early successes producing marketable products, rapid scientific technological developments, “ industrial biology produce broad range chemical products continue accelerate. growth field enable biology produce high- valued chemical products produced high purity high yield traditional chemical synthesis.”220 developments continue include high biochemicals obtained natural sources. Consumer preferences beginning move natural ingredients “clean labels”. Consumer research data demonstrates meaning ‘natural’ significant marketplace, premium consumers pay, consumer concern confusion natural product claims, proliferation lawsuits United States alleging ‘natural’ claims meet consumer expectations.221 United States Courts held “ FDA’ informal ‘natural’ policy pre-empt lawsuits alleging deceptive business practices false advertising”222 lawsuits targeted companies products GMOs advertised ‘natural’.223 case filed 2012 alleged “Jamba Juice mislabeled smoothie kits ‘ natural’ ‘unnaturally processed, synthetic / -natural ingredients’ including … steviol glycosides.”224 case settled 2015 trial, Jamba Juice agreeing longer smoothie kits ‘-natural’.225 significant number lawsuits ‘natural’ claims demonstrates consumers feeling misled term natural, consequences consumer acceptance SynBio products. consumers confused meaning claims products,226 “incorrectly [believing] ‘organic’ ‘natural’ similar meaning share attributes. specifically, consumers incorrectly term ‘natural,’ food labels, comprises multiple attributes, ‘ toxic pesticides/fertilizers,’ ‘ GMOs,’ ‘ artificial colors flavours,’ ‘ artificial ingredients,’ ‘minimally processed,’ ‘enforced government standard.’”227 broad public knowledge SynBio ingredients increasingly present products ‘natural’ label, undermine consumer confidence label. Commercial actors recognize consumer preference natural ingredients key driver marketplace.228 commitment numerous major multinational corporations transition sustainable sourcing, natural ingredients, “clean labels” boon BioTrade natural ingredients naturally procured sustainable sources. Alternatively, regulations continue SynBio products ‘natural’, transition harmful effects due product substitution 20 SYNTHETIC BIOLOGY displacement. enterprises decide choose high cost naturally sourced products (.. vanilla bean extract) due higher marketplace, cost SynBio products products labelled ‘natural’ commitment sustainable biodiversity- based sourcing model. question companies comparative quality advantage justifies higher price naturally sourced product. sector specific decision. cost benefit analysis demonstrates ‘natural’ SynBio product satisfactory manufacturer’ purposes, naturally sourced product preferred option. 2. Potential implications SynBio ABS SynBio positive negative implications ABS. positive perspective, SynBio relies genetic resources, sourced developing countries ABS transaction based prior informed consent (PIC) mutually agreed terms (MAT). provide added genetic resources result monetary / -monetary benefits shared provider countries communities. DSI increasingly important biotechnology sector, “[]atural products derivatives remain important resource discovery bioactive compounds. represent significant portion chemical entities playing important role identification druggable targets pathways development synthetic compounds.”229 , compounds interest produced quantities species origin230 SynBio build bio-economies based natural products developing countries. Synthetic biology increase yield plant natural products, reduce susceptibility crops pathogens, develop products address local .231 developing countries rich natural resources channeled biotech enterprises proper support, developing countries “developing national strategies plans related [SynBio], industrialization biology, future bioeconomy, including emerging markets South Africa, Brazil, Mexico.”232 , SynBio negative effects ABS. , emergence “ABS bypass tools” tools “digital misappropriation” real concern. availability tools publicly accessible United States National Center Biotechnology Information (NCBI) Standard Nucleotide Basic Local Alignment Search Tool (BLAST) “facilitates finding sequence organisms ( sequence information publicly accessible internet database), providing ABS bypass tool researchers inclined misstate true origin information utilized.”233 Academics companies easily “ genetic code uploaded internet, , DNA synthesizer, recreate modify code produce substances, tests, organisms, meaningful … track origin genetic information formed basis discovery.”234 , concerns expressed potential BLAST similar pieces software “ABS bypass tool”, researchers locate sequences interest countries ABS rules, match sequences species countries looser ABS requirements.235 disclosure standard origin, source / legal provenance genetic resources address issue, remain challenge determine origins genetic information, private sector. 3. Recommendations BioTrade important policymakers national international levels engage positive benefits negative impacts SynBio economic development, social issues, natural resource , environment.236 SynBio remains field evolution, governments abreast developments field assess implications BioTrade. World Economic Forum highlighted 2015 Global Risks report “ invention cheap synthetic alternatives high- agricultural exports … suddenly destabilize vulnerable economies removing source income farmers rely.”237 , clear assess socio‐ economic impacts SynBio products processes livelihoods production consumption patterns,238 develop innovative business models.239 SynBio impacts chains, “[]otential benefits potential adverse effects synthetic biology 21AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING applications assessed case--case basis, balance reasoning based evidence - scenarios.”240 explicitly recommended Stevia case.241 regard, important note “current foreseeable future applications synthetic biology considered assessment potential benefits potential adverse effects stages development, ranging theoretical early active areas research market. , timeframe potential benefits potential adverse effects applications realized vary considerably.”242 Governments proactive informing supply chain actors marketplace addressing displacement issues,243 involve providing assistance producers understanding changing markets / transitioning BioTrade chains. consistent Criterion  3.3 BT &, “BioTrade organizations seek promote greater interaction , hand, local communities economic actors , , markets promote opportunities offer promoting maximum information accessing markets.”244 consistent aspects Principle 4 BT  &, addresses socioeconomic sustainability. , Criterion 4.1 BT &, notes “[] guarantee sustainability, BioTrade products market potential related existence specific markets products services. specific product service (market creation) terms trade tools, information, strategic partnerships advertising considered.”245 , Criterion  4.2 states “BioTrade organization high potential long-term financial sustainability, activities organizational system enterprise.”246 , Criterion 4.3 “[]ocal development added values BioTrade organization. perspective, generation employment improvement standard living local communities providing natural resources important. ways organizations support improvement provide tools enable communities enhance commercial practices add supply chain.”247 United States Presidential Commission Bioethics report suggested principle justice fairness inform development SynBio.248 principle relates distribution benefits burdens society, extending international community . context technologies SynBio, principle’ application suggests society seek ensure benefits burdens technologies shared, individuals groups receive legitimately expect. complex assessment, demonstrated ( reflected light artemisinin case study ): “, , measure compare benefits technological innovation leads effective medical treatment unprecedented scale cost costs imposed disruption displacement pre- viously existing technologies people livelihoods depend ”249 principle justice fairness suggests society seek ensure unavoidable burdens technological advances ( SynBio) fall disproportionately individual group.250 Socioeconomic impact assessments alignment chains BT & ensure producers unduly suffer potential disruption substitution displacement naturally sourced ingredients marketplace. displacement inevitable, governments providing economic / technical support producers livelihoods disrupted innovations. Consumer responses SynBio products — positive negative — crucially important success products marketplace, resulting likelihood natural product substitution displacement. Consumers presently sufficient knowledge “food ingredients, food technology, food ingredient terminology, marketing claims [] places disadvantage evaluate product ingredient “natural.””251 Regulators obligation ensure manufacturers clear guidance labelling SynBio ingredients consumers choices purchase naturally sourced products products SynBio ingredients. 22 SYNTHETIC BIOLOGY food context, suggested labelling SynBio products important inform consumers ingredients produced GMOs fact final product GMOs. long term benefits, “[] enable consumer distinguish natural product complex mixture flavour compounds biotechnologically produced product composed important flavour compounds natural extract.”252 , SynBio products authentically considered promoted environmentally friendly substitutes identical compounds obtained large-scale chemical synthesis misleading consumers origin.253 important justified label SynBio flavours natural, general public sufficiently informed understand food labels -evident obvious unclear labelling policies increasing consumer suspicions ‘natural’ flavourings entire food industry.254 Clarification SynBio products fall definition term ‘natural’ ingredient foods, fragrances cosmetics priority regulators. matter international law, matter national standards commercial standards established industries. Businesses “rely standards regulations order maintain transparency economic playing field”,255 clear definition ‘natural’ adopted, manufacturers naturally sourced ingredients face unfair competition companies adopt looser standard.256 harm companies committed BioTrade products, harm actors chain, producers. supplier flavour fragrances industry suggested “ defined set global ingredients standards needed industry order flavour houses food beverage manufacturers streamline ingredient sourcing processes.”257 “ingredients suppliers guide customers complex regulatory maze source ingredient required support product claims.”258 ISO adopted cosmetics guidelines (ISO 16128) “offer framework determine natural, natural origin, organic organic origin content products based ingredient characterization”259 guidelines address “product communication (.. claims labelling), human safety, environmental safety socio-economic considerations (.. fair trade), characteristics packaging materials regulatory requirements applicable cosmetics.”260 time , differentiate BioTrade products SynBio products, governments chain actors focus promoting natural origin BioTrade products cross- cutting benefits sustainable development achievement 2030 Agenda Sustainable Development Sustainable Development Goals (SDGs) (.. biodiversity conservation, carbon benefits, jobs, poverty reduction, gender benefits). Consumers increasingly interested purchasing products naturally sourced, sustainably produced, furnish mutiple socioeconomic benefits.261 BioTrade actors capitalize trend. voluntary certification schemes (.. COSMOS, NATRUE, -GMO, Organic). Lastly, BT & revision provisions address types technologies products falling broad umbrella synthetic biology. include establishing specific requirements considerations linked specific synthetic biology technologies products based sustainable biological resources leads conservation biological diversity socio- economic development. keeping current approach (implicitly) prohibits GMOs BioTrade products focus goods services derived native biodiversity. 23AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING Recommendations 1. Provider countries conducting socioeconomic impact assessments nationally important chains synthetic biology alternative appears market order determine potential impact jobs livelihoods. 2. significant risk jobs livelihoods, provider countries assist producers transition BioTrade chains prevent impact livelihoods biodiversity result shift existing chain. 3. potential implications defining “natural product” “goods services derived native biodiversity” context BioTrade. challenging undertaking preferable leave national decision makers standard-setting bodies. 4. addressing BioTrade Principles Criteria address specific types technologies products falling broad scope synthetic biology. include question broad approach preferable, case--case approach based sustainability criteria . 5. case--case approach products fabricated genetically modified/ synthetic biology organisms BioTrade products demonstrably sustainable naturally derived counterparts (.. trade ban CITES, listed IUCN Red List). 6. case--case approach adopted, development traceability mechanism ingredients derived CITES-listed species prove fabricated SynBio processes species. 24 SYNTHETIC BIOLOGY ANNEX : DEFINITIONS OF SYNTHETIC BIOLOGY 2009 United Kingdom Royal Academy Engineering report SynBio defined aiming “ design engineer biologically based parts, devices systems redesigning existing, natural biological systems.”262 2010 report United States Presidential Commission Study Bioethical Issues relating SynBio defined “[aiming] apply standardized engineering techniques biology create organisms biological systems specialized functions address countless .”263 notes “ standard biology treats structure chemistry living natural phenomena understood explained, synthetic biology treats biochemical processes, molecules, structures raw materials tools potentially ways, independent natural roles.”264 2014 Organisation Economic -operation Development (OECD) report SynBio defines SynBio “[attempting] bring engineering standardisation biotechnology enable decades biotechnology research pay form mass-market applications.”265 2014 European Commission Scientific Committees (ECSC) Opinion SynBio adopted operational definition: “SynBio application science, technology engineering facilitate accelerate design, manufacture / modification genetic materials living organisms.”266 2015 report United States Committee Industrialization Biology defines SynBio “seeking deliver greater speed, cost-effectiveness, predictability design biological systems. field applies engineering principles reduce genetics DNA ‘parts’ understand combined build desired functions living cells.”267 similar definition 2017 report United States Committee Future Biotechnology Products, defines SynBio “[] application engineering principles reduce genetics DNA ‘parts’ parts understood terms combined build desired functions living cells.”268 commonalities definitions SynBio include: recognition shift approach focused discipline biology approach based diverse scientific disciplines ( engineering); focus standardization, modularity rational design organisms; , orientation commercial industrial applications. SynBio work date focused microorganisms produce drugs high chemicals (aka “cell factories”).269 , “advances plant science showing potential plants vastly efficient productive producers vaccines, therapeutics, customizable chemicals microorganisms traditional chemical synthesis.”270 commercialization plant-based SynBio platforms remains horizon. 25AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING ANNEX II: SELECTED SYNTHETIC BIOLOGY TOOLS AND TECHNIQUES 1. BioBrick engineering BioBrick engineering cited central approach literature SynBio.271 inspired electronic computer software engineering traditional engineering concepts (.. modularization standardization). goal engineering biological systems standardized parts.272 standardized biological parts aims accelerate innovation “[enabling] reuse previously engineered devices, creating ability design complex systems predictably, rapidly, failures.”273 overcome limitations earlier gene assembly techniques, BioBricks assembly standard developed 2003.274 assembly standard parts, result “ product standard assembly BioBrick parts usable, larger composite BioBrick.”275 limitations, assembly standard “ prototypes tested replaced tuned, professional final products, experience BioBricks assembly paves researchers tackle complex projects synthetic biology.”276 annual International Genetically Engineered Machine (iGEM) competition defining event field, bringing thousands participants multidisciplinary teams world “design, build, test, measure system design interchangeable biological parts standard molecular biology techniques.”277 iGEM established open-source Registry Standard Biological Parts, 20,000 BioBricks. parts iGEM competition teams 370 ( growing) registered academic labs.278 iGEM competition produced significant advances SynBio, “ iGEM projects published important scientific advances.”279 BioBricks Foundation (BBF) --profit organization started 2004 “ represent public interest foundational technologies define field synthetic biology.”280 original goal “invent bring life legal framework accelerates enables accrual open collection functional genetic elements encoding standard biological parts.”281 order support goal, BBF aimed developing legal technical standards field, engaging developing SynBio community.282 legal tool developed BBF BioBrick Public Agreement (BPA),283 “meant support maturation open technology platform supporting genetic engineering”284 facilitating sharing BioBrick parts intellectual property free basis. open-source approach basic biological parts perceived global public good, benefiting researchers developing countries industrialized .285 2018, BBF, cooperation OpenPlant Synthetic Biology Research Centre, launched Open Material Transfer Agreement286 (OpenMTA) 2018 provide “simple, standardized legal tool sharing biological materials broadly undue restrictions, respecting rights creators promoting safe practices responsible research.”287 OpenMTA formulated applied worldwide, explicitly recognizing “ transfer specific materials subject laws, rules, regulations context dependent, jurisdictional, subject change time ( , [ABS] obligations aris ing Convention Biological Diversity Nagoya Protocol).”288 BBF Free Genes project, “ sequences requested synthetic biology research community synthesized cost.”289 2. Bioinformatics Bioinformatics “ hybrid science links biological data techniques information storage, distribution, analysis support multiple areas scientific research.”290 “fed high-throughput data-generating experiments, including genomic sequence determinations…”291 DSI stored databases, public private, organized annotated research. DSI databases publicly accessible free charge, databases forming International Nucleotide Sequence Database Collaboration (INSDC), DNA Data Bank Japan (DDBJ) Center Information Biology National Institute Genetics, European Nucleotide Archive European Bioinformatics Institute European Molecular Biology Laboratory 26 SYNTHETIC BIOLOGY (EMBL-EBI), GenBank NCBI National Institutes Health (NIH).292 500,000 taxa represented databases 1 January 2017, 2,650 trillion DNA bases assembled/ annotated August 2017.293 Growth databases incredibly rapid, “scientific journals require nucleotide sequences deposited publicly accessible database condition publication article.”294 , patent claims genes, jurisdictions require related sequences publicly disclosed application.295 sequences subsequently integrated databases mentioned INSDC. existing international standard necessarily require disclosure machine-readable format,296 World Intellectual Property Organisation (WIPO) adopted electronic standard disclosure (Standard ST.26) “designed facilitate computerized searching sequence listing data data exchanged electronic form introduced computerized databases.”297 full transition Standard ST.26 occur January 2022. sheer amount DSI places bioinformatics research squarely realm “big data”,298 “ phenomenon massive complex data sets scale conventional data processing applications handle.”299 effectively amount DSI biotechnology purposes led development sophisticated analytical tools public private sector. publicly tool BLAST, “ sequence similarity search program quickly search sequence database matches query sequence.”300 3. Design tools aim SynBio “ reduce minimum experimental laboratory work scientific enquiry discipline … [] turn predictable technology suitable systematic biological design industrialisation.”301 important tool enabling goal development effective Computer-Aided Design (CAD) software environments biology (aka BioCAD).302 BioCAD programs, “DNA sequences parts devices treated modules virtually assembled ‘drag- -drop’ environment. functioning virtual assemblies variety conditions simulated optimal design finalised, parts list full DNA sequence design detailed instructions laboratory researcher robotic platform assemble test .”303 pieces BioCAD software address aspects concept.304 GenoCAD, users design synthetic DNA sequences -step process, building libraries parts, designing sequences , simulating sequence quality control purposes sending synthesis.305 examples BioCAD software include Cello306 j5 (exclusively licensed TeselaGen).307 Standard computer markup languages Figure 4: GenoCAD online platform Source: “GenoCAD: CAD Software Synthetic Biology” online: genocad., accessed 13 March 2019. 27AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING developed design tools order enable sharing standardized information design purposes.308 4. Construction tools Genome-editing technologies tools clustered regularly interspaced short palindromic repeats (CRISPR), transcription activator- effector nucleases (TALEN), zinc-finger nucleases (ZFN) meganucleases, genetic engineering cheaper precise decades.309 development significance emergence Multiplex Automated Genome Engineering (MAGE), AHTEG-SB noted 2017, recognizing “[] development gene editing tools enables simultaneous targeting multiple sites, multiplexing, genome step.”310 significantly accelerates testing development SynBio organisms. Gene synthesis technologies Technological developments DNA synthesis decades exponentially reduced cost producing genes, allowing large-scale gene assembly.311 silicon-based synthesis platform developed Twist Bioscience.312 , traditional chemical-based synthesis process produces toxic waste, processes developed address drawback— enzymatic DNA synthesis. demonstration enzymatic process synthesizing DNA published 2018,313 process commercialized Ansa Biotechnologies.314 company Molecular Assemblies working commercialize enzyme-based DNA synthesis process.315 Biofoundries Biofoundries “centralized facilities leverage software automation dramatically increase number organisms engineered parallel.”316 intended “automate design- Figure 5: Traditional Twist Bioscience DNA synthesis platform Source: Leproust, “Rewriting DNA Synthesis” (2016) 112 (9) Chemical Engineering Progress 30–35. build-test engineering cycles effort accelerate [&] processes.”317 increasing number public private biofoundries “ expected substantial effect rate introduction biotechnology products marketplace, enabling academic laboratories companies complete development multiple biotechnology products year.”318 Existing biofoundries concentrated North America Europe, emerging East Asia. Examples include Agile Biofoundry,319 Concordia University Genome Foundry,320 DAMP Lab,321 Earlham DNA Foundry,322 Edinburgh Genome Foundry,323 GeneMill,324 Ginkgo Bioworks,325 Lifefoundry,326 London DNA Foundry,327 MIT-Broad Foundry,328 NUS Synthetic Biology Foundry,329 SYNBIOCHEM.330 28 SYNTHETIC BIOLOGY GLOSSARY Note: glossary purposes handbook. definitions evolve vary significantly national/regional context . Access benefit sharing: Process , result accessing biodiversity components (.. specimens, samples, biochemicals), genetic resources related traditional knowledge, research development chains, types benefits generated shared equitably provider user (UNCTAD 2017).331 BioBricks: DNA biological parts standardised prefix suffix DNA sequences routinely assembled (Baldwin 2016).332 Biochemical compound: compound carbon living . biochemicals classified classes: carbohydrates, proteins, lipids (fats) nucleic acids (UNCTAD 2017). Biotechnology: technological application biological systems, living organisms, derivatives thereof, modify products processes specific (CBD 1992). BioTrade initiatives/projects/companies: Business ventures stages development headed economic actors (communities community-based associations, ) meet BioTrade Principles Criteria (UNCTAD 2016).333 Figure 6: architecture typical biofoundry Source: Boston University, “ Hands Approach” online: https://www.bu./eng/2018/02/26/-hands--approach/ 29AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING BioTrade products services: BioTrade activities generally oriented production, transformation commercialization products derived sustainable biological resources, provision services derived resources. BioTrade products include coming wild collection cultivation practices. refers products derived cultivation native species (domesticated wild varieties) activities agriculture aquaculture. Products derived wild collection include products fauna (.. ornamental fish), fauna derivatives (.. crocodile leather meat) flora (.. medicinal plants, flowers foliage). Services include, , carbon sequestration sustainable tourism (UNCTAD 2016). Derivative: naturally occurring biochemical compound resulting genetic expression metabolism biological genetic resources, functional units heredity (Nagoya Protocol Access Benefit-Sharing). DNA: biological macromolecule encodes information organism function. Consists deoxyribose (sugar)-phosphate backbone bases: Adenine, Thymine, Cytosine Guanine (Baldwin 2016). DNA Sequencing: technique determine nucleotide sequence DNA. Fine chemicals: Speciality chemicals, high retail , large scale. , pharmaceutical drugs fine chemicals (Baldwin 2016). Gene synthesis: construction double-stranded DNA 200 base pairs long chemicals (Baldwin 2016). Genetic material: material plant, animal, microbial origin functional units heredity (CBD 1992). Genetic resources: Genetic material actual potential (CBD 1992). Genetic engineering: introduction change DNA, RNA, proteins human manipulation effect change organism’ genome epigenome (National Academies 2017).334 Genome engineering: rational -writing, editing complete design genomes (Baldwin 2016). Feedstock: starting material manufacturing process. form biomass, crude refined petroleum hydrocarbon product, material chemically modified (National Research Council 2015).335 Fermentation: metabolic process converts sugar product (National Research Council 2015). Living modified organism: living organism possesses combination genetic material obtained modern biotechnology (Cartagena Protocol Biosafety 2000). MAGE: Multiplex Automated Genomic Engineering, simultaneous targeting locations chromosome modification single cell population cells (National Research Council 2015). Metabolic engineering: directed modification metabolic pathways microbial synthesis products (Stephanopoulos 2012).336 Microbe: single-celled, microscopic organism (Baldwin 2016). Synthetic biology: development dimension modern biotechnology combines science, technology engineering facilitate accelerate understanding, design, redesign, manufacture / modification genetic materials, living organisms biological systems (AHTEG- SB 2015).337 Utilization genetic resources: conduct research development genetic / biochemical composition genetic resources, including application biotechnology (Nagoya Protocol Access Benefit Sharing 2010). Valorization: holistic approach , utilization activities, national measures intellectual property tools, enhance provide additional values biological resources (UNCTAD 2017). chain: Coordinated relationships established actors involved indirectly productive activity aim moving product service supplier customer. involves alliances producers, processors, distributors, traders, regulatory support institutions, , departing market demand products services, establish joint vision identify mutual work jointly achievement goals, share risks benefits, invest time, energy, resources realizing goals (UNCTAD 2007).338 30 SYNTHETIC BIOLOGY Notes 1 UNCTAD, BioTrade Access Benefit Sharing: concept practice. handbook policymakers regulators, United Nations Doc. UNCTAD/DITC/TED/2017/6. 2 UNCTAD, 20 Years BioTrade: Connecting People, Planet Markets, United Nations Doc. UNCTAD/ DITC/TED/2016/4 3. 3 Leonard Katz al, “Synthetic biology advances applications biotechnology industry: perspective” (2018) 45:7 Journal Industrial Microbiology & Biotechnology 449. 4 Presidential Commission Study Bioethical Issues, Directions: Ethics Synthetic Biology Emerging Technologies (Presidential Commission Study Bioethical Issues, 2010) 38. 5 KE French, “Harnessing Synthetic Biology Meet 2030 UN Sustainable Development Goals” (2019) Preprints 2019010022 1. 6 SCENIHR, SCCS & SCHER, Opinion : Synthetic Biology: Definition (European Commission Scientific Committees, 2014) 6. 7 Benjamin Raimbault, Jean-Philippe Cointet & Pierre-Benoî Joly, “Mapping Emergence Synthetic Biology” (2016) 11:9 PLOS ONE e0161522 2. 8 National Research Council, Industrialization Biology: Roadmap Accelerate Advanced Manufacturing Chemicals ( National Academies Press, 2015) 18. 9 Secretariat Convention Biological Diversity, Synthetic Biology: Updated Reports, United Nations Doc. UNEP/CBD/COP/12/20 8. 10 Convention Biological Diversity, 5 June 1992, 31 ILM 822 [Convention Biological Diversity]. Confirmed Secretariat Convention Biological Diversity, Report Ad Hoc Technical Expert Group Synthetic Biology, United Nations Doc. UNEP/CBD/SYNBIO/AHTEG/2015/1/3, para 38: “living organisms, components products synthetic biology fall scope Convention objectives”. 11 OECD, “Overview Methodologies” Schooling Tomorrow Knowledge Base, online: https://www.oecd.org/ site/schoolingfortomorrowknowledgebase/futuresthinking/overviewofmethodologies.htm 12 MC Jewett & Ellis, “Editorial Overview: Synthetic Biology: Frontiers Synthetic Biology” (2017) 40 Current Opinion Chemical Biology A1 A1. 13 RA Hughes & AD Ellington, “Synthetic DNA Synthesis Assembly: Putting Synthetic Synthetic Biology” (2017) 9 Cold Spring Harbor Perspectives Biology a023812 1. 14 Ibid 2. 15 technologies reduced cost sequencing DNA orders magnitude 2002–2015. National Academies Sciences, Engineering, Medicine, Preparing Future Products Biotechnology ( National Academies Press, 2017) 28. 16 Ibid. 17 term placeholder CBD debates. Note Executive Secretary Digital Sequence Information Genetic Resources (CBD/SBSTTA/22/2), reported participants meeting Ad Hoc Technical Expert Group Digital Sequence Information Genetic Resources noted “DSI” include, , “() nucleic acid sequence reads data; () Information sequence assembly, annotation genetic mapping. information describe genomes, individual genes fragments thereof, barcodes, organelle genomes single nucleotide polymorphisms; () Information gene expression; () Data macromolecules cellular metabolites; () Information ecological relationships, abiotic factors environment; () Function, behavioural data; () Structure, including morphological data phenotype; () Information related taxonomy; () Modalities .” (Annex, para. 2). 18 National Research Council, supra note 8 3. 19 Ibid 36. 20 CBD COP, Decision XI/11. emerging issues relating conservation sustainable biodiversity, United Nations Doc. UNEP/CBD/COP/DEC/XI/11. 21 Ibid, para 3. 22 Ibid, para 3(). 23 Ibid, para 3(). 24 Ibid, para 3(). 25 Ibid, para 3(). 26 CBD COP, Decision IX/29. Operations Convention, United Nations Doc. UNEP/CBD/COP/DEC/IX/29, para 12. 27 CBD SBSTTA, Recommendation XVIII/7. emerging issues: synthetic biology, United Nations Doc. UNEP/CBD/COP/12/3, Annex, para 1. 31AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING 28 CBD COP, Decision XII/24. emerging issues: synthetic biology, United Nations Doc. UNEP/CBD/COP/ DEC/XII/24, paras 1, 4. 29 CBD COP, supra note 28, Annex, para (). 30 Secretariat Convention Biological Diversity, supra note 10, para 24. 31 CBD COP, Decision XIII/17. Synthetic biology, United Nations Doc. UNEP/CBD/COP/DEC/XIII/17, para 4. 32 Ibid, Annex, para 1(). 33 Secretariat Convention Biological Diversity, Analysis criteria set paragraph 12 decision IX/29, United Nations Doc. CBD/SBSTTA/22/INF/17. 34 Decision 14/19. Synthetic biology, United Nations Doc. UNEP/CBD/COP/DEC/14/19, Annex, para (). 35 Ibid, para (). 36 Ibid, para (). 37 Decision XII/24. emerging issues: synthetic biology, para 8. 38 Raimbault, Cointet & Joly, supra note 7 11. 39 Hans-örg Rheinberger & Staffan üller‐Wille, Gene: Genetics Postgenomics, revised translation ed (Chicago University Press, 2017) 2–3. 40 Geoff Baldwin, Synthetic Biology - Primer, revised ed (Imperial College Press, 2016) 164. 41 Secretariat Convention Biological Diversity, Report Ad Hoc Technical Expert Group Synthetic Biology, United Nations Doc. UNEP/CBD/SYNBIO/AHTEG/2017/1/3, para 15(). 42 National Academies Sciences, Engineering, Medicine, supra note 15 16. 43 Ibid. 44 Ibid 51. 45 Overview Work Response Decision XIII/17 Background Information Facilitate Deliberations Ad Hoc Technical Expert Group Synthetic Biology, United Nations Doc. UNEP/ CBD/SYNBIO/ AHTEG/2017/1/2, para 44 (). 46 National Academies Sciences, Engineering, Medicine, supra note 15 16. 47 National Research Council, supra note 8 3. 48 Ibid 36. 49 Gregory Stephanopoulos, “Synthetic Biology Metabolic Engineering” (2012) 1:11 ACS Synth Biol 514 523. 50 National Research Council, supra note 8 17. 51 Katz al, . 454. 52 National Research Council, supra note 8 40. 53 Stephanopoulos, supra note 49 515. 54 Ibid 523. 55 Li, Zhang & Liu, “Cell-free synthetic biology vitro biosynthesis pharmaceutical natural products” (2018) 3:2 Synthetic Systems Biotechnology 83. 56 Ibid 84. 57 Overview Work Response Decision XIII/17 Background Information Facilitate Deliberations Ad Hoc Technical Expert Group Synthetic Biology, para. 57 (). 58 automated Design–Build-Test–Learn cycle optimizing metabolic pathways, Pablo Carbonell al, “ automated Design-Build-Test-Learn pipeline enhanced microbial production fine chemicals” (2018) 1:1 Communications Biology 66. 59 generally National Research Council, supra note 8. 60 Chemical synthesis (2019) Encyclopaedia Brittanica Academic. 61 Ibid. 62 Ibid. 63 National Research Council, supra note 8 12. 64 Ibid 55. 65 Fermentation (2019) Encyclopaedia Brittanica Academic. 66 National Research Council, supra note 8 4. 67 Brian Yeh & Wendell Lim, “Synthetic biology: lessons history synthetic organic chemistry” (2007) 3 Nature Chemical Biology 521 524. 68 Margo Bagley, “Towering wave tempest teapot Synthetic biology, access benefit sharing, 32 SYNTHETIC BIOLOGY economic development” Frankel & DJ Gervais, eds, Intellectual Property Regulation Internet (Victoria, NZ: Victoria University Press, 2017) 85 102 citing Meienberg al. Stevia: Path Benefit Sharing Agreement (Public Eye, 2016). 69 National Academies Sciences, Engineering, Medicine, supra note 15 52. 70 Melody Bomgardner, “Artificial Ingredients Crosshairs”, (2015), online: &EN Chemistry Year Review http://2015.cenmag.org/artificial-ingredients-crosshairs-html/; Daniele Asioli al, “Making sense ‘clean label’ trends: review consumer food choice behavior discussion industry implications” (2017) 99 Food Research International 58. 71 NJ Gallage & BL øller, “Vanillin—Bioconversion Bioengineering Popular Plant Flavor De Novo Biosynthesis Vanilla Orchid” (2015) 8 Molecular Plant 40 40. 72 Ibid 53. 73 Ibid 54. 74 Ibid 40. 75 Holly Dressel, ed, Synthetic Biology, Biodiversity Farmers: Case studies exploring impact synthetic biology natural products, livelihoods sustainable biodiversity (ETC Group, 2016) 59; Melody Bomgardner, “ problem vanilla: vowing natural, food brands face shortage favored flavor” (2016) 94:36 Chemical & Engineering News 38 40. 76 Bomgardner, supra note 75 39. 77 Dressel, supra note 75 60; Bomgardner, supra note 75 42. Cured pods 2 percent extractable flavor. 78 Bomgardner, supra note 75 40–41. 79 Ibid 39. 80 Gallage & øller, supra note 71 41. 81 Ibid. 82 Bomgardner, supra note 75 41. 83 Gallage & øller, supra note 71 47. 84 Gallage & øller, supra note 71. 85 Bomgardner, supra note 75 41. 86 Trademark Electronic Search System, “ Vanilla” online: tmsearch.uspto.gov/bin/showfieldf=doc&state= 4802:u6p188.2.1. 87 Evolva, “Vanillin”, online: www.evolva./vanillin. 88 John Leffingwell Diane Leffingwell, “Biotechnology—Conquests Challenges Flavors & Fragrances” (2015) 7 (2) Leffingwell Reports 1-11. 89 .. Friends Earth, “ Synbio Vanilla” online: https://foe.org/projects/food--technology/ -synbio-vanilla/. 90 Online: https://www.evolva./wp-content/uploads/2019/02/Evolva-AR18-EN.pdf. 91 Kent Redford al, eds, Genetic frontiers conservation: assessment synthetic biology biodiversity conservation (IUCN, 2019) 108. 92 Bagley, supra note 68. 93 Bomgardner, supra note 75 38; author interviews. 94 Bomgardner, supra note 75. 95 Ibid 42. 96 Dressel, supra note 75 26. 97 Bancroft, “Synbio Perfumery: Making Smells Flavors Microbes” online: labiotech.eu/industrial/ synbio-perfumery-tasty-smells-ingredients-microbes/; Ibid 25. 98 Ibid 26. 99 Ibid 25. 100 Online: https://www.firmenich./uploads/files/ingredients/marketing-sheet/perfumery/. CLEARWOOD_970953.pdf. 101 Brittany Xu al, “ Comparison Volatile Components Cold Pressed Hamlin Valencia (Citrus sinensis (.) Osbeck) Orange Oils Affected Huanglongbing” (2017) Journal Food Quality Article ID 6793986 1. 102 Martin Laqua, “Biomanufacturing: smell success”, online: european-biotechnology./--date/ backgrounds-stories/story/biomanufacturing--smell--success.html. 33AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING 103 Wageningen University “Organic odour flavouring orange peels redundant” online: www.wur.nl/en/ show/Organic-odour--flavouring--orange-peels-redundant.htm. 104 Xu al, supra note 101. 105 Online: http://www.isobionics./index-Valencene.html. 106 Onine: https://www.evolva./valencene-citrus-flavor. 107 Martin Laqua, “Biomanufacturing: smell success” online: https://european-biotechnology./-- date/backgrounds-stories/story/biomanufacturing--smell--success.html. 108 SynBioBeta, “Evolva teams FCI expand nootkatone valencene sales & marketing Europe” 20 March 2017, online: synbiobeta./evolva-teams-fci-expand-nootkatone-valencene-sales-marketing-europe. 109 DSM, “DSM Nutritional Products Isobionics announce exclusive partnership distribute Valencene Nootkatone”, 21 2014, online: https://www.dsm./corporate/media/informationcenter- news/2014/05/2014-05-21-dsm-nutritional-products--isobionics-announce-exclusive-partnership-- distribute-valencene--nootkatone.html. 110 Roberto Lemus-Mondaca al, “Stevia rebaudiana Bertoni, source high-potency natural sweetener: comprehensive review biochemical, nutritional functional aspects” (2012) 132:3 Food Chemistry 1121 1122. 111 Ibid 1123, 1127. 112 Francois Meienberg al, Bitter Taste Stevia: Commercialisation Stevia-derived sweeteners violating rights indigenous peoples, misleading marketing controversial SynBio production (Berne Declaration, 2015) 10. 113 Ibid. 114 Ibid 11; Dressel, supra note 75 55. 115 Meienberg al, supra note 112 12. 116 Dressel, supra note 75 56. 117 “ Stevia approved FDA sweetener” online: www.fda.gov/aboutfda/transparency/ basics/ucm194320.htm. 118 “Import Alert 45-06” online: www.accessdata.fda.gov/cms_ia/importalert_119.html. 119 Peter Berry-Ottaway & Sam Jennings, “Continuing Legal Barriers International Food Trade” Gabriela Steier & Kiran Patel, eds, International food law policy (Springer, 2016) 189–190. 120 European Union Food Catalogue, online: ec.europa.eu/food/safety/novel_food/catalogue/search/public/ index.cfm. 121 Commission Regulation (EU) 1131/2011 11 November 2011 amending Annex II Regulation (EC) 1333/2008 European Parliament Council regard steviol glycosides, OJ  295, 12.11.2011, 205–211. 122 Cargill , “EverSweet™ -calorie Sweetener”, online: www.cargill./food-bev/na/eversweet-sweetener; Evolva, “Cargill officially starts producing -generation sweetener EverSweet” 20 March 2018, online: www.evolva./press-release/cargill-officially-starts-producing---generation-sweetener-eversweet/. 123 FDA, “GRN . 626” 1 March 2016, online: https://www.fda.gov/downloads/Food/. IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm505151.pdf. 124 FDA, “Agency Response Letter GRAS Notice . GRN 000626” 27 2016, online: www.fda.gov/Food/ IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm512620.htm. 125 Melody Bomgardner, “Cargill, DSM join -calorie sweeteners” (2018) 96:46 &EN Global Enterprise 12. 126 Melody Bomgardner, “Newcomers head -calorie sweetener market” (2018) 96:49 &EN Global Enterprise 11. 127 Meienberg al, supra note 112 11. 128 Bagley, supra note 68. 129 Bomgardner, supra note 126. 130 Ibid. 131 Sanne de Ridder, Frank van der Kooy & Robert Verpoorte, “Artemisia annua -reliant treatment malaria developing countries” (2008) 120:3 Journal Ethnopharmacology 302. 132 Ibid; “Artemisinin” (2014) 20:7 Emerging Infectious Disease journal 1217. 133 Nsengiyumva Bati Daddy al, “Artemisia annua dried leaf tablets treated malaria resistant ACT .. artesunate: Case reports” (2017) 32 Phytomedicine 37; Pamela Weathers al, “Dried-leaf Artemisia annua: practical malaria therapeutic developing countries” (2014) 3:4 World Journal Pharmacology 39. 134 Frank van der Kooy & Shaun Edward Sullivan, “ complexity medicinal plants: traditional Artemisia 34 SYNTHETIC BIOLOGY annua formulation, current status future perspectives” (2013) 150:1 Journal Ethnopharmacology 1; Mostafa Elfawal al, “Dried plant Artemisia annua antimalarial therapy” (2012) 7:12 PloS e52746. 135 World Health Organisation, “Overview malaria treatment”, online: www..int/malaria/areas/treatment/ overview/en. 136 Stephanie Kung al, “Approaches Developments Commercial Production Semi- Synthetic Artemisinin” (2018) 9:87 Frontiers Plant Science 1 1. 137 De-Yu Xie al, “Artemisinin biosynthesis Artemisia annua metabolic engineering: questions, challenges, perspectives” (2016) 15:6 Phytochemistry Reviews 1093 1102. 138 de Ridder, van der Kooy & Verpoorte, supra note 131. 139 Unitaid, Global Malaria Diagnostic Artemisinin Treatment: Commodities Demand Forecast 2017-2021 (World Health Organisation, 2018). 140 Dressel, supra note 75 19. 141 de Ridder, van der Kooy & Verpoorte, supra note 131. 142 Mark Peplow, “Searching Cheaper Malaria Medicines” (2018) 96:11 Chemical & Engineering News 29 29. 143 Michael Kanellos, “Gates foundation promote synthetic biology”, (18 November 2005), online: www.cnet. /news/gates-foundation--promote-synthetic-biology. 144 Kung al, supra note 136 4–5. 145 Ibid 5–6. 146 Unitaid, supra note 139 7. 147 Peplow, supra note 142 29. 148 Ibid 30. 149 Bagley, supra note 68. 150 Susann Triemer al, “Literally Green Chemical Synthesis Artemisinin Plant Extracts” (2018) 57:19 Angewandte Chemie International Edition 5525. 151 Peplow, supra note 142 31. 152 Mark Peplow, “Synthetic biology’ malaria drug meets market resistance” 530 Nature 389” (2016) 530 Nature 389. 153 Peplow, supra note 142 30. 154 table indicative intended comprehensive. compounds obtained natural sources. 155 Stephen Gardner, Amanda Howell & Erika Knudsen, “ Natural Solution: FDA Define ‘Natural’ Foods” (2014) 4:9 Food Drug Policy Forum 1 1. 156 Nicole Negowetti, Food Labeling Litigation: Exposing Gaps FDA’ Resources Regulatory Authority (Brookings Institution, 2014) 23. 157 United States America, Food Labeling: Nutrient Content Claims, General Principles Petitions, Definition Terms, 56 Federal Register 60421, . 60466; 58 FR 2302 2407. 158 Nicole Negowetti, “ National ‘Natural’ Standard Food Labeling” (2013) 65:2 Maine Law Review 582 585. 159 United States America, Term “Natural” Labeling Human Food Products; Request Information Comments, 80 Federal Register 69905, . 69906. 160 Negowetti, supra note 158 600. 161 Term “Natural” Labeling Human Food Products; Request Information Comments, supra note 159. 162 Ibid, . 69907. 163 Bagley, supra note 68. 164 United States America, National Bioengineered Food Disclosure Standard—Final Rule, 83 FR 65814. 165 Ibid. Implementation begins 1 January 2020, extended implementation date small manufacturers 1 January 2021, voluntary compliance ends 31 December 2021, mandatory compliance begins 1 January 2022. 166 Brandon Neuschafer Merrit Jones, “Bioengineered Food Disclosure Rules Finalized, Require Disclosure ‘Detectable’ GMOs online: bclpdigest./ bioengineered-food-disclosure-rules-finalized-require-disclosure--detectable-gmos. 167 United Kingdom, “Genetically Modified Foods: Information genetically modified (GM) foods assess safety labelling requirements products” 9 January 2018, online: www.food.gov.uk/ safety-hygiene/genetically-modified-foods. 35AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING 168 Regulation (EC) 1334/2008 European Parliament Council 16 December 2008 flavourings food ingredients flavouring properties foods amending Council Regulation (EEC) 1601/91, Regulations (EC) 2232/96 (EC) 110/2008 Directive 2000/13/EC, OJ 354, 31.12.2008, . 34–50, Article 3(2)(). Article 16 “Specific requirements term ‘natural’”. 169 Commission notice questions answers application Regulation (EU) 1169/2011 European Parliament Council provision food information consumers, /2018/3241, OJ  196, 8.6.2018, . 1–14. 170 Allyson Bartolomeo, “ Proposal FDA Label Regulations Uniform Certifications Organic -Food ‘Natural’ Products” (2017) 23:1 Barry Law Review 65 71. 171 FDA, “FDA Authority Cosmetics: Cosmetics FDA-Approved, FDA-Regulated” online: www.fda.gov/Cosmetics/GuidanceRegulation/LawsRegulations/ucm074162.htm. 172 Ibid. 173 Ibid. 174 Ibid. 175 Federal Trade Commission, “ Companies Agree Stop Falsely Promoting Personal-Care Products “ Natural” “100% Natural”; Charged Commission Complaint” online: www.ftc.gov/ news-events/press-releases/2016/04/-companies-agree-stop-falsely-promoting--personal-care. 176 Technical document cosmetic claims, 28 July 2017, online: ec.europa.eu/docsroom/documents/24847. 177 Ibid 3. 178 Commission Regulation (EU) 655/2013 10 July 2013 laying common criteria justification claims relation cosmetic products, OJ  190, 11.7.2013, . 31–34, Annex, para. 2 (1). 179 Ibid, Annex, para. 5 (1) (2). 180 Ibid, Annex, para. 6 (1)-(3). 181 -GMO Project, “-GMO Project Standard Version 14.3”, 31 October 2018, 4, online: www. nongmoproject.org/product-verification/-standard-2-2. 182 Ibid 5. 183 Ibid 8. 184 Gesetz zur Durchführung der Verordnungen der Europäischen Gemeinschaft oderder Europäischen Union auf dem Gebiet der Gentechnik und über die Kennzeichnung ohne Anwendung gentechnischer Verfahren hergestellter Lebensmittel–EG-Gentechnik-Durchführungsgesetz –EGGenTDurchfG 185 Verband Lebensmittel ohne Gentechnik, “GMO-free Labeling” online: www.ohnegentechnik.org/index. phpid=467. 186 Verband Lebensmittel ohne Gentechnik, Ohne Gentechnik” Production Certification Standard Version 19.01, 1 October 2018 ( force 1 January 2019) 9, online: www.ohnegentechnik.org/index. phpid=674. 187 COSMOS Standard, . 5.1.2, online: cosmos-standard.org/forms--documents. 188 COSMOS Standard, . 4. 189 COSMOS Standard, . 6.1.4. 190 NATRUE, NATRUE Label Criteria Version 3.7, 15 December 2017, 2, online: www.natrue.org/information-/ manufacturers/natrue-criteria. 191 Ibid 2. 192 Ibid 3. 193 Ibid 5. 194 Secretariat Convention Biological Diversity, supra note 10, para 30. 195 Ibid, para 41. 196 Bagley, supra note 68. 197 Decision 14/19. Synthetic Biology, United Nations Doc. UNEP/CBD/COP/DEC/14/19, paras. 14–15. 198 Bagley, supra note 68. 199 Andrew Pollack, “Exotic Flavors, Cooked Vats Yeast, Imperil Small Farmers”, York Times (20 October 2013) A14. 200 Bagley, supra note 68; Study wildlife products produced synthetic cultured DNA, CITES Doc. SC70 Doc. 33, para 69 201 Ibid; Pollack, supra note 199; Dressel, supra note 75. 36 SYNTHETIC BIOLOGY 202 Bagley, supra note 68. 203 Pollack, supra note 199. 204 Nigel Dudley & Sasha Alexander, “Agriculture biodiversity: review” (2017) 18:2–3 Biodiversity 45; National Research Council, supra note 8 5: “Today, feedstock biomanufacturing chemicals fermentable sugar”. 205 Hugh Douglas Goold, Philip Wright & Deborah Hailstones, “Emerging Opportunities Synthetic Biology Agriculture” (2018) 9 Genes 341 343; Redford al, supra note 91 121. 206 Bagley, supra note 68. 207 Presidential Commission Study Bioethical Issues, supra note 4 137. 208 National Research Council, supra note 8 48. 209 Study wildlife products produced synthetic cultured DNA, supra note 199, para 59: “ chemicals purified, markers origin product. instances, difference product produced artificially derived organism.” 210 Ibid, para 69; Redford al, supra note 91 122. 211 Ibid, para 85. 212 Ibid, para 72. 213 Bagley, supra note 68. 214 Ibid. 215 Ibid. 216 Ibid. 217 ETC Group, Haiti, Essential Oils & Synthetic Biology: Potential Impacts Haiti’ Farming Communities (ETC Group, 2016), 25. 218 National Research Council, supra note 8 67. 219 National Academies Sciences, Engineering, Medicine, supra note 15 6. 220 National Research Council, supra note 8 4. 221 Negowetti, supra note 158 583; Bagley, supra note 68 100. 222 Holk . Snapple Beverage Corp., 575 .3d 329, 340 (3d Cir. 2009) cited Negowetti, supra note 158 593. 223 Negowetti, supra note 156 14. 224 Anderson . Jamba Juice ., . 12-CV-01213 (.. Cal. filed Mar. 12, 2012). 225 Elaine Watson, “Jamba Juice settles ‘-natural’ lawsuit, pay damages’ 24 March 2015, online: https://www.foodnavigator-usa./Article/2015/03/24/ Jamba-Juice-settles-natural-lawsuit---pay--damages 226 Negowetti, supra note 158 594. Organic Trade Association, : Term “Natural” labeling Human Food Products; Request Information Comments, Docket . FDA-2014--1207, 10 2016, 2 4, online: www.regulations.gov/documentD=FDA-2014--1207-7242. 227 Organic Trade Association, supra note 246 2. 228 Pollack, supra note 199. Interviews author. 229 National Research Council, supra note 8 56. 230 Ibid. 231 French, . 3 232 National Research Council, supra note 8 35. 233 Bagley, supra note 68. 234 Ibid 91–92. 235 Bagley, supra note 68. 236 Ibid. 237 World Economic Forum, Global Risks 2015, 10th ed (World Economic Forum, 2015) 37. 238 Redford al, supra note 91 122. 239 Marta Norton & Peder Fode, Catalogue Social Science Research Topics Synthetic Biology (ERASynBio, 2014) 9. 240 Secretariat Convention Biological Diversity, supra note 10, para 46. 241 Meienberg al, supra note 112 28. 242 Secretariat Convention Biological Diversity, supra note 10, para 51. 37AND ITS POTENTIAL IMPLICATIONS FOR BIOTRADE AND ACCESS AND BENEFIT-SHARING 243 Bagley, supra note 68. 244 UNCTAD, BioTrade Principles Criteria, United Nations Doc. 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